laxative Oral

Class Name: laxative (Oral route)

Commonly used brand name(s)

In the U.S.

• A-3 Revised


• Alocass


• Amitiza


• Benefiber


• Black-Draught


• Cholan-HMB


• Citrate Of Magnesia


• Citrucel


• Colace


• Colyte


• Doc-Q-Lax


• Docucal


• Dulcolax


• Fibercon


• Fleet Mineral Oil


• GaviLAX


• GaviLyte-N with Flavor Pack


• GlycoLax


• Kristalose


• Mag-Gel 600


• Metamucil


• Nulytely


• Phillips Milk of Magnesia


• Phospho-Soda


• Purge


• Resource Benefiber


• Rite Aid Senna


• Senna-S


• Senokot


• Suprep Bowel Prep Kit


• Unifiber

In Canada

• Acilac


• Alpha-Lac


• Aromatic Cascara Fluid Extract


• Biolax Cascara Sagrada


• Biolax Sp


• Bulk Fiber Therapy


• Cascara Sagrada Aromatic Fluid Extract


• Castor Oil


• Cephulac


• Chronulac

Available Dosage Forms:

• Tablet


• Oil


• Capsule, Liquid Filled


• Liquid


• Tablet, Chewable


• Capsule


• Syrup


• Flake


• Suspension


• Powder for Suspension


• Wafer


• Granule


• Powder for Solution


• Emulsion


• Kit


• Gum


• Solution


• Tablet, Enteric Coated


• Tablet, Delayed Release


• Packet

Uses For This Medicine

Oral laxatives are medicines taken by mouth to encourage bowel movements to relieve constipation.

There are several different types of oral laxatives and they work in different ways. Since directions for use are different for each type, it is important to know which one you are taking. The different types of oral laxatives include:

Bulk-formers—Bulk-forming laxatives are not digested but absorb liquid in the intestines and swell to form a soft, bulky stool. The bowel is then stimulated normally by the presence of the bulky mass. Some bulk-forming laxatives, like psyllium and polycarbophil, may be prescribed by your doctor to treat diarrhea.

Hyperosmotics—Hyperosmotic laxatives encourage bowel movements by drawing water into the bowel from surrounding body tissues. This provides a soft stool mass and increased bowel action.

There are three types of hyperosmotic laxatives taken by mouth—the saline, the lactulose , and the polymer types:

• The saline type is often called "salts." They are used for rapid emptying of the lower intestine and bowel. They are not used for long-term or repeated correction of constipation. With smaller doses than those used for the laxative effect, some saline laxatives are used as antacids. The information that follows applies only to their use as laxatives. Sodium phosphate may also be prescribed for other conditions as determined by your doctor.


• The lactulose type is a special sugar-like laxative that works the same way as the saline type. However, it produces results much more slowly and is often used for long-term treatment of chronic constipation. Lactulose may sometimes be used in the treatment of certain medical conditions to reduce the amount of ammonia in the blood. It is available only with your doctor's prescription.


• The polymer type is a polyglycol (polyethylene glycol), a large molecule that causes water to be retained in the stool; this will soften the stool and increase the number of bowel movements. It is used for short periods of time to treat constipation.

Lubricants—Lubricant laxatives, such as mineral oil, taken by mouth encourage bowel movements by coating the bowel and the stool mass with a waterproof film. This keeps moisture in the stool. The stool remains soft and its passage is made easier.

Stimulants—Stimulant laxatives, also known as contact laxatives, encourage bowel movements by acting on the intestinal wall. They increase the muscle contractions that move along the stool mass. Stimulant laxatives are a popular type of laxative for self-treatment. However, they also are more likely to cause side effects. One of the stimulant laxatives, dehydrocholic acid, may also be used for treating certain conditions of the biliary tract.

Stool softeners (emollients)—Stool softeners encourage bowel movements by helping liquids mix into the stool and prevent dry, hard stool masses. This type of laxative has been said not to cause a bowel movement but instead allows the patient to have a bowel movement without straining.

Combinations—There are many products that you can buy for constipation that contain more than one type of laxative. For example, a product may contain both a stool softener and a stimulant laxative. In general, combination products may be more likely to cause side effects because of the multiple ingredients. In addition, they may not offer any advantage over products containing only one type of laxative. If you are taking a combination laxative, make certain you know the proper use and precautions for each of the different ingredients.

Most laxatives (except saline laxatives) may be used to provide relief:

• during pregnancy.


• for a few days after giving birth.


• during preparation for examination or surgery.


• for constipation of bedfast patients.


• for constipation caused by other medicines.


• following surgery when straining should be avoided.


• following a period of poor eating habits or a lack of physical exercise in order to develop normal bowel function (bulk-forming laxatives only).


• for some medical conditions that may be made worse by straining, for example:
  
  • Heart disease
  
  
  • Hemorrhoids
  
  
  • Hernia (rupture)
  
  
  • High blood pressure (hypertension)
  
  
  • History of stroke
  
  

Saline laxatives have more limited uses and may be used to provide rapid results:

• during preparation for examination or surgery.


• for elimination of food or drugs from the body in cases of poisoning or overdose.


• for simple constipation that happens on occasion (although another type of laxative may be preferred).


• in supplying a fresh stool sample for diagnosis.

Laxatives are available both over-the-counter (OTC) and with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, psyllium hydrophilic mucilloid is used in certain patients with the following medical conditions:

• Hypercholesterolemia (high cholesterol)

For patients taking psyllium hydrophilic mucilloid for high cholesterol:

• Importance of diet—Before prescribing medicine for your condition, your doctor will probably try to control your condition by prescribing a personal diet for you. Such a diet may be low in fats, sugars, and/or cholesterol. Many people are able to control their condition by carefully following their doctor's orders for proper diet and exercise. Medicine is prescribed only when additional help is needed. Follow carefully the special diet your doctor gave you , since the medicine is effective only when a schedule of diet and exercise is properly followed.


• Remember that this medicine will not cure your cholesterol problem but it will help control it. Therefore, you must continue to take it as directed by your doctor if you expect to lower your cholesterol level.

Importance of Diet

Laxatives are to be used to provide short-term relief only, unless otherwise directed by a doctor. A proper diet containing roughage (whole grain breads and cereals, bran, fruit, and green, leafy vegetables), with 6 to 8 full glasses (8 ounces each) of liquids each day, and daily exercise are most important in maintaining healthy bowel function. Also, for individuals who have problems with constipation, foods such as pastries, puddings, sugar, candy, cake, and cheese may make the constipation worse.

Make certain your health care professional knows if you are on any special diet, such as a low-sodium or low-sugar diet. Some laxatives have large amounts of sodium or sugars in them.

Before Using This Medicine

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Laxatives should not be given to young children (up to 6 years of age) unless prescribed by their doctor. Since children usually cannot describe their symptoms very well, they should be checked by a doctor before being given a laxative. The child may have a condition that needs other treatment. If so, laxatives will not help, and may even cause unwanted effects or make the condition worse.

Mineral oil should not be given to young children (up to 6 years of age) because a form of pneumonia may be caused by the inhalation of oil droplets into the lungs.

Also, bisacodyl tablets should not be given to children up to 6 years of age because if chewed they may cause stomach irritation.

Geriatric

Mineral oil should not be taken by bedridden elderly persons because a form of pneumonia may be caused by the inhalation of oil droplets into the lungs. Also, stimulant laxatives (e.g., bisacodyl or casanthranol), if taken too often, may worsen weakness, lack of coordination, or dizziness and light-headedness.

Polyethylene glycol 3350 should be discontinued if diarrhea occurs, especially in elderly persons in nursing homes.

Pregnancy

Although laxatives are often used during pregnancy, some types are better than others. Stool softeners (emollient) laxatives and bulk-forming laxatives are probably used most often. If you are using a laxative during pregnancy, remember that:

• Some laxatives (in particular, the bulk-formers) contain a large amount of sodium or sugars, which may have possible unwanted effects such as increasing blood pressure or causing water to be held in the body.


• Saline laxatives containing magnesium, potassium, or phosphates may have to be avoided if your kidney function is not normal.


• Mineral oil is usually not used during pregnancy because of possible unwanted effects on the mother or infant. Mineral oil may interfere with the absorption of nutrients and vitamins in the mother. Also, if taken for a long time during pregnancy, mineral oil may cause severe bleeding in the newborn infant.


• Stimulant laxatives may cause unwanted effects in the expectant mother if improperly used. Castor oil in particular should not be used as it may cause contractions of the womb.

Breast Feeding

Laxatives containing cascara and danthron may pass into the breast milk. Although the amount of laxative in the milk is generally thought to be too small to cause problems in the baby, your doctor should be told if you plan to use such laxatives. Some reports claim that diarrhea has been caused in the infant.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Cisapride


• Dronedarone


• Mesoridazine


• Pimozide


• Sparfloxacin


• Thioridazine

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfuzosin


• Amiodarone


• Amitriptyline


• Amoxapine


• Amygdalin


• Apomorphine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Azathioprine


• Azithromycin


• Chloroquine


• Chlorpromazine


• Ciprofloxacin


• Citalopram


• Clarithromycin


• Clomipramine


• Clozapine


• Crizotinib


• Cyclosporine


• Dasatinib


• Deferoxamine


• Desipramine


• Disopyramide


• Dofetilide


• Dolasetron


• Droperidol


• Erythromycin


• Flecainide


• Fluconazole


• Gatifloxacin


• Gemifloxacin


• Granisetron


• Halofantrine


• Haloperidol


• Hyaluronidase


• Ibutilide


• Iloperidone


• Imipramine


• Lapatinib


• Levofloxacin


• Levomethadyl


• Licorice


• Lopinavir


• Lumefantrine


• Mefloquine


• Methadone


• Moxifloxacin


• Mycophenolate Mofetil


• Mycophenolic Acid


• Nilotinib


• Norfloxacin


• Nortriptyline


• Octreotide


• Ofloxacin


• Ondansetron


• Paliperidone


• Pazopanib


• Perflutren Lipid Microsphere


• Posaconazole


• Procainamide


• Prochlorperazine


• Promethazine


• Propafenone


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Ranolazine


• Rilpivirine


• Salmeterol


• Saquinavir


• Sodium Polystyrene Sulfonate


• Solifenacin


• Sorafenib


• Sotalol


• St John's Wort


• Sunitinib


• Telavancin


• Telithromycin


• Terfenadine


• Tetrabenazine


• Toremifene


• Trazodone


• Trifluoperazine


• Trimipramine


• Vandetanib


• Vardenafil


• Vemurafenib


• Voriconazole


• Ziprasidone

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Using medicines in this class with any of the following is not recommended. Your doctor may decide not to treat you with a medication in this class, change some of the other medicines you take, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

• Appendicitis (or signs of) or


• Rectal bleeding of unknown cause—These conditions need immediate attention by a doctor.

• Colostomy or


• Intestinal blockage or


• Ileostomy—The use of laxatives may create other problems if these conditions are present.

• Type 2 diabetes mellitus—Diabetic patients should be careful since some laxatives contain large amounts of sugars, such as dextrose, galactose, and/or sucrose.

• Heart disease or


• High blood pressure—Some laxatives contain large amounts of sodium, which may make these conditions worse.

• Kidney disease—Magnesium and potassium (contained in some laxatives) may build up in the body if kidney disease is present; a serious condition may develop.

• Swallowing difficulty—Mineral oil should not be used since it may get into the lungs by accident and cause pneumonia; also, bulk-forming laxatives may get lodged in the esophagus of patients who have difficulty in swallowing.

Proper Use of This Medicine

For safe and effective use of your laxative:

• Follow your doctor's instructions if this laxative was prescribed.


• Follow the manufacturer's package directions if you are treating yourself.

With all kinds of laxatives, at least 6 to 8 glasses (8 ounces each) of liquids should be taken each day. This will help make the stool softer.

For patients taking laxatives containing a bulk-forming ingredient:

• Do not try to swallow in the dry form. Mix with liquid following the directions on the product label.


• To allow bulk-forming laxatives to work properly and to prevent intestinal blockage, it is necessary to drink plenty of fluids during their use. Each dose should be taken in or with a full glass (8 ounces) or more of cold water or fruit juice. This will provide enough liquid for the laxative to work properly. A second glass of water or juice by itself is often recommended with each dose for best effect and to avoid side effects.


• When taking a product that contains only a bulk-forming ingredient, results often may be obtained in 12 hours. However, this may not occur for some individuals until after 2 or 3 days.

For patients taking laxatives containing a stool softener (emollient):

• Liquid forms may be taken in milk or fruit juice to improve flavor.


• When taking a product that contains only a stool softener, results usually occur 1 to 2 days after the first dose. However, this may not occur for some individuals until after 3 to 5 days.

For patients taking laxatives containing a hyperosmotic ingredient:

• Each dose should be taken in or with a full glass (8 ounces) or more of cold water or fruit juice. This will provide enough liquid for the laxative to work properly. A second glass of water or juice by itself is often recommended with each dose for best effect and, in the case of saline laxatives, to prevent you from becoming dehydrated.


• The unpleasant taste produced by some hyperosmotic laxatives may be improved by following each dose with citrus fruit juice or citrus-flavored carbonated beverage.


• Lactulose may not produce laxative results for 24 to 48 hours.


• Polyethylene glycol may not produce laxative results for 2 to 4 days.


• Saline laxatives usually produce results within 30 minutes to 3 hours following a dose. When a larger dose is taken on an empty stomach, the results are quicker. When a smaller dose is taken with food, the results are delayed. Therefore, large doses of saline laxatives are usually not taken late in the day on an empty stomach.

For patients taking laxatives containing mineral oil:

• Mineral oil should not be taken within 2 hours of meals because of possible interference with food digestion and absorption of nutrients and vitamins.


• Mineral oil is usually taken at bedtime (but not while lying down) for convenience and because it requires about 6 to 8 hours to produce results.

For patients taking laxatives containing a stimulant ingredient:

• Stimulant laxatives are usually taken on an empty stomach for rapid effect. Results are slowed if taken with food.


• Many stimulant laxatives (but not castor oil) are often taken at bedtime to produce results the next morning (although some may require 24 hours or more).


• Castor oil is not usually taken late in the day because its results occur within 2 to 6 hours.


• The unpleasant taste of castor oil may be improved by chilling in the refrigerator for at least an hour and then stirring the dose into a full glass of cold orange juice just before it is taken. Also, flavored preparations of castor oil are available.


• Bisacodyl tablets are specially coated to allow them to work properly without causing irritation and/or nausea. To protect this coating, do not chew, crush, or take the tablets within an hour of milk or antacids.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using This Medicine

Do not take any type of laxative:

• if you have signs of appendicitis or inflamed bowel (such as stomach or lower abdominal pain, cramping, bloating, soreness, nausea, or vomiting). Instead, check with your doctor as soon as possible.


• for more than 1 week unless your doctor has prescribed or ordered a special schedule for you. This is true even when you have had no results from the laxative.


• within 2 hours of taking other medicine because the desired effect of the other medicine may be reduced.


• if you do not need it, as for the common cold, "to clean out your system" or as a "tonic to make you feel better."


• if you miss a bowel movement for a day or two.


• if you develop a skin rash


• while taking a laxative or if you had a rash the last time you took it. Instead, check with your doctor.

If you notice a sudden change in bowel habits or function that lasts longer than 2 weeks, or that keeps returning off and on, check with your doctor before using a laxative. This will allow the cause of your problem to be determined before it may become more serious.

The "laxative habit"—Laxative products are overused by many people. Such a practice often leads to dependence on the laxative action to produce a bowel movement. In severe cases, overuse of some laxatives has caused damage to the nerves, muscles, and tissues of the intestines and bowel. If you have any questions about the use of laxatives, check with your health care professional.

Many laxatives often contain large amounts of sugars, carbohydrates, and sodium. If you are on a low-sugar, low-caloric, or low-sodium diet, check with your health care professional before using a laxative.

For patients taking laxatives containing mineral oil:

• Mineral oil should not be taken often or for long periods of time because:
  
  • gradual build-up in body tissues may create additional problems.
  
  


• the use of mineral oil may interfere with the body's ability to absorb certain food nutrients and vitamins A, D, E, and K.

Large doses of mineral oil may cause some leakage from the rectum. The use of absorbent pads or a decrease in dose may be necessary to prevent the soiling of clothing.

Do not take mineral oil within 2 hours of a stool softener (emollient laxative). The stool softener may increase the amount of mineral oil absorbed.

For patients taking laxatives containing a stimulant ingredient:

• Stimulant laxatives are most often associated with:
  
  • overuse and the laxative habit.
  
  
  • skin rashes.
  
  
  • intestinal cramping after dosing (especially if taken on an empty stomach).
  
  
  • potassium loss.
  
  

Side Effects of This Medicine

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

For bulk-forming-containing

• Difficulty in breathing


• intestinal blockage


• skin rash or itching


• swallowing difficulty (feeling of lump in throat)

For hyperosmotic-containing

• Confusion


• dizziness or light-headedness


• irregular heartbeat


• muscle cramps


• unusual tiredness or weakness

For stimulant-containing

• Confusion


• irregular heartbeat


• muscle cramps


• pink to red, red to violet, or red to brown coloration of alkaline urine (for cascara, danthron, and/or senna only)


• skin rash


• unusual tiredness or weakness


• yellow to brown coloration of acid urine (for cascara, and/or senna only)

For stool softener (emollient)-containing

• Skin rash

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

For hyperosmotic-containing

• Bloating


• cramping


• diarrhea


• nausea


• gas


• increased thirst

For lubricant-containing

• Skin irritation surrounding rectal area

For stimulant-containing

• Belching


• cramping


• diarrhea


• nausea

For stool softener (emollient)-containing

• Stomach and/or intestinal cramping


• throat irritation (liquid forms only)

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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Xenical

Dosage Form: capsule
FULL PRESCRIBING INFORMATION

Indications and Usage for Xenical

Xenical is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. Xenical is also indicated to reduce the risk for weight regain after prior weight loss. Xenical is indicated for obese patients with an initial body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 in the presence of other risk factors (eg, hypertension, diabetes, dyslipidemia).

Table 1 illustrates body mass index (BMI) according to a variety of weights and heights. The BMI is calculated by dividing weight in kilograms by height in meters squared. For example, a person who weighs 180 lbs and is 5′5″ would have a BMI of 30.

Table 1 Body Mass Index (BMI), kg/m2*

* Conversion Factors: Weight in lbs ÷ 2.2 = weight in kilograms (kg) Height in inches × 0.0254 = height in meters (m) 1 foot = 12 inches

Xenical Dosage and Administration

Recommended Dosing

The recommended dose of Xenical is one 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal).

The patient should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of Xenical can be omitted.

Because Xenical has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition [see Warnings and Precautions (5.1)]. The vitamin supplement should be taken at least 2 hours before or after the administration of Xenical, such as at bedtime.

 For patients receiving both Xenical and cyclosporine therapy, administer cyclosporine 3 hours after Xenical.

For patients receiving both Xenical and levothyroxine therapy, administer levothyroxine and Xenical at least 4 hours apart. Patients treated concomitantly with Xenical and levothyroxine should be monitored for changes in thyroid function.

Doses above 120 mg three times a day have not been shown to provide additional benefit.

Based on fecal fat measurements, the effect of Xenical is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours.

Dosage Forms and Strengths

Xenical 120 mg dark-blue capsules imprinted with Roche and Xenical 120 in light-blue ink or turquoise capsules imprinted with ROCHE and Xenical 120 in black ink

Contraindications

Xenical is contraindicated in:

•  Pregnancy [see Use in Specific Populations (8.1)]


• Patients with chronic malabsorption syndrome


• Patients with cholestasis


• Patients with known hypersensitivity to Xenical or to any component of this product

Warnings and Precautions

Concomitant Drug and Vitamin Use

Data from a Xenical and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when Xenical was coadministered with cyclosporine. Therefore, Xenical and cyclosporine should not be simultaneously coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 3 hours before or after Xenical in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered.

Patients should be strongly encouraged to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because Xenical has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene [see Dosage and Administration (2)]. In addition, the levels of vitamin D and beta-carotene may be low in obese patients compared with non-obese subjects. The supplement should be taken once a day at least 2 hours before or after the administration of Xenical, such as at bedtime.

Table 2 illustrates the percentage of adult patients on Xenical and placebo who developed a low vitamin level on two or more consecutive visits during 1 and 2 years of therapy in studies in which patients were not previously receiving vitamin supplementation.

Table 2 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline Values - First and Second Year)

	Placebo*	Xenical*
* Treatment designates placebo plus diet or Xenical plus diet
Vitamin A	1.0%	2.2%
Vitamin D	6.6%	12.0%
Vitamin E	1.0%	5.8%
Beta-carotene	1.7%	6.1%

Table 3 illustrates the percentage of adolescent patients on Xenical and placebo who developed a low vitamin level on two or more consecutive visits during the 1-year study.

Table 3 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Pediatric Patients With Normal Baseline Values*)

	Placebo†	Xenical†
* All patients were treated with vitamin supplementation throughout the course of the study † Treatment designates placebo plus diet or Xenical plus diet
Vitamin A	0.0%	0.0%
Vitamin D	0.7%	1.4%
Vitamin E	0.0%	0.0%
Beta-carotene	0.8%	1.5%

Weight-loss may affect glycemic control in patients with diabetes mellitus. A reduction in dose of oral hypoglycemic medication (eg, sulfonylureas) or insulin may be required in some patients [see Clinical Studies (14)].

Liver Injury

There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with Xenical, with some of these cases resulting in liver transplant or death. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain) while taking Xenical. When these symptoms occur, Xenical and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained.

Increases in Urinary Oxalate

 Some patients may develop increased levels of urinary oxalate following treatment with Xenical. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing Xenical to patients at risk for renal impairment and use with caution in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.

Cholelithiasis

Substantial weight loss can increase the risk of cholelithiasis. In a clinical trial of Xenical for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to Xenical and 1.8% (30/1655) for patients randomized to placebo.

Miscellaneous

Organic causes of obesity (eg, hypothyroidism) should be excluded before prescribing Xenical.

Patients should be advised to adhere to dietary guidelines [see Dosage and Administration (2)]. Gastrointestinal events [see Adverse Reactions (6.1)] may increase when Xenical is taken with a diet high in fat (>30% total daily calories from fat). The daily intake of fat should be distributed over three main meals. If Xenical is taken with any one meal very high in fat, the possibility of gastrointestinal effects increases.

Adverse Reactions

Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients.

Commonly Observed (based on first year and second year data)

Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events associated with the use of Xenical in the seven double-blind, placebo-controlled clinical trials and are primarily a manifestation of the mechanism of action. (Commonly observed is defined as an incidence of ≥5% and an incidence in the Xenical 120 mg group that is at least twice that of placebo.)

Table 4 Commonly Observed Adverse Events

Adverse Event	Year 1		Year 2
	Xenical* % Patients (N=1913)	Placebo* % Patients (N=1466)	Xenical* % Patients (N=613)	Placebo* % Patients (N=524)
* Treatment designates Xenical three times a day plus diet or placebo plus diet † Oily discharge may be clear or have a coloration such as orange or brown.
Oily Spotting†	26.6	1.3	4.4	0.2
Flatus with Discharge	23.9	1.4	2.1	0.2
Fecal Urgency	22.1	6.7	2.8	1.7
Fatty/Oily Stool†	20.0	2.9	5.5	0.6
Oily Evacuation†	11.9	0.8	2.3	0.2
Increased Defecation	10.8	4.1	2.6	0.8
Fecal Incontinence	7.7	0.9	1.8	0.2

In general, the first occurrence of these events was within 3 months of starting therapy. Overall, approximately 50% of all episodes of GI adverse events associated with Xenical treatment lasted for less than 1 week, and a majority lasted for no more than 4 weeks. However, GI adverse events may occur in some individuals over a period of 6 months or longer.

Discontinuation of Treatment

In controlled clinical trials, 8.8% of patients treated with Xenical discontinued treatment due to adverse events, compared with 5.0% of placebo-treated patients. For Xenical, the most common adverse events resulting in discontinuation of treatment were gastrointestinal.

Other Adverse Clinical Events

The following table lists other treatment-emergent adverse events from seven multicenter, double-blind, placebo-controlled clinical trials that occurred at a frequency of ≥2% among patients treated with Xenical 120 mg three times a day and with an incidence that was greater than placebo during year 1 and year 2, regardless of relationship to study medication.

Table 5 Other Treatment-Emergent Adverse Events From Seven Placebo-Controlled Clinical Trials

Body System/Adverse Event	Year 1		Year 2
	Xenical* % Patients (N=1913)	Placebo* % Patients (N=1466)	Xenical* % Patients (N=613)	Placebo* % Patients (N=524)
– None reported at a frequency ≥2% and greater than placebo
* Treatment designates Xenical 120 mg three times a day plus diet or placebo plus diet
Gastrointestinal System
Abdominal Pain/Discomfort	25.5	21.4	–	–
Nausea	8.1	7.3	3.6	2.7
Infectious Diarrhea	5.3	4.4	–	–
Rectal Pain/Discomfort	5.2	4.0	3.3	1.9
Tooth Disorder	4.3	3.1	2.9	2.3
Gingival Disorder	4.1	2.9	2.0	1.5
Vomiting	3.8	3.5	–	–
Respiratory System
Influenza	39.7	36.2	–	–
Upper Respiratory Infection	38.1	32.8	26.1	25.8
Lower Respiratory Infection	7.8	6.6	–	–
Ear, Nose & Throat Symptoms	2.0	1.6	–	–
Musculoskeletal System
Back Pain	13.9	12.1	–	–
Pain Lower Extremities	–	–	10.8	10.3
Arthritis	5.4	4.8	–	–
Myalgia	4.2	3.3	–	–
Joint Disorder	2.3	2.2	–	–
Tendonitis	–	–	2.0	1.9
Central Nervous System
Headache	30.6	27.6	–	–
Dizziness	5.2	5.0	–	–
Body as a Whole
Fatigue	7.2	6.4	3.1	1.7
Sleep Disorder	3.9	3.3	–	–
Skin & Appendages
Rash	4.3	4.0	–	–
Dry Skin	2.1	1.4	–	–
Reproductive, Female
Menstrual Irregularity	9.8	7.5	–	–
Vaginitis	3.8	3.6	2.6	1.9
Urinary System
Urinary Tract Infection	7.5	7.3	5.9	4.8
Psychiatric Disorder
Psychiatric Anxiety	4.7	2.9	2.8	2.1
Depression	–	–	3.4	2.5
Hearing & Vestibular Disorders
Otitis	4.3	3.4	2.9	2.5
Cardiovascular Disorders
Pedal Edema	–	–	2.8	1.9

In the 4-year XENDOS study, the general pattern of adverse events was similar to that reported for the 1- and 2-year studies with the total incidence of gastrointestinal-related adverse events occurring in year 1 decreasing each year over the 4-year period.

In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed.

Pediatric Patients

In clinical trials with Xenical in adolescent patients ages 12 to 16 years, the profile of adverse reactions was generally similar to that observed in adults.

Postmarketing Surveillance

The following adverse reactions have been identified during postapproval use of Xenical. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Xenical exposure.

• Rare cases of increase in transaminases and in alkaline phosphatase and hepatitis that may be serious have been reported. There have been reports of hepatic failure observed with the use of Xenical in postmarketing surveillance, with some of these cases resulting in liver transplant or death [see Warnings and Precautions (5.2)].


• Cases of reduced concentrations of cyclosporine have been reported when cyclosporine was co-administered with Xenical [see Warnings and Precautions (5.1) and Drug Interactions (7.2)].


• Rare cases of hypersensitivity have been reported with the use of Xenical. Signs and symptoms have included pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare cases of bullous eruption have been reported.


• Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with Xenical and anticoagulants [see Drug Interactions (7.4)].


• Hypothyroidism has been reported in patients treated concomitantly with Xenical and levothyroxine [see Drug Interactions (7.3)].


• Acute oxalate nephropathy after treatment with Xenical has been reported in patients with or at risk for renal disease [see Warnings and Precautions (5.3)].


• Pancreatitis has been reported with the use of Xenical in postmarketing surveillance. No causal relationship or physiopathological mechanism between pancreatitis and obesity therapy has been definitively established.


• Lower gastrointestinal bleeding has been reported in patients treated with Xenical. Most reports are nonserious; severe or persistent cases should be investigated further.

Drug Interactions

Cyclosporine

Data from a Xenical and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when Xenical was coadministered with cyclosporine. Xenical and cyclosporine should not be simultaneously coadministered. Cyclosporine should be administered 3 hours after the administration of Xenical [see Dosage and Administration (2), Warnings and Precautions (5.1), and Adverse Reactions (6.2)].

Fat-soluble Vitamin Supplements and Analogues

Data from a pharmacokinetic interaction study showed that the absorption of beta-carotene supplement is reduced when concomitantly administered with Xenical. Xenical inhibited absorption of a vitamin E acetate supplement. The effect of Xenical on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time [see Pharmacokinetics (12.3)].

Levothyroxine

Hypothyroidism has been reported in patients treated concomitantly with Xenical and levothyroxine postmarketing [see Adverse Reactions (6.2)]. Patients treated concomitantly with Xenical and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and Xenical at least 4 hours apart [see Dosage and Administration (2)].

Warfarin

Vitamin K absorption may be decreased with Xenical. Patients on chronic stable doses of warfarin who are prescribed Xenical should be monitored closely for changes in coagulation parameters [see Pharmacokinetics (12.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X

Xenical is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. No embryotoxicity or teratogenicity was seen in animals that received orlistat at doses much higher than the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.

Animal Data

Reproduction studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity. This dose is 23 and 47 times the daily human dose calculated on a body surface area (mg/m2) basis for rats and rabbits, respectively.

Nursing Mothers

It is not known if Xenical is present in human milk. Caution should be exercised when Xenical is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

The safety and efficacy of Xenical have been evaluated in obese adolescent patients aged 12 to 16 years. Use of Xenical in this age group is supported by evidence from adequate and well-controlled studies of Xenical in adults with additional data from a 54-week efficacy and safety study and a 21-day mineral balance study in obese adolescent patients aged 12 to 16 years. Patients treated with Xenical in the 54-week efficacy and safety study (64.8% female, 75% Caucasians, 18.8% Blacks, and 6.3% Other) had a mean reduction in BMI of 0.55 kg/m2 compared with an average increase of 0.31 kg/m2 in placebo-treated patients (p=0.001). In both adolescent studies, adverse effects were generally similar to those described in adults and included fatty/oily stool, oily spotting, and oily evacuation. In a subgroup of 152 Xenical and 77 placebo patients from the 54-week study, changes in body composition measured by DEXA were similar in both treatment groups with the exception of fat mass, which was significantly reduced in patients treated with Xenical compared to patients treated with placebo (-2.5 kg vs -0.6 kg, p=0.033). Because Xenical can interfere with the absorption of fat-soluble vitamins, all patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. The vitamin supplement should be taken at least 2 hours before or after Xenical [see Dosage and Administration (2), Warnings and Precautions (5.1), and Clinical Pharmacology (12.2)].

Plasma concentrations of orlistat and its metabolites M1 and M3 were similar to those found in adults at the same dose level. Daily fecal fat excretions were 27% and 7% of dietary intake in Xenical and placebo treatment groups, respectively.

Geriatric Use

Clinical studies of Xenical did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients [see Clinical Studies (14)].

Drug Abuse and Dependence

Abuse

As with any weight-loss agent, the potential exists for abuse of Xenical in inappropriate patient populations (eg, patients with anorexia nervosa or bulimia). See Indications and Usage (1) for recommended prescribing guidelines.

Overdosage

Single doses of 800 mg Xenical and multiple doses of up to 400 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings.

Should a significant overdose of Xenical occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, systemic effects attributable to the lipase-inhibiting properties of Xenical should be rapidly reversible.

Xenical Description

Xenical (orlistat) is a gastrointestinal lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats.

Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester. Its empirical formula is C29H53NO5, and its molecular weight is 495.7. It is a single diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at 529 nm. The structure is:

Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no pKa within the physiological pH range.

Xenical is available for oral administration as a dark-blue or turquoise hard-gelatin capsule. The dark blue capsule is imprinted with light blue and the turquoise capsule is imprinted with black. Each capsule contains a pellet formulation consisting of 120 mg of the active ingredient, orlistat, as well as the inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc. The dark blue capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 1, with printing of pharmaceutical glaze NF, titanium dioxide, and FD&C Blue No. 1 aluminum lake. The turquoise capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 2 with black printing ink containing pharmaceutical grade shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonium solution, potassium hydroxide and black iron oxide.

Xenical - Clinical Pharmacology

Mechanism of Action

Orlistat is a reversible inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control.

Pharmacodynamics

Dose-response Relationship

The dose-response relationship for orlistat in human volunteers is shown in Figure 1. The effect is the percentage of ingested fat excreted, referred to as fecal fat excretion percentage. Both individual data (open circles) and the curve predicted for the population with the maximum-effect model (continuous line) are shown in Figure 1.

Figure 1 Dose-Response Relationship for Orlistat in Human Volunteers

At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.

Ethanol does not affect orlistat's effect on preventing the absorption of fat.

Other Short-term Studies

Adults

In several studies of up to 6-weeks duration, the effects of therapeutic doses of Xenical on gastrointestinal and systemic physiological processes were assessed in normal weight and obese subjects. Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of Xenical in two studies but not significantly different from placebo in two other experiments. There were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity, or colonic cell proliferation rate, and no clinically significant reduction of gastric emptying time or gastric acidity. In addition, no effects on plasma triglyceride levels or systemic lipases were observed with the administration of Xenical in these studies. In a 3-week study of 28 healthy male volunteers, Xenical (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, copper, and iron.

Pediatrics

In a 3-week study of 32 obese adolescents aged 12 to 16 years, Xenical (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, or copper. The iron balance was decreased by 64.7 µmole/24 hours and 40.4 µmole/24 hours in Xenical and placebo treatment groups, respectively.

Pharmacokinetics

Absorption

Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 µM), without evidence of accumulation, and consistent with minimal absorption.

Distribution

In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes.

Metabolism

Based on an oral 14C-orlistat mass balance study in obese patients, two metabolites, M1 ((the hydrolyzed β-lactone ring product of orlistat) and M3 (sequential metabolite after M1's cleavage of the N-formyl leucine side-chain), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open β-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 eliminated at a slower rate (half-life approximately 13.5 hours).

Elimination

Following a single oral dose of 360 mg 14C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Orlistat and its M1 and M3 metabolites were also subject to biliary excretion. Approximately 97% of the administered radioactivity was excreted in feces; 83% of that was found to be unchanged orlistat. The cumulative renal excretion of total radioactivity was <2% of the given dose of 360 mg 14C-orlistat. The time to reach complete excretion (fecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese subjects. Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours.

Specific Populations

No pharmacokinetic study was conducted for specific populations such as geriatric, different races, and patients with renal and hepatic impairment.

Drug Interactions

Alcohol

In a multiple-dose study in 30 normal-weight subjects, coadministration of Xenical and 40 grams of alcohol (eg, approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat.

Cyclosporine

In a multiple-dose study, coadministration of 50 mg cyclosporine twice daily with 120 mg Xenical three times daily decreased cyclosporine AUC and Cmax by 31 and 25%, respectively. In the same study, administration of 50 mg cyclosporine twice daily three hours after the administration of 120 mg Xenical three times daily decreased cyclosporine AUC and Cmax by 17 and 4%, respectively.

Digoxin

In 12 normal-weight subjects receiving Xenical 120 mg three times a day for 6 days, Xenical did not alter the pharmacokinetics of a single dose of digoxin.

Fat-soluble Vitamin Supplements and Analogues

A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with Xenical. Xenical inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of Xenical on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time.

Glyburide

In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide.

Levothyroxine

Hypothyroidism has been reported in patients treated concomitantly with Xenical and levothyroxine postmarketing.

Nifedipine (extended-release tablets)

In 17 normal-weight subjects receiving Xenical 120 mg three times a day for 6 days, Xenical did not alter the bioavailability of nifedipine (extended-release tablets).

Oral Contraceptives

In 20 normal-weight female subjects, the treatment of Xenical 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives.

Phenytoin

In 12 normal-weight subjects receiving Xenical 120 mg three times a day for 7 days, Xenical did not alter the pharmacokinetics of a single 300-mg dose of phenytoin.

Pravastatin

In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving Xenical 120 mg three times a day for 6 days, Xenical did not affect the pharmacokinetics of pravastatin.

Warfarin

In 12 normal-weight subjects, administration of Xenical 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with Xenical administration, vitamin K levels tended to decline in subjects taking Xenical. Therefore, as vitamin K absorption may be decreased with Xenical, patients on chronic stable doses of warfarin who are prescribed Xenical should be monitored closely for changes in coagulation parameters.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies in rats and mice did not show a carcinogenic potential for orlistat at doses up to 1000 mg/kg/day and 1500 mg/kg/day, respectively. For mice and rats, these doses are 38 and 46 times the daily human dose calculated on an area under concentration vs time curve basis of total drug-related material.

Orlistat had no detectable mutagenic or genotoxic activity as determined by the Ames test, a mammalian forward mutation assay (V79/HPRT), an in vitro clastogenesis assay in peripheral human lymphocytes, an unscheduled DNA synthesis assay (UDS) in rat hepatocytes in culture, and an in vivo mouse micronucleus test.

When given to rats at a dose of 400 mg/kg/day in a fertility and reproduction study, orlistat had no observable adverse effects. This dose is 12 times the daily human dose calculated on a body surface area (mg/m2) basis.

Clinical Studies

The long-term effects of Xenical on morbidity and mortality associated with obesity have not been established.

The effects of Xenical on weight loss, weight maintenance, and weight regain and on a number of comorbidities (eg, type 2 diabetes, lipids, blood pressure) were assessed in the 4-year XENDOS study and in seven long-term (1- to 2-years duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year of therapy, the studies of 2-year duration assessed weight loss and weight maintenance. During the second year of therapy, some studies assessed continued weight loss and weight maintenance and others assessed the effect of Xenical on weight regain. These studies included over 2800 patients treated with Xenical and 1400 patients treated with placebo (age range 17-78 years, 80.2% women, 91.0% Caucasians, 5.7% Blacks, 2.3% Hispanics, 0.1% Other). The majority of these patients had obesity-related risk factors and comorbidities. In the XENDOS study, which included 3304 patients (age range 30-58 years, 55% women, 99% Caucasians, 1% other), the time to onset of type 2 diabetes was assessed in addition to weight management. In all these studies, treatment with Xenical and placebo designates treatment with Xenical plus diet and placebo plus diet, respectively.

During the weight loss and weight maintenance period, a well-balanced, reduced-calorie diet that was intended to result in an approximate 20% decrease in caloric intake and provide 30% of calories from fat was recommended to all patients. In addition, all patients were offered nutritional counseling.

One-year Results: Weight Loss, Weight Maintenance, and Risk F

Felimazole

Generic Name: methimazole

Dosage Form: tablet, sugar coated
Felimazole Coated Tablets

Methimazole

For oral use in cats only.

CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Felimazole Description

Methimazole is a thioureylene antithyroid drug, which inhibits the synthesis of thyroid hormones. Methimazole (1-methylimidazole-2-thiol) is a white, crystalline substance that is freely soluble in water. The chemical formula is C4H6N2S. Molecular weight is 114.16.

Methimazole Chemical Structure

INDICATION

Felimazole (methimazole) Coated Tablets are indicated for the treatment of hyperthyroidism in cats.

Felimazole Dosage and Administration

The starting dose of Felimazole Coated Tablets is 2.5 mg administered every 12 hours. Following 3 weeks of treatment, the dose should be titrated to effect based on individual serum total T4 (TT4) levels and clinical response. Dose adjustments should be made in 2.5 mg increments. The maximum total dosage is 20 mg per day divided, not to exceed 10 mg as a single administration.

Hematology, biochemistry, and TT4 should be evaluated prior to initiating treatment and monitored after 3 weeks and 6 weeks of treatment. Thereafter, bloodwork should be monitored every 3 months and the dose adjusted as necessary. Cats receiving doses greater than 10 mg per day should be monitored more frequently.

Contraindications

Do not use in cats with hypersensitivity to methimazole, carbimazole or the excipient, polyethylene glycol.

Do not use in cats with primary liver disease or renal failure.

Do not use in cats with autoimmune disease. See ADVERSE REACTIONS.

Do not use in cats with hematological disorders (such as anemia, neutropenia, lymphopenia, or thrombocytopenia) or coagulopathies. See ADVERSE REACTIONS.

Do not use in pregnant or lactating queens. Laboratory studies in rats and mice have shown evidence of teratogenic and embryotoxic effects of methimazole.

Warnings

Methimazole has anti-vitamin K activity and may induce bleeding diathesis without evidence of thrombocytopenia. See ADVERSE REACTIONS.

HUMAN WARNINGS

Not for use in humans. Keep out of reach of children. For use in cats only.

Wash hands with soap and water after administration to avoid exposure to drug. Do not break or crush tablets. Wear protective gloves to prevent direct contact with litter, feces, urine, or vomit of treated cats, and broken or moistened tablets. Wash hands after contact with the litter of treated cats.

Methimazole is a human teratogen and crosses the placenta concentrating in the fetal thyroid gland. There is also a high rate of transfer into breast milk. Pregnant women or women who may become pregnant, and nursing mothers should wear gloves when handling tablets, litter or bodily fluids of treated cats.

Methimazole may cause vomiting, gastric distress, headache, fever, arthralgia, pruritus, and pancytopenia. In the event of accidental ingestion/overdose, seek medical advice immediately and show the product label to the physician.

Precautions

Use of Felimazole Coated Tablets in cats with renal dysfunction should be carefully evaluated. Reversal of hyperthyroidism may be associated with decreased glomerular filtration rate and a decline in renal function, unmasking the presence of underlying renal disease.

Due to potentially serious adverse reactions such as hepatopathy, immune mediated anemia, thrombocytopenia, and agranulocytosis, cats on methimazole therapy should be monitored closely for any sign of illness including fever, lymphadenopathy or signs of anemia. If a cat becomes ill while on Felimazole Coated Tablets, the drug should be stopped and appropriate hematological and biochemical testing should be done.

Anticoagulants may be potentiated by the anti-vitamin K activity of Felimazole Coated Tablets. Concurrent use of phenobarbital may reduce the clinical effectiveness of Felimazole Coated Tablets. A reduction in dose of certain drugs (β-adrenergic blocking agents, digitalis glycosides, and theophylline) may be needed when the patient becomes euthyroid.

Methimazole is known to reduce the hepatic oxidation of benzimidazole anthelmintics (e.g. fenbendazole), leading to increased plasma concentration of these anthelmintics when administered concurrently.

Felimazole Coated Tablets caused delayed maturation of the testes in young male cats in the 12-week safety study. See ANIMAL SAFETY. The safety of Felimazole Coated Tablets has not been evaluated in male cats intended for breeding.

Adverse Reactions

In a US field study with 113 cats, the most common adverse reactions included change in food consumption (increase or decrease), lethargy, vomiting, diarrhea/loose stool, skin lesions, and abnormal vocalization. Three cats were withdrawn early from the study, one due to unmasking of latent renal disease and two due to the development of skin lesions. Over the course of the study there was a decreasing trend in the mean counts of red blood cells, lymphocytes, neutrophils and monocytes; however, means remained within or near normal ranges for the testing laboratory.

In the extended use phase of the US field study with 101 cats, the most common adverse reactions reported in the study above (lethargy, anorexia) were also observed. Additional signs occurring more frequently in the long-term study were: depression/withdrawn behavior, weight loss, haircoat abnormalities, increased blood urea nitrogen (BUN), weakness, agitation and diarrhea. Most of the adverse reactions reported were mild and transient.

Serum chemistry and hematology results in the extended use study were consistent with the trends noted during the field study. The mean alanine transaminase (ALT) was above the reference range at the first two quarterly visits, but within the normal reference range (10-100 U/L) through the next two quarterly visits. Mean lymphocyte counts decreased consistently during the study period, to slightly below the reference range (1200-8000 cells/mcL) at the fourth quarterly visit.

Sixteen cats experienced elevated ANA titers at one or more points during long-term therapy with Felimazole Coated Tablets, but the significance was not determined.

Eighteen cats died or were euthanized during the extended use study, four of which may have been related to Felimazole Coated Tablets due to the unmasking/acceleration of chronic renal failure. See PRECAUTIONS.

In a foreign field study with 26 cats using a starting dose of 5 mg twice daily (twice the recommended starting dose), one cat was withdrawn due to lethargy, vomiting and facial excoriations. Marked thrombocytopenia was reported in two cats; the platelet count returned to normal in one cat when Felimazole Coated Tablets was discontinued. Two cats collapsed and died within 12 days of starting Felimazole Coated Tablets at a dose of 5 mg twice daily. Both cats were reported with lethargy, vomiting, anorexia, and bloody diarrhea; one cat also had pallor.

In a second foreign field study with 78 cats using a starting dose of 2.5 mg twice daily, 4 cats were withdrawn due to suspected adverse reactions to Felimazole Coated Tablets including anemia, cholangiohepatitis, excoriations, vomiting, lethargy, jaundice, and anorexia. One cat receiving 2.5 mg three times daily collapsed and died after 8 weeks of treatment. Adverse reactions included pallor, anorexia, dehydration, jaundice, bleeding diathesis, and anemia. The most frequently reported adverse reactions included mild, transient, self-limiting vomiting, lethargy, and anorexia.

Foreign Market Experience

The following events were reported voluntarily during post-approval use of Felimazole Coated Tablets in foreign markets: facial pruritus, self-induced excoriations of the head and neck, generalized lymphadenopathy, thrombocytopenia, hematemesis, epistaxis, and elevation of serum liver enzymes and bilirubin.

If overdosage occurs, stop treatment and give symptomatic and supportive care.

Felimazole - Clinical Pharmacology

Methimazole is an antithyroid drug that acts by blocking the biosynthesis of thyroid hormone in vivo. The primary action is to inhibit binding of iodide to the enzyme thyroid peroxidase, thereby preventing the catalyzed iodination of thyroglobulin and T3 and T4 synthesis.

Felimazole Coated Tablets are well absorbed following oral administration. Maximum plasma concentrations are achieved within 1-1½ hours after dosing and methimazole is rapidly eliminated from the blood (T½ is approximately 3 hours). Administration of Felimazole Coated Tablets in a fasted state enhances absorption.

EFFECTIVENESS

In a US effectiveness field study with 113 cats, the product was considered effective if both the TT4 concentration was ≤ 4.0 mcg/dL, and the Investigator's clinical assessment documented clinical improvement. Of the 105 evaluable cases, 64 (61%) were considered treatment successes. The decrease in TT4 concentration was significant from the pre-enrollment visit to the Day 42 visit. A TT4 of ≤ 4.0 mcg/dl occurred in 59.1% and 61.9% of cats on Day 21 and Day 42, respectively. Investigators assessed 91.8% and 87.6% of cats as clinically improved on Days 21 and 42, respectively.

In the extended use phase of the US effectiveness field study with 101 cats, effectiveness was based on a combination of Investigator's clinical assessment, maintenance of TT4 concentrations at or near the laboratory reference range of 0.8-4.0 mcg/dL, and the presence or absence of adverse reactions. Mean TT4 concentrations were within or near the laboratory reference range during the first four quarterly visits. At the first quarterly visit, investigators categorized 80.9% of cats as stable or improved relative to their baseline assessment. By the fourth quarterly visit, 75.8% were deemed to be stable or improved.

The average maintenance dose required in the extended use phase was 2.5 mg twice daily, with a minimum of 2.5 mg per cat and a maximum of 15 mg per cat on a daily basis.

ANIMAL SAFETY

In a 12 week safety study, healthy young cats were dosed with 0, 10, 20, and 30 mg Felimazole Coated Tablets per day, divided into two doses. Cats in all treated groups experienced anorexia, vomiting, loose stool and lethargy. Cats in the 20 and 30 mg/day groups also had facial excoriations, pruritus, and lymphadenopathy. The following hematological changes were seen: neutropenia, lymphopenia, anemia, and thrombocytopenia. The following biochemical changes were seen: increased globulin, increased magnesium, increased blood urea nitrogen, increased creatinine and decreased phosphorus. There was a dose dependent occurrence of anti-nuclear antibodies. Most of the clinical pathology changes were mild in nature. One cat dosed with 20 mg/day experienced a six-fold increase in ALT during the study. This cat had loose stool, but was otherwise healthy throughout the study. Hepatomegaly was seen in this cat at necropsy and the histopathological examination was comparable to other treated cats with hepatomegaly and normal ALT.

Gross necropsy findings in all treated groups included hepatomegaly, thymus atrophy and thyroid hyperplasia and darkening. Some treated males had delayed maturation of the testes.

The 30 mg/day dose was poorly tolerated and resulted in the clinical deterioration and euthanasia of four of the six cats in that group. Two of the cats showed signs of immune mediated hemolytic anemia, thrombocytopenia and severe clinical deterioration. One had been on the drug for 34 days, the other for 9 weeks. The drug was discontinued in a third cat treated with 30 mg/day while it received supportive care. It was euthanized on day 55 after becoming anorexic. This cat had anemia (HCT 21.6%) and red blood cell agglutination. Necropsy showed inflammation of the muscular layer of the stomach and a small erosion in the stomach. A fourth cat treated with 30 mg/day was euthanized after several days of anorexia when the decision was made to discontinue dosing in this group. All 30 mg/day cats that died had generalized lymphadenopathy. Necropsies revealed reactive lymph nodes and varying degrees of inflammation throughout the body. The remaining 2 cats in the 30 mg/day group were taken off Felimazole Coated Tablets at week 9 and fully recovered.

STORAGE INFORMATION

Store at controlled room temperature 25°C (77°F) with excursions between 15°–30°C (59°-86°F) permitted.

Keep the container tightly closed in order to protect from moisture.

How is Felimazole Supplied

Felimazole Coated Tablets are available in 2.5 mg or 5 mg in bottles containing 100 tablets.

NADA 141-292, Approved by FDA

Distributed by:

Dechra Veterinary Products

7015 College Boulevard

Suite 525

Overland Park, KS 66211

For a copy of the Material Safety Data Sheet (MSDS) or to report adverse reactions call Dechra Veterinary Products at (866) 933-2472.

Felimazole is a trademark of Dechra Ltd

© 2008, Dechra Ltd

PRINCIPAL DISPLAY PANEL - 2.5mg bottle label

2.5 mg

Felimazole™

(methimazole) Coated Tablets

100 Tablets

For oral use in cats only.

CAUTION: Federal (USA) law

restricts this drug to use by or on

the order of a licensed veterinarian.

NADA 141-292, Approved by FDA.

PRINCIPAL DISPLAY PANEL - 2.5 mg carton label

2.5 mg

Felimazole™

(methimazole)

Coated Tablets

100 Tablets

Felimazole (methimazole) Coated Tablets

are indicated for the treatment of

hyperthyroidism in cats.

CAUTION: Federal (USA) law restricts this drug

to use by or on the order of a licensed

veterinarian.

NADA 141-292, Approved by FDA.

NDC 17033-225-10

Dechra

PRINCIPAL DISPLAY PANEL - 5mg bottle label

5 mg

Felimazole™

(methimazole) Coated Tablets

100 Tablets

For oral use in cats only.

CAUTION: Federal (USA) law

restricts this drug to use by or on

the order of a licensed veterinarian.

NADA 141-292, Approved by FDA.

PRINCIPAL DISPLAY PANEL - 5 mg carton label

5 mg

Felimazole™

(methimazole)

Coated Tablets

100 Tablets

Felimazole (methimazole) Coated Tablets

are indicated for the treatment of

hyperthyroidism in cats.

CAUTION: Federal (USA) law restricts this drug

to use by or on the order of a licensed

veterinarian.

NADA 141-292, Approved by FDA.

NDC 17033-250-10

Dechra

Felimazole  methimazole  tablet, sugar coated

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 17033-225 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength methimazole (methimazole) methimazole 2.5 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color PINK Score no score Shape ROUND Size 6mm Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 17033-225-10 1 BOTTLE In 1 CARTON contains a BOTTLE 1 100 TABLET In 1 BOTTLE This package is contained within the CARTON (17033-225-10)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141292	06/15/2009

Felimazole  methimazole  tablet, sugar coated

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 17033-250 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength methimazole (methimazole) methimazole 5 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color ORANGE Score no score Shape ROUND Size 6mm Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 17033-250-10 1 BOTTLE In 1 CARTON contains a BOTTLE 1 100 TABLET In 1 BOTTLE This package is contained within the CARTON (17033-250-10)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141292	06/15/2009

Labeler - Dechra Veterinary Products (362142734)

Establishment
Name	Address	ID/FEI	Operations
Cipla Limited Goa		650072015	MANUFACTURE

Revised: 03/2010Dechra Veterinary Products

More Felimazole resources

• Felimazole Side Effects (in more detail)
• Felimazole Use in Pregnancy & Breastfeeding
• Drug Images
• Felimazole Drug Interactions
• Felimazole Support Group
• 0 Reviews for Felimazole - Add your own review/rating

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• Hyperthyroidism

Maalox Concentrate

Pronunciation: a-LOO-min-uhm/mag-NEE-zee-uhm
Generic Name: Aluminum/Magnesium
Brand Name: Examples include Alamag and Maalox

Maalox Concentrate is used for:

Treating acid indigestion, heartburn, and sour stomach. It may also be used for other conditions as determined by your doctor.

Maalox Concentrate is an antacid. It works by neutralizing acid in the stomach.

Do NOT use Maalox Concentrate if:

• you are allergic to any ingredient in Maalox Concentrate


• you are also taking citrate salts (found in some calcium supplements, antacids, and laxatives)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Maalox Concentrate:

Some medical conditions may interact with Maalox Concentrate. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have Alzheimer disease, appendicitis, diarrhea, a stomach blockage, kidney problems, or an ileostomy


• if you have recently had stomach bleeding

Some MEDICINES MAY INTERACT with Maalox Concentrate. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Cation exchange resins (eg, sodium polystyrene sulfonate) and citrate salts (found in some calcium supplements, antacids, and laxatives) because they may increase the actions and the risk of Maalox Concentrate's side effects


• Anticoagulants (eg, warfarin), quinidine, or sulfonylureas (eg, glyburide) because their actions and the risk of their side effects may be increased


• Angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril), beta-blockers (eg, propranolol), bisphosphonates (eg, risedronate), cephalosporins (eg, cephalexin), corticosteroids (eg, hydrocortisone), cyclosporine, delavirdine, digoxin, imidazoles (eg, ketoconazole), mycophenolate, penicillamine, quinolones (eg, ciprofloxacin), tetracyclines (eg, doxycycline), or thyroid hormones (eg, levothyroxine) because their effectiveness may be decreased by Maalox Concentrate, especially when taken at the same time as Maalox Concentrate

This may not be a complete list of all interactions that may occur. Ask your health care provider if Maalox Concentrate may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Maalox Concentrate:

Use Maalox Concentrate as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Maalox Concentrate by mouth with or without food.


• Shake well before each use.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


• Do not use Maalox Concentrate within 2 hours before or after taking a beta-blocker (eg, propranolol), bisphosphonate (eg, risedronate), cephalosporin (eg, cephalexin), corticosteroid (eg, hydrocortisone), delavirdine, digoxin, imidazole (eg, ketoconazole), penicillamine, or sulfonylurea (eg, glyburide) because their effectiveness may be decreased by Maalox Concentrate.


• If you miss a dose of Maalox Concentrate and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Maalox Concentrate.

Important safety information:

• Do NOT take more than the recommended dose or take the maximum dose for longer than 2 weeks without checking with your doctor.


• If your symptoms do not get better within 2 weeks or if they get worse, or if you experience black, tarry stools or vomit that looks like coffee grounds, check with your doctor.


• Maalox Concentrate has aluminum and magnesium in it. Before you begin taking any new prescription or over-the-counter medicine, read the ingredients to see has aluminum or magnesium in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Maalox Concentrate while you are pregnant. If you are or will be breast-feeding while you use Maalox Concentrate, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Maalox Concentrate:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); loss of appetite; muscle weakness; nausea; slow reflexes; vomiting.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Maalox Concentrate:

Store Maalox Concentrate between 59 and 86 degrees F (15 and 30 degrees C). Store in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Maalox Concentrate out of the reach of children and away from pets.

General information:

• If you have any questions about Maalox Concentrate, please talk with your doctor, pharmacist, or other health care provider.


• Maalox Concentrate is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Maalox Concentrate. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Maalox resources

• Maalox Use in Pregnancy & Breastfeeding
• Maalox Drug Interactions
• Maalox Support Group
• 0 Reviews for Maalox - Add your own review/rating

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• Duodenal Ulcer
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• Stress Ulcer Prophylaxis
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