Reliance Formulation Pvt. Ltd.

ChromoZinc - The key to complete diabetic management

2006-12-28T21:11:00.000-08:00

Reliance Formulation (Pvt.) Ltd. provides the doctor with a powerful armamentarium to fight and keep in control blood sugar. ChromoZinc is not a substitute to a doctor’s prescription in sugar control. ChromoZinc is the key to complete a doctor’s prescription in the management of diabetes.

ChromoZinc contains:

Chromium picolinate: 500 mcg
Zinc sulphate monohydrate: 27.5 mg
Methylcobalamin: 750 mcg
Alpha-lipoic acid: 100 mg,
Vitamin B6: 3 mg
Folic acid: 1mg

Chromium

A highly refined diet that contains too few micronutrients has been recognized as the dominant factor in the rising incidence of diabetes and other insulin related conditions. Among the missing micronutrients, chromium has the greatest impact on insulin response. Until recently, few physicians recognized the importance of supplementing chromium in the management of diabetes. However, research has revealed that chromium plays an important role` in amplifying insulin response in diabetics.

Chromium is now proven to be the key to complete the diabetes management. We all know that insulin is a hormone whose primary role is to regulate the body's response to carbohydrates, proteins and fats.

Insulin is produced in the pancreas. Following a meal the pancreas releases insulin into the bloodstream, as glucose, or blood sugar, levels from the digested meal begin to rise; Glucose is the primary fuel for energy production within all body tissues including the brain. But it can't get into cells without the help of insulin. The more the sugar that enters the blood, the more the insulin is required to transport it into cells. Eating refined carbohydrates and sugary foods quickly raises glucose levels making these foods particularly troublesome for anyone with a blood sugar imbalance such as diabetes.

While glucose transport is the primary role of insulin, chromium's main function is increasing insulin's efficiency in regulating blood sugar levels. But this hormone produces much more complex and far-reaching effects. These include the transport of amino acids and electrolytes into cells, several enzymatic activities and cellular growth. Numerous studies show that chromium alters lipoprotein abnormalities (unhealthy LDL and HDL levels) that are believed to increase the risk of cardiovascular disease. Chromium supplementation also appears useful in treating obesity in other research, increasing lean muscle mass and improving athletic performance.

Symptoms of chromium deficiency;

Ø Fasting hyperglycemia (too much of fasting blood sugar)
Ø Hypoglycemia (to little of blood sugar)
Ø Elevated percentage of fat in the body
Ø Peripheral neuropathy
Ø Fatigue
Ø Anxiety

A minimum of 200 mcg of chromium daily is needed for at least three months to have a noticeable effect on insulin response. Anyone with diabetes who uses insulin should consult with a healthcare provider about chromium supplements, since the insulin dosage may have to be adjusted. If required up to 500 mcg can be administered.

What is chromium picolinate?

This popular nutritional supplement is a combination of the element chromium and picolinic acid. Chromium is a naturally occurring mineral, trace amounts of which are found in everyday foods like meat, poultry, fish, and whole-grain breads. When foods are processed, they are stripped of natural chromium, making our diets generally very low in chromium; studies estimate an average daily chromium consumption of 33 mcg in an average non-vegetarian diet.
In 1968, it was demonstrated that when subjects do not receive adequate levels of chromium, insulin is not optimally effective, and damage to insulin-dependent systems can occur (Schroeder, 1968). This led the FDA to recommend a daily chromium intake of approximately 130 mcg (100 mcg chromium picolinate is equivalent to 23mcg elemental chromium), as infinitesimal amounts of chromium are needed to aid the transport of blood glucose across cell membranes

Zinc sulphate monohydrate

Diabetics should probably take zinc supplements! Zinc plays a key role in the regulation of insulin production by pancreatic tissues and glucose utilization by muscles and fat cells.

The abilities to synthesize and secrete insulin and use glucose are impaired in the zinc deficient state. Intestinal zinc absorption rates and plasma zinc levels in diabetic patients are reduced. Zinc is involved in the regulation of insulin receptor-initiated signal transduction mechanisms and insulin receptor synthesis.

Scientists at Notre Dame* and at the University of Illinois have discovered that zinc has an insulin-like effect on the manifestation of diabetes.

Insulin, they note, promotes the transport of glucose and amino acids (proteins) and decreases the breakdown of muscles while healthfully enhancing their buildup.“.... failure to enhance glucose transport, " they say, "into insulin-sensitive cells is a hallmark of diabetes [emphasis added.] They have found that zinc enhances this glucose movement.

Zinc Sulphate 200mg (45mg elemental Zinc) - Zinc is alos documented to be an essential element for normal growth and good vision.

Methylcobalamin

Methylcobalamin is a type of Vitamin B12. Vitamin B12 comes in several kinds including hydroxy-, cyano-, and adenosyl-, but only the methyl form is used in the central nervous system.

Deficiency states are fairly common and vitamin B12 deficiency mimics many other disease states of a neurological or psychological kind, and it causes anemia. Cyanocobalamin (the kind in vitamin supplements) is converted by the liver into methylcobalamin but not in therapeutically significant amounts. Vitamin B12 deficiency is caused by a wide range of factors including low gastric acidity (common in older people,) use of acid blockers such as PPI’s or H2A’s or excessive laxative use, lack of intrinsic factor, poor absorption from the intestines, lack of Calcium, heavy metal toxicity, or excessive Vitamin B12 degradation.

Methylcobalamin donates methyl groups to the myelin sheath that insulates nerve fibers and regenerates damaged neurons. In a B12 deficiency, toxic fatty acids destroy the myelin sheath but high enough doses of B12 can repair it.

Methylcobalamin supplements increase alertness and body temperature. Methylcobalamin may slightly help those with diabetic neuropathy. Methylcobalamin has been found to be helpful in Bell's palsy. Methylcobalamin taken orally is effective in the treatment of pernicious anemia, says a Japanese study. Methylcobalamin may inhibit the ototoxic (hearing damage) side effects of the antibiotic Gentamycin.

Despite intensive searches for therapeutic agents, few substances have been convincingly shown to enhance nerve regeneration in patients with peripheral neuropathies. Recent biochemical evidence suggests that an ultra-high dose of methylcobalamin (methyl-B12) may up-regulate gene transcription and thereby protein synthesis.

Alpha-Lipoic Acid

Alpha-lipoic acid, also known as thioctic acid, is a disulfide compound that is a cofactor in vital energy-producing reactions in the body.

It is also a potent biological antioxidant. Alpha-lipoic acid was once thought to be a vitamin for animals and humans. It is made endogenously in humans - the details of its synthesis are still not fully understood. There are, however, certain situations, for example, diabetic polyneuropathy, where alpha-lipoic acid might have conditional essentiality.

Recent research indicates that the antioxidant roles of alpha-lipoic acid may confer several health benefits. Alpha-lipoic acid is found widely in plant and animal sources.

Alpha-lipoic acid is approved in Germany as a drug for the treatment of polyneuropathies, such as diabetic and alcoholic polyneuropathies, and liver disease.

Actions And Pharmacology

Alpha-lipoic acid has biological antioxidant activity, antioxidant recycling activity and activity in enhancing biological energy production.

Mechanism Of Action

Alpha-lipoic acid and its reduced metabolite, dihydrolipoic acid (DHLA), form a redox couple and may scavenge a wide range of reactive oxygen species. Both alpha-lipoic acid and DHLA can scavenge hydroxyl radicals, the nitric oxide radical, peroxynitrite, hydrogen peroxide and hypochlorite. Alpha-lipoic acid, but not DHLA, may scavenge singlet oxygen, and DHLA, but not alpha-lipoic acid, may scavenge superoxide and peroxyl reactive oxygen species.

Further, alpha-lipoic acid and its redox couple DHLA have been found to have antioxidant activity in aqueous, as well as in lipophilic regions, and in extracellular and intracellular environments. Finally, with regard to alpha-lipoic acid's antioxidant activity, alpha-lipoic acid appears to participate in the recycling of other important biologic antioxidants, such as vitamins E and C, ubiquinone and glutathione.

Exogenous alpha-lipoic acid has been shown to increase ATP production and aortic blood flow during reoxygenation after hypoxia in a working heart model.

Pharmacokinetics

Alpha-lipoic acid is absorbed from the small intestine and distributed to the liver via the portal circulation and to various tissues in the body via the systemic circulation.

Indications and Usage

Alpha Lipoic acid shows evidence of being effective in the treatment of diabetic neuropathy and may be useful in treating some other aspects of diabetes. It may help prevent the oxidation of LDL cholesterol and may be protective, generally, against oxidative stress and, specifically, against atherosclerosis, ischemia-reperfusion injury and various radiologic and chemical toxins. It may also be useful in some inborn metabolic disorders. It has been suggested that lipoic acid may slow aging of the brain and that it may be an anti-aging substance, in general.

Research Summary on Alpha Lipoic acid

Supplemental alpha-lipoic acid may lower blood glucose levels. Those with diabetes on antidiabetic medication should have their blood glucose monitored and antidiabetic drug dose appropriately adjusted, if necessary, to avoid possible hypoglycemia.

In some experiments, alpha lipoic acid, administered for up to three months, significantly reversed the increase in nerve vascular resistance. Nerve conduction velocity was entirely restored in some nerve groups after three months of treatment.

In a larger, multi-center, double blind, randomized, placebo-controlled study of 328 patients with type 2 diabetes, significant improvements were recorded in several clinical measures of diabetic polyneuropathy, including pain, numbness, paresthesia and burning sensations. These results were evident after three weeks of intravenous lipoic acid given five times weekly in doses of 600 and 1200 milligrams.

There is evidence, too, that lipoic acid may help prevent or slow the development of the atherosclerosis for which diabetics are at higher risk. It may do this, in part, through a gene-regulatory mechanism that helps prevent endothelial cell activity that has been implicated in the progression of atherosclerosis.

With respect to atherosclerosis, in general, lipoic acid's antioxidant and metabolic effects appear to offer some protection, as demonstrated in various animal models. Recently, researchers demonstrated, in a 16-week randomized trial, that lipoic acid, in oral doses of 600 milligrams daily for eight weeks, significantly inhibits the oxidation of LDL-cholesterol in healthy human subjects. The supplements also significantly reduced levels of F-2 isoprostanes, markers of oxidative stress. In this study, lipoic acid proved to be superior to vitamin E in decreasing levels of plasma protein carbonyls. Protein oxidation and LDL-cholesterol oxidation are implicated in heart disease.
Claims that alpha lipoic acid slows aging of the brain and is an anti-aging substance generally seem to be related to its potent antioxidant properties. Direct proof of anti-aging is lacking, but there is some animal work suggestive of some possible anti-aging effects.

Contraindications

None known.

Precautions

Because of lack of long-term safety data, alpha-lipoic acid should be avoided by pregnant women and nursing mothers.

Those with diabetes and problems with glucose intolerance are cautioned that supplemental alpha-lipoic acid may lower blood glucose levels. Blood glucose should be monitored and antidiabetic drug dose adjusted, if necessary, to avoide possible hypoglycemia.

Adverse Reactions

To date, alpha-lipoic acid in doses up to 600 milligrams daily has been well tolerated.
Interactions

Dosage and administration

Alpha-lipoic acid is available as a racemic mixture of D- and L- entantiomers. Some studies showing significant antioxidant effects have used doses of the racemic mixture of 600 milligrams daily.

Vitamin B6 (Pyridoxine)

Vitamin B6, also called pyridoxine, is one of eight water-soluble B vitamins. The B vitamins help the body to convert carbohydrates into glucose (sugar), which is "burned" to produce energy. These vitamins, often referred to as the B complex, are also essential in the metabolism of fats and protein. B complex vitamins also play an important role in maintaining muscle tone in the gastrointestinal tract and promoting the health of the nervous system, skin, hair, eyes, mouth, and liver

Uses

Heart Disease

Low dietary intake of vitamin B6 is associated with higher risk of having heart disease. This may be related to the fact that vitamin B6, together with vitamin B9 (folic acid) and vitamin B12, help to keep homocysteine levels under control. Homocysteine is an amino acid. Elevated levels of this amino acid are associated with increased risk of heart disease and increased risk of stroke. Preliminary evidence suggests that vitamin B6 may help control blood sugar in people with diabetes. In a study of people with diabetes, those who received pyridoxine alpha-ketoglutarate (a form of vitamin B6) for one month experienced significant reductions in fasting blood sugar levels compared to those who did not receive the supplement. More research in this area is needed before conclusions can be drawn about the relationship between vitamin B6 and diabetes.

Folic acid:

Folic acid deficiency is widespread and is associated with an increased risk for heart disease, cancer, depression and many other disorders. There is no question that folic acid is extremely important to health and well-being. Not only is it important for heart health, mental health and women's health, but also it is now also clear that it affects many other facets of health and disease. Researchers at the Cleveland Clinic Foundation have found that patients with end- stage renal disease have extremely high homocysteine levels and can be protected from cardiovascular events by supplementing with folic acid, vitamins B6 and B12. Diabetes patients tend to have high homocysteine levels and folate is especially important for them. Recent research has also shown that low folate levels (high homocysteine levels) are implicated in age-related hearing loss, psoriasis, and restless leg syndrome.

It is indeed astounding that one single vitamin, folic acid, can have such a profound effect on our health and yet perhaps it is not so surprising when one considers its vital role in DNA synthesis and homocysteine metabolism.

ChromoZinc, therefore, is the indispensable addition in a doctor’s armamentarium while managing diabetes mellitus and diabetic neuropathy.

Posted:
28th December 2006
Reliance Formulation (Pvt.) Ltd., Ahmedabad
For more details on ChromoZinc, please e-mail to

Mr. Mukesh Vankani – General Manager (Marketing & Sales)

Mr. Deepak Shah B. Pharma. M.B.A.

reliancehealthcare@yahoo.co.in

Pantab/ Pantab D – The best of the two worlds in Acid-Peptic Disorder

2006-07-21T22:43:00.000-07:00

Pantab/ Pantab D – The best of the two worlds in acid-peptic disorder

Many patients and caretakers are not familiar with GERD and its potential consequences, even though it afflicts millions of individuals.

Reliance Health Care believes it is important to share this educational information about GERD with the public as well as with caretakers and physicians.

It is not intended to recommend any particular treatment plan or to replace the advice of physicians. It is important that individuals seek and rely on the advice of health care professionals regarding individual medical conditions

GERD is an acronym. It stands for Gastro Esophageal Reflux Disease. It is often called "reflux," "reflux esophagitis," or sometimes inaccurately referred to as "hiatus hernia." Gastro esophageal reflux is the term used to describe a backflow of acid from the stomach into the swallowing tube or esophagus.

Almost everyone experiences gastro-esophageal reflux at some time. The usual symptom is heartburn, an uncomfortable burning sensation behind the breastbone, most commonly occurring after a meal. In some individuals reflux is frequent or severe enough to cause more significant problems and to be considered a disease. When it reaches that point, it is a medical condition called GERD. So GERD isn’t just “something you ate.” It’s a real disease and a real problem for millions of sufferers.
FAQ’s on GERD

1. What is GERD?

GERD stands for Gastro Esophageal Reflux Disease. Gastro-esophageal reflux describes a backflow of acid from the stomach into the swallowing tube or esophagus. This acid can irritate and sometimes damage the delicate lining on the inside of the esophagus. Almost everyone experiences gastro-esophageal reflux at some time. The usual symptom is heartburn, an uncomfortable burning sensation behind the breastbone, most commonly occurring after a meal. In some individuals this reflux is frequent or severe enough to cause more significant problems that is a disease. Thus, gastro-esophageal reflux disease is a clinical condition that occurs when reflux of stomach acid into the esophagus is severe enough to impact the patient’s life and/or damage the esophagus.

2. I have never heard of GERD. Is it a new disease?

No. GERD has probably been around as long as heartburn. The term is relatively new (about 20 years), however, and has really come into common usage over the past few years. GERD is often called "reflux," "reflux esophagitis," or sometimes even "hiatus hernia” (although hiatus hernia is a specific diagnosis that may or may not have anything to do with GERD). GERD is the preferred term because it accurately describes the problem - reflux of stomach acid up into the esophagus where it can produce symptoms and sometimes damage. Many patients are not familiar with GERD and its potential consequences, and thus may not have heard the term previously.

3. What are some symptoms of GERD?

The four major symptoms of GERD are:
· Heartburn (uncomfortable, rising, burning sensation behind the breastbone).
· Regurgitation of gastric acid or sour contents into the mouth.
· Difficult and/or painful swallowing.
· Chest pain.

Heartburn is the most common symptom of GERD.

In some patients it may be accompanied by other GERD symptoms, such as regurgitation of gastric contents into the mouth, chest pain and difficulty swallowing. Pulmonary manifestations, such as asthma, coughing, or intermittent wheezing and vocal cord inflammation with hoarseness, occur in some GERD patients.

In addition, acid can be regurgitated into the lungs in some GERD patients, causing wheezing or cough. Acid refluxed into the throat can cause sore throat. If acid reaches the mouth, it can dissolve enamel of the teeth.

4. How do people get GERD? What causes GERD?

GERD is caused by reflux of stomach acid into the esophagus. In most patients this is due to a transient relaxation of the “gate” or sphincter that keeps the lower end of the esophagus closed when a person is not swallowing food or liquids. This transient relaxation happens a few times each day in people without GERD. Why it happens more frequently in GERD patients isn’t known. The esophagus is not able to cope with acid as well as the stomach and is easily injured. It's the acid refluxing into the esophagus that produces the symptoms and potentially damages the esophagus.

5. How many people are afflicted with GERD?

Recent statistics from the US Department of Health and Human Services indicate that about seven (7) million people in the US alone suffer from GERD.
(Source: Digestive Diseases in the United States: Epidemiology and Impact, National Digestive Diseases Data Working Group, James E. Everhart, MD, MPH, Editor, US Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No. 94-1447, May 1994)

6. Who is afflicted with GERD?

GERD afflicts people of every socioeconomic class, ethnic group and age. However, the incidence does seem to increase quite dramatically above the age of 40. Greater than 50 percent of those afflicted with GERD are between the ages of 45-64 (both male and female).

7. Do children get GERD?

Yes. GERD is most common in adults over age 40 but virtually anyone can get GERD, even infants.

8. What is the difference between GERD and GORD?
The British spelling of esophagus is oesophagus. Hence, GERD is GORD in many European countries.

9. What is the difference between heartburn and GERD?

GERD is a disease and heartburn is its most common symptom. Heartburn is defined as a rising, burning sensation behind the breastbone caused by reflux of stomach acid into the esophagus. Nearly everyone has or will experience heartburn on occasion. Frequent heartburn that disrupts one's lifestyle suggests the diagnosis of GERD.

10. What is the difference between GERD and a hiatus hernia?

Hiatus hernia refers to dislocation of the stomach through the "hiatus" of the diaphragm and into the chest. This is a common condition that increases in frequency with age. It may or may not be associated with GERD. When GERD is severe enough to be complicated by erosive esophagitis, seen as breaks in the lining of the esophagus, a hiatus hernia is usually present. However, most patients with a hiatus hernia do not have GERD.

11. What is endoscopy and when is it used in GERD patients?

Endoscopy is a diagnostic test wherein a thin, flexible tube is swallowed by the patient to allow the physician to directly inspect the lining of the upper gastrointestinal tract. This procedure can be used to identify complications of GERD and to take small samples (biopsies) for further analysis. GERD patients who have certain symptoms, such as difficulty in swallowing or painful swallowing, should be considered for endoscopy. Patients who fail to respond to therapy are also candidates for endoscopy. Some physicians advocate endoscopy for all patients with long-standing GERD in order to rule out Barrett's esophagus.

12. What are the complications of GERD?

Only a minority of patients develops complications of GERD. These complications include breaks in the lining of the esophagus (esophageal erosions), esophageal ulcer, and narrowing of the esophagus (esophageal stricture). In some patients, the normal esophageal lining or epithelium may be replaced with abnormal (Barrett's) epithelium. This condition (Barrett's esophagus) has been linked to cancer of the esophagus and must be carefully watched.

Lung (pulmonary) aspiration, asthma and inflammation of the vocal cords or throat may also be caused by GERD.

13. What makes GERD symptoms worse?

The major factor is meals. Meals stimulate the stomach to produce more acid that can reflux up into the esophagus. In some patients, lying down or taking certain medications can worsen acid reflux.

14. Does eating spicy food cause GERD or make GERD worse?

Spicy foods do not cause GERD, although they do seem to worsen GERD symptoms in some people. Food (in general) can make GERD worse. This is because food fills the stomach and induces more transient relaxations of the lower esophageal sphincter. In addition, all meals stimulate acid production in the stomach to aid digestion and can increase reflux into the esophagus in GERD sufferers. Any very large meal might be expected to produce heartburn in some people. The spicy food story is so compelling, however, that GERD sufferers often relate a spicy (or greasy) meal to their symptoms. Often they are told to avoid certain foods whether or not these foods have anything to do with their symptoms. In this way, many GERD sufferers end up on a very restricted diet or end up blaming their symptoms on dietary indiscretion. If avoiding spicy foods and/or other dietary advice helps, that's great. If it doesn't, GERD sufferers shouldn't feel that they are doing something wrong. They should seek medical advice on managing their disease.

15. What about GERD and smoking?

Smoking doesn't cause GERD and there is little evidence that smoking significantly worsens GERD. Stopping smoking is a good idea anyway.

16. Do any medications make GERD worse?

Yes. Medicines that delay emptying of acid from the stomach or that increase acid backup into the esophagus can worsen GERD. If you have, or suspect you have, GERD and you require medication for other conditions, you should make sure you inform your doctor about all medications you are taking including prescription and over-the-counter medications.

17. What should people with GERD avoid?

GERD is a disease that is caused by gastric acid. However, certain foods can trigger symptoms in some patients. Lying down after a meal, wearing tight-fitting clothing, and even performing certain activities, such as bending over, can also trigger symptoms in patients. A good way to identify these "triggers" is to keep a diary of GERD symptoms noting when they occur. If symptoms follow a pattern and occur after certain foods or activities, these foods or activities should be avoided. A diary will also help patients continue to enjoy those foods or activities that do not seem to provoke symptoms, so that their lifestyle is not restricted unnecessarily. Patients should review their symptoms with their doctor, who can evaluate their condition and advise an appropriate treatment plan.

18. Can GERD cause cancer?

Severe, long-standing GERD can damage the esophagus and cause a condition known as Barrett's esophagus wherein the normal lining of the esophagus is replaced by a lining more like that of the stomach or intestine. It is thought that this replacement may be an attempt by the body to protect itself from further injury by acid. The risk of esophageal cancer appears to increase significantly in patients with Barrett's esophagus. The only way to diagnose Barrett's esophagus is by endoscopy. Some studies suggest that intensive treatment of Barrett's esophagus can reduce the amount of abnormal lining in the esophagus. It is not yet clear whether such treatment will prevent esophageal cancer in GERD patients, but this is under active investigation.

19. Are there long-term consequences of GERD?

Long-standing GERD can lead to damage of the esophagus. This damage usually consists of breaks in the lining of the esophagus. In some cases ulcers can develop. In some patients, such damage can result in scarring and narrowing of the esophagus, making swallowing painful or difficult. A condition called Barrett's esophagus is thought to result from long-standing GERD in some patients. Barrett's esophagus is a risk factor for the development of esophageal cancer. In some patients, acid backup caused by GERD is thought to result in damage to the vocal cords or teeth and may even cause asthma.

20. Is there relationship between GERD and asthma?

Many investigators believe that there is a link between asthma and reflux of stomach acid up into the throat and then down into the lungs in some patients. It appears that some patients who suffer from asthma might benefit from treatment of GERD. This is a topic of active research at the moment.

21. Can GERD cause inflammation of the throat?
In some patients, acid can reflux into the throat causing inflammation of the back of the throat which can lead to pharyngitis, or into the vocal cords, which can lead to laryngitis and hoarseness. Although there are many other causes for sore throat and laryngitis, GERD should be suspected in a patient with chronic sore throat or other GERD symptoms or when no other cause can be found.

22. Can GERD be cured?

Unfortunately, GERD, in general, cannot be cured at present. In some cases, it may be a temporary condition associated with a specific aggravating factor such as pregnancy. In such cases, GERD will go away on its own when the pregnancy has ended. In most cases GERD is a chronic condition. However, it can be effectively managed with medications and lifestyle modifications in almost everybody. In severe cases, surgery is an option. Surgery does not cure the underlying problem, but wraps part of the stomach around the lower end of the esophagus to help keep acid from getting back up into the esophagus. A doctor can evaluate the condition and advise on an appropriate treatment plan.

23. I think I have GERD. What should I do?

See your doctor. Your doctor can establish the diagnosis and work with you to get you symptom-free. Primary care and physicians of many specialties are becoming increasingly familiar with GERD. Gastro-enterologists and some gastrointestinal surgeons are usually very familiar with GERD and its treatment.

24. Where can I go for more information about GERD?

If you think you might have GERD - see your doctor OR gastro-enterologists who can determine if you have GERD and, if so, can evaluate its severity.
GERD in Children Studies* show that GERD is common and may be overlooked in infants and children. It can cause repeated vomiting, coughing, and other respiratory problems. Children's immature digestive systems are usually to blame, and most infants grow out of GERD by the time they are 1 year old. Still, you should talk to your child's doctor if the problem occurs regularly and causes discomfort. Your doctor may recommend simple strategies for avoiding reflux, like burping the infant several times during feeding or keeping the infant in an upright position for 30 minutes after feeding. If your child is older, the doctor may recommend avoiding

Sodas that contain caffeine
Chocolate and peppermint
Spicy foods like pizza
Acidic foods like oranges and tomatoes
Fried and fatty foods
Avoiding food 2 to 3 hours before bed may also help.

The doctor may recommend that the child sleep with head raised. If these changes do not work, the doctor may prescribe medicine for your child. In rare cases, a child may need surgery.*( Jung AD. Gastroesophageal reflux in infants and children. American Family Physician. 2001;64(11):1853–1860.)

How is GERD treated?

If you have had heartburn or any of the other symptoms for a while, you should see your doctor. You may want to visit an internist, a doctor who specializes in internal medicine, or a gastroenterologist, a doctor who treats diseases of the stomach and intestines. Depending on how severe your GERD is, treatment may involve one or more of the following lifestyle changes and medications or surgery.

Lifestyle Changes
If you smoke, stop.
Do not drink alcohol.
Lose weight if needed.
Eat small meals.
Wear loose-fitting clothes.
Avoid lying down for 3 hours after a meal.
Raise the head of your bed 6 to 8 inches by putting blocks of wood under the bedposts—just using extra pillows will not help.
Medications

Your doctor may recommend over-the-counter antacids, which you can buy without a prescription, or medications that stop acid production or help the muscles that empty your stomach.

Antacids, such as Diovol Suspension, are usually the first drugs recommended to relieve heartburn and other mild GERD symptoms. Many brands on the market use different combinations of three basic salts—magnesium, calcium, and aluminum—with hydroxide or bicarbonate ions to neutralize the acid in your stomach. Antacids, however, have side effects. Magnesium salt can lead to diarrhea, and aluminum salts can cause constipation. Aluminum and magnesium salts are often combined in a single product to balance these effects.

Calcium carbonate antacids can also be a supplemental source of calcium. They can cause constipation as well.

Foaming agents, work by covering your stomach contents with foam to prevent reflux. These drugs may help those who have no damage to the esophagus.

H2 blockers, such as cimetidine, famotidine, nizatidine and ranitidine impede acid production. They are available on prescription strength. These drugs provide short-term relief, but over-the-counter H2 blockers should not be used for more than a few weeks at a time. They are effective for about half of those who have GERD symptoms. Many people benefit from taking H2 blockers at bedtime in combination with a proton pump inhibitor.

Proton pump inhibitors include omeprazole (Romecid), lansoprazole, pantoprazole (Pantab), rabeprazole and esomeprazole which are all available by prescription. Proton pump inhibitors are more effective than H2 blockers and can relieve symptoms in almost everyone who has GERD.

Another group of drugs, prokinetics, helps strengthen the sphincter and makes the stomach empty faster. This group includes bethanechol, metoclopramide and domperidone.

Because drugs work in different ways, combinations of drugs may help control symptoms. People who get heartburn after eating may take both antacids and H2 blockers. The antacids work first to neutralize the acid in the stomach, while the H2 blockers act on acid production. By the time the antacid stops working, the H2 blocker will have stopped acid production. Your doctor is the best source of information on how to use medications for GERD.

What if symptoms persist?

If your heartburn does not improve with lifestyle changes or drugs, you may need additional tests.

A barium swallow radiograph uses x rays to help spot abnormalities such as a hiatal hernia and severe inflammation of the esophagus. With this test, you drink a solution and then x rays are taken. Mild irritation will not appear on this test, although narrowing of the esophagus—called stricture—ulcers, hiatal hernia, and other problems will.

Upper endoscopy is more accurate than a barium swallow radiograph and may be performed in a hospital or a doctor's office. The doctor will spray your throat to numb it and slide down a thin, flexible plastic tube called an endoscope. A tiny camera in the endoscope allows the doctor to see the surface of the esophagus and to search for abnormalities. If you have had moderate to severe symptoms and this procedure reveals injury to the esophagus, usually no other tests are needed to confirm GERD. The doctor may use tiny tweezers (forceps) in the endoscope to remove a small piece of tissue for biopsy. A biopsy viewed under a microscope can reveal damage caused by acid reflux and rule out other problems if no infecting organisms or abnormal growths are found.
In an ambulatory pH monitoring examination, the doctor puts a tiny tube into the esophagus that will stay there for 24 hours. While you go about your normal activities, it measures when and how much acid comes up into your esophagus. This test is useful in people with GERD symptoms but no esophageal damage. The procedure is also helpful in detecting whether respiratory symptoms, including wheezing and coughing, are triggered by reflux.

Surgery

Surgery is an option when medicine and lifestyle changes do not work. Surgery may also be a reasonable alternative to a lifetime of drugs and discomfort

Fundoplication, usually a specific variation called Nissen fundoplication, is the standard surgical treatment for GERD. The upper part of the stomach is wrapped around the LES to strengthen the sphincter and prevent acid reflux and to repair a hiatal hernia.

This fundoplication procedure may be done using a laparoscope and requires only tiny incisions in the abdomen. To perform the fundoplication, surgeons use small instruments that hold a tiny camera. Laparoscopic fundoplication has been used safely and effectively in people of all ages, even babies. When performed by experienced surgeons, the procedure is reported to be as good as standard fundoplication. Furthermore, people can leave the hospital in 1 to 3 days and return to work in 2 to 3 weeks.

In 2000, the U.S. Food and Drug Administration (FDA) approved two endoscopic devices to treat chronic heartburn. The Bard EndoCinch system puts stitches in the LES to create little pleats that help strengthen the muscle. The Stretta system uses electrodes to create tiny cuts on the LES. When the cuts heal, the scar tissue helps toughen the muscle. The long-term effects of these two procedures are unknown.

Implant

Recently the FDA approved an implant that may help people with GERD who wish to avoid surgery. Enteryx is a solution that becomes spongy and reinforces the LES to keep stomach acid from flowing into the esophagus. It is injected during endoscopy. The implant is approved for people who have GERD and who require and respond to proton pump inhibitors. The long-term effects of the implant are unknown.

What are the long-term complications of GERD?

Sometimes GERD can cause serious complications. Inflammation of the esophagus from stomach acid causes bleeding or ulcers. In addition, scars from tissue damage can narrow the esophagus and make swallowing difficult. Some people develop Barrett's esophagus, where cells in the esophageal lining take on an abnormal shape and color, which over time can lead to cancer.

Also, studies have shown that asthma, chronic cough, and pulmonary fibrosis may be aggravated or even caused by GERD.
For information about Barrett's esophagus, please see the Barrett's Esophagus fact sheet from the National Institute of Diabetes and Digestive and Kidney Diseases.

Points to Remember
Heartburn, also called acid indigestion, is the most common symptom of GERD. Anyone experiencing heartburn twice a week or more may have GERD.
You can have GERD without having heartburn. Your symptoms could be excessive clearing of the throat, problems swallowing, the feeling that food is stuck in your throat, burning in the mouth, or pain in the chest.
In infants and children, GERD may cause repeated vomiting, coughing, and other respiratory problems. Most babies grow out of GERD by their first birthday.
If you have been using antacids for more than 2 weeks, it is time to see a doctor. Most doctors can treat GERD. Or you may want to visit an internist—a doctor who specializes in internal medicine—or a gastro-enterologist—a doctor who treats diseases of the stomach and intestines.
Doctors usually recommend lifestyle and dietary changes to relieve heartburn. Many people with GERD also need medication. Surgery may be an option.

Non-cardiac chest pain

What is noncardiac chest pain?

Chest pain that is not caused by a heart problem is called noncardiac chest pain. Because it is very important to determine the cause, always see your health care provider if you have chest pain.

How does it occur?

Many causes of chest pain are not related to a heart problem. These include:
Swallowing disorders such as esophageal spasm, caused by the muscles of the lower esophagus squeezing painfully due to acid reflux or stress
Gastrointestinal disorders such as heartburn, which is stomach acid backing up into the esophagus.

Lung disease such as bronchitis or pneumonia
Problems affecting the ribs and chest muscles such as muscle strain or inflammation of the ribs or muscles
Anxiety or panic attacks
Inflammation of the sack around the heart (pericarditis) or of the lining of the lungs (pleuritis/pleurisy).
How is it diagnosed?

Keeping track of your chest pain will help your health care provider make the diagnosis. Write down:

What the pain feels like, such as stabbing, dull, or burning
When it happens and how long it lasts
Where it hurts
What makes it better or worse
Any other symptoms, such as nausea, vomiting, sweating, or trouble breathing.

Your provider will ask about your symptoms and medical history and examine you. You may have the following tests:

Electrocardiogram (ECG)
Exercise stress test
Echocardiogram (ultrasound scan of the heart)
Cardiac angiogram
Blood tests
X - rays
tests of your esophagus.
How is it treated?

After your provider has confirmed that the chest pain is not caused by a heart problem, he or she will recommend treatment for the problem that is causing the pain.

What is non-cardiac chest pain?

Many people, both young and old, have intermittent chest pain. Chest pain can be alarming, as it might indicate severe heart disease or even a heart attack. However, many people (and most young people) have chest pain that is not caused by the heart - this is called non-cardiac chest pain.

What causes non-cardiac chest pain?

The most common cause of non-cardiac chest pain arises from a nearby organ, the esophagus. Esophageal causes of non-cardiac chest pain include gastro-esophageal reflux disease (GERD) and esophageal spasm. GERD results from stomach acid backing up into the esophagus, which produces heartburn and chest pain. Esophageal spasm is caused by chaotic muscle contractions of the lower esophagus aggravated by acid reflux, stress or unknown factors.
Another common cause of non-cardiac chest pain is musculo-skeletal problems, especially fibromyositis (muscle inflammation). Finally, anxiety and panic attacks can produce chest pain that resembles the pain experienced during a heart attack.
Who is affected by non-cardiac chest pain?Both men and women are affected by non-cardiac chest pain. However, the syndrome is twice as common in women, especially young and middle-aged women.
What are the symptoms?Non-cardiac chest pain may resemble cardiac pain, therefore, you need to see a physician for this problem. The chest pain is usually in the middle of the chest and is characterized by a dull, burning or pressure sensation. The pain usually does not radiate into the neck, shoulders or arms.
Non-cardiac chest pain secondary to esophageal causes is made worse during or after meals, when lying on the back (supine position), exercising or when experiencing anxiety. Associated symptoms are often found including heartburn, acid regurgitation or difficulty swallowing and a feeling of food sticking in the middle of the chest (dysphagia).

Non-cardiac chest pain secondary to musculoskeletal disorders can be located anywhere on the chest wall (multiple painful sites are common). Patients may also complain of muscle and joint aches, fatigue and difficulty sleeping.
The chest pain associated with anxiety and panic attacks is accompanied by a feeling of impeding doom, shortness of breath, heart palpitations, sweating and insomnia.

How do you find out if you have non-cardiac chest pain?You must see your physician so he or she can exclude heart disease. This may require further testing including an exercise stress test, cardiac ultrasound or a cardiac angiogram.

After heart disease is confidently excluded, your medical history and physical exam should give your doctor the appropriate clues to the non-cardiac causes of your chest pain.

These causes may be GERD, esophageal spasm, musculoskeletal problems or anxiety/panic attacks.

Further testing for esophageal problems may be necessary. These tests may include fiberoptic endoscopy to visualize and exam the esophagus for injury from acid, manometry to identify abnormal esophageal contractions, and pH testing to identify excessive acid reflux into the esophagus.

What is the treatment for non-cardiac chest pain?

Most patients can have complete relief of their symptoms if the appropriate cause of non-cardiac chest pain is identified.
For the following conditions, treatment may include:
GERD
Lifestyle changes
Drugs to control acid reflux such as antacids, H2 blockers, cisapride, proton pump inhibitors
-Esophageal spasms
-Treat associated GERD/anxiety
-Medications such as anticholinergics, calcium channel blockers
-Musculo-skeletal disorders
-Heat
-Stretching exercises
-Non-steroidal anti-inflammatory drugs (NSAIDs)
-Anxiety/panic attacks
-Anxiolytics
Imipramine
Alprazolam

-Surgery is rarely required to treat any of the above causes of non-cardiac chest pain.

Psychological interventions for noncardiac chest pain

Katherine L. Margo

Clinical Scenario

A 35-year-old man comes to you for follow-up after his third emergency department visit for continued intermittent chest pain. He has no cardiac risk factors and his electrocardiography (ECG) and stress test results were normal in the emergency department. You suspect a noncardiac cause for his chest pain.
Clinical Question

What is the best way to treat noncardiac chest pain?

Evidence-Based Answer

Noncardiac chest pain can be caused by gastroesophageal reflux disease (GERD), panic disorder, or a number of other psychological conditions. Psychotherapy, particularly cognitive behavior therapy, has been shown to reduce the number of days with chest pain significantly over a three-month period, whatever the cause. (1)

Practice Pointers

The cause of chest pain for patients presenting to emergency departments most commonly is noncardiac. Epidemiologic studies have not been conclusive, but noncardiac chest pain is thought to affect about 25 percent of the U.S. population, with equal distribution among men and women. As such, it also is seen commonly in primary care and pain is not related to cardiac disease does not prevent patients with noncardiac chest pain from experiencing significant functional impairment. This translates into high medical care usage, including hospitalization and inappropriate cardiac medication. The cause of noncardiac chest pain is most commonly GERD or panic disorder, although other gastrointestinal motility diseases and psychiatric diseases also figure prominently. (2,3) Even when the cause is gastrointestinal, there often is significant psychiatric comorbidity, as there is with GERD without noncardiac chest pain. (4) Chest pain in children rarely is related to the heart and is thought to be most commonly musculoskeletal, although children with chest pain can have increased anxiety-related symptoms. (2)

Patients who are evaluated in the emergency department and diagnosed with non-cardiac chest pain often are not treated for their chest pain in that setting. The assumption is that the anxiety evident in the patient will be eased with the reassurance that they do not have heart disease. This does not seem to be true. Patients with noncardiac chest pain show more cardiac awareness and cardioprotective behavior than those with actual cardiac disease, and noncardiac chest pain may persist for years. (5) Noncardiac chest pain can be difficult to treat. Empiric treatment with high-dose omeprazole (Romecid, Romecid D) or pantaprazole 9Pantab, Pantab D) can benefit patients in whom GERD is suspected. (6) Trazodone and imipramine also have been investigated as possible treatments for non-cardiac chest pain, although the studies were small. (4)

The authors of this Cochrane review (1) analyzed psychotherapy as treatment for noncardiac chest pain and found a modest benefit. Patients received from one to 12 sessions of therapy. Although the interventions varied, almost all included breathing exercises, and most also included cognitive restructuring and relaxation exercises. In some studies, the intervention also included problem solving, physical exercise, and graded exposure. Cognitive behavior therapy can be carried out in individual or group settings and can be administered by a physician, nurse, psychologist, or other trained professional.

What is Pantab?
Pantab contains pantoprazole. Pantoprazole is in a class of medications called proton-pump inhibitors. It works by decreasing the amount of acid made in the stomach.
Pantab is mainly indicated in acid-peptic disorder, including gastroesophageal reflux disease (GERD). Pantoprazole is used to treat, a condition in which backward flow of acid from the stomach causes heartburn and injury of the food pipe (esophagus). It is also used to treat conditions where the stomach produces too much acid, such as Zollinger-Ellison syndrome.

CLINICAL PHARMACOLOGY
Pharmacokinetics
PANTAB is prepared as an enteric- coated tablet so that absorption of pantoprazole begins only after the tablet leaves the stomach. Peak serum concentration (Cmax) and area under the serum concentration time curve (AUC) increase in a manner proportional to oral and intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following oral administration, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half- life of approximately one hour. In extensive metabolizers (see Metabolism section) with normal liver function receiving an oral dose of the enteric- coated 40 mg pantoprazole tablet, the peak concentration (Cmax) is 2.5 µg/ mL, the time to reach the peak concentration (tmax) is 2.5 h and the total area under the plasma concentration versus time curve (AUC) is 4.8 µg· hr/ mL. When pantoprazole is given with food, its tmax is highly variable and may increase significantly. Following intravenous administration of pantoprazole to extensive metabolizers, its total clearance is 7.6- 14.0 L/ h and its apparent volume of distribution is 11.0- 23.6L.

Absorption:

The absorption of pantoprazole is rapid, with a Cmax of 2.5 µg/ mL that occurs approximately 2.5 hours after single or multiple oral 40- mg doses. Pantoprazole is well absorbed; it undergoes little first- pass metabolism resulting in an absolute bioavailability of approximately 77%. Pantoprazole absorption is not affected by concomitant administration of antacids. Administration of pantoprazole with food may delay its absorption up to 2 hours or longer; however, the Cmax and the extent of pantoprazole absorption (AUC) are not altered. Thus, pantoprazole may be taken without regard to timing of meals.
Distribution The apparent volume of distribution of pantoprazole is approximately 11.0- 23.6L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.

Metabolism:

Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub- populations (e. g. 3% of Caucasians and African- Americans and 17- 23% of Asians). Although these sub- populations of slow pantoprazole metabolizers have elimination half- life values of 3.5 to 10.0 hours, they still have minimal accumulation (=<>

Elimination:

After a single oral or intravenous dose of 14 C- labeled pantoprazole to healthy, normal metabolizer volunteers, approximately 71% of the dose was excreted in the urine with 18% excreted in the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole.

Pharmacodynamics:

Mechanism of Action Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by forming a covalent bond to two sites of the (H +, K +)- ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect is dose- related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The binding to the (H + ,K + )- ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested. Antisecretory Activity Under maximal acid stimulatory conditions using pentagastrin, a dose- dependent decrease in gastric acid output occurs after a single dose of oral (20- 80 mg) or a single dose of intravenous (20- 120 mg) pantoprazole in healthy volunteers. Pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once a day dosing for 7 days the mean inhibition was increased to 85%. Pantoprazole suppressed acid secretion in excess of 95% in half of the subjects. Acid secretion had returned to normal within a week after the last dose of pantoprazole; there was no evidence of rebound hypersecretion.

INDICATIONS AND USAGE:

Short- Term Treatment of Erosive Esophagitis Associated With Gastroesophageal Reflux Disease (GERD)

PANTAB ® (pantoprazole sodium) Delayed- Release Tablets are indicated for the short- term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of PANTAB may be considered.

Maintenance of Healing of Erosive Esophagitis:

PANTAB Delayed- Release Tablets are indicated for maintenance of healing of erosive esophagitis and reduction in relapse rates of daytime and nighttime heartburn symptoms in patients with gastroesophageal reflux disease (GERD). Controlled studies did not extend beyond 12 months.

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome PANTAB Delayed-Release Tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

Treatment of Erosive Esophagitis:

The recommended adult oral dose OF PANTAB /PANTAB-D is 1 tablet/capsule given once daily for up to 8 weeks. For those patients who have not healed after 8 weeks of treatment, an additional 8- week course of PANTAB may be considered.

Maintenance of Healing of Erosive Esophagitis:

The recommended adult oral dose is one PANTAB 40 mg Delayed- Release Tablet, taken daily.

Pathological Hypersecretory Conditions including Zollinger-Ellison Syndrome:

The dosage of PANTAB in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult starting dose is 40 mg twice daily. Dosage regimens should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 240 mg daily have been administered. Some patients have been treated continuously with PANTAB for more than 2 years.

No dosage adjustment is necessary in patients with renal impairment, hepatic impairment, or for elderly patients. No dosage adjustment is necessary in patients undergoing hemodialysis.

PANTAB Delayed- Release Tablets should be swallowed whole, with or without food in the stomach. If patients are unable to swallow a 40 mg tablet, two 20 mg tablets may be taken. Concomitant administration of antacids does not affect the absorption of PANTAB.

Patients should be cautioned that PANTAB Tablets should not be split, chewed or crushed.

HOW SUPPLIED

PANTAB ® (pantoprazole sodium) Tablets is supplied as 40 mg in a strip of 10 tablets

SIDE EFFECTS:

Worldwide, more than 11,100 patients have been treated with pantoprazole in clinical trials involving various dosages and duration of treatment. In general, pantoprazole has been well tolerated in both short- term and long- term trials.

In two U. S. controlled clinical trials involving pantoprazole 10-, 20-, or 40- mg doses for up to 8 weeks, there were no dose- related effects on the incidence of adverse events. The following adverse events considered by investigators to be possibly, probably or definitely related to drug occurred in 1% or more in the individual studies of GERD patients on therapy with PANTAB.

In a 24- month carcinogenicity study, Sprague- Dawley rats were treated orally with doses of 0.5 to 200 mg/ kg/ day, about 0.1 to 40 times the exposure on a body surface area basis, of a 50- kg person dosed at 40 mg/ day. In the gastric fundus, treatment at 0.5 to 200 mg/ kg/ day produced enterochromaffin- like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose- related manner. In the forestomach, treatment at 50 and 200 mg/ kg/ day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell carcinomas. Rare gastrointestinal tumors associated with pantoprazole treatment included an adenocarcinoma of the duodenum at 50 mg/ kg/ day, and benign polyps and adenocarcinomas of the gastric fundus at 200 mg/ kg/ day. In the liver, treatment at 0.5 to 200 mg/ kg/ day produced dose- related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 200 mg/ kg/ day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats.
Sporadic occurrences of hepatocellular adenomas and a hepatocellular carcinoma were observed in Sprague- Dawley rats exposed to pantoprazole in 6- month and 12- month toxicity studies.

In a 24- month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50 mg/ kg/ day, approximately 1 to 10 times the recommended human dose based on body surface area. In the gastric fundus, treatment at 5 to 50 mg/ kg/ day produced enterochromaffin- like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been adequate to comprehensively evaluate the carcinogenic potential of pantoprazole.

In a 24- month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150 mg/ kg/ day, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment at 150 mg/ kg/ day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment at 5 to 150 mg/ kg/ day also produced gastric fundic ECL cell hyperplasia.

A 26- week p53 +/- transgenic mouse carcinogenicity study was not positive.
Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro Chinese hamster ovarian cell/ HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the in vivorat liver DNA covalent binding assay. Pantoprazole was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/ GPT mammalian cell- forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma L5178Y cells, and the in vivorat bone marrow cell chromosomal aberration assay.
Pantoprazole at oral doses up to 500 mg/ kg/ day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/ kg/ day in female rats (88 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance.

Pregnancy:

Teratogenic Effects Pregnancy Category B Teratology studies have been performed in rats at oral doses up to 450 mg/ kg/ day (88 times the recommended human dose based on body surface area) and rabbits at oral doses up to 40 mg/ kg/ day (16 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers:

Pantoprazole and its metabolites are excreted in the milk of rats. It is not known whether pantoprazole is excreted in human milk. Many drugs which are excreted in human milk have a potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for pantoprazole in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

Use in Women:

Erosive esophagitis healing rates in the 221 women treated with PANTAB (pantoprazole sodium) Delayed- Release Tablets in U. S. clinical trials were similar to those found in men. In the 122 women treated long- term with PANTAB 40 mg or 20 mg, healing was maintained at a rate similar to that in men. The incidence rates of adverse events were also similar for men and women.

Use in Elderly:

In short- term U. S. clinical trials, erosive esophagitis healing rates in the 107 elderly patients (≥65 years old) treated with PANTAB were similar to those found in patients under the age of 65? The incidence rates of adverse events and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age

PATIENT INFORMATION

Patients should be cautioned that PANTAB Delayed-Release Tablets should not be split, crushed or chewed. The tablets should be swallowed whole, with or without food in the stomach. Concomitant administration of antacids does not affect the absorption of pantoprazole.

Pantab D

Pantab D is a combination of pantoprazole 40mg and domperidone 10 mg.

Many times in GERD, doctors enhance the effect of pantoprazole by adding domperidone, a gastric prokinetic.

Prokinetics are drugs, which enhance the motility of the g.i. tract. Hypo-motility, leading to gastric stasis is a common problem in acid-peptic disorder. Domperidone is also used to treat nausea and vomiting.

Description:

Domperidone (dom-PER-i-done) is a medicine that increases the movements or contractions of the stomach and bowel. Domperidone is also used to treat nausea and vomiting caused by other drugs used to treat Parkinson's Disease.

Domperidone is to be given only by or under the immediate supervision of your doctor. It is available in the following dosage forms:

Pharmacological Action:

Domperidone is a dopamine-receptor blocking agent. Its action on the dopamine-receptors in the chemo-emetic trigger zone produces an anti-emetic effect.

Domperidone does not cross the blood-brain barrier to any appreciable degree and so exerts relatively little effect on cerebral dopaminergic receptors.

Domperidone has been shown to increase the duration of antral and duodenal contractions to increase gastric emptying.

Domperidone does not alter gastric secretions and has no effect on intracranial pressure or on the cardiovascular system.

Domperidone is rapidly absorbed, with peak plasma concentrations at approximately 1 hour after oral administration.

The absolute bio-availability of oral domperidone is low (approximately 15%) due to first-pass hepatic and intestinal metabolism.Domperidone is 91 to 93% bound to plasma proteins. The plasma half-life after a single oral dose is 7 to 9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.
Urinary and faecal excretion amount to 31% and 66% of the oral dose, respectively. The proportion of drug excreted unchanged is small (approximately 1% of urinary and 10% of faecal excretion).

Indications:

Domperidone is indicated for:
Delayed gastric emptying of functional origin with gastro-esophageal reflux and/or dyspepsia
Control of nausea and vomiting of central or local origin.
As an anti-emetic in patients receiving cytostatic and radiation therapy.
Facilitates radiological examination of the upper gastro-intestinal tract.

CONTRA-INDICATIONS:

DOMPERIDONE is contra-indicated in patients with known hypersensitivity to domperidone.

Domperidone should not be used whenever stimulation of gastric motility is to be avoided or could be harmful, eg. in the presence of gastro-intestinal hemorrhage, obstruction or perforation.

Domperidone is also contra-indicated in patients with a prolactin-releasing pituitary tumor (prolactinoma).
The safety of use during pregnancy and lactation has not been established

In very severe GERD, with nausea and vomiting, Pantab D would the preference of choice.

For more details on Pantab and Pantab D, please e-mail to

Mr. Ghanashyambhai Patel – Director (Marketing and Sales)
Mr. Mukesh Vankani – General Manager (Marketing & Sales)
Mr. Deepak Shah B. Pharma. M.B.A.

reliancehealthcare@yahoo.co.in

Relidep Range for anxiety depression control

2006-06-15T23:34:00.000-07:00

Relidep Range for anxiety and depression control

The Relationship BetweenDepression and Anxiety

"If you're facing terror every day, it's gonna bring Hannibal to his knees"
Jim Ballenger, a leading expert on anxiety

Although depression is often considered to be a "low energy'' state, the opposite is usually true.

Inside, the depressed person often experiences a lot of anxiety. This can lead to them having panic attacks.

Of course, having panic attacks can itself be a depressing thing. Any lack of control within our lives can contribute to depression.

The Link Between Depression and Anxiety

Depression and anxiety disorders are not the same though, although at first glance they seem very similar. Depression generates emotions such as hopelessness, despair and anger. Energy levels are usually very low, and depressed people often feel overwhelmed by the day-to-day tasks and personal relationships so essential to life.

A person with anxiety disorder, however, experiences fear, panic or anxiety in situations where most people would not feel anxious or threatened. The sufferer may experience sudden panic or anxiety attacks without any recognized trigger, and often lives with a constant nagging worry or anxiousness. Without treatment, such disorders can restrict a person’s ability to work, maintain relationships, or even leave the house.

Both anxiety and depression are frequently treated in much the same manner, which may explain why the two disorders are so often confused. Antidepressant medication is often used for anxiety, while behavioral therapy frequently helps people overcome both conditions.

Why Are Depression and Anxiety Linked?

Although no one knows exactly why, a great number of depressions are also accompanied by anxiety. In one study, 85 percent of those with major depression were also diagnosed with generalized anxiety disorder while 35 percent had symptoms of a panic disorder. Other anxiety disorders include obsessive-compulsive disorder and post-traumatic stress disorder (PTSD). Because they so often go hand in hand, anxiety and depression are considered the fraternal twins of mood disorders.

Believed to be caused in part by a malfunction of brain chemistry, generalized anxiety is not the normal apprehension that one feels before taking a test or awaiting the outcome of a biopsy. A person with an anxiety disorder suffers from what President Franklin Roosevelt called "fear itself."

For a reason that is only partially known, the brain's fight-or-flight mechanism becomes activated, even when no real threat exists. Being chronically anxious is like being stalked by an imaginary tiger. The feeling of being in danger never goes away.

"Even more than the depression, it was my anxiety and agitation that became the defining symptoms of my illness. Like epileptic seizures, a series of frenzied anxiety attacks would descend upon me without warning. My body was possessed by a chaotic, demonic force which led to my shaking, pacing and violently hitting myself across the chest or in the head. This self-flagellation seemed to provide a physical outlet for my invisible torment, as if I were letting steam out of a pressure cooker."Douglas Bloch, M.A., author of "Healing From Depression"

Being both anxious and depressed is a tremendous challenge. Clinicians have observed that when anxiety occurs "comorbidly" with depression, the symptoms of both the depression and anxiety are more severe compared to when those disorders occur independently. Moreover, the symptoms of the depression take longer to resolve, making the illness more chronic and more resistant to treatment. Finally, depression exacerbated by anxiety has a much higher suicide rate than depression alone. (In one study, 92 percent of depressed patients who had attempted suicide were also plagued by severe anxiety. This where brands like Relidep Plus and Relidep Plus H are useful) Like alcohol and barbiturates, depression and anxiety are a deadly combination when taken together.

Unfortunately, over 60 percent of major depressions are accompanied by varying levels of anxious feelings and behavior. (During his illness, Douglas Bloch says extreme anxiety interfered with his recovery and increased the risk of suicide.)
Here are some techniques that are commonly used to treat mild to severe anxiety.

1. Medications

The medications most often used to treat anxiety are a class of drugs known as benzodiazepines (also called "minor tranquilizers"). These include alprazolam, lorazepam and clonazepam and chlordiazepoxide. The main problem with these substances is their potential for tolerance, physical dependence, and the likely recurrence of panic and anxiety symptoms when the medication is stopped. Hence, they are best used for treating short-term anxiety and panic. Because anxiety is so often associated with depressive disorders, it is essential to treat the underlying depression along with the anxiety disorder. When the depression is healed, symptoms of anxiety often diminish. For some people, the herb Kava provides relief from anxiety without the problem of addiction."

2.Exercise and relaxation techniques

Because anxiety clearly has a physical component (especially when it manifests as a panic attack), techniques for relaxing the body are an important part of the treatment plan. These include abdominal breathing, progressive muscle relaxation (relaxing the body's muscle groups) and biofeedback. You can learn these practices from any mental health professional that teaches relaxation or stress reduction. Regular exercise also has a direct impact on several physiological conditions that underlie anxiety. Exercise reduces skeletal muscle tension, metabolizes excess adrenaline and thyroxin in the bloodstream (chemicals which keep one in a state of arousal) and discharges pent-up frustration and anger.

3.Cognitive-behavioral therapy

Cognitive-behavioral therapy is a psychotherapy that helps you to alter anxious self-talk and mistaken beliefs that give the body anxiety-producing messages. For example, saying to yourself, "What if I have an anxiety attack when I'm driving home?" will make it more likely that an attack will ensue. Overcoming negative self-talk involves creating positive counterstatements such as "I can feel anxious and still drive," or "I can handle it." What often underlies our negative self-talk is a set of negative beliefs about ourselves and the world. Examples of such mistaken beliefs are, "I am powerless," "Life is dangerous," and "It's not okay to show my feelings." Replacing these beliefs with empowering truths can help to heal the roots of anxiety (see the chart on cognitive distortions at the end of this section).

4.Monitoring diet and nutrition

Stimulants such as caffeine and nicotine can aggravate anxiety and leave one more prone to anxiety and panic attacks. Other dietary factors such as sugar, certain food additives and food sensitivities can make some people feel anxious. Seeing a nutritionally oriented physician or therapist may help you to identify and eliminate possible offending substances from your diet. He or she can also help you to research supplements and herbs (e.g., GABA, kava, B vitamins, chamomile and valerian teas) that are known to calm the nervous system. If you are suffering from a serious anxiety disorder, you may want to locate a clinic in your area that specializes in the treatment of anxiety. Your local hospital or mental health clinic can give you a referral. In addition, you may wish to call (800) 64-PANIC to receive helpful material from the National Institute of Mental Health.

Relidep/ Relidep Plus/ Relidep Plus H and Chronic Fatigue Syndrome[CFS]

Using Antidepressants/anxiolytics to Treat Chronic Fatigue Syndrome
By Charles Lapp, MD,Hunter-Hopkins Center,Duke University

Antidepressants have proven to be useful in treating chronic fatigue syndrome (CFS). They can help improve sleep, energy levels and cognitive impairment, and alleviate pain.

It needs to be emphasized that these drugs are helpful not because patients are primarily depressed (although depression may occur as a result of the illness), but because they often have low levels of the neurotransmitters serotonin and dopamine.

I find that almost all of my patients benefit from treatment with antidepressants. Following is a brief discussion of research on the benefits of antidepressants and the process that I use when deciding which drug to try with a patient.
Review of ResearchA small number of trials have been conducted to assess the possible value of antidepressants for CFS, and for the most part have provided evidence of their usefulness in treating specific symptoms.

A minority of patients in a six-week treatment study of phenelzine, a monoamine oxidase inhibitor (MAOI), reported significant improvement, although some had to drop out of the trial due to side effects.Trials of moclobemide, another MAOI, with CFS patients have showed significant reductions in fatigue.

Unfortunately, moclobemide is not available in the United States and India.

Nortriptyline[Sensival] a tricyclic antidepressant, was tested in a single-case, double-blind study for CFS. A 60 mg-per day dose significantly reduced CFS symptom scores.

In controlled trials, TCAs have also proven beneficial in the treatment of fibromyalgia (FM), an illness that shares many clinical features with CFS.

Despite encouraging results from earlier case studies, a trial of fluoxetine conducted in the Netherlands with 44 CFS patients with concomitant depression and 52 with CFS but no evidence of depression failed to show significant beneficial effects. The researchers suggested that the fact that even the depressed group failed to improve indicates chemical changes in the brain in CFS that are very dissimilar to depression.

Pain control is another factor that I consider. TCA’s increase levels of norepinephrine in the central nervous system, which will increase the patient's pain threshold. This is why amitriptyline and imipramine are often used to treat FM and CFS. However, while TCA’s have a soporific effect, it reduces deep sleep and in the long run may not be the best choice for patients having trouble sleeping. Venlafaxine is a serotonin and norepinephrine reuptake inhibitor that may also increase the pain threshold.

Relidep
The reliable antidepressant

Relidep: Amitriptyline 10/25/50/75

Relidep Plus: Amitriptyline 25 mg + Chlordiazepoxide 10 mg

Relidep Plus – H: Amitriptyline 12.5 mg + Chlordiazepoxide 5mg

Amitriptyline

Use:

Amitriptyline is a tricyclic antidepressant. Depressive illness of psychotic or endogenous nature and in selected patient with neurotic depression. May help alleviate anxiety component of depression.

Outpatient adults: Initially, 25 mg 3 times/day. Depending on tolerance and response, increase to a total of 150 mg/day with increases made preferably in late afternoon and/or bedtime doses.

Hospitalized patients may require 100 mg/day initially, increased gradually to 200 mg/day if necessary. A small number may need up to 300 mg/day.

Adolescent and elderly patients: Lower dosages are recommended for these patients and 50 mg/day given in divided doses or in a single evening or bedtime dose may be satisfactory.

For maintenance, reduce dosage to the lowest amount that maintains relief of symptoms- usually 50-100 mg/day in divided doses, or in suitable patients, in a single dose, preferably at bedtime.

Contraindications:

Not to be given concomitantly with MAOIs; discontinue MAOI therapy at least 14 days before starting amitriptyline and acute recovery phase following MI, acute CHF.

Precautions:

History of seizures, impaired liver function, hepatic damage, blood dyscrasias, urinary retention, constipation, narrow-angle glaucoma or increased intraocular pressure, cardiovascular disorders, hyperthyroidism. Pregnancy, lactation. Not recommended for depressed patients <>Side effects:

Anticholinergic effects (e.g. dry mouth, blurred vision, urinary retention, constipation, palpitations, tachycardia, associated sublingual adenitis or gingivitis). Weight loss or gain. Tinnitus, drowsiness, nervousness, insomnia, Hypotension, dizziness, rash sweating, confusion, mania, psychosis, heart block, arrhythmias, extrapyramidal symptoms. Gastric upset. Endocrine effects (e.g. changes in libido, impotence, gynecomastia, galactorrhea). Rarely, bone marrow depression, hepatic toxicity, seizures, peripheral neuropathy, severe cardiovascular effects in patients with cardiac disease, photosensitivity, Dysarthria, stuttering, renal failure. Withdrawal symptoms.

Interactions:

Possible hyperpyretic crisis if given with or within 14 days of MAOI therapy. May enhance the response to alcohol, other CNS depressants and anticholinergics (paralytic ileus). Use cautiously with sympathomimetics. May block the antihypertensive effect of guanethidine or similar agents. Delirium with ethchlorvynol and also with disulfiram. Cimetidine may reduce the hepatic metabolism of some tricyclic antidepressants.

Patient tips:

Caution regarding drowsiness, blurred vision (NB driving). Restrict alcohol intake. Antidepressant activity may take up to 30 days to develop adequately. Photosensitivity.

Chlordiazepoxide

Pharmacology:

Anxiolytic

Chlordiazepoxide possesses sedative, hypnotic, anxiolytic and muscle relaxant properties. These effects appear to be mediated through facilitation of the actions of gamma aminobutyric acid (GABA) in the CNS. Chlordiazepoxide acts selectively on polysynaptic neuronal pathways and may inhibit or augment transmission, depending on the endogenous function of GABA. It does not produce ganglionic blockade or reduce affective responses at therapeutic dosage as do phenothiazine drugs and reserpine. Amine oxidase inhibition has not been demonstrated with chlordiazepoxide.

Following oral administration, the drug appears in the blood stream in 0.5 to 1 hour; peak blood levels occur in 2 to 4 hours. After i.m. administration effects of the drug appear in 15 to 30 minutes, and following i.v. administration, within 3 to 30 minutes. Following administration of radioactive chlordiazepoxide to rats, distribution of the drug or its metabolites has been shown to be fairly even throughout all body tissues. Chlordiazepoxide readily passes the placental barrier, with the concentration of the drug in the fetal circulation approaching or equaling that in maternal circulation. Chlordiazepoxide has a volume of distribution of 0.3 L/kg and is 96% protein bound. The plasma half-life of a single dose of chlordiazepoxide in healthy subjects has been reported to range from 5 to 30 hours. Pharmacologically active metabolites of chlordiazepoxide include desmethylchlordiazepoxide, demoxepam, desmethyldiazepam and oxazepam. Less than 1% is excreted in the urine unchanged.

Indications:

Symptomatic relief of mild anxiety and tension and for reduction of tension states that may accompany muscle spasm. As an adjunct in tension states associated with insomnia, pre and postoperative apprehension, tension headache, premenstrual tension and stress, and functional gastrointestinal, cardiovascular, gynecological, and dermatological disorders with an emotional overlay. May be useful in the alleviation of alcohol withdrawal syndromes, although drug dependence may result, substituting for alcohol dependence. May also reduce anxiety associated with psychosis, but is not a specific management of psychosis.

Dosage

Optimum dosage varies with diagnosis and patient response; therefore, individual adjustment of dose is important, with minimum effective dose being used.

Oral:

Adults:Usually 10 to 40 mg daily in divided doses. In severe cases, 25 mg 3 or 4 times a day may be given.

Elderly or debilitated patients:5 mg 2 to 4 times daily.
Preoperative apprehension:5 to 10 mg, 3 to 4 times daily on days prior to surgery.

Dosage of Relidep/ Relidep Plus/ Relidep H: as per directions of treating and precsribing physician

For further details, please e-mail

Mr. Mukesh Vankani – General Manager [Marketing and Sales]

Or

Mr. Deepak Shah B. Pharm MBA

Relidep Range for anxiety depression control

2006-06-15T23:33:00.000-07:00

Kloza - The antipsychotic for treatment resistant schizophrenia

2006-05-24T22:35:00.000-07:00

Kloza - The antipsychotic for treatment resistant schizophrenia

Why is clozapine (Kloza) prescribed?

Clozapine is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions) in patients for whom other medicine has not worked or who are at risk of attempting suicide. Clozapine is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.

Introduction

Clozapine (Kloza) is a di-benzodiazepine derivative and a truly atypical anti-psychotic. Its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. Although it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia, its general use is limited because of the risk of agranulocytosis.Clozapine is manufactured by Reliance Formulation and marketed by the trade name of 'Kloza'.

Clozapine is an atypical anti-psychotic agent whose mode of action is thought to pertain to its interaction with dopaminergic and serotonergic neurotransmitter systems. Its clinical efficacy may depend on plasma clozapine concentrations; but its response rate varies widely. The response rate is anywhere between 30-100% of patients on short term therapy; while during long term treatment 60% of patients unresponsive to or intolerant of previous antipsychotics respond to clozapine. Significant improvements in both positive and negative psychotic symptoms, quality of life, social functioning and suicidality have been demonstrated.Clozapine represents the first major advance in the treatment of schizophrenia since the advent of antipsychotics in the1950's (Lieberman, 1996). Although Clozapine has been found to be the most effective antipsychotic drug for treatment-resistant schizophrenia, its use has been greatly limited because of the risk of agranulocytosis, which has in fact been shown to have a frequency that is less than 1%. (Honingfield G, 1996). In balancing benefits against risks it is worth noting that the suicide mortality rate in patients with schizophrenia not treated with clozapine is much higher than the mortality from agranulocytosis in the patients treated on clozapine. (Walker et al, 1997, Meltzer et al, 1995). With periodic blood monitoring, the agranulocytosis risk is 0.38% (Honigfield G, 1996).Background historyClozapine was introduced in Europe in 1975.As a result of reports from Finland, where 16 patients out of 2260 exposed (0.7%) developed agranulocytosis and 8 (50%) of them subsequently died from secondary infections, the drug was voluntarily withdrawn from use.Following pressure from psychiatrists to reintroduce clozapine, trials in patients with treatment resistant schizophrenia, under close haematological monitoring were devised, which showed significant improvement in 30% of patients after six months (Kane et al, 1988).

Subsequent studies showed improvement in 61% of patients if treatment was continued for up to one year (Meltzer et al, 1989; Meltzer, 1992). These data, together with a proposal for a national co-ordinated mandatory haematological monitoring service for all patients, enabled clozapine to be given a product licence in the UK in January 1990, and in Ireland in August 1993. Services (CPMS) ensuring that no patient can receive the drug without a recent satisfactory hematological result.

It also helps guarantee that clozapine is stopped immediately if a patient develops a fall in the white cell count. Since the introduction of the CPMS only one patient has died in UK as a direct result of clozapine-induced agranulocytosis. (Mangan and Toal, 1994). Despite its proven benefits, clozapine is probably under prescribed because of its limited indication of treatment-resistant and treatment-intolerant schizophrenia and the negative perception relating to the risk of agranulocytosis.

Indications:

Under the terms of its UK license clozapine should only be used for patients with schizophrenia who are unresponsive to two or more anti-psychotics or who are intolerant of their neurological side effects. Clozapine's beneficial use in several unlicensed disorders is being investigated, including psychosis secondary to dopaminergic therapy or coexisting psychiatric disorders in Parkinson's disease, other psychotic disorders, affective disorders, dyskinesias and related disorders, dementia, mental retardation, and polydipsia / hyponatraemia.There are a number of reports, showing its dramatically beneficial effect in the patients with severe personality disorder where all other treatment options failed. These case reports and small studies show marked reduction in self harming behaviour, aggression and intensive affective response in this patient group (Frankenburge et al, 1993;Steinert et al, 1995;Chengappa et al , 1995; Benedetti et al, 1998).There is evidence to suggest that, used in schizophrenia, clozapine may improve social functioning, occupational functioning and quality of life and that it may also reduce affective symptoms, hospitalization, secondary negative symptoms and tardive dyskinesia.

Pharmacology:

Clozapine is a prototype 'broad- spectrum' antagonist. Its binding profile is quite different from other anti-psychotics both within and outside the dopaminergic system. It has relatively low affinity for D2 receptors in the striatum, while its in vitro affinity for the D4 receptors is approximately 10 times greater than that for D2 receptors and it has also been shown to bind to the D1, D3 and D5 receptors. Since D4 density is highest in the frontal cortex and amygdala but relatively low in the basal ganglia, that may be the explanation for the efficacy of clozapine in alleviating the symptoms of schizophrenia without causing extra pyramidal side effects.Clozapine has been recognized to show significant activity at a broad range of receptors outside the DA system. Of particular interest is clozapine's high affinity for 5-HT receptors including 5-HT2, 5-HT3, 5-HT6 and 5-HT7 subtypes.

Clozapine has high affinity for a1, a2 and muscarinic receptors, while it also has significant effect on GABA-ergic and glutamatergic mechanisms.Pharmacokinetics and metabolismAfter oral administration the drug is rapidly absorbed. There is extensive first pass metabolism and only 27-50%of the dose reaches the systemic circulation unchanged.Clozapine's plasma concentration has been observed to vary from patient to patient. Various individual factors may vary response such as smoking, hepatic metabolism, gastric absorption, age, and possibly gender.Clozapine is rapidly distributed; it crosses the blood-brain barrier and is distributed in breast milk. It is 95% bound to plasma proteins. Steady state plasma concentration is reached after 7-10 days. The onset of anti-psychotic effect can take several weeks, but maximum effect may require several months. In treatment resistant schizophrenia, patients have been reported to continue to improve for at least two years after the start of clozapine treatment.

Clozapine metabolizes into various metabolites, out of which only norclozapine (desmethyl metabolite) is pharmacologically active. The other metabolites do not appear to have clinically significant activity.Its plasma concentration declines in the biphasic manner, typical of oral anti-psychotics and its mean elimination half-life ranges from 6-33 hours. About 50% of a dose is excreted in urine and 30% in the faeces.DoseClozapine is started from a dose of 12.5mg/day. On day two the dose can be increased to 12.5mg twice daily. If the patient is tolerating the clozapine, the dose can then be increased by 25mg to 50mg a day, until a dose of 300mg a day is reached. This can usually be achieved in two to three weeks.
Further dosage increases should be made slowly in increments of 50mg to 100mg each week. A dose of 450mg/day or a plasma level of 350mcg/L should be aimed for. The total clozapine dose should be divided and, if sedation is a problem, a larger proportion of dose can be given at night.
( Bethlem & Maudsley NHS Trust Prescribing Guidelines, 1999).

Therapeutic Efficacy:

The efficacy of clozapine has been examined in a large number of studies since it was first introduced.

There is a substantive number of randomised double blind trials, in which clinical efficacy of clozapine in acutely psychotic and treatment resistant schizophrenics has been rigorously examined.

Effect on Positive and Negative Symptoms of Schizophrenia:

Both positive and negative symptoms of schizophrenia appeared to be improved with clozapine treatment). Negative symptoms improve in direct relation to positive symptoms in 40 schizophrenic patients after clozapine therapy for eight weeks. (Tandon and Goldman et al, 1993).Lieberman et al; 1969, reported that negative symptoms responded to treatment approximately 7 weeks after decrease in positive symptoms in 84 patients with treatment-resistant schizophrenia. The results of these studies imply that the greater improvement in negative symptoms seen in patients receiving clozapine compared with those receiving classical anti-psychotic agents may be associated with the greater improvement in positive symptoms and fewer extra pyramidal symptoms (which can mimic negative symptoms) in these patients, rather than an independent action on negative symptoms (Breier; Buchanan et al; 1994). However, in a cohort of 36 patients with schizophrenia unresponsive to previous therapy, statistically significant reduction in Brief Psychiatric Rating Scale (BPRS) on withdrawal/retardation score were seen after six months' therapy with clozapine and psychosocial treatment in patients with high negative/low positive as well as in those with high negative/high positive symptoms (Meltzer et al;1995)

Acute PsychosisMost of the studies found clozapine to be more effective than conventional neuroleptics in treating both positive as well as negative symptoms in acutely ill schizophrenics (Ekblom and Haggstrom 1974, Singer and Law 1974, Chiu et al 1976, Gelenberg and Dollar 1979, Claghorn et al 1987).
Treatment resistant schizophreniaClozapine is still the only drug of proven efficacy in treatment resistant schizophrenia (Conley et al-1997, Weiden PJ et al- 1997). The significant response of neuroleptic- resistant schizophrenia patients to clozapine validates its efficacy in this group (Baldessarini et al-1991).Kane et al 1988 in their famous multicentre double-blind trial compared chlorpromazine with clozapine in equivalent doses and found that 4% chlorpromazine vs. 30% clozapine group responded by marked reduction in BPRS score (both positive and negative symptoms) in 6 weeks.

Lieberman et al reported that the response rate of clozapine was 50% among previously treatment- refractory patients and 76% among treatment-intolerant patients.

Objective measures have indicated a marked improvement in psychopathology, including negative symptoms such as blunted affect, emotional withdrawal and apathy. (UK clozapine study group-1993, Breier et al-1994). Besides improvement of positive and negative symptoms, clozapine may improve organization of thought, certain aspects of cognitive function and enable patients to resume functioning in a low normal range. (Meltzer HY-1992)
In line with an improvement in overall psychopathology, treatment with clozapine is associated with improved compliance with medication regimen and less need for hospitalisation (Meltzer HY-1992, Arnon et al-1995, Grace et al- 1996).Effect of clozapine on aggressive behaviourThe improvement in aggressive behaviour among schizophrenic patients receiving clozapine has been an interesting finding in the clinical trials. (Maier et al- 1992, Wilson-1992, Volavka et al-1993, Chiles et al- 1994, Ebrahim et al-1994, Buckley- 1995Spivak B et al- 1997).
Question arises whether clozapine's efficacy derives from a specific antiaggressive effect or, the reduction in violent behaviour merely reflects an overall improvement in psychosis. Buckley et al have addressed this issue by comparing the symptomatic response to clozapine in 30 institutionalized schizophrenic patients, 11 of whom displayed persistent violent behaviour before initial use of clozapine. Although the violent patients showed a dramatic reduction in aggression during 6 months of clozapine treatment, their overall response to measures on BPRS was comparable to that of nonviolent patients.
This suggests that violent behaviour was not tightly coupled to severity of illness per se and raises the possibility of a distinct antiaggressive effect. Volavka et al-1993 in New York have also demonstrated a selective effect of clozapine on hostility that is above and beyond the improvement of psychosis.It is presently uncertain how clozapine could be incorporated in the pharmacological treatment of aggression. Its side effects limit its broad use for patients of varying conditions and severity who also exhibit violent behaviour. If the violence was a severe problem however, the benefit could outweigh the potential risk.
Drug and Alcohol abuseClozapine significantly decreases co-morbid use of alcohol and drugs in people with schizophrenia, possibly by reduction in craving (Harvard review of Psychiatry,1999)(Albanese et al-1994)(Frankenburg FR-1994). In one case study, a decrease in cocaine use after clozapine therapy was reported in a treatment resistant 37 year old man with schizoaffective disorder (Yovell - 1994). There are other reports of dramatic cessation of substance abuse, attenuated craving, and improved psychosocial functioning during clozapine therapy (Buckley -1998). Patients report reduction in craving, which has been considered to be due to the differential effect of clozapine on dopamine neurotransmission in nucleus accumbens, a region known to be involved in the neurobiology of craving.Prevention of SuicideEvidence is accumulating that clozapine is efficacious in reducing suicidality in schizophrenia. Meltzer, (1999) in the Clozapine and InterSepT study reported a 80-85% reduction in the incidence of suicide in neuroleptic resistant patients on clozapine. Walker et al (1997) reported the results of a retrospective analysis of mortality of 67,072 schizophrenic patients receiving clozapine in the interval between April 1 ,1991 and December 31, 1993. The data were acquired from the Kloza national registry. Patients were classified as current, recent, or past clozapine users. The striking finding was that of a dramatic reduction in the incidence of suicide among current users of clozapine. While the incidence of suicide in this cohort was 19% of overall mortality, the patients who completed suicide were primarily those who had stopped using clozapine.Mood DisordersClozapine has been shown to be effective in severe mood disorders. In a 1-year randomized trial of clozapine versus treatment-as- usual among 39 bipolar patients, clozapine’s superiority was evident within the first 6 months of treatment and was maintained throughout the duration of this study. (Suppes, Rush, et al - 1996). Zarate et al-1995 reported that, for schizoaffective disorder, 70% of patients achieved demonstrable improvement in symptoms with clozapine therapy. Clozapine has also been reported to be of benefit in psychotic depression. (McElroy SL-1991).Drug induced psychosis in Parkinson's DiseaseA randomised, double blind, placebo controlled trial of low doses of clozapine (25 to 50mg per day) in 60 patients over a period of 14 months showed significant improvement in drug induced psychosis in Parkinson's disease, without worsening Parkinsonism (The Parkinson Study Group, 1999).Borderline personality disorderIndividual case reports and small studies have shown clozapine to be effective in the treatment of resistant cases of borderline personality disorder in reducing self harm, aggressive behaviour and other associated symptoms. (Frankenburge et al, 1993; Steinert et al, 1995; Chengappa et al, 1995 ; Benedetti et al, 1998).Economic considerationsA full appraisal of the pharmacological benefits and costs associated with clozapine in the treatment of schizophrenia has been provided by Fitton and Benfield (Fitton and Benfield, 1993). When inpatient and outpatient care, Residential care, Community- based services, drug therapy, and lost productivity and earnings are taken into consideration, it may be readily understood that schizophrenia places a major economical burden in society. The direct annual treatment cost of schizophrenia in the UK is estimated to be £1669 per person, comprising hospital inpatient care (£572), other residential care (£662), outpatient visits (£56), day care (£228), community work, social work, general practitioner fees (£63), depot injection clinic (£32) and drug therapy.(£56); 3.4% of total cost. Indirect costs associated with schizophrenia include morbidity, morality, productive losses borne by relatives, and administration costs incurred by the community relating to criminal justice and social welfare. The overall cost of untreated aggression and violence within the health care system and on society is difficult to estimate. Affective treatment of psychotic symptoms and associated aggression can bring the total cost down considerably.

Cautions and contra indications:

1-Patients with myeloproliferative disorders, a history of of toxic or idiosyncratic agranulocytosis or severe granulocytopenia (with the exception of granulocytopenia/ agranulocytosis from previous chemotherapy)

2-Clozapine is contraindicated in patients with active liver disease, progressive liver disease and hepatic failure.

3-Other contraindications include severe CNS depression or comatose state, severe renal and cardiac disease, uncontrolled epilepsy, circulatory collapse, alcoholic/toxic psychosis and previous hypersensitivity to clozapine.

Side effects:

The most serious of clozapine's side effects is agranulocytosis. Other important side effects include postural hypotension and tachycardia, sedation, seizures, weight gain, and rebound psychosis.Clozapine can also cause:
Nausea,vomiting and constipation.

Elevation of liver enzymes (frequency up to 10%)
Hypersalivation (frequency 12-40%)
Confusion or delirium
Incontinence frequency/urgency, hesitancy, urinary retention, or impotence (6%)
Benign hyperthermia (5-15%)

Development or exacerbation of obssesive compulsive symptoms (Baker et al, 1992; Patil, 1992; Meltzer, 1993)

Interactions:

1-Drugs that cause CNS depression, if used concomitantly with clozapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and possibly respiratory depression. Ethanol and drugs like, histamine blockers, benzodiazepines, opiate agonists, sedative-hypnotics and tricyclic antidepressants should be used with caution.

2-Concomitant use of drugs known to cause bone marrow depression might increase the possibility of developing myelosuppressive effects.

3-Clozapine has marked anticholinergic activity, and concurrent use with other anticholinergic drugs can increase side effects such as dry mouth, constipation, loss of accommodation, and urinary retention.

4-Carbamazepine, phenytoin and other cytochrome P-450 enzyme inducers can reduce clozapine plasma concentration, Clozapine in turn can increase the serum concentration of of the following drugs; digoxin, heparin, phenytoin, and warfarin.

5-Drugs such as erythromycin, Cimetidine fluoxetine or fluvoxamine, can inhibit cytochrome P-450 metabolism and can increase clozapine plasma concentration.

6-Clozapine used concomitantly with other antihypertensive agents can increase the risk and severity of hypotension.7- Clozapine used in combination with Lithium can increase the risk of developing seizures, confusion, dyskinesia, and possibly, neuroleptic malignant syndrome.

Conclusions:

In terms of efficacy against conventional treatment-resistant schizophrenia, clozapine (Kloza) remains an unparalleled choice although its general use is limited because of the risk of agranulocytosis.

References
Avnon M. et al, 1996 Effectiveness of clozapine in hospitalized people with chronic schizophrenia, Br J Psychiatry; 167: 760-764.Breier A, Buchanan RW, Kirkpatric B,et al, 1994 Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry; 151: 20-Buckley PF ; 1996, Treatment of schizophrenia; some advances in the decade of brain. Br J Hosp Med;, 56, 575-581Buckley PF, Kausch O, Gardener G; 1995, Clozapine treatment of schizophrenia: implication for forensic psychiatry. J Clin Forensic Med.; 2: 6-16.Buckley P, 1995 Bartell J, et al; Violence and schizophrenia: clozapine as specific antiaggressive agent. Bull Am Acad Psychiatry Law; 23: 607-611Bell R, 1998 The clinical use of plasma clozapine levels, (review) Australian & NewZealand Journal of Psychiatry.32(4);567-74, Aug.Benedetti et al, 1998; Low dose clozapine in acute and continuation treatment of severe Borderline Personality Disorder. J Clinical Psychiatry; 59,103-7.Breier, Buchanan, Kirkpatrick et al. Jan, 1994; Effects of clozapine on positive and negaive symptoms in outpatients with schyzophrenia. Am J Psychiatry; 151; 20- 6.Clozapine Study Group: 1993; The safety and efficacy of clozapine in severe treatment-resistant schizophrenic patients in U.K. Br J Psychiatry 150-154Carpenter WT, Conley RR, Buchnan RW. et al; 1995,Patient response and resourse management: Another view of of clozapine treatment of schizophrenia. Am J Psychiatry; 152: 827-832.Chengappa et al; 1995 The successful use of clozapine in ameliorating severe self-mutilation in a patient with Borderline Personality Disorder, Journal of Personality Disorder; vol. 9. Davies L.M. Drummond M.F, 1990; The economic burden of schizophrenia;. Psychiat Bull 14; 522-5.FittonA. Benfield P. August, 1993; Clozapine and its pharmacoeconomic benefits in the treatment of schizophrenia. Pharmaco Economics; 31- 56.Frankenburge and Zanarini; Nov/Dec, 1993; Comprehensive Psychiatry, 34(6).Harvard review of Psychiatry, 1999 Mar-Apr ( Green AL et al) Clozapine for comorbid substance use disorder and schizophrenia; do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine?. 6(6);287-96, Kane J, Honigfield G, Singer J, et al: 1989 Clozapine for the treatment-resistant schizophrenic; result of a US multicentre trial, Psychopharmocology ;; 99, 560-563Kane J, Honigfield G, Singer J, et al: 1988 Clozapine for the treatment-resistant schizophrenic; a double blind comparison with chlorpromazine (Kloza collaborative study). Arch. Gen. Psychiatry;, 45; 789-796Kerwin JR. Taylor D; 1996; New antipsychotics a review of their current status and clinical potential. Drugs 6. 71-82Lindstrom LH, 1989 A retrospective study on the long-term efficacy of clozapine in 96 schizophrenic and schizo-effective patients during a 13-year period. Psychopharmacol.; 99; 84-86Lieberman JA, Safferman AZ, Pollack S, et al; 1994; Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 151:1744-1752.Meltzer HY et al; 1990 Effects of six months clozapine treatment on the quality of life of chronic schizophrenic patients, Hosp Comm Psychiatry; 41: 892-897.Meltzer HY et al; 1995 Clozapine; is another view valid? Am J psychiatry; 152 (6); 821-5.Marcus P, Snyder R; 1994; Reduction of comorbid substance abuse with clozapine. Am J Psychiatry 151:959.McElroy SL, et al; 1991 Clozapine in the treatment of psychotic mood disorders, schizoeffective disorder and schizophrenia.J Clin Psychiatry; 52; 411-414.Meltzer HY, 1999.Suicide and Schizophrenia; clozapine and the InterSept study, Journal of Clinical Psychiatry. 60 Suppl 12; 47-50, Suppes T, Rush AJ, Web A et al: 1996; A one year randomized trial of clozapine v's usual care in Bipolar I patients, Biol Psychiatry 39:531.Spivak B, Mester R, et al; 1997; Reduction of aggressiveness and impulsiveness during clozapine treatment in chronic treatment resistant schizophrenic patients. Clin Neuropharmacol 20: 442-446.Steinert et al; 1996. A case report, Pharmacopsychiat.29; 111-114, Tandon and Goldman et al;. Oct- Dec, 1993; Positive and negative symptom, during clopazine treatment in schyzophrenia. J Psychiatry Res;; 341- 7.The Parkinson's Study Group; 1999; Low dose clozapine for the treatment of drug induced psychosis in Parkinson's Disease; N Engl J Med. 340, 757-63Volavka J, 1999.The effect of clozapine on aggression and substance abuse in schizophrenic patients, (Review) Journal of Clinical Psychiatry. 60 Suppl 12; 43-6, -Volavka et al; 1993; Clozapine effects on hostility and aggression in schizophrenia. J Clin Psychopharmacol. 13; 287-289Walker et al; 1997 Mortality in current and former users of clozapine. Epidemiology; 8; 671-677.Zarate et al; 1995; Clozapine in severe mood disorder, J Clin Psychiatry 56: 411-417.

For further details, please e-mail to:

Mr. Mukesh Vankani - General Manager

or

Mr. Deepak Shah - B.Pharma, MBA

at

reliancehealthcare@yahoo.co.in

Apiz: Product Information

2006-05-19T22:56:00.000-07:00

Apiz - Product Information

Pharmacology

Aripiprazole possesses a novel mechanism of action when compared to the other FDA approved atypical antipsychotics. Aripiprazole appears to mediate its antipsychotic effects primarily by partial agonism at the D2 receptor. Partial agonism at D2 receptors has been shown to modulate dopaminergic activity in areas where dopamine activity may be high or low, such as the mesolimbic and mesocortical areas of the schizophrenic brain, respectively. In addition to partial agonist activity at the D2 receptor, aripiprazole is also a partial agonist at the 5-HT1A receptor, and like the other atypical antipsychotics, aripiprazole displays an antagonist profile at the 5-HT2A receptor. Aripiprazole has moderate affinity for histamine and alpha adrenergic receptors, and no appreciable affinity for cholinergic muscarinic receptors.

Pharmacokinetics

Aripiprazole displays linear kinetics with an elimination half-life of approximately 75 hours. Accordingly, steady state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved in 3-5 hours after oral dosing. The bioavailabilty of the oral tablets is about 90%. The drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation). The active major metabolite is dehydro-aripiprazole with an elemination half-life of about 94 hours. The parent drug is excreted only in traces and the metabolites, whether active or not, are excreted via feces and urine.

Metabolism

Aripiprazole is metabolized by the cytochrome P450 isoenzymes 3A4 and 2D6. Accordingly, coadministration of aripiprazole with medications that may inhibit (e.g paroxetine, fluoxetined) or induce (e.g. carbamazepine) these metabolic enzymes may increase or decrease, respectively, plasma concentrations of aripiprazole

Adverse events

Adverse events reported in the package insert for aripiprazole include headache, nausea, vomiting, somnolence, insomnia and akathisia. It appears that aripiprazole has a very low incidence of EPS (extrapyramidal side effects). The risk of tardive dyskinesia with prolonged aripiprazole use is unclear.

Dosage forms

Apiz is available as 10 and 15 mg tablets.

Dosage:

10 -15mg per day or as directed by physician. It has been observed that increasing the dose beyond 15 mg per dayb does not impart any particular therapeutic benefit. On the other hand, it may only add to the cost of treatment.

Warning about drugs having similar names

A warning has gone out recently because of this drug's name. The '-prazole' ending of this drug name makes this drug sound like it is one of the proton pump inhibitors (such as omeprazole, pantoprazole, lansoprazole) which are used in treating peptic ulcer disease. However, aripiprazole and these drugs are in an entirely different class of drugs altogether and confusing the two can lead to some unnecessary side effects.

Why is aripiprazole prescribed?

Aripiprazole is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions). It is also used to treat episodes of mania (frenzied, abnormally excited or irritated mood) or mixed episodes (symptoms of mania and depression that happen together) in patients with bipolar I disorder (manic depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Aripiprazole is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.

How should this medicine be used?

Aripiprazole comes as a tablet to be taken by mouth. It is usually taken once a day with or without food. Take aripiprazole at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take aripiprazole exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may start you on a low dose of aripiprazole and increase your dose after at least 2 weeks.

Aripiprazole controls schizophrenia but does not cure it. It may take 2 weeks or longer before you feel the full benefit of aripiprazole. Continue to take aripiprazole even if you feel well. Do not stop taking aripiprazole without talking to your doctor.

What special precautions should I follow?
Before taking aripiprazole,
tell your doctor and pharmacist if you are allergic to aripiprazole or any other medications. Tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention any of the following: amiodarone (Cordarone, Pacerone); antidepressants (mood elevators); antifungals such as fluconazole (Diflucan), itraconazole (Sporanox), and ketoconazole (Nizoral); antihistamines; bupropion (Wellbutrin); carbamazepine (Tegretol); celecoxib (Celebrex); chlorpromazine (Thorazine); cimetidine (Tagamet); clarithromycin (Biaxin); clomipramine (Anafranil); cyclosporine (Neoral, Sandimmune); danazol (Danocrine); delavirdine (Rescriptor); dexamethasone (Decadron); diltiazem (Cardizem, Dilacor, Tiazac); doxorubicin (Adriamycin); erythromycin (E.E.S., E-Mycin, Erythrocin); ethosuximide (Zarontin); fluoxetine (Prozac, Sarafem); fluvoxamine (Luvox); HIV protease inhibitors such as indinavir (Crixivan) and ritonavir (Norvir); ipratropium (Atrovent); isoniazid (INH, Nydrazid); medications for anxiety, blood pressure, irritable bowel disease, mental illness, motion sickness, Parkinson's disease, seizures, ulcers, or urinary problems; metoclopramide (Reglan); methadone (Dolophine); metronidazole (Flagyl); nefazodone (Serzone); oral contraceptives (birth control pills); paroxetine (Paxil); phenobarbital (Luminal, Solfoton); phenytoin (Dilantin); primidone (Mysoline); quinidine (Cardioquin, Quinaglute, Quinidex); ranitidine (Zantac); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); sedatives; sertraline (Zoloft); sleeping pills; terbinafine (Lamisil); tranquilizers; troglitazone (Rezulin); troleandomycin (TAO); verapamil (Calan, Covera, Isoptin, Verelan); and zafirlukast (Accolate). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
tell your doctor if you have or have ever had heart disease, heart failure, high or low blood pressure, a stroke, a ministroke, seizures, Alzheimer's disease, any condition that makes it difficult for you to swallow, or if you or anyone in your family has or has ever had diabetes. Also tell your doctor if you have ever had to stop taking a medication for mental illness because of severe side effects.
tell your doctor if you are pregnant or plan to become pregnant. If you become pregnant while taking aripiprazole, call your doctor. Do not breastfeed while taking aripiprazole. If you are having surgery, including dental surgery, tell the doctor or dentist that you are taking aripiprazole.

you should know that aripiprazole may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
remember that alcohol can add to the drowsiness caused by this medication. Do not drink alcohol while taking aripiprazole.

you should know that you may have increases in your blood sugar (hyperglycemia) while you are taking this medication, even if you do not already have diabetes. If you have schizophrenia, you are more likely to develop diabetes than people who do not have schizophrenia, and taking aripiprazole or similar medications may increase this risk. Tell your doctor immediately if you have any of the following symptoms while you are taking aripiprazole: extreme thirst, frequent urination, extreme hunger, blurred vision, or weakness. It is very important to call your doctor as soon as you have any of these symptoms, because high blood sugar can cause more serious symptoms, such as dry mouth, upset stomach and vomiting, shortness of breath, breath that smells fruity, or decreased consciousness, and may become life-threatening if it is not treated at an early stage.

you should know that aripiprazole may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking aripiprazole. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
you should know that aripiprazole may make it harder for your body to cool down when it gets very hot. Tell your doctor if you plan to do vigorous exercise or be exposed to extreme heat. Make sure to drink plenty of fluids.

What special dietary instructions should I follow?

Talk to your doctor about drinking grapefruit juice while taking this medicine.
What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
What side effects can this medication cause?

Aripiprazole may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

headache
nervousness
difficulty falling asleep or staying asleep
drowsiness
lightheadedness
restlessness
upset stomach
vomiting
constipation
increased salivation
weight gain
coughing
runny nose
shaking hands that you cannot control
dry skin
itchy eyes
loss of appetite

Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them or those listed in the SPECIAL PRECAUTIONS section, call your doctor immediately:

rash
dizziness
fainting
slow, fast, or irregular heartbeat
chest pain
swelling of hands, feet, ankles, or lower legs
depression
seizures
difficulty swallowing
unusual movements of your body or face that you cannot control
urgent need to urinate
high fever
muscle stiffness
confusion
sweating
abnormal excitement

Aripiprazole may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

For further information on Apiz, please write to:
Mr. Mukesh Vanakani – General Manager
Or
Mr. Deepak Shah B.Pharma. MBA
At

reliancehealthcare@yahoo.co.in

Apiz - Summary of Clinical Trials on Aripiprazole

2006-05-16T23:32:00.000-07:00

Apiz - Summary of Clinical Trials on Aripiprazole
GENERIC NAME: aripiprazole

BRAND NAME: Apiz (Reliance Formulation)

DRUG CLASS AND MECHANISM:

Aripiprazole is an anti-psychotic drug for treating psychoses. Like other anti-psychotic drugs, the mechanism of action of aripiprazole is unknown. Moreover, like other anti-psychotics, it blocks several receptors on the nerves of the brain for several neurotransmitters (chemicals that nerves use to communicate with each other). It is thought that its beneficial effect is due to its effects on dopamine and serotonin receptors. Its effects on these receptors are complex, involving stimulation of the receptors but to a lesser degree than the naturally occurring neurotransmitters (a process called partial agonism). The FDA approved aripiprazole as a treatment for schizophrenia in November of 2002.
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ARIPIPRAZOLE (Apiz):

Emerging as Next Great Hope for Schizophrenia

Editor's note: My son was diagnosed with schizophrenia in 1999 at the age of eighteen. We tried risperidone, ziprasidone, quetiapine, and clozapine without success or reduction of voices and symptoms, in fact, things just got worse. In December 2002, he switched to aripiprazole. Almost immediately there was a dramatic improvement, which has continued until today. Now he is more independent, has a renewed interest in life, has returned to college, and has an active social life. Things that previously were beyond our wildest hopes are now routine for him. Do not give up the search for something that works, every patient is unique! (June 2004)

Aripiprazole is being touted as the first member of the new generation of atypical antipsychotic drugs. This once-daily novel antipsychotic has undergone a number of studies, revealing that aripiprazole is significantly better at controlling both the positive and negative symptoms of schizophrenia than placebo and has equaled haloperidol and risperidone in its ability to control these symptoms.

On October 31, 2001, Bristol-Myers Squibb and Otsuka Pharmaceutical Co. filed a New Drug Application (NDA) with the FDA and the two companies anticipate the launch of aripiprazole late in the third quarter of 2002.

Stephen M. Stahl, M.D., Ph.D., Professor of Psychiatry at the University of California at San Diego, places aripiprazole in the class of antipsychotics called dopamine system stabilizers (DSSs). Stahl dubs these new therapeutic agents “Goldilocks” because of their ability to strike a balance between too much and too little dopamine. With “just right” result, negative and cognitive symptoms are reduced and motor side effects or prolactin elevation is absent.
Previous atypical drugs block dopamine D2 receptors resulting in motor side effects such as pseudo-parkinsonism, and ultimately tardive dyskinesia.

Robert McQuade, Ph.D., director of Global Medical Marketing for Bristol-Myers Squibb, cites the evolution of antipsychotic medications and how their mechanisms of action have changed over time. “The big disadvantage was the side effects,” he says. “The atypicals were designed to address symptoms such as EPS, but brought about different side effects.” Each drug within the atypical category elicited its own particular adverse event, according to McQuade. Literature suggests, he says, that olanzapine causes weight gain, ziprasidone increases the QTc interval and risperidone increases plasma prolactin.

“These drugs solved some problems, but created others.” “From a psychopharmacologic viewpoint, aripiprazole is bringing new science to the field,” he says. Unlike the older atypical antipsychotics that reduce positive symptoms of psychosis, such as delusions and hallucinations, by blocking D2 receptors, aripiprazole stabilizes or modulates them. McQuade underscores the multi-faceted benefits of aripiprazole based on the results of several controlled trials, some of which lasted up to 52 weeks in duration, involving more than 3,400 patients with schizophrenia. Aripiprazole was statistically superior to placebo on positive and negative symptoms and superior to haloperidol for negative symptoms, according to McQuade. “Aripiprazole delivers a package of tolerability that enhances the benefit to the patient and thus enhances compliance,” he concludes.
Potential problem with akathisia

According to Larry Ereshefsky, Pharm.D., professor of pharmacy, pharmacology and psychiatry at the University of Texas Health Science Center at San Antonio, the novel partial dopamine agonist mechanism of action augments the 5-Htla and 5-HT2 effects of aripiprazole. “These effects should lead to greater dopaminergic throughput and cortical activity which is good for thinking,” says Ereshefsky. “But it also might possibly explain the increased rates of akathisia at the middle doses (15 mg/d) in some studies. There is clearly a greater effect on the Barnes akathisia scale than from risperidone, and about half the effect of haloperidol.” Ereshefsy adds, “Akathisia is a potential side effect which bares further evaluation in long-term studies to see whether it abates.”
(Akathisia is having a feeling of inner restlessness and the urge to move, rocking while standing or sitting, lifting of the feet as if marching on the spot, and crossing and uncrossing of the legs while sitting)

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Title: New Antipsychotic Aripiprazole Shows Promise for Acute Mania: Presented at APA
"New Antipsychotic Aripiprazole Shows Promise for Acute Mania: Presented at APA"

By Alison Palkhivala PHILADELPHIA, PA -- May 23, 2002 --

Aripiprazole, a new investigational antipsychotic drug, is showing promise for the treatment of acute mania in patients with bipolar disorder. Studies on the drug were presented here this week at the annual meeting of the American Psychiatric Association (APA). As part of a phase III, multicenter, double-blind, randomized, placebo-controlled trial, 262 patients diagnosed with acute mania were treated with either aripiprazole or placebo. The study's lead author was Paul E. Keck Jr., MD, from the department of psychiatry at the University of Cincinnati College of Medicine in Cincinnati, Ohio. On day 4, patients in the treatment group began to show more improvement than the placebo group with respect to acute manic symptoms. These included elevated mood, irritability, thought disorder, abnormal thought content, and disruptive-aggressive behavior. A significant difference was also found between the two groups with respect to mean change from baseline on the total score of the Young Mania Rating Scale (Y-MRS), with the aripiprazole group showing more improvement than the placebo group. This difference increased as the three-week trial progressed. Response to therapy was defined as a decrease of 50 percent or more in Y-MRS total score. Based on this criterion, 40 percent of patients on aripiprazole responded to treatment compared to 19 percent on placebo. A second placebo-controlled study of aripiprazole did not reveal a difference between the drug and a placebo with respect to response rate. However, response rate in the placebo group was abnormally high: both the treatment and placebo groups had response rates of 40 percent. The most common side effects associated with aripiprazole therapy were headache, nausea, dyspepsia, somnolence, and agitation. Most side effects began early in treatment and few lasted more than a week. Aripiprazole has a mechanism of action that is different from other antipsychotic drugs, affecting both dopamine and serotonin receptors. It is the product of a cooperative effort between Bristol-Myers Squibb and Otsuka Pharmaceuticals. Together, they filed a regulatory applications in the US and Europe in 2001 for the drug to be approved for the treatment of schizophrenia.

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Title: Aripiprazole for Long-Term Maintenance Treatment in Schizophrenia: Presented at APA

"Aripiprazole for Long-Term Maintenance Treatment in Schizophrenia: Presented at APA"
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 --

The investigative antipsychotic drug aripiprazole produced improvements in positive, negative and depressive symptoms of schizophrenia during a 52-week study, researchers reported at the annual meeting of the American Psychiatric Association (APA). "Beyond the short-term clinical trials that have demonstrated acute efficacy, this study looks at aripiprazole in more long-term or maintenance treatment for schizophrenia. This is a chronic disorder with frequent relapses. In this study we looked at patients having acute relapses of their illness, at their stabilization with aripiprazole and then maintenance of the efficacy of the effect of this treatment over a one-year period," said Mary J. Kujawa, MD, medical director of US neuroscience medical affairs at Bristol-Myers Squibb Company in Princeton, New Jersey. The mechanism of action of aripiprazole appears to be different from other available antipsychotics. Aripiprazole shows potent partial agonism of D2 dopamine receptors, partial agonism of 5HT1A serotonin receptors and antagonism of 5HT2A serotonin receptors. Partial agonism means that aripiprazole blocks the receptor if it is overstimulated and stimulates it if it when activity is needed. The investigators in this multicenter, randomized, double-blind study recruited 1,294 subjects suffering an acute relapse of chronic schizophrenia. They randomized 861subjects to aripiprazole 30 mg/day and 433 to haloperidol 10 mg/day. They allowed a one-time dose reduction to aripiprazole 20 mg/day and haloperidol 7 mg/day. The investigators used Positive and Negative Symptoms for Schizophrenia (PANSS) and the Montgomery-Asberg Depression Rating Scale (MADRS) scores to evaluate efficacy throughout the study. Compared to the haloperidol cohort, a much larger percentage of patients treated with aripiprazole showed a therapeutic response and remained in treatment at weeks 8, 26, and 52 (week 52: 40 percent vs. 27 percent, p<0.001). Compared to haloperidol, aripiprazole elicited statistically significant improvements in the PANSS negative subscale and in depressive symptoms as shown in the MADRS. Extrapyramidal effect-related adverse events were significantly lower with aripiprazole than with haloperidol (p<0.001). Weight gain was comparable in both groups of subjects. QTc interval were also comparable between the groups. "One of the most difficult challenges in treating patients with schizophrenia is long-term adherence," said Jeffrey Lieberman, MD, professor of psychiatry and pharmacology at the University of North Carolina Medical School in Chapel Hill. "Data from this study suggests the potential for significant benefits of aripiprazole in the long-term treatment of schizophrenia, a chronic mental illness that affects approximately 1 percent of the world's population."

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Title: Switching to Aripiprazole Safe and Effective in Schizophrenia: Presented at APA
By Alison Palkhivala PHILADELPHIA, PA -- May 23, 2002 --

Switching schizophrenic patients to new antipsychotic aripiprazole from both conventional and atypical antipsychotics appears to be both safe and well tolerated. For the study, 311 stable schizophrenic patients taking olanzapine, risperidone, or haloperidol were switched to aripiprazole using one of three switching strategies. These strategies consisted of a switch to a full dose of aripiprazole without titration from prior antipsychotic treatment, switching to a full dose of aripiprazole along with tapering of the previous treatment for two weeks, or switching to aripiprazole with titration up along with titration down of the previous medication over two weeks. The study was led by Daniel E. Casey, MD, from the Mental Illness Research, Education, and Clinical Center of the Portland Veterans Affairs Medical Center in Oregon. The study was presented here this week at the annual meeting of the American Psychiatric Association (APA). Regardless of the switching strategy employed, the switching process was generally safe and well tolerated. Eight weeks after switching to aripiprazole, patients showed improvements in extrapyramidal symptoms (EPS) and reductions in prolactin levels and weight. They also showed statistically significant improvements in the Positive and Negative Syndrome Scale (PANSS). Patients switched from olanzapine showed a statistically significant weight loss of 2.03 kg (p<0.001) as well as a decrease in prolactin levels and improvement in EPS. Those switched from risperidone also had statistically significant decreases in prolactin levels (p<0.001), as well as reductions in weight and EPS. Those switched from haloperidol had improvements in EPS and decreased prolactin levels. Aripiprazole was generally well-tolerated, with the most common side effect being insomnia. Most side effects were mild to moderate. Aripiprazole, a novel antipsychotic, is jointly produced by Bristol-Myers Squibb and Otsuka Pharmaceuticals. In 2001, they submitted the drug for approval to regulatory agencies in the United States and Europe.

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Title: Aripiprazole Versus Placebo in the Treatment of Chronic Schizophrenia: Presented at APA
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 --

The investigative drug aripiprazole provides effective and safe antipsychotic treatment in patients with chronic schizophrenia, researchers reported here this week at the annual meeting of the American Psychiatric Association (APA). "The most important implication of this study is that it shows that aripiprazole is effective in significantly reducing the time-to-relapse as well as the rate of relapse in patients with schizophrenia who are being treated with medication," said lead investigator Teresa Pigott, MD, director of clinical trials in the department of psychiatry at the University of Florida School of Medicine in Gainesville, Florida. The purpose of the study was to assess the time to relapse with aripiprazole, compared to placebo, over 26 weeks in stable patients with chronic schizophrenia. The multicenter, randomized, double-blind, placebo-controlled study enrolled 310 subjects with chronic schizophrenia who were evaluated as stable, with no significant improvement or worsening in the previous three months and baseline on the Positive and Negative Symptoms for Schizophrenia (PANSS) scale of 82. They were randomized to aripiprazole 15 mg/day or placebo. Efficacy was determined by time to relapse, PANSS Total Score, and Clinical Global Improvement (CGI) score. Significantly fewer patients in the aripiprazole group (34 percent) relapsed by study end point compared to placebo (57 percent). Aripiprazole also increased the time to relapse by two fold. The agent was well tolerated , with an adverse events rate comparable to placebo, the researchers found. No significant changes occurred in Simpson-Angus Scale (SAS), Involuntary Movement Scale (AIMS), and Barnes Akathisia scores in either group. Weight gain in the aripiprazole group was comparable to placebo, Dr. Pigott said.

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Title: Meta-Analysis of the Efficacy of Aripiprazole in Schizophrenia: Presented at APA

By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 –

Aripiprazole improves positive and negative symptoms of schizophrenia, with significant effects appearing one week after initiation of treatment. "The most important implication of this study is that aripiprazole 15 mg is shown to be effective in the treatment of schizophrenia. We also saw replicative efficacy in one or more studies in doses of 15 mg and above," said co-investigator William Carson, MD, group director in research and development at Bristol-Myers Squibb Research Institute in Wallingford, Connecticut. The presentation was made at the annual meeting of the American Psychiatric Association (APA). The meta-analysis included four- to six-week multicenter, double-blind, fixed-dose, placebo-controlled studies involving a total of 1,545 patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder. The investigators randomized 898 subjects to aripiprazole, 381 to placebo, and the rest to active control: 167 to haloperidol 10 mg/day and 99 to risperidone 6 mg/day. Daily aripiprazole doses ranged from 2-30 mg. Weekly efficacy assessments included Positive and Negative Symptoms for Schizophrenia (PANSS) and Clinical Global Impression (CGI) scales. In the meta-analysis, aripiprazole showed superior efficacy to placebo at doses over 2 mg. The researchers also noted that aripiprazole dosing over 2 mg elicited significant improvement in PANSS-total score by week 1 (p<0.05). In examining the individual studies, the researchers found that aripiprazole dosing at 15 mg, 20 mg and 30 mg consistently produced significant improvements in PANSS-total score. They found similar PANSS-score changes from baseline for all aripiprazole groups. Across all of the studies, aripiprazole 15 mg, 20 mg and 30 mg produced significant improvements in other efficacy scores compared with placebo. In studies with active control, haloperidol and risperidone separated from placebo. "We had active comparator arms. Two of the active comparator drugs were haloperidol and risperidone. We saw efficacy that was comparable between aripiprazole and a typical antipsychotic, haloperidol, as well as an atypical antipsychotic, risperidone." Dr. Carson added. The study was supported by Bristol-Myers-Squibb.

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The Canadian Journal of Psychiatry (CJP) – February 2004
Aripirazole–Olanzapine Combination for Treatment of Schizophrenia

Dear Editor:

Recent literature is equivocal about antipsychotic combination in schizophrenia (1). However, the advent of the new antipsychotic aripiprazole, which has a mechanism of action different from other atypical antipsychotics, rekindles interest in this field. I describe a patient with schizophrenia showing partial response to olanzapine alone, but showing a marked improvement in symptoms (particularly the negative symptoms) on augmentation with aripiprazole. The possible mechanism of aripiprazole’s efficacy in negative symptoms is discussed.
Case Report
Mrs A, a 47-year-old woman with a long-standing history of schizophrenia, was admitted with a psychotic exacerbation precipitated by discontinuation of medicines. On mental status examination, she had marked psychomotor retardation, poverty of speech, flat affect, persecutory and referential delusions, loosening of association, and poor insight and judgment. She scored 122 on the Positive and Negative Symptom Scale (PANSS) with predominant negative symptoms (negative score 46, positive score 25). The patient was restarted on her previous antipsychotic; namely, olanzapine titrated to 20 mg daily, with further increase precluded by increased sedation. Despite 6 weeks on this dosage of olanzapine, there was modest improvement in positive symptoms but none at all in negative symptoms. In view of her partial response to olanzapine, aripiprazole was added at 15 mg daily as an augmenting agent. Within 2 weeks of this addition, the patient began to show improvement in her symptomatology. Her PANSS score dropped to 54 (a drop of 56%) after 6 weeks of olanzapine and aripiprazole combined. The positive, negative, and general psychopathology score decreased by 50%, 69%, and 45%, respectively. The patient was discharged on this combination and continues to maintain her improvement 2 months after discharge, at the same dosage of the 2 drugs. The notable improvement in negative symptoms deserves further attention; possible mechanisms are discussed below.
Olanzapine has a D2 receptor occupancy of 71% to 80% in the usual clinical dosage range of 10 to 20 mg daily, with the occupancy rising with dosage increase (2). Aripiprazole also shows a dose- dependent D2 receptor occupancy above 85% at dosages of 10 to 30 mg daily (3). With both olanzapine and aripiprazole having a high D2 receptor occupancy, one may question the rationale of combining these drugs. However, even at D2 occupancy values above 90%, extrapyramidal symptoms (EPS) are not observed with aripirazole (3). This may be attributed to aripiprazole’s being a partial agonist at the D2 autoreceptor. It would be interesting to explore how this mechanism may contribute toward improvement in negative symptoms.
Negative symptoms of schizophrenia have been hypothesized to result from a decrease in tonic dopamine transmission (4). Further, D2 autoreceptors tonically inhibit dopaminergic neurons (5). Stimulation of these receptors, as is the case with aripiprazole, induces their desensitization, leading to increased dopamine release (4). This novel mechanism may underlie aripiprazole’s low propensity to cause EPS and may also contribute toward its possible efficacy in negative symptoms. The previous generation of atypical antipsychotics, including clozapine, relies mainly on 5-HT2A antagonism for their greater efficacy in negative symptoms (6). Though aripiprazole also has a 5-HT2A antagonistic action, its role as a dopamine autoreceptor agonist may provide additional benefits for countering negative symptoms. Indeed, the study by Kane and colleagues showed that 15 mg daily, but not 30 mg daily, of aripiprazole produced a significantly greater improvement in PANSS negative subscale score, compared with placebo (7). There is some evidence to suggest that dopamine autoreceptor agonists do improve negative symptoms in schizophrenia patients with predominant negative symptoms (8). As aripiprazole acts as a dopamine agonist in the presence of significant receptor reserve for dopamine (which may be secondary to receptor upregulation following a hypodopaminergic state) (9), it can be speculated that schizophrenia patients with residual negative symptoms who are on potent D2 antagonists may benefit from the addition of small doses of aripiprazole. Further studies of aripiprazole at lower and higher dosages in primary negative symptoms are encouraged.
References
1. Freudenreich O, Goff DC. Antipsychotic combination in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002;106:323–30.
2. Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA, and others. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 1998;155:921–8.
3. Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF, and others. Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C] raclopride. Neuropsychopharmacology 2002;27:248–59.
4. Moore H, West AR, Grace AA. The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry 1999;46:40–55.
5. Millan MJ, Gobert A, Newman-Tancredi A, Lejuene F, Cussac D, Rivet JM, and others. S33084, a novel, potent, selective, and competitive antagonist at dopamine D3-receptors: I. Receptor, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 2000; 293:1048–62.
6. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21(Suppl 2):106S–15S.
7. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito G, Zimbroff DL, and others. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763–71.
8. Wetzel H, Hillert A, Grunder G, Benkert O. Roxindole, a dopamine autoreceptor agonist, in the treatment of positive and negative schizophrenic symptoms. Am J Psychiatry 1994; 151:1499–2.
Harpreet S Duggal, MD, DPMPittsburgh,USA

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Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder
.Swainston Harrison T, Perry CM.Adis International Limited, Auckland, New Zealand.
Demail@adis.co.nz

Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia. Aripiprazole 10 or 15 mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (> or =1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia.

Pharmacological properties:

Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1A, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole's partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1A receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound. Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15 mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours. Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein. Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased).

Therapeutic Efficacy:

The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment. The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomized trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients. Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neuro-cognitive parameters evaluated compared with recipients of olanzapine 10-15 mg/day.

Tolerability:

Aripiprazole 10-30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial). In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%). Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial.

For further information, you can contact the following gentlemen:

Mr. Mukesh Vankani - General Manager (Cell# 09825032571) OR

Mr. Dipak Shah B.Pharm. MBA

at

reliancehealthcare@yahoo.co.in

Valporil CR/Dixval in Migraine, Bipolar Disorder, Seizure Disorder

2006-04-21T02:38:00.000-07:00

Valporil/ Valporil CR/ Dixval in Seizure Disorders, Bipolar disorder and migraine attacks

What is a seizure?

Any involuntary behavior that occurs abnormally may represent a seizure. Seizures are classified into several categories.
Generalized (Grand Mal) Seizures - This is the most common form of seizure in small animals. The entire body is involved in stiffness and possibly stiffness/contraction cycles (tonic/clonic action). The animal loses consciousness and may urinate or defecate.Partial Seizures - This form of seizure originates from some specific area in the brain and thus involves the activity of a specific region of the body. Partial seizures may "generalize" to involve the whole body.

Psychomotor Seizures - This type of seizure is predominantly behavioral with the animal involuntarily howling, snapping, circling, etc. The abnormal behavior may be followed by a generalized seizure.

Seizures (neurological events) are often difficult to tell from fainting spells (cardiovascular events). Classically, true seizures are preceded by an aura, or special feeling associated with a coming seizure. As animals cannot speak, we usually do not notice any changes associated with the aura. The seizure is typically followed by a post-ictal period during which the animal appears disoriented, even blind. This period may last only a few minutes or may last several hours. Fainting animals are usually up and normal within seconds of the spell.

*** Post-Ictal Disorientation Is The Hallmark Of The Seizure ***

Causes of seizures and diagnostics:

Seizures may be caused by situations within the brain (such as trauma or infection) or by situations centered outside the brain (such as low blood sugar, circulating metabolic toxins, or external poisons). The first step is to rule out situations centered outside the brain, easily done with a blood test. An ophthalmic exam may also be performed as the retina may show signs of a brain infection. If these tests are negative, the next step is determined by the age of the pet.

Animals Less Than Age One Year - seizures are usually caused by infections of the brain. Analysis of cerebrospinal fluid, obtained by a tap under anesthesia, would be important.

Animals Between Ages 1 And 5 - In these animals, usually no cause can be found and the term "epilepsy," which simply means "seizure disorder," is applied. If seizures are occurring frequently enough, medication is used to suppress them. Schnauzers, Basset hounds, Collies, and Cocker spaniels have 2-3 times as much epilepsy as other breeds.

Animals More Than Age Five Years - In this group, seizures are usually caused by a tumor growing off the skull and pressing on the brain (a “meningioma”). Most such tumors are operable if found early. A CAT scan or MRI would be the next step. Special referral is necessary for this type of imaging. For patients where surgery is not an option, corticosteroids may be used to reduce swelling in the brain. Treatment to suppress seizures may also be needed (see below).
Epilepsy is the name given to seizure disorders for which no cause can be found. It is not a unique disease in and of itself.

There are two kinds of seizure disorders:

1] An isolated, non-recurrent attack, such as may occur during a febrile illness or after head trauma

2] Epilepsy – a recurrent, paroxysmal disorder of cerebral function characterized by sudden, brief attacks of altered consciousness, motor activity, sensory phenomena, or inappropriate behavior caused by excessive discharge of cerebral neurons.

If given a sufficient stimulus (eg, convulsant drugs, hypoxia, hypoglycemia), even the normal brain can discharge excessively, producing a seizure. In epileptics, seizures are rarely precipitated by exogenous factors, such as sound, light, and touch.

Auras are sensory or psychic manifestations that immediately precede complex partial or generalized tonic-clonic seizures and represent seizure onset.

A postictal state may follow a seizure (most commonly a generalized seizure) and is characterized by deep sleep, headache, confusion, and muscle soreness.
Simple partial seizures consist of motor, sensory, or psychomotor phenomena without loss of consciousness. The specific phenomenon reflects the affected area of the brain. In jacksonian seizures, focal motor symptoms begin in one hand and then "march" up the extremity. Other focal attacks can first affect the face area, then spread down the body to involve an arm and sometimes a leg. Some partial motor seizures begin with raising the arm and turning the head toward the moving part. Some proceed to generalized convulsions.
In complex partial seizures, the patient loses contact with the surroundings for 1 to 2 min. At first, the patient may stare, perform automatic purposeless movements, utter unintelligible sounds without understanding what is said, and resist aid. Mental confusion continues another 1 or 2 min after motor components of the attack subside. These seizures may develop at any age, and structural pathology (eg, mesial temporal sclerosis, low-grade astrocytomas) should be ruled out. Complex partial seizures most commonly originate in the temporal lobe but may originate in any lobe of the brain.

Complex partial seizures are not characterized by unprovoked aggressive behavior. However, if restrained during a complex partial seizure, a patient may lash out at the person restraining him, as may a patient in a postictal confused state after a generalized seizure. Between seizures, patients with temporal lobe epilepsy have a higher incidence of psychiatric disorders than does the general population; 33% may have psychologic difficulties, and 10% may have symptoms of schizophreniform or depressive psychoses.

Generalized seizures cause loss of consciousness and motor function from the onset. Such attacks often have a genetic or metabolic cause. They may be primarily generalized (bilateral cerebral cortical involvement at onset) or secondarily generalized (local cortical onset with subsequent bilateral spread). Types of generalized seizures include infantile spasms and absence, tonic-clonic, atonic, and myoclonic seizures.

Infantile spasms are primarily generalized seizures characterized by sudden flexion of the arms, forward flexion of the trunk, and extension of the legs. Seizures last a few seconds and are repeated many times a day. They occur only in the first 3 yr of life and then are replaced by other types of seizures. Developmental abnormalities are usually apparent.

Absence seizures (formerly called petit mal) consist of brief, primarily generalized attacks manifested by a 10- to 30-sec loss of consciousness and eyelid fluttering at a rate of 3/sec, with or without loss of axial muscle tone. Affected patients do not fall or convulse; they abruptly stop activity and resume it just as abruptly after the seizure, with no postictal symptoms or even knowledge that an attack has occurred. Absence seizures are genetic and occur predominantly in children. Without treatment, such seizures are likely to occur many times a day. Seizures often occur when the patient is sitting quietly and can be precipitated by hyperventilation. They rarely occur during exercise.

Generalized tonic-clonic seizures typically begin with an outcry; they continue with loss of consciousness and falling, followed by tonic, then clonic contractions of the muscles of the extremities, trunk, and head. Urinary and fecal incontinence may occur. Seizures usually last 1 to 2 min. Secondarily generalized tonic-clonic seizures begin with a simple partial or complex partial seizure.

Atonic seizures are brief, primarily generalized seizures in children. They are characterized by complete loss of muscle tone and consciousness. The child falls or pitches to the ground, so that seizures pose the risk of serious trauma, particularly head injury.

Myoclonic seizures are brief, lightning-like jerks of a limb, several limbs, or the trunk. They may be repetitive, leading to a tonic-clonic seizure. There is no loss of consciousness.

Febrile seizures are associated with fever without evidence of intracranial infection. They affect about 4% of children between the ages of 3 mo and 5 yr. Benign febrile seizures are brief, solitary, and generalized tonic-clonic in form; complicated febrile seizures are either focal, last > 15 min, or recur >= 2 times in < 24 h. Overall, the occurrence of febrile seizures is associated with a 2% incidence of subsequent epilepsy; the incidence of epilepsy and the risk of recurrent febrile seizures are much greater among children with complicated febrile seizures, preexisting neurologic abnormalities, onset before age 1 yr, or a family history of epilepsy.

In status epilepticus, seizures follow one another with no intervening periods of normal neurologic function. Generalized convulsive status epilepticus may be fatal. It may result from too-rapid withdrawal of anticonvulsants. Confusion may be the only manifestation of complex partial or absence status epilepticus, and an EEG may be needed to diagnose seizure activity.

An Epilepsia partialis continuum is a rare form of focal (usually hand or face) motor seizures that recur at intervals of a few seconds or minutes for days to years at a time. In adults, it is usually due to a structural lesion, such as a stroke. In children, it is usually due to a focal cerebral cortical inflammatory process (Rasmussen's encephalitis), possibly caused by a chronic viral infection or autoimmune processes.

Treatment

General principles: Treatment aims primarily to control seizures. A causative disorder may need to be treated as well.

A normal life should be encouraged. Exercise is recommended; even such sports as swimming and horseback riding can be permitted with proper safeguards. Most state licensing agencies permit automobile driving after seizures have stopped for1 yr. Social activities should be encouraged. Alcohol intake should be minimized. Cocaine and several other illicit drugs can trigger seizures.
Family members must be taught a commonsense attitude toward the patient. Overprotection should be replaced with sympathetic support that lessens feelings of inferiority and self-consciousness and other emotional handicaps; prevention of invalidism should be emphasized. Institutional care is rarely advisable and should be reserved for severely retarded patients and for patients with seizures so frequent and violent despite drug therapy that they cannot be cared for elsewhere.

During a seizure, injury should be prevented. Protecting the tongue should not be attempted because teeth may be damaged. Inserting a finger to straighten the tongue is dangerous and unnecessary. Clothing around the neck should be loosened, and a pillow placed under the head. The patient should be rolled onto his side to prevent aspiration. A responsible fellow worker may be trained to give emergency aid if the patient agrees.

Causative or precipitating factors should be eliminated. Progressive structural lesions of the brain (eg, tumors, abscesses) should be sought and promptly treated. After definitive treatment of structural lesions, continued medical treatment (eg, anticonvulsants) is usually necessary. Other physical disorders (eg, systemic infections, endocrine abnormalities) should be corrected.Head injuries with skull fractures, intracranial hemorrhages, focal neurologic deficits, or amnesia cause posttraumatic epilepsy in 25 to 75% of cases. Prophylactic treatment with anticonvulsant drugs after the head injury reduces the probability of early posttraumatic seizures during the first few weeks after the injury but does not prevent the development of permanent posttraumatic epilepsy months or years later.

Drug therapy:

No single drug controls all types of seizures, and different drugs are required for different patients. Patients rarely require several drugs. The drug of choice for the particular type of epilepsy is started at relatively low dose and increased over about 1 wk to the standard therapeutic dose. After about 1 wk at this dose, blood levels are measured to determine whether the effective therapeutic level has been reached. If seizures continue, the daily dose is increased by small increments. If toxic blood levels or toxic symptoms develop before seizures are controlled, a second anticonvulsant is added, again guarding against toxicity. Interaction between drugs can interfere with their rate of metabolic degradation. The initial, failed anticonvulsant is then withdrawn gradually. Once seizures are controlled, the drug should be continued without interruption until at least 1 yr is seizure-free. At that time, discontinuing the drug should be considered, because about 2/3 of such patients remain seizure-free without drugs. Static encephalopathy and structural brain lesions increase the risk of relapse off medication. Patients whose attacks were initially difficult to control, those who failed a drug-free trial, and those with important social reasons for avoiding seizures should be treated indefinitely.

Once the drug response is known, blood levels are less useful to follow than the clinical course. Some patients have toxic symptoms at low levels; others tolerate high levels without symptoms.

For generalized tonic-clonic seizures, phenytoin, carbamazepine, or valproate is the drug of choice. For adults, phenytoin can be given in divided doses or at bedtime. If seizures continue, the dose can be increased cautiously to 500 mg/day with blood level monitoring. At a higher dose, dividing the daily dose may reduce toxic symptoms.
For partial seizures, treatment begins with carbamazepine, phenytoin, or valproate. If seizures persist despite high doses of these drugs, gabapentin, lamotrigine, or topiramate may be added. For absence seizures, ethosuximide orally is preferred. Valproate and clonazepam orally are effective, but tolerance to clonazepam often develops. Acetazolamide is reserved for refractory cases.
Atonic seizures, myoclonic seizures, and infantile spasms are difficult to treat. Valproate is preferred, followed, if unsuccessful, by clonazepam. Ethosuximide is sometimes effective, as is acetazolamide (in dosages as for absence seizures). Phenytoin has limited effectiveness. For infantile spasms, corticosteroids for 8 to 10 wk are often effective. The optimal corticosteroid regimen is controversial. ACTH 20 to 60 U/day IM may be used. A ketogenic diet may help but is difficult to maintain. Carbamazepine may make patients with primary generalized epilepsy and multiple seizure types worse.

Status epilepticus can be terminated by giving diazepam 10 to 20 mg (for adults) IV or up to 2 doses (if necessary) of lorazepam 4 mg IV. For children, IV diazepam up to 0.3 mg/kg or lorazepam up to 0.1 mg/kg is given. For adults, phenytoin 1.5 g IV may be given to prevent recurrence. Fosphenytoin, a water-soluble product, is an alternative that in equivalent doses reduces the incidence of hypotension and phlebitis. Anesthetic IV doses of phenobarbital, lorazepam, or pentobarbital may be necessary in refractory cases; in such instances, intubation and O2 therapy are required to prevent hypoxemia.In acute generalized tonic-clonic seizures due to febrile illnesses, ingestion of alcohol or other toxins, or acute metabolic disturbance, the causative condition must be treated as well as the seizures. Status epilepticus should be treated at once. If only one seizure has occurred, phenytoin should be given in full dosage for 7 to 10 days; afterward, a decision concerning long-term therapy must be made. After a first seizure, 1/3 of patients have recurrent attacks, followed by chronic epilepsy. Anticonvulsants are of little value in preventing alcohol withdrawal seizures.

Benign febrile convulsions do not require treatment because of the favorable prognosis compared with the potential toxic effects of anticonvulsants in a young child. For patients with complicated febrile seizures or other risk factors for recurrence ,recurrence rates for febrile seizures can be reduced by continuous prophylactic treatment with phenobarbital 5 to 10 mg/kg/day. However, no evidence suggests that such treatment of complicated febrile seizures prevents the development of recurrent nonfebrile seizures (epilepsy). Furthermore, phenobarbital given chronically to children measurably reduces their learning capacity.

Adverse effects:

All anticonvulsants may cause an allergic scarlatiniform or morbilliform rash.

Patients receiving carbamazepine should have a CBC once a month for the first year of therapy. If the WBC or RBC count decreases significantly, the drug should be discontinued immediately. Patients receiving valproate should have liver function tests every 3 mo for 1 yr; if serum transaminases or ammonia levels increase significantly (to > 2 times the upper limit of normal), the drug should be discontinued. An increase in ammonia up to 1.5 times the upper limit of normal can be tolerated safely.

When an overdose reaction occurs, the amount of drug is reduced until the reaction subsides. When more serious acute poisoning occurs, the patient is given ipecac syrup or, if obtunded, is lavaged. After emesis or lavage activated charcoal activated charcoal is administered, followed by a saline cathartic (eg, magnesium citrate). The suspect drug should be discontinued, and a new anticonvulsant started simultaneously.

Fetal antiepileptic drug syndrome (cleft lip, cleft palate, cardiac defects, microcephaly, growth retardation, developmental delay, abnormal facies, digital hypoplasia) occurs in 4% of the children of epileptic women who take anticonvulsants during pregnancy. Among commonly used drugs, carbamazepine appears to be the least teratogenic, but only slightly so; valproate may be the most teratogenic. Yet, because uncontrolled generalized seizures during pregnancy lead to fetal injury and death, continued treatment with anticonvulsants is generally advisable

Surgical therapy: About 10 to 20% of patients have seizures that are refractory to medical treatment. Most patients whose seizures originate from a local area of abnormal brain function improve markedly when the epileptic focus is resected. Some are completely cured. Because extensive monitoring and skilled medical-surgical teamwork are required, these patients are best managed in specialized centers.

Vagus nerve stimulation: Intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker-like device reduces the number of partial seizures by one third. After the device is programmed, patients can activate it with a magnet when they sense a seizure is imminent. Vagus nerve stimulation is used as an adjunct to an anticonvulsant. Adverse effects include a deepening of the voice during stimulation, cough, and hoarseness. Complications are minimal. Duration of effectiveness is not well established.

Sodium Valproate/ Valproic Acid (Valporil / Valporil CR) & Divalproex sodium (Dixval)

Valproic acid, valproate sodium, and divalproex belong to the group of medicines called anticonvulsants. They are used to control certain types of seizures in the treatment of epilepsy. Valproic acid, valproate sodium, and divalproex may be used alone or with other seizure medicine. Divalproex is also used to treat the manic phase of bipolar disorder (manic-depressive illness), and to help prevent migraine headaches.

Divalproex and valproate sodium form valproic acid in the body and gets converted to valproate ions. Therefore, the following information applies to all of these medicines.

About Sodium Valproate:

This belongs to the group of medicines known as antiepileptics.
Sodium Valproate controls the convulsions (fits or seizures) in some forms of epilepsy by reducing the activity in the brain.

Sodium valproate is also helpful in preventing absence seizures (where people appear to 'switch off' for short periods of time).

Sodium valproate is available in enteric-coated tablet, crushable tablet. It is also available as a controlled release preparation, which means sodium valproate is released slowly over the day to give an even effect.

VALPORIL/ VALPORIL CR & DIXVAL IN EPILEPSY

The brain works by sending lots of messages. It manages the number of messages it sends and where it sends them.

Sometimes extra messages are sent which do not go down the normal routes. This can upset the normal function of the brain and can cause an epileptic seizure. A person is said to have epilepsy when they have repeated seizures.
Sodium valproate belongs to a class of medicines called Anti-Epileptics. It can stop these extra messages in the brain. In this way it makes epileptic seizures less likely

What is sodium valproate for?

This form of sodium valproate is used in all types of epilepsy.

Getting Valporil CR to work for you

Valporil (Sodium valproate) is available as 200 mg gastro-resistant tablets, 200 mg controlled release tablets 300 mg controlled -release tablets, 500 mg controlled -release tablets

People who take Valporil / Valporil CR the right way can often get control of their seizures. For the best results, you need to take Valporil CR every day. It is a good idea

Dosage: Valproate sodium, like lithium, is all about blood levels. However none of the PI sheets seemed all that concerned with blood levels. Dosage was good enough, with blood levels just getting a mention.

Everyone recommends starting at 600mg a day divided into two doses, ramping up by 200mg every three days until your symptoms were under control or you hit 2000 to 2500mg a day (based on weight, allowing 30mg/kg/day). Although you just might want to check those blood levels to see if you hit that sweet spot between 45 and 125.

Well, at least that's somewhat saner than the US recommendations for valproates. But unless you're really spazing out, I think you can wait a week between increases. And you can get blood levels done to see how you're doing at 600, 800, 1000mg. And with a half-life of 8-12 hours taking it three times a day would probably work better. I haven't found any studies on valproate sodium and TID dosing, just Divalproex sodium, but people taking Divalproex sodium three times a day seem to complain about some of the side effects less.

Days to Reach a Steady State:

Valproate sodium's non-linear. You can't pin down a hard number on it. I haven't found a number for it in any study. Based on the usual formula of 6 * half-life, approximately three days.

When you're fully saturated with the medication and less prone to peaks and valleys of effects. You still might have peaks of effect after taking many meds, but with a lot of the meds you'll have fewer valleys after this point. In theory anyway.

How long it takes to Work: In theory you should start feeling results once you're in the therapeutic range of your blood levels. So for epilepsy that's generally in the neighborhood of 50-100, and for bipolar it's a wider range of 40-150. Getting to that blood level is between you and your liver. Once there it's up to your brain if it's going to respond to a valproate or not. So unlike most anticonvulsants where you feel something in a matter of days, or there's a definite dosage where we can write, "here is where you should notice effect or not," it's just not like that with the valproates. So once you're there, here's a study with PET scans indicating 2-6 weeks to start feeling something.

Half-Life & Average Time to Clear Out of Your System: 8-12 hours. You should thus step down the dosage by however much you increased it a day every two to three days.

Like any anticonvulsant, if you've been taking valproate sodium for more than a couple months and you've reached the therapeutic blood levels, you just can't stop cold turkey if you're not at the therapeutic dosage for another anticonvulsant that is known to work for you, otherwise you risk partial onset or absence seizures to tonic-clonic grand mals, even if you've never had a seizure disorder before! The risk is worse if you're taking a lithium variant, and/or any antidepressant, especially bupropion. Anyone with a history of a seizure disorder who needs to stop taking an anticonvulsant cold turkey needs to be discussing that with two neurologists and not getting your information from some stupid web site. Get off your computer and start making appointments!
If you've worked your way up to a particular dosage, it's usually best to spend this many days at the next lowest dosage before going down the next lowest dosage before that and so forth. This is the least sucky way to avoid problems when stopping any psychiatric medication. Presuming you have the option of slowly tapering off them.

What is divalproex (Dixval)?

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis (2-propylpentanoate). Divalproex sodium occurs as a white powder with a characteristic odor.
Dixval tablets are for oral administration. Dixval tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid.

Difference between divalproex and sodium valproate/valproic acid

The molar relation of sodium valproate: valproic acid is 2.3:1 in Valporil/ Valporil CR, while in Dixval it is in the ratio of 1:1
This may not make a difference as far as it’s therapeutic benefits are considered, as it is the valproate ion, which is the active moiety.

Here is a letter from Dr. Phelps to a reader downloaded from the net:

"Forms of the active ingredient, the valproate ion (you could think of that as V-) Sodium valproate (V. Na; dissolving into V- and Na+ when it hits the fluids in the stomach) Valproic acid (V. H); dissolving into V- and H+ when it hits the fluids in the stomach)

Combinations of the two

a) "Divalproex sodium" (Dixval), which is a 1:1 mixture

b) A mixture of 2.3:1 mixture of sodium valproate and valproic acid (Valporil / Valporil CR).

Now, does it make any difference? I'm not aware of any literature comparing the two mixtures (1:1 versus 2.3:1). From what I know so far, always open to learning more, it shouldn't make any difference in the effectiveness of the medications, because all of these forms end up yielding the valproate ion, which is the active form of the medication. The difference is said to be, as I understand it, that the combinations are better in terms of side effects than the Sodium Valproate version. The latter causes little more stomach irritation and thus nausea.

So if your friend is not having stomach problems with the current one, and there's no other reason to look at switching, I don't think there would be any improvement to be had from switching.

Thanks. Dr. Phelps

CLINICAL PHARMACOLOGY
Pharmacodynamics

Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

Pharmacokinetics

Absorption/Bioavailability

Equivalent oral doses of Dixval (divalproex sodium) products and Valporil (valproic acid) deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment.
For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).

While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown.

Co-administration of oral valproate products with food and substitution formulations should cause no clinical problems in the management of patients with epilepsy. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.

Distribution

Protein Binding:
The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mg/mL to 18.5% at 130 mg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). (See PRECAUTIONS, Drug Interactions for more detailed information on the pharmacokinetic interactions of valproate with other drugs.)

CNS Distribution:

Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).

Metabolism:

Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial b-oxidation is the other major metabolic pathway, typically accounting for over 40% o f the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.

Elimination

Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.

Special Populations

Effect of Age:

Neonates - Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months.
Children - Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.Elderly - The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly

Effect of Disease:

Liver Disease – Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.

Renal Disease - A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance <>hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.

Plasma Levels and Clinical Effect

The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mg/mL to 18.5% at 130 mg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemia c patients, and in patients with hepatic and renal diseases.

Epilepsy:

The therapeutic range in epilepsy is commonly considered to be 50 to 100 mg/mL of total valproate, although some patients may b e controlled with lower or higher plasma concentrations.

Mania:

In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mg/mL

Indications and usage

Mania

Dixval (divalproex sodium) is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgement, aggressiveness, and possible hostility.

The efficacy of divalproex sodium was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania .

The safety and effectiveness of divalproex sodium for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use divalproex sodium for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient.

Epilepsy

Divalproex sodium is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

MigraineDivalproex sodium is indicated for prophylaxis of migraine headaches. There is no evidence that Divalproex sodium is useful in the acute treatment of migraine headaches. Because valproic acid may be a hazard to the fetus, Divalproex sodium should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment.

DOSAGE AND ADMINISTRATION

Mania

Divalproex sodium tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Divalproex sodium treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the benefits of Divalproex sodium in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Divalproex sodium, the safety of Divalproex sodium in long-term use is supported by data from record reviews involving approximately 360 patients treated with Divalproex sodium for greater than 3 months.

Epilepsy

Divalproex sodium tablets are administered orally. Divalproex sodium is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Divalproex sodium dosage is titrated upward, concentrations of phenobarbital, carbamazepine, and/or phenytoin may be affected

Complex Partial Seizures: For adults and children 10 years of age or older.

Monotherapy (Initial Therapy):

Divalproex sodium has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mg/mL). No recomme n-dation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mg/mL in females and 135 mg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibil ity of a greater incidence of adverse reactions.

Conversion to Monotherapy:

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100mg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Divalproex sodium therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy:

Divalproex sodium may be added to the patient’s increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mg/mL). No recommendation regarding the safety of valproate fo r use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to Divalproex sodium, no adjustment of carbamazepine or phenytoin dosage was needed However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy .
Simple and Complex Absence Seizures: The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mg/mL. Some patient s may be controlled with lower or higher serum concentrations.
As the Divalproex sodium dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected.

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving valproic acid (Valporil) therapy, Divalproex sodium tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Divalproex sodium tablets, a dosing schedule of two or three times a day may be elected in selected patients.

Migraine

Divalproex sodium tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy.

General Dosing Advice:

Dosing in Elderly Patients - Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response . Dose-Related Adverse Events - The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ³110mg/mL (females) or ³135 mg/mL (males). The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I. Irritation - Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

SIDE EFFECTS
Mania
The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of divalproex sodium in the treatment of manic episodes associated with bipolar disorder. The adverse events were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, divalproex sodium, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, divalproex sodium, and lithium carbonate groups, respectively.

The following adverse events occurred at an equal or greater incidence for placebo than for divalproex sodium: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse events were reported by greater than 1% but not more than 5% of the 89-divalproex sodium-treated patients in controlled clinical trials. Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.

Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation.
Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess.

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Edema, peripheral edema.
Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching.Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo.

Respiratory System: Dyspnea, rhinitis.

Skin and Appendages: Alopecia, discoid lupus erythematosis, dry skin, furunculosis, maculopapular rash, seborrhea.Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.

Urogenital System: Dysmenorrhoea, dysuria, urinary incontinence
MigraineBased on two placebo-controlled clinical trials and their long term extension, divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to divalproex sodium in the placebo-controlled trials,17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse events reported as the primary reason for discontinuation by ³1% of 248 divalproex sodium -treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).

Those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the divalproex sodium -treated group was greater than 5% and was greater than that for placebo patients.

The following adverse events occurred in at least 5% of divalproex sodium -treated patients and at an equal or greater incidence for placebo than for divalproex sodium flu syndrome and pharyngitis.

The following additional adverse events were reported by greater than 1% but not more than 5% of the 202 divalproex sodium-treated patients in the controlled clinical trials:

Body as a Whole: Chest pain, chills, face edema, fever and malaise.
Cardiovascular System: Vasodilatation.
Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase.

Musculoskeletal System: Leg cramps and myalgia.

Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.

Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.
Skin and Appendages: Pruritus and rash.

Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
EpilepsyBased on a placebo-controlled trial of adjunctive therapy for treatment of complex

partial seizures divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium -treated patients (6%), compared to 1% of placebo-treated patients
Other Patient Populations
Adverse events that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate.
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.
Musculoskeletal: Weakness.Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage, Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (eg, SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity.
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function testsThere have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.Pancreatic: Acute pancreatitis including fatalities.
Metabolic: Hyperammonemia, hyponatremia, and inappropriate ADH secretion.There have been rare reports of Fanconi’s syndrome occurring chiefly in children.Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.
DRUG INTERACTIONS
Effects of co-administered Drugs on Valproate Clearance:

Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.

Drugs for which a potentially important interaction has been observed:

Aspirin - A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The b-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.

Felbamate - A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.

Meropenem - Subtherapeutic valproic acid levels have been reported when meropenem was coadministered.

Rifampin - A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed:

Antacids - A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.

Chlorpromazine - A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.

Haloperidol - A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.

Cimetidine and Ranitidine - Cimetidine and ranitidine do not affect the clearance of valproate.

Effects of Valproate on Other Drugs:

Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.

Drugs for which a potentially important valproate interaction has been observed:

Amitriptyline/Nortriptyline - Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.

Carbamazepine/carbamazepine-10,11-Epoxide - Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.

Clonazepam - The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures.

Diazepam - Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.

Ethosuximide - Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosux-imide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Lamotrigine - In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.

Phenobarbital - Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations.
All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.

Phenytoin - Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.

Tolbutamide - From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.

Warfarin - In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if divalproex sodium therapy is instituted in patients taking anticoagulants.

Zidovudine - In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed:

Acetaminophen - Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.

Clozapine - In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine.

Lithium - Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium.

Lorazepam - Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.

Oral Contraceptive Steroids - Administration of a single-dose of ethinyloestradiol (50 mg)/levonorgestrel (250 mg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction

CONTRAINDICATIONS
DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION.
Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug.Divalproex sodium is contraindicated in patients with known urea cycle disorders.

PATIENT INFORMATION

Important Information for Women Who Could Become Pregnant

About the Use of Valporil/Dixval Tablets

Please read this leaflet carefully before you take Valporil/Dixval tablets. This leaflet provides a summary of important information about taking Valporil/Dixval to women who could become pregnant. If you have any questions or concerns, or want more information about Valporil/Dixval, contact your doctor.

Information For Women Who Could Become Pregnant

Valporil/Dixval can be obtained only by prescription from your doctor. The decision to use Valporil/Dixval is one that you and your doctor should make together, taking into account your individual needs and medical condition.

Before using Valporil/Dixval, women who can become pregnant should consider the fact that Valporil/Dixval has been associated with birth defects, in particular, with spina bifida and other defects related to failure of the spinal canal to close normally. Approximately 1 to 2% of children born to women with epilepsy taking Valporil/Dixval in the first 12 weeks of pregnancy had these defects (based on data from the Centers for Disease Control, a U.S. agency based in Atlanta). The incidence in the general population is 0.1 to 0.2%.

For further information, e-mail to

Mr. Mukesh Vankani or

Mr. Deepak Shah B. Pharma. MBA at

reliancehealthcare@yahoo.co.in