Colestipol

Dosage Form: tablet
Micronized Colestipol Hydrochloride Tablets

Colestipol Description

The active ingredient in micronized Colestipol hydrochloride tablets is micronized Colestipol hydrochloride, which is a lipid lowering agent for oral use. Colestipol is an insoluble, high molecular weight basic anion-exchange copolymer of diethylenetriamine and 1-chloro-2, 3-epoxypropane, with approximately 1 out of 5 amine nitrogens protonated (chloride form). It is a light yellow water-insoluble resin which is hygroscopic and swells when suspended in water or aqueous fluids.

Each micronized Colestipol hydrochloride tablet contains one gram of micronized Colestipol hydrochloride. Micronized Colestipol hydrochloride tablets are light yellow in color and are tasteless and odorless. Inactive ingredients: cellulose acetate phthalate, glyceryl triacetate, carnauba wax, hypromellose, magnesium stearate, povidone, silicon dioxide. Micronized Colestipol hydrochloride tablets contain no calories.

Colestipol - Clinical Pharmacology

Cholesterol is the major, and probably the sole precursor of bile acids. During normal digestion, bile acids are secreted via the bile from the liver and gall bladder into the intestines. Bile acids emulsify the fat and lipid materials present in food, thus facilitating absorption. A major portion of the bile acids secreted is reabsorbed from the intestines and returned via the portal circulation to the liver, thus completing the enterohepatic cycle. Only very small amounts of bile acids are found in normal serum.

Colestipol hydrochloride binds bile acids in the intestine forming a complex that is excreted in the feces. This nonsystemic action results in a partial removal of the bile acids from the enterohepatic circulation, preventing their reabsorption. Since Colestipol hydrochloride is an anion exchange resin, the chloride anions of the resin can be replaced by other anions, usually those with a greater affinity for the resin than the chloride ion.

Colestipol hydrochloride is hydrophilic, but it is virtually water insoluble (99.75%) and it is not hydrolyzed by digestive enzymes. The high molecular weight polymer in Colestipol hydrochloride apparently is not absorbed. In humans, less than 0.17% of a single 14C-labeled Colestipol hydrochloride dose is excreted in the urine when given following 60 days of dosing of 20 grams of Colestipol hydrochloride per day.

The increased fecal loss of bile acids due to Colestipol hydrochloride administration leads to an increased oxidation of cholesterol to bile acids. This results in an increase in the number of low-density lipoprotein (LDL) receptors, increased hepatic uptake of LDL and a decrease in beta lipoprotein or LDL serum levels, and a decrease in serum cholesterol levels. Although Colestipol hydrochloride produces an increase in the hepatic synthesis of cholesterol in man, serum cholesterol levels fall.

There is evidence to show that this fall in cholesterol is secondary to an increased rate of clearance of cholesterol-rich lipoproteins (beta or low-density lipoproteins) from the plasma. Serum triglyceride levels may increase or remain unchanged in Colestipol hydrochloride treated patients.

The decline in serum cholesterol levels with Colestipol hydrochloride treatment is usually evident by one month. When Colestipol hydrochloride is discontinued, serum cholesterol levels usually return to baseline levels within one month. Periodic determinations of serum cholesterol levels as outlined in the National Cholesterol Education Program (NCEP) guidelines, should be done to confirm a favorable initial and long-term response.1

In a large, placebo-controlled, multiclinic study, the LRC-CPPT2, hypercholesterolemic subjects treated with cholestyramine, a bile-acid sequestrant with a mechanism of action and an effect on serum cholesterol similar to that of Colestipol hydrochloride, had reductions in total and LDL-C. Over the 7-year study period the cholestyramine group experienced a 19% reduction (relative to the incidence in the placebo group) in the combined rate of coronary heart disease (CHD) death plus nonfatal myocardial infarction (cumulative incidences of 7% cholestyramine and 8.6% placebo). The subjects included in the study were middle-aged men (aged 35–59) with serum cholesterol levels above 265 mg/dL, LDL-C above 175 mg/dL on a moderate cholesterol-lowering diet, and no history of heart disease. It is not clear to what extent these findings can be extrapolated to other segments of the hypercholesterolemic population not studied.

Treatment with Colestipol results in a significant increase in lipoprotein LpAI. Lipoprotein LpAI is one of the two major lipoprotein particles within the high-density lipoprotein (HDL) density range3, and has been shown in cell culture to promote cholesterol efflux or removal from cells4. Although the significance of this finding has not been established in clinical studies, the elevation of the lipoprotein LpAI particle within the HDL fraction is consistent with an antiatherogenic effect of Colestipol hydrochloride, even though little change is observed in HDL cholesterol (HDL-C).

In patients with heterozygous familial hypercholesterolemia who have not obtained an optimal response to Colestipol hydrochloride alone in maximal doses, the combination of Colestipol hydrochloride and nicotinic acid has been shown to further lower serum cholesterol, triglyceride, and LDL-cholesterol (LDL-C) values. Simultaneously, HDL-C values increased significantly. In many such patients it is possible to normalize serum lipid values.5–7

Preliminary evidence suggests that the cholesterol-lowering effects of lovastatin and the bile acid sequestrant, Colestipol hydrochloride, are additive.

The effect of intensive lipid-lowering therapy on coronary atherosclerosis has been assessed by arteriography in hyperlipidemic patients. In these randomized, controlled clinical trials, patients were treated for two to four years by either conventional measures (diet, placebo, or in some cases low-dose resin), or with intensive combination therapy using diet and Colestipol hydrochloride granules plus either nicotinic acid or lovastatin. When compared to conventional measures, intensive lipid-lowering combination therapy significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions in patients with or at risk for coronary artery disease.8–11

Indications and Usage for Colestipol

Since no drug is innocuous, strict attention should be paid to the indications and contraindications, particularly when selecting drugs for chronic long-term use.

Micronized Colestipol hydrochloride tablets are indicated as adjunctive therapy to diet for the reduction of elevated serum total and LDL-C in patients with primary hypercholesterolemia (elevated LDL-C) who do not respond adequately to diet. Generally, micronized Colestipol hydrochloride tablets have no clinically significant effect on serum triglycerides, but with their use, triglyceride levels may be raised in some patients.

Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Treatment should begin and continue with dietary therapy (see NCEP guidelines). A minimum of six months of intensive dietary therapy and counseling should be carried out prior to initiation of drug therapy. Shorter periods may be considered in patients with severe elevations of LDL-C or with definite CHD.

According to the NCEP guidelines, the goal of treatment is to lower LDL-C, and LDL-C is to be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy. The NCEP treatment guidelines are shown below.

		LDL-Cholesterol mg/dL (mmol/L)
Definite Atherosclerotic Disease*	Two or More Other Risk Factors†	Initiation Level	Goal
* Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease). † Other risk factors for coronary heart disease (CHD) include: age (males: ≥45 years; female: ≥55 years or premature menopause without estrogen replacement therapy); family history of premature CHD; current cigarette smoking; hypertension; confirmed HDL-C <35 mg/dL (0.91 mmol/L); and diabetes mellitus. Subtract one risk factor if HDL-C is ≥60 mg/dL (1.6 mmol/L).
No	No	≥190 (≥4.9)	<160 (<4.1)
No	Yes	≥160 (≥4.1)	<130 (<3.4)
Yes	Yes or No	≥130 (≥3.4)	≤100 (≤2.6)

Contraindications

Micronized Colestipol hydrochloride tablets are contraindicated in those individuals who have shown hypersensitivity to any of their components.

Precautions

Prior to initiating therapy with micronized Colestipol hydrochloride tablets, secondary causes of hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism), should be excluded, and a lipid profile performed to assess total cholesterol, HDL-C, and triglycerides (TG). For individuals with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:

LDL-C = Total cholesterol − [(Triglycerides/5) + HDL-C]

For TG levels >400 mg/dL, this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases micronized Colestipol hydrochloride tablets may not be indicated.

Because it sequesters bile acids, Colestipol hydrochloride may interfere with normal fat absorption and, thus, may reduce absorption of folic acid and fat soluble vitamins such as A, D, and K.

Chronic use of Colestipol hydrochloride may be associated with an increased bleeding tendency due to hypoprothrombinemia from vitamin K deficiency. This will usually respond promptly to parenteral vitamin K1 and recurrences can be prevented by oral administration of vitamin K1.

Serum cholesterol and triglyceride levels should be determined periodically based on NCEP guidelines to confirm a favorable initial and adequate long-term response.

Micronized Colestipol hydrochloride tablets may produce or severely worsen pre-existing constipation. The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction. In patients with pre-existing constipation, the starting dose should be 2 grams once or twice a day. Increased fluid and fiber intake should be encouraged to alleviate constipation and a stool softener may occasionally be indicated. If the initial dose is well tolerated, the dose may be increased as needed by a further 2 to 4 grams/day (at monthly intervals) with periodic monitoring of serum lipoproteins. If constipation worsens or the desired therapeutic response is not achieved at 2 to 16 grams/day, combination therapy or alternate therapy should be considered. Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease. Constipation associated with micronized Colestipol hydrochloride tablets may aggravate hemorrhoids.

While there have been no reports of hypothyroidism induced in individuals with normal thyroid function, the theoretical possibility exists, particularly in patients with limited thyroid reserve.

Since Colestipol hydrochloride is a chloride form of an anion exchange resin, there is a possibility that prolonged use may lead to the development of hyperchloremia acidosis.

Carcinogenesis, Mutagenesis and Impairment of Fertility

In studies conducted in rats in which cholestyramine resin (a bile acid sequestering agent similar to Colestipol hydrochloride) was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts, and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin treated rats than in control rats.

The relevance of this laboratory observation from studies in rats with cholestyramine resin to the clinical use of Colestipol hydrochloride is not known. In the LRC-CPPT study referred to above, the total incidence of fatal and nonfatal neoplasms was similar in both treatment groups. When the many different categories of tumors are examined, various alimentary system cancers were somewhat more prevalent in the cholestyramine group. The small numbers and the multiple categories prevent conclusions from being drawn. Further follow-up of the LRC-CPPT participants by the sponsors of that study is planned for cause-specific mortality and cancer morbidity. When Colestipol hydrochloride was administered in the diet to rats for 18 months, there was no evidence of any drug related intestinal tumor formation. In the Ames assay, Colestipol hydrochloride was not mutagenic.

Use in Pregnancy

Since Colestipol hydrochloride is essentially not absorbed systemically (less than 0.17% of the dose), it is not expected to cause fetal harm when administered during pregnancy in recommended dosages. There are no adequate and well-controlled studies in pregnant women, and the known interference with absorption of fat-soluble vitamins may be detrimental even in the presence of supplementation.

Nursing Mothers

Caution should be exercised when micronized Colestipol hydrochloride tablets are administered to a nursing mother. The possible lack of proper vitamin absorption described in the "Pregnancy" section may have an effect on nursing infants.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Information for Patients

Micronized Colestipol hydrochloride tablets may be larger than pills you have taken before. If you have had swallowing problems or choking with food, liquids or other tablets or capsules in the past, you should discuss this with your doctor before taking micronized Colestipol hydrochloride tablets.

It is important that you take micronized Colestipol hydrochloride tablets correctly:

1. Always take one tablet at a time and swallow promptly.


2. Swallow each tablet whole. Do not cut, crush, or chew the tablets.


3. Micronized Colestipol hydrochloride tablets must be taken with water or another liquid that you prefer. Swallowing the tablets will be easier if you drink plenty of liquid as you swallow each tablet.

Difficulty swallowing and temporary obstruction of the esophagus (the tube between your mouth and stomach) have been rarely reported in patients taking micronized Colestipol hydrochloride tablets. If a tablet does get stuck after you swallow it, you may notice pressure or discomfort. If this happens to you, you should contact your doctor. Do not take micronized Colestipol hydrochloride tablets again without your doctor's advice.

If you are taking other medications, you should take them at least one hour before or four hours after taking micronized Colestipol hydrochloride tablets.

DRUG INTERACTIONS

Since Colestipol hydrochloride is an anion exchange resin, it may have a strong affinity for anions other than the bile acids. In vitro studies have indicated that Colestipol hydrochloride binds a number of drugs. Therefore, micronized Colestipol hydrochloride tablets may delay or reduce the absorption of concomitant oral medication. The interval between the administration of micronized Colestipol hydrochloride tablets and any other medication should be as long as possible. Patients should take other drugs at least one hour before or four hours after micronized Colestipol hydrochloride tablets to avoid impeding their absorption.

Repeated doses of Colestipol hydrochloride given prior to a single dose of propranolol in human trials have been reported to decrease propranolol absorption. However, in a follow-up study in normal subjects, single-dose administration of Colestipol hydrochloride and propranolol and twice-a-day administration for 5 days of both agents did not affect the extent of propranolol absorption, but had a small yet statistically significant effect on its rate of absorption; the time to reach maximum concentration was delayed approximately 30 minutes. Effects on the absorption of other beta-blockers have not been determined. Therefore, patients on propranolol should be observed when micronized Colestipol hydrochloride tablets are either added or deleted from a therapeutic regimen.

Studies in humans show that the absorption of chlorothiazide as reflected in urinary excretion is markedly decreased even when administered one hour before Colestipol hydrochloride. The absorption of tetracycline, furosemide, penicillin G, hydrochlorothiazide, and gemfibrozil was significantly decreased when given simultaneously with Colestipol hydrochloride; these drugs were not tested to determine the effect of administration one hour before Colestipol hydrochloride.

No depressant effect on blood levels in humans was noted when Colestipol hydrochloride was administered with any of the following drugs: aspirin, clindamycin, clofibrate, methyldopa, nicotinic acid (niacin), tolbutamide, phenytoin or warfarin. Particular caution should be observed with digitalis preparations since there are conflicting results for the effect of Colestipol hydrochloride on the availability of digoxin and digitoxin. The potential for binding of these drugs if given concomitantly is present. Discontinuing Colestipol hydrochloride could pose a hazard to health if a potentially toxic drug that is significantly bound to the resin has been titrated to a maintenance level while the patient was taking Colestipol hydrochloride.

Bile acid binding resins may also interfere with the absorption of oral phosphate supplements and hydrocortisone.

Adverse Reactions

Gastrointestinal

The most common adverse reactions are confined to the gastrointestinal tract. To achieve minimal GI disturbance with an optimal LDL-C lowering effect, a gradual increase of dosage starting with 2 grams, once or twice daily is recommended. Constipation is the major single complaint and at times is severe. Most instances of constipation are mild, transient, and controlled with standard treatment. Increased fluid intake and inclusion of additional dietary fiber should be the first step; a stool softener may be added if needed. Some patients require decreased dosage or discontinuation of therapy. Hemorrhoids may be aggravated.

Other, less frequent gastrointestinal complaints consist of abdominal discomfort (abdominal pain and cramping), intestinal gas (bloating and flatulence), indigestion and heartburn, diarrhea and loose stools, and nausea and vomiting. Bleeding hemorrhoids and blood in the stool have been infrequently reported. Peptic ulceration, cholecystitis, and cholelithiasis have been rarely reported in patients receiving Colestipol hydrochloride granules, and are not necessarily drug related.

Difficulty swallowing and transient esophageal obstruction have been rarely reported in patients taking micronized Colestipol hydrochloride tablets.

Transient and modest elevations of aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) and alkaline phosphatase were observed on one or more occasions in various patients treated with Colestipol hydrochloride.

The following nongastrointestinal adverse reactions have been reported with generally equal frequency in patients receiving micronized Colestipol hydrochloride tablets, Colestipol granules, or placebo in clinical studies:

Cardiovascular

Chest pain, angina, and tachycardia have been infrequently reported.

Hypersensitivity

Rash has been infrequently reported. Urticaria and dermatitis have been rarely noted in patients receiving Colestipol hydrochloride granules.

Musculoskeletal

Musculoskeletal pain, aches and pains in the extremities, joint pain and arthritis, and backache have been reported.

Neurologic

Headache, migraine headache, and sinus headache have been reported. Other infrequently reported complaints include dizziness, light-headedness, and insomnia.

Miscellaneous

Anorexia, fatigue, weakness, shortness of breath, and swelling of the hands or feet, have been infrequently reported.

Overdosage

Overdosage of micronized Colestipol hydrochloride tablets has not been reported. Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.

Colestipol Dosage and Administration

For adults, micronized Colestipol hydrochloride tablets are recommended in doses of 2 to 16 grams/day given once or in divided doses. The starting dose should be 2 grams once or twice daily. Dosage increases of 2 grams, once or twice daily should occur at 1- or 2-month intervals. Appropriate use of lipid profiles as per NCEP guidelines including LDL-C and triglycerides, is advised so that optimal but not excessive doses are used to obtain the desired therapeutic effect on LDL-C level. If the desired therapeutic effect is not obtained at a dose of 2 to 16 grams/day with good compliance and acceptable side effects, combined therapy or alternate treatment should be considered.

Micronized Colestipol hydrochloride tablets must be taken one at a time and be promptly swallowed whole, using plenty of water or other appropriate liquid. Do not cut, crush, or chew the tablets. Patients should take other drugs at least one hour before or four hours after micronized Colestipol hydrochloride tablets to minimize possible interference with their absorption. (See DRUG INTERACTIONS.)

Before Administration of Micronized Colestipol Hydrochloride Tablets

1. Define the type of hyperlipoproteinemia, as described in NCEP guidelines.


2. Institute a trial of diet and weight reduction.


3. Establish baseline serum total and LDL-C and triglyceride levels.

During Administration of Micronized Colestipol Hydrochloride Tablets

1. The patient should be carefully monitored clinically, including serum cholesterol and triglyceride levels. Periodic determinations of serum cholesterol levels as outlined in the NCEP guidelines should be done to confirm a favorable initial and long-term response.


2. Failure of total or LDL-C to fall within the desired range should lead one to first examine dietary and drug compliance. If these are deemed acceptable, combined therapy or alternate treatment should be considered.


3. Significant rise in triglyceride level should be considered as indication for dose reduction, drug discontinuation, or combined or alternate therapy.

How is Colestipol Supplied

Micronized Colestipol hydrochloride tablets are yellow, elliptical, imprinted with a "G" on one side and "450" on the other side, and are supplied as follows:

Bottles of 120       NDC 59762-0450-1

Each tablet contains 1 gram of Colestipol hydrochloride.

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

REFERENCES

1. Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993; 269(23):3015–3023.


2. Lipid Metabolism-Atherogenesis Branch, National Heart, Lung, and Blood Institute, Bethesda, MD: The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in Incidence of Coronary Heart Disease. JAMA 1984; 251:351–364.


3. Parra HJ, et al. Differential electroimmunoassay of human LpA-I lipoprotein particles on ready-to-use plates. Clin. Chem. 1990; 36(8):1431–1435.


4. Barbaras R, et al. Cholesterol efflux from cultured adipose cells is mediated by LpAI particles but not by LpAI:AII particles. Biochem. Biophys. Res. Comm. 1987; 142(1):63–69.


5. Kane JP, et al. Normalization of low-density-lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen. N Engl. J. Med. 1981; 304:251–258.


6. Illingworth DR, et al. Colestipol plus nicotinic acid in treatment of heterozygous familial hypercholesterolemia. Lancet 1981; 1:296–298.


7. Kuo PT, et al. Familial type II hyperlipoproteinemia with coronary heart disease: Effect of diet-Colestipol-nicotinic acid treatment. Chest 1981; 79:286–291.


8. Blankenhorn DH, et al. Beneficial Effects of Combined Colestipol-Niacin Therapy on Coronary Atherosclerosis and Coronary Venous Bypass Grafts. JAMA 1987; 257(23):3233–3240.


9. Cashin-Hemphill L, et al. Beneficial Effects of Colestipol-Niacin on Coronary Atherosclerosis: A 4-Year Follow-up. JAMA 1990; 264:3013–3017.


10. Brown G. et al. Regression of Coronary Artery Disease as a Result of Intensive Lipid-Lowering Therapy in Men with High Levels of Apolipoprotein B. N. Engl. J. Med. 1990; 323:1289–1298.


11. Kane JP, et al. Regression of Coronary Atherosclerosis During Treatment of Familial Hypercholesterolemia with Combined Drug Regimens. JAMA 1990; 264:3007–3012.

Rx only

LAB-0359-2.0

May 2008

PRINCIPAL DISPLAY PANEL - 1 Gram Tablets

NDC 59762-0450-1

120 Tablets

GREENSTONE® BRAND

micronized Colestipol

hydrochloride

tablets

1 g

Rx only

Colestipol HYDROCHLORIDE  Colestipol hydrochloride  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 59762-0450 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Colestipol Hydrochloride (Colestipol) Colestipol Hydrochloride 1 g

Inactive Ingredients Ingredient Name Strength triacetin   carnauba wax   hypromellose   magnesium stearate   povidone   silicon dioxide

Product Characteristics Color YELLOW Score no score Shape OVAL (elliptical) Size 19mm Flavor Imprint Code G;450 Contains

Packaging # NDC Package Description Multilevel Packaging 1 59762-0450-1 120 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA authorized generic	NDA020222	07/19/1994

Labeler - Greenstone LLC (825560733)

Establishment
Name	Address	ID/FEI	Operations
Pharmacia and Upjohn Company		829076566	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Catalent Pharma Solutions, LLC		829672745	MANUFACTURE

Revised: 12/2009Greenstone LLC

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• colestipol Advanced Consumer (Micromedex) - Includes Dosage Information


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Compare Colestipol with other medications

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Tegretol

Generic Name: carbamazepine

Dosage Form: chewable tablets, tablets, extended release tablets and oral suspension
Tegretol

Tegretol®

carbamazepine USP

Chewable Tablets of 100 mg - red-speckled, pink

Tablets of 200 mg – pink

Suspension of 100 mg/5 mL

Tegretol®-XR

(carbamazepine extended-release tablets)

100 mg, 200 mg, 400 mg

Rx only

Prescribing Information

WARNINGS

SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE

SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH Tegretol. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH Tegretol. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH Tegretol UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS).

APLASTIC ANEMIA AND AGRANULOCYTOSIS

APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF Tegretol. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.

ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF Tegretol, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.

BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON Tegretol ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.

Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential.

DESCRIPTION

Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and its structural formula is

Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27.

Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).

CLINICAL PHARMACOLOGY

In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Mechanism of Action

Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.

The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been established.

Pharmacokinetics

In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.

The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).

The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.

INDICATIONS AND USAGE

Epilepsy

Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:

1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types.
   


2. Generalized tonic-clonic seizures (grand mal).
   


3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).

Trigeminal Neuralgia

Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.

Beneficial results have also been reported in glossopharyngeal neuralgia.

This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.

CONTRAINDICATIONS

Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated.

WARNINGS

Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

SJS/TEN and HLA-B*1502 Allele

Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.

Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of the population in Japan and Korea.

HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).

Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS, Laboratory Tests).

Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on Tegretol.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).

Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable.

Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Aplastic Anemia and Agranulocytosis

Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication	Placebo Patients with Events Per 1,000 Patients	Drug Patients with Events Per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1,000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

General

Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy.

Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased seizure frequency.

Usage in Pregnancy

Carbamazepine can cause fetal harm when administered to a pregnant woman.

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. In treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. 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 to the fetus.

Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.

In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.

Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.

Antiepileptic drugs should not be discontinued abruptly 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 individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may represent a neonatal withdrawal syndrome.

To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

PRECAUTIONS

General

Before initiating therapy, a detailed history and physical examination should be made.

Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE).

Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol.

AV heart block, including second and third degree block, have been reported following Tegretol treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances.

Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug.

Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients).

Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.

Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If positive, caution should be used in prescribing carbamazepine.

In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal®).

Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).

Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance.

Information for Patients

Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking Tegretol.

Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use.

Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers

Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the event a skin reaction should occur while taking Tegretol, patients should consult with their physician immediately (see WARNINGS).

Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription medications or herbal products.

Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive sedative effect.

Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks.

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).

Laboratory Tests

For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.

Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.

Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.

Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes.

Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction.

Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used.

Thyroid function tests have been reported to show decreased values with Tegretol administered alone.

Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other drugs.

Interference with some pregnancy tests has been reported.

Drug Interactions

There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

Agents That May Affect Tegretol Plasma Levels

CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include:


      cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,

      fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine,

      omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene,

      azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil,

      ticlopidine, grapefruit juice, protease inhibitors, valproate*.

CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include:


      cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,

      methsuximide, theophylline, aminophylline.

When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

*increased levels of the active 10,11-epoxide

†decreased levels of carbamazepine and increased levels of the 10,11-epoxide

Effect of Tegretol on Plasma Levels of Concomitant Agents

Increased levels: clomipramine HCl, phenytoin, primidone

Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of co-medications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be expected to cause, decreased levels of the following:

      acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine),

      citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,

      dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine,

      levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal

      contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors,

      risperidone, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g.,

      imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.

In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.

Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS).

Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.

Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.

Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium).

Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.

Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.

Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.

Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.

Usage in Pregnancy

Pregnancy Category D (see WARNINGS).

Labor and Delivery

The effect of Tegretol on human labor and delivery is unknown.

Nursing Mothers

Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the epoxide.

Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.

Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.

The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available.

Geriatric Use

No systematic studies in geriatric patients have been conducted.

ADVERSE REACTIONS

If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards.

The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED WARNING), the liver, and the cardiovascular system.

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the low dosage recommended.

The following additional adverse reactions have been reported:

Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda.

Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.

Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.

Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure.

Pancreatic: Pancreatitis.

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.

Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.

Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome.

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.

Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs.

Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.

Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes.

Musculoskeletal System: Aching joints and muscles, and leg cramps.

Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium leading to osteoporosis have been reported.

Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and abnormal liver function tests. These signs and symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and PRECAUTIONS, Information for Patients).

Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

DRUG ABUSE AND DEPENDENCE

No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or physical dependence in humans.

OVERDOSAGE

Acute Toxicity

Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).

Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.

Signs and Symptoms

The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (>60 g) have been ingested.

Respiration: Irregular breathing, respiratory depression.

Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.

Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.

Gastrointestinal Tract: Nausea, vomiting.

Kidneys and Bladder: Anuria or oliguria, urinary retention.

Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias.

Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.

Treatment

The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.

Elimination of the Drug: Induction of vomiting.

Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol.

Measures to Reduce Absorption: Activated charcoal, laxatives.

Measures to Accelerate Elimination: Forced diuresis.

Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children.

Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen.

Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.

Convulsions: Diazepam or barbiturates.

Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).

Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days.

Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery.

Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels.

Metamucil Plus Calcium

Pronunciation: SILL-i-um/KAL-see-uhm
Generic Name: Psyllium/Calcium
Brand Name: Metamucil Plus Calcium

Metamucil Plus Calcium is used for:

Treating occasional constipation and restoring regularity. It may also be used for other conditions as determined by your doctor.

Metamucil Plus Calcium is a fiber laxative. It works by absorbing water and swelling in the intestines. This helps the stool form the bulk necessary to be easily passed.

Do NOT use Metamucil Plus Calcium if:

• you are allergic to any ingredient in Metamucil Plus Calcium


• you have appendicitis, difficulty swallowing, severe constipation, intestinal blockage, undiagnosed rectal bleeding, or high levels of calcium in your blood

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

Before using Metamucil Plus Calcium:

Some medical conditions may interact with Metamucil Plus Calcium. 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 a sudden change in bowel habits persisting for more than 2 weeks


• if you have stomach or intestinal pain, nausea, vomiting


• if you have kidney problems, kidney stones, sarcoidosis, high levels of calcium in your urine, or if you are dehydrated

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

• Thyroid hormones (eg, levothyroxine) because effectiveness may be decreased by Metamucil Plus Calcium

This may not be a complete list of all interactions that may occur. Ask your health care provider if Metamucil Plus Calcium 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 Metamucil Plus Calcium:

Use Metamucil Plus Calcium as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Metamucil Plus Calcium may be taken with or without food.


• If your dose consists of more than 1 capsule, be sure to swallow only 1 capsule at a time.


• Take Metamucil Plus Calcium with a full glass of water (8 oz/240 mL).


• Do not take other oral medicines within 2 hours before or 2 hours after taking Metamucil Plus Calcium.


• If you miss a dose of Metamucil Plus Calcium, 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 Metamucil Plus Calcium.

Important safety information:

• If your symptoms do not improve within 7 days or if they become worse, check with your doctor.


• Do not take additional laxatives or stool softeners with Metamucil Plus Calcium unless directed by your doctor.


• Do not use Metamucil Plus Calcium if you experience stomach pain, nausea, vomiting, or rectal bleeding, except under the direction of your doctor.


• If you notice a sudden change in bowel habits that lasts for 2 weeks or more, do not continue using Metamucil Plus Calcium. Instead, check with your doctor.


• Taking this product without enough liquid may cause it to swell and block your throat or esophagus and may cause choking. Do not take this product if you have difficulty swallowing. If you experience chest pain, vomiting, or difficulty swallowing or breathing after taking this product, seek immediate medical attention.


• Use of Metamucil Plus Calcium is not recommended in CHILDREN younger than 12 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Metamucil Plus Calcium, discuss with your doctor the benefits and risks of using Metamucil Plus Calcium during pregnancy. It is unknown if Metamucil Plus Calcium is excreted in breast milk. If you are or will be breast-feeding while you are using Metamucil Plus Calcium, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Metamucil Plus Calcium:

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:

Abdominal fullness; minor bloating.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; difficulty swallowing; trouble breathing; 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.

See also: Metamucil Plus Calcium side effects (in more detail)

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 Metamucil Plus Calcium:

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

General information:

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


• Metamucil Plus Calcium 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 Metamucil Plus Calcium. 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 Metamucil Plus Calcium resources

• Metamucil Plus Calcium Side Effects (in more detail)
• Metamucil Plus Calcium Support Group
• 0 Reviews for Metamucil Plus Calcium - Add your own review/rating

Compare Metamucil Plus Calcium with other medications

• Constipation
• Dietary Supplementation

Solarcaine Cool Aloe Topical

Generic Name: lidocaine and prilocaine (Gingival route)

LYE-doe-kane, PRIL-oh-kane

Commonly used brand name(s)

In the U.S.

• Oraqix

Available Dosage Forms:

• Gel/Jelly

Therapeutic Class: Anesthetic, Amino Amide Combination

Chemical Class: Amino Amide

Uses For Solarcaine Cool Aloe

Lidocaine and prilocaine periodontal (gingival) gel is used on the gums to cause numbness or loss of feeling during dental procedures. This medicine contains a mixture of two topical local anesthetics (numbing medicines). It deadens the nerve endings in the gum.

This medicine is available only with your dentist's prescription.

Before Using Solarcaine Cool Aloe

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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

Appropriate studies have not been performed on the relationship of age to the effects of lidocaine and prilocaine periodontal gel in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of lidocaine and prilocaine periodontal gel in the elderly. However, elderly patients are more likely to have age-related kidney or liver problems, which may require caution and an adjustment in the dose for patients receiving lidocaine and prilocaine periodontal gel.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

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.

Other Medical Problems

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

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency, history of or


• Heart disease or


• Heart rhythm problems—May cause side effects to become worse.

• Methemoglobinemia (blood disorder), history of—Should not use in patients with this condition.

• Liver disease, severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Proper Use of lidocaine

This section provides information on the proper use of a number of products that contain lidocaine. It may not be specific to Solarcaine Cool Aloe. Please read with care.

A dentist or other trained health professional will give you this medicine in an office or clinic setting. The medicine is applied to the gums using a special dispenser.

Precautions While Using Solarcaine Cool Aloe

It is very important that your dentist check you closely for any problems or unwanted effects that may be caused by this medicine.

This medicine may cause serious types of allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your dentist right away if you have a rash; itching; hoarseness; trouble with breathing; trouble with swallowing; or any swelling of your hands, face, or mouth after you receive the medicine.

This medicine may cause a rare, but serious blood problem called methemoglobinemia. Call your dentist right away if you develop a blue or bluish purple color on the lips, fingernails, or skin, or have headaches, dizziness, fainting, sleepiness, or trouble with breathing after you receive this medicine.

During the time that the gum feels numb, serious injury can occur. Be especially careful to avoid injury until the numbness wears off and you have normal feeling in the area. Avoid foods or liquids that are very hot or very cold. Do not chew gum or food while your mouth feels numb. You may accidentally bite your tongue or the inside of your cheeks.

Solarcaine Cool Aloe Side Effects

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 or nurse immediately if any of the following side effects occur:

More common

• Gum numbness that continues


• gum swelling or irritation


• nausea

Rare

• Itching


• hoarseness or trouble with swallowing


• rash


• shortness of breath


• swelling of the eyelids, face, lips, or tongue


• tightness in the chest


• trouble with breathing


• wheezing

Incidence not known

• Blue or blue-purple color of lips, fingernails, mouth, or skin


• blurred or double vision


• convulsions


• dark urine


• dizziness or drowsiness


• fainting


• feeling hot, cold, or numb


• headache


• irregular or fast heartbeat


• muscle twitching or trembling


• nausea or vomiting


• ringing or buzzing in the ears


• shortness of breath or troubled breathing


• unusual excitement, nervousness, or restlessness


• unusual tiredness or weakness

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:

More common

• Bad or bitter taste


• headache


• mouth pain or soreness


• mouth ulcers


• tiredness

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.

See also: Solarcaine Cool Aloe Topical side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Solarcaine Cool Aloe Topical resources

• Solarcaine Cool Aloe Topical Side Effects (in more detail)
• Solarcaine Cool Aloe Topical Use in Pregnancy & Breastfeeding
• Solarcaine Cool Aloe Topical Support Group
• 2 Reviews for Solarcaine Cool Aloe Topical - Add your own review/rating

Compare Solarcaine Cool Aloe Topical with other medications

• Anesthesia

Lamisil Tablets 250mg

LAMISIL Tablets 250 mg

(terbinafine)

Patient Information Leaflet

What you need to know about Lamisil Tablets

Your doctor has decided that you need this medicine to help treat your condition.

Please read this leaflet carefully before you start to take your medicine. It contains important information. Keep the leaflet in a safe place because you may want to read it again.

If you have any other questions, or if there is something you don’t understand, please ask your doctor or pharmacist.

This medicine has been prescribed for you. Never give it to someone else. It may not be the right medicine for them even if their symptoms seem to be the same as yours.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What Lamisil Tablets are, and what they are used for


• 2. Things to consider before you start to take Lamisil Tablets


• 3. How to take Lamisil Tablets


• 4. Possible side effects


• 5. How to store Lamisil Tablets


• 6. Further information

What Lamisil Tablets are and what they are used for

Terbinafine, the active ingredient in Lamisil Tablets, is an antifungal medicine.

Lamisil Tablets are used to treat a number of fungal infections of the skin and nails.

Things to consider before you start to take Lamisil Tablets

Some people MUST NOT take Lamisil Tablets. Talk to your doctor if:

• you think you may be allergic to terbinafine or to any of the other ingredients of Lamisil Tablets. (These are listed in Section 6.)


• you are breast-feeding.

You should also ask yourself these questions before taking Lamisil Tablets. If the answer to any of these questions is YES, tell your doctor or pharmacist because Lamisil Tablets might not be the right medicine for you.

• Are you pregnant or trying to become pregnant?


• Do you have any problems with your kidneys or liver?


• Do you have psoriasis?

Children should not normally be given Lamisil Tablets.

Are you taking other medicines?

Some medicines can interfere with your treatment. Tell your doctor if you are taking any of the following:

• Rifampicin for infections


• Cimetidine for gastric problems such as indigestion or ulcer


• Antidepressants including tricyclic antidepressants, SSRIs (selective serotonin reuptake inhibitors), or MAOIs (monoamine oxidase inhibitors)


• Oral contraceptives (as irregular periods and breakthrough bleeding may occur in some female patients)


• Beta-blockers or anti-arrhythmics for heart problems


• Warfarin, a medicine used to thin your blood


• Medicines to treat heart problems (eg propafenone)


• Ciclosporin, a medicine used to control your body’s immune system in order to prevent rejection of transplanted organs


• Caffeine

Always tell your doctor about all the medicines you are taking. This means medicines you have bought yourself as well as medicines on prescription from your doctor.

Will there be any problems with driving or using machinery?

Some people have reported feeling dizzy or giddy while they are taking Lamisil Tablets. If you feel like this you should not drive or operate machinery.

How to take Lamisil Tablets

The doctor will decide what dose of Lamisil Tablets you should take. Always take the tablets exactly as your doctor has told you to. The dose will be on the pharmacist’s label. Check the label carefully. It should tell you how many tablets to take, and how often. If you are not sure, ask your doctor or pharmacist. Keep taking the tablets for as long as you have been told unless you have any problems. In that case, check with your doctor.

The usual dose for adults, including the elderly, is 250 mg once a day.

• For skin infections continue taking the tablets for 2 to 6 weeks.


• For nail infections treatment usually lasts for between 6 weeks and 3 months, although some patients with toenail infections may need to be treated for 6 months or longer.


• If your kidneys are not working very well, your doctor may reduce the dose of Lamisil Tablets you take.


• Swallow the tablets whole with a glass of water.

What if you forget to take a dose?

If you miss taking a Lamisil Tablet, do not worry. Take it as soon as you remember. Take your next tablet at the usual time, then carry on as normal until you have finished all the tablets. It is important that you finish all the tablets you have been given unless your doctor tells you to stop taking them.

What if you take too many tablets?

All tablets can be risky if you take too many. If you take too many Lamisil Tablets at once, tell your doctor or hospital casualty department as soon as possible. Take your medicine pack with you so that people can see what you have taken.

Possible side effects

Lamisil Tablets are suitable for most people, but, like all medicines, they can sometimes cause side effects. Any side effects are usually mild or moderate and don’t last for too long.

Some side effects can be serious

Stop taking the tablets and tell your doctor immediately if you notice any of the following rare symptoms:

• Yellowing of your skin or eyes. Unusually dark urine or pale faeces, unexplained persistent nausea, stomach problems, loss of appetite or unusual tiredness or weakness (this may indicate liver problems)


• Severe skin reactions including rash, light sensitivity, blistering or wheals, and swelling, mainly of the face or throat.


• Weakness, unusual bleeding, bruising or frequent infections (this may be a sign of blood disorders)

The most common side effects are:-

• Headache


• Stomach problems such as loss of appetite, ache, indigestion, feeling bloated or sick


• Diarrhoea


• Itching, rash or swelling


• Pains in the muscles and joints.

The side effects listed below have also been reported.

Up to 1 in 100 people have experienced:

Taste loss and taste disturbance. This usually disappears when you stop taking the medicine. However, a very small number of people, (less than 1 in 10,000), have reported that the taste disturbance lasts for some time and, as a result, they go off their food and lose weight.

Up to 1 in 1,000 people have experienced:

• Feeling unwell, dizzy.


• Numbness or tingling.

Up to 1 in 10,000 people have experienced:

• Feeling tired.


• Decrease in the number of some blood cells. You may notice that you seem to bleed or bruise more easily than normal, or you may catch infections easily and these might be more severe than usual.


• Depression and anxiety.


• Psoriasis like skin eruptions, or worsening of any psoriasis.


• Vertigo.


• Onset or worsening of a condition called lupus (a long-term illness with symptoms including skin rash and pain in the muscles and joints).

The following have also been reported:

Psoriasis like skin eruptions, or worsening of psoriasis, severe skin reactions including a rash or eruption of small pus containing blisters. Signs of blood disorders: weakness, unusual bleeding, bruising or frequent infections.

If any of the symptoms become troublesome, or if you notice anything else not mentioned here, please go and see your doctor. He/she may want to give you a different medicine.

How to store Lamisil Tablets

Store the tablets in their original pack away from direct light. Do not store above 25ºC.

Keep all medicines out of the reach and sight of children.

Do not take the tablets after their expiry date which is printed on the outside of the pack.

If your doctor tells you to stop taking Lamisil Tablets, please take any unused tablets back to your pharmacist to be destroyed. Only keep the tablets if the doctor tells you to. Do not throw them away with your normal household water or waste. This will help to protect the environment.

Further information

Lamisil Tablets are round, whitish or very pale yellow tablets marked with a score line on one side and ‘LAMISIL 250’ on the other, and they contain 250 mg of the active ingredient terbinafine. They also contain the inactive ingredients magnesium stearate, colloidal anhydrous silica, hydroxypropylmethylcellulose, sodium carboxymethyl starch and microcrystalline cellulose.

They come in blister packs of 7, 14 or 28 tablets. Not all pack sizes are marketed.

The product licence holder is

Novartis Pharmaceuticals UK Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

England

Lamisil Tablets are made by

Novartis Pharmaceuticals UK Ltd

Wimblehurst Road

Horsham

West Sussex

RH12 5AB

England

The leaflet was revised in November 2009.

If you would like any more information, or would like the leaflet in a different format, please contact Medical Information at Novartis Pharmaceuticals UK Ltd, telephone number 01276 698370.

LAMISIL is a registered trade mark

Copyright Novartis Pharmaceuticals UK Limited

Lithostat

Generic Name: acetohydroxamic acid (a SEET oh HYE drox AM ik AS id)

Brand Names: Lithostat

What is Lithostat (acetohydroxamic acid)?

Acetohydroxamic acid works by preventing bacteria from increasing ammonia levels in urine. Increased ammonia in urine can lead to a certain type of kidney stone.

Acetohydroxamic acid is used together with antibiotics to treat bladder infections caused by bacteria that can increase ammonia levels in the urine.

Acetohydroxamic acid may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Lithostat (acetohydroxamic acid)?

This medication can cause birth defects. Do not use if you are pregnant. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Before using acetohydroxamic acid, tell your doctor if you have kidney disease, a history of blood clot or stroke, hemolytic anemia (a lack of red blood cells), or a weak immune system.

Take acetohydroxamic acid on an empty stomach, at least 1 hour before or 2 hours after a meal. Acetohydroxamic acid is usually taken 3 or 4 times daily. Follow your doctor's instructions. Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Acetohydroxamic acid is not an antibiotic and will not treat a bacterial infection alone. Take your antibiotic medication as directed. Avoid drinking alcohol. Drinking alcohol while taking this medication can cause you to have warmth, redness, or tingling under your skin. This may be an unpleasant side effect. Call your doctor at once if you have a serious side effect such as chest pain, fast or pounding heartbeats, pale or yellowed skin, dark colored urine, fever, confusion or weakness, mood changes, confusion, anxiety, tremors or shaking, easy bruising or bleeding, flu symptoms, or pain or swelling in one or both legs.

What should I discuss with my health care provider before taking Lithostat (acetohydroxamic acid)?

Before using acetohydroxamic acid, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  kidney disease;

  
  


• 
  

  a history of blood clot or stroke;

  
  


• 
  

  hemolytic anemia (a lack of red blood cells); or

  
  


• 
  

  a weak immune system.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely use acetohydroxamic acid.

FDA pregnancy category X. This medication can cause birth defects. Do not use acetohydroxamic acid if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use effective birth control while you are using this medication. Acetohydroxamic acid may pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Lithostat (acetohydroxamic acid)?

Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Take acetohydroxamic acid on an empty stomach, at least 1 hour before or 2 hours after a meal.

Acetohydroxamic acid is usually taken 3 or 4 times daily. Follow your doctor's instructions.

Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Acetohydroxamic acid is not an antibiotic and will not treat a bacterial infection alone. Take your antibiotic medication as directed.

To be sure this medication is not causing harmful effects, your blood may need to be tested on a regular basis. Do not miss any scheduled appointments.

Store acetohydroxamic acid at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

Remember to acetohydroxamic acid on an empty stomach.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include weakness, loss of appetite, nausea, vomiting, or tremors.

What should I avoid while taking Lithostat (acetohydroxamic acid)?

Avoid drinking alcohol. Drinking alcohol while taking this medication can cause you to have warmth, redness, or tingling under your skin. This may be an unpleasant side effect.

Avoid taking vitamin or mineral supplements that contain iron, unless your doctor has told you to.

Lithostat (acetohydroxamic acid) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

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  chest pain, fast or pounding heartbeats;

  
  


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  pale or yellowed skin, dark colored urine, fever, confusion or weakness;

  
  


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  mood changes, confusion, anxiety;

  
  


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  tremors or shaking;

  
  


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  easy bruising or bleeding;

  
  


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  sore throat, body aches, flu symptoms; or

  
  


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  pain or swelling in one or both legs.

  
  

Less serious side effects may include:

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  mild nausea, vomiting, upset stomach;

  
  


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  loss of appetite;

  
  


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  headache; or

  
  


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  hair loss.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Lithostat (acetohydroxamic acid)?

There may be other drugs that can interact with acetohydroxamic acid. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Lithostat resources

• Lithostat Side Effects (in more detail)
• Lithostat Use in Pregnancy & Breastfeeding
• Lithostat Drug Interactions
• Lithostat Support Group
• 1 Review for Lithostat - Add your own review/rating

• Lithostat MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Lithostat with other medications

• Bladder Infection
• Urinary Tract Infection

Where can I get more information?

• Your pharmacist can provide more information about acetohydroxamic acid.

See also: Lithostat side effects (in more detail)