Mylan Glyburide Tablets

GLYBURIDE

TABLETS, USP (micronized) 1.5 mg, 3 mg and 6 mg

Rx only

 

DESCRIPTION

Glyburide tablets, USP (micronized) contain glyburide, which is an oral blood glucose-lowering drug of the sulfonylurea class. Glyburide is a white, crystalline compound.

Each tablet, for oral administration, contains 1.5 mg, 3 mg or 6 mg of micronized glyburide, USP. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, pregelatinized starch (corn), and sodium lauryl sulfate. In addition, the 3 mg tablets contain the following ingredient: D&C Yellow No. 10 Aluminum Lake and the 6 mg tablets contain the following ingredients: D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake.
The chemical name for glyburide is 1-[[p-[2-(5-Chloro-o-anisamido) ethyl] phenyl]-sulfonyl]-3-cyclohex-ylurea and the molecular weight is 494.01.

 

CLINICAL PHARMACOLOGY

Actions

Glyburide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in type 2 diabetic patients, the blood glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The combination of glyburide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms.

Some patients who are initially responsive to oral hypoglycemic drugs, including glyburide, may become unresponsive or poorly responsive over time. Alternatively, glyburide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs.

In addition to its blood glucose-lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Disulfiram-like reactions have very rarely been reported in patients treated with glyburide.

 

Pharmacokinetics

Single-dose studies with glyburide tablets (micronized) in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about 2 to 3 hours, and low but detectable levels at 24 hours.

Bioavailability studies have demonstrated that micronized glyburide tablets 3 mg provide serum glyburide concentrations that are not bioequivalent to those from non-micronized glyburide tablets 5 mg. Therefore, the patient should be retitrated.

In a single-dose bioavailability study in which subjects received micronized glyburide tablets 3 mg and non-microized glyburide tablets 5 mg with breakfast, the peak of the mean serum glyburide concentration-time curve was 97.2 ng/mL for the micronized gyburide tablets 3 mg and 87.5 ng/mL for non-micronized glyburide tablets 5 mg. The mean of the individual maximum serum concentration values of glyburide (Cmax) from micronized glyburide tablets 3 mg was 106 ng/mL and that from non-micronized glyburide tablets 5 mg was 104 ng/mL. The mean glyburide area under the serum concentration-time curve (AUC) for this study was 568 ng x hr/mL for micronized glyburide tablets 3 mg and 746 ng x hr/mL for non-micronized glyburide tablets 5 mg.

Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Multiple-dose studies with glyburide in diabetic patients demonstrate drug level concentration time curves similar to single-dose studies, indicating no buildup of drug in tissue depots.

In a steady-state study in diabetic patients receiving micronized glyburide tablets 6 mg once daily or micronized glyburide tablets 3 mg twice daily, no difference was seen between the two dosage regimens in average 24 hour glyburide concentrations following 2 weeks of dosing. The once daily and twice daily regimens provided equivalent glucose control as measured by fasting plasma glucose levels, 4 hour postprandial glucose AUC values, and 24 hour glucose AUC values. Insulin AUC response over the 24 hour period was not different for the two regimens. There were differences in insulin response between the regimens for the breakfast and supper 4 hour postprandial periods, but these did not translate into differences in glucose control.

The serum concentration of glyburide in normal subjects decreased with a half-life of about 4 hours.

In single-dose studies in fasting normal subjects who were administered glyburide tablets (non-micronized) in doses ranging from 1.25 mg to 5 mg, the degree and duration of blood glucose-lowering is proportional to the dose administered and to the area under the drug level concentration-time curve. The blood glucose-lowering effect persists for 24 hours following single morning doses in non-fasting diabetic patients. Under conditions of repeated administration in diabetic patients, however, there is no reliable correlation between blood drug levels and fasting blood glucose levels. A one year study of diabetic patients treated with glyburide showed no reliable correlation between administered dose and serum drug level.

The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glyburide) in rabbits.

Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.

Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding will result in fewer drug-drug interactions with glyburide in clinical use.

 

INDICATIONS AND USAGE

Glyburide tablets, USP (micronized) are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

 

CONTRAINDICATIONS

Glyburide tablets (micronized) are contraindicated in patients with:

1. Known hypersensitivity or allergy to the drug.

2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

3. Type 1 diabetes mellitus.

4. Concomitant administration of bosentan.

 

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to 1 of 4 treatment groups (Diabetes, 19 (Suppl. 2):747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2 ½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glyburide tablets (micronized) and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

 

PRECAUTIONS

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glyburide tablets (micronized) or any other antidiabetic drug.

Bioavailability studies have demonstrated that micronized glyburide tablets 3 mg provide serum glyburide concentrations that are not bioequivalent to those from non-micronized glyburide tablets 5 mg. Therefore, patients should be retitrated when transferred from non-micronized glyburide tablets or other oral hypoglycemic agents.
General

Hypoglycemia

All sulfonylureas including glyburide are capable of producing severe hypoglycemia. Proper patient selection and dosage and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated drug levels of glyburide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. The risk of hypoglycemia may be increased with combination therapy.

 

Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control may occur. At such times it may be necessary to discontinue glyburide and administer insulin.

The effectiveness of any hypoglycemic drug, including glyburide tablets (micronized), in lowering blood glucose to a desired level decreases in many patients over a period of time which may be due to progression of the severity of diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when glyburide is first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

 

Hemolytic Anemia

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glyburide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

 

In formation For Patients

Patients should be informed of the potential risks and advantages of glyburide and of alternative modes of therapy. They also should be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure also should be explained.

 

Physician Counseling Information for Patients

In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. Use of glyburide tablets (micronized) or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of glyburide tablets (micronized) or other antidiabetic medications. Maintenance or discontinuation of glyburide tablets (micronized) or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations.

 

Laboratory Tests

Therapeutic response to glyburide tablets (micronized) should be monitored by frequent urine glucose tests and periodic blood glucose tests. Measurement of glycosylated hemoglobin levels may be helpful in some patients.

 

Drug Interactions

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving glyburide tablets (micronized), the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glyburide tablets (micronized), the patient should be observed closely for loss of control.
An increased risk of liver enzyme elevations was observed in patients receiving glyburide tablets (micronized) concomitantly with bosentan. Therefore concomitant administration of glyburide tablets (micronized) and bosentan is contraindicated.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretic, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glyburide tablets (micronized), the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glyburide tablets (micronized), the patient should be observed closely for hypoglycemia.

A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism of action for this interaction is not known.

A potential interaction between oral miconazole and oral hypoglycemic agent s leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.

 

Metformin

In a single-dose interaction study in NIDDM subjects, decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain. Co-administration of glyburide tablets (micronized) and metformin did not result in any changes in either metformin pharmacokinetics or pharmacodynamics.

 

Colesevelam

Concomitant administration of colesevelam and glyburide tablets (micronized resulted in reductions in glyburide AUC and Cmax of 32% and 47%, respectively. The reductions in glyburide AUC and Cmax were 20% and 15%, respectively when administered one hour before, and not significantly changed (-7% and 4%, respectively) when administered 4 hours before colesevelam.

 

Topiramate

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in Cmax and a 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, and Cmax was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

 

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in rats at doses up to 300 mg/kg/day for 18 months showed no carcinogenic effects. Glyburide is nonmutagenic when studied in the Salmonella micro- some test (Ames test) and in the DNA damage/alkaline elution assay.

No drug-related effects were noted in any of the criteria evaluated in the 2 year oncogenicity study of glyburide in mice.

 

Pregnancy: Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible.

 

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If glyburide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date.

 

Nursing Mothers

Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

 

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

 

Geriatric Use

Elderly patients are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see DOSAGE AND ADMINISTRATION).

Elderly patients are prone to develop renal insufficiency, which may put them at risk of hypolycemia. Dose selection should include assessment of renal function.

 

ADVERSE REACTIONS

Hypoglycemia

See PRECAUTIONS and OVER-DOSAGE Sections.

 

Gastrointestinal Reactions

Cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; glyburide should be discontinued if this occurs.

Liver function abnormalities, including isolated transaminase elevations, have been reported.

Gastrointestinal disturbances, e.g. nausea, epigastric fullness, and heartburn are the most common reactions, having occurred in 1.8% of treated patients during clinical trials. They tend to be dose related and may disappear when dosage is reduced.

 

Dermatologic Reactions

Allergic skin reactions, e.g., pruritus, erythema, urticarial, and morbilliform or maculopapular eruptions occurred in 1.5% of treated patients during clinical trials. These may be transient and may disappear despite continued use of glyburide. If skin reactions persist, the drug should be discontinued.

Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

 

Hematologic Reactions

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas.

 

Metabolic Reactions

Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, hepatic porphyria has not been reported with glyburide and disulfiram-like reactions have been reported very rarely.

Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.

 

Other Reactions

Changes in accommodation and/or blurred) vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia and vasculitis have been reported.

 

OVERDOSAGE

Overdosage of sulfonylureas, including glyburide, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate which will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery.

 

DOSAGE AND ADMINISTRATION

Patients should be retitrated when transferred from non-micronized glyburide tablets or other oral hypoglycemic agents.

There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets (micronized). In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy.

Short-term administration of glyburide tablets (micronized) may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

 

Usual Starting Dose

The suggested starting dose of glyburide tablets (micronized) is 1.5 mg to 3 mg daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 0.75 mg daily. (See PRECAUTIONS section for patients at increased risk.) Failure to follow an appropriate dosage regimen nay precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy.

Transfer from Other Hypoglycemic Therapy; Patients Receiving Other Oral Antidiabetic Therapy

Patients should be retitrated when transferred from non-micronized gIyburide tablets or other oral hypoglycemic agents. The initial daily dose should be 1.5 mg to 3 mg. When transferring patients from oral hypoglycemic agents other than chlorpropamide to micronized glyburide tablets, no transition period and no initial or priming dose are necessary. When transferring patients from chlorpropamide, particular care should be exercised during the first 2 weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may provoke hypoglycemia.

 

Patients Receiving Insulin

Some type 2 diabetic patients being treated with insulin may respond satisfactorily to glyburide tablets (micronized). If the insulin dose is less than 20 units daily, substitution of glyburide tablets (micronized) 1.5 mg to 3 mg as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on glyburide tablets (micronized) 3 mg daily as a single dose. If the insulin dose is more than 40 units daily, a transition period is required for conversion to micronized glyburide tablets. In these patients, insulin dosage is decreased by 50% and glyburide tablets (micronized) 3 mg daily is started. Please refer to Titration to Maintenance Dose for further explanation.

 

Patients Receiving Colesevelam

When colesevelam is coadministered with glyburide tablets (micronized), the maximum plasma concentration and total exposure to glyburide is reduced. Therefore, micronized glyburide tablets should be administered a least 4 hours prior to coleveselam.

 

Titration to Maintenance Dose

The usual maintenance dose is in the range of 0.75 mg to 12 mg daily, which may be given as a single dose or in divided doses (see Dosage Interval). Dosage increases should be made in increments of no more than 1.5 mg at weekly intervals based upon the patient’s blood glucose response.

No exact dosage relationship exists between micronized glyburide tablets and the other oral hypoglycemic agents, including non-micronized glyburide tablets. Although patients may be transferred from the maximum dose of other sulfonylureas, the maximum starting dose of 3 mg of glyburide tablets (micronized) should be observed. A maintenance dose of 3 mg of glyburide tablets (micronized) provide approximately the same degree of blood glucose control as 250 mg to 375 mg chlorpropamide, 250 mg to 375 mg tolazamide, 5 mg of non-micronized glyburide, 500 mg to 750 mg acetohexamide, or 1000 mg to 1500 mg tolbutamide.

When transferring patients receiving more than 40 units of insulin daily, they may be started on a daily dose of glyburide tablets (micronized) 3 mg concomitantly with a 50% reduction in insulin dose. Progressive withdrawal of insulin and increase of glyburide tablets (micronized) in increments of 0.75 mg to 1.5mg every 2 to 10 days is then carried out. During this conversion period when both insulin and glyburide tablets (micronized) are being used, hypoglycemia may occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least 3 times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a type 1 diabetic who requires insulin therapy.

 

Concomitant Glyburide and Metformin Therapy

Glyburide tablets (micronized) should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after 4 weeks (see Usual Starting Dose and Titration to Maintenance Dose). Refer to metformin package insert.

With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal. With concomitant glyburide and metformin therapy, the risk of hypoglycemia associated With sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken (see PRECAUTIONS).

 

Maximum Dose

Daily doses of more than 1 mg are not recommended.

 

Dosage Interval

Once-a-day therapy is usually satisfactory. Some patients, particularly those receiving more than mg daily, may have a more satisfactory response with twice-a-day dosage.

 

Specific Patient Populations

Glyburide tablets (micronized) are not recommended for use in pregnancy or for use in pediatric patients.

In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. (See PRECAUTIONS).

 

HOW SUPPLIED

Glyburide Tablets, USP (micronized) are available containing 1.5 mg, 3 mg or 6 mg of glyburide, USP.

The 1 .5 mg tablets are white, oval, scored tablet debossed with M to the left of the score and 113 to the right of the score on one side of the tablets and blank on the other side.

They are available as follows:

NDC 0378-1113-01 bottles of 100 tablets

 

The 3 mg tablets are light yellow, oval, scored tablets debossed with M to the left of the score and 125 to the right of the score on one side of the tablets and blank on the other side.

They are available as follows:

NDC 0378-1125-01 bottles of 100 tablets

NDC 0378-1125-10 bottles of 1000 tablets

 

The 6 mg tablets are green, oval, scored tablets debossed with M to the left of the score and 142 to the right of the scene on one side of the tablets and blank on the other side. They are available as follows:

NDC 0378-1142-01 bottles of 100 tables

 

Store at 20o to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

 

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

 

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Revised June 2015

Teva Glimepiride Tablets

GLIMEPIRIDE 1,2,3 & 4 MG TABLETS

Glimepiride

 

INFORMATION FOR THE USER

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.

• If you have further questions, ask your doctor or pharmacist.

• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

• If you get any side effects, talk to your doctor, or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

 

What is in this leaflet

1 What Glimepiride is and what it is used for

2 What you need to know before you take GIimepiride

3 How to take Glimepiride

4 Possible side effects

5 How to store Glimepiride

6 Contents of the pack and other information

 

1 What Glimepiride is and what it is used for

• Glimepiride contains the active substance glimepiride.

• Glimepiride is a medicine to reduce blood sugar levels (antidiabetic medicine taken orally).

• Glimepiride is used in a certain form of diabetes (type 2 diabetes mellitus), when diet, exercise and weight loss alone do not have an adequate effect.

 

2 What you need to know before you take Glimepiride

Do not take Glimepiride

• If you are allergic to glimepiride or other drugs of the same group (sulfonylureas and sulfonamides) or any of the other ingredients of GlimepirideTablets (listed in section 6).

• If your kidney or liver function is severely impaired.

• If you have insulin-dependent (type 1) diabetes.

• If you have diabetic ketoacidosis (a complication of diabetes with rapid weight loss, nausea or vomiting).

• In the case of somnolence and loss of consciousness due to a strongly increased blood sugar level (diabetic coma).

In cases of severe renal or hepatic functional disorders, a change-over to insulin is required.

 

Warnings and precautions

Talk to your doctor or pharmacist before taking Glimepiride.

During Glimepiride treatment regular monitoring of your blood sugar level is necessary.

Your doctor may also take blood tests to monitor your blood cell levels and liver function.

You should observe the treatment plan prescribed by your doctor to achieve proper blood sugar Ievels. This means that, apart from regular tablet intake, you observe the dietary regimen, have physical exercise and, where necessary, reduce weight. Also take care that you have your blood (and possibly urine) sugar levels determined regularly as prescribed by your doctor.

In the first few weeks of treatment the risk of having reduced blood sugar levels (hypoglycaemia) may be increased, therefore it is vital that you are carefully monitored by your doctor.

Reduced blood sugar may occur if:

• You take meals irregularly or skip meals altogether.

• You are fasting.

• You are malnourished.

• You change your diet.

• You increase your physical activity and your carbohydrate intake is not increased to match this.

• You consume alcohol, especially in combination with skipped meals.

• You take other medicines or natural remedies at the same time.

• You take high doses of Glimepiride.

• You suffer from particular hormone-induced disorders (functional disorders of the thyroid gland, of the pituitary gland or adrenal cortex).

• Your renal function is decreased.

• Your liver function is seriously decreased.

• You do not observe the instructions given by your doctor or in this patient package leaflet.

Please inform your doctor of such risks so that he/she can either adjust the dosage of Glimepiride or revise the entire treatment plan to change it where necessary.

If you suffer from low blood sugar (hypoglycaemia) you may have the following signs:

Headache, hunger, exhaustion, nausea, vomiting, weariness, sleepiness, sleep disorders, restlessness, aggressiveness, impaired concentration, reduced alertness and reaction time, depression, confusion, speech and visual disorders, difficulty using or understanding language (aphasia), shaking, slight paralysis, sensory disturbances, dizziness, and helplessness.

The following signs may also occur:

Sweating, clammy skin, anxiety, accelerated heart beat, high blood pressure, a feeling of an abnormally strong or irregular heartbeat (palpitations), sudden strong pain in the breast that may radiate into neighbouring areas (angina pectoris), and cardiac arrhythmias.

If blood sugar levels continue to drop you may suffer from considerable confusion (delirium), develop cerebral convulsions, lose self control, breathing may be shallow and your heart beat slowed down, you may fall into unconsciousness. The symptoms of a severe reduced blood sugar level may resemble that of a stroke.

In most cases the signs of reduced blood sugar vanish very quickly when you consume some form of sugar, e.g. grape sugar, sugar cubes, sweet juice, sweetened tea.

You should therefore always take some form of sugar with you (grape sugar, sugar cubes). Remember that sweeteners are not effective. Please contact your doctor or the next hospital if taking sugar does not help or if the symptoms recur.

Signals of reduced blood sugar may be absent or less pronounced or develop very slowly. You are not aware in time that your blood sugar level has dropped. This may happen in elderly patients taking certain medicinal products (e.g. those acting on the central nervous system and betablockers). It may also happen when you suffer from certain disorders of the endocrine system (e.g. certain disorders of thyroid function and anterior pituitary or adreneocortical insufficiency). Impaired liver function may affect counter regulation.

In stress-situations (e.g. accidents, acute operations, infections with fever, etc.) a temporary switch to insulin may be indicated.

Signs of raised blood sugar (hyperglycaemia – it may occur when Glimepiride has not yet sufficiently reduced the blood sugar, when you have not complied with the treatment plan prescribed by your doctor or in special stress situations) may include thirst, frequent urination, dry mouth and dry itching skin, fungal or skin infections and reduced performance.

In such a case, you must contact your doctor.

If you have a deficiency in the enzyme glucose-6-phosphate dehydrogenase, or G6PD, glimepiride could cause a decrease in your blood haemoglobin levels, which might lead to low red blood cell levels (haemolytic anaemia).You should tell your doctor if you have G6PD deficiency.

 

Children and adolescents

There is not enough information on efficacy and safety of glimepiride in children and adolescents. Glimepiride tablets are not recommended in children and adolescents.

 

Other medicines and Glimepiride

The activity and safety of this treatment may be affected if this medicine is taken at the same time as certain other medicines. Conversely, other medicines may be affected if they are taken at the same time as Glimepiride. TelI your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. The blood sugar lowering effect of glimepiride may be strengthened and signs of low blood sugar levels may occur when one of the following drugs is taken:

– Other oral antidiabetic drugs (e.g. metformin), and insulin.

– Antibiotics (e.g. chloramphenicol, or clarithromycin, quinolones, tetracyclines, sulfonamides).

– Painkillers or antirheumatics (pyrazolone-derivates, e.g. phenylbutazone, azapropazone, oxyfenbutazone).

– Painkillers (salicylates).

– Products to treat tuberculosis (p-amino-salicylic acid).

– Products supporting muscle build-up (anabolics and male sex hormones).

– Products inhibiting blood clotting (coumarin).

– Products to treat fungal infections (miconazole, fluconazole).

– Products lowering blood pressure or heart beat (ACE-inhibitors, betablockers, sympatholytics).

– Products elevating mood/antidepressants (fluoxetine, MAO-inhibitors).

– Products suppressing appetite (fenfluramine).

– Products lowering increased fat levels in the blood (fibrates).

– Certain products to treat cancer (cyclo- tro-and iphosphamides).

– Products to treat allergies (tritoqualine).

– Infusion of high dose of products to increase blood flow (pentoxiphylline).

– Products to treat gout (probenecid, allopurinol, sulphinpyrazone).

– Disopyramide which is used to treat irregular heart rhythm.

 

The blood glucose lowering effect of Glimepiride may be weakened and raised blood sugar levels may occur when one of the following drugs is taken:

• Female sex hormones (oestrogens and progestagens).

• Products supporting urine production (saluretics, thiazide diuretics).

• Thyroid hormones.

• Products inhibiting inflammation (glucocorticoids).

• Products to treat cramps or schizophrenia (phenytoin, phenothiazine derivates).

• Products lowering blood pressure (diazoxide).

• Products to treat tuberculosis (rifampicin).

• Products to treat low blood sugar (gIucagon).

• Sleeping pills (barbiturate).

• Products to treat certain eye diseases (acetazolamide).

• Products to raise heart beat (adrenaline in and sympathicomimetics).

• Products lowering increased fat levels in the blood (nicotinic acid derivatives).

• Long term use of products relieving evacuation (laxatives).

Products to treat ulcers in the stomach or duodenum (H2 receptor-antagonists) or blood pressure lowering products (betablockers, clonidine and reserpine) may either strengthen or weaken the blood sugar lowering effect of Glimepiride.

Medicinal products with effects on the central nervous system (betablockers, clonidine, guanethidine or reserpine) may mask or totally suppress the signs of reduced blood sugar.

 

Glimepiride with food, drink and alcohol

Alcohol can enhance or diminish the ability of Glimepiride to reduce blood sugar in an unpredictable manner.

 

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

 

Pregnancy

Glimepiride should not be taken during pregnancy. If pregnancy is planned you should discuss the treatment plan with your doctor. If you become pregnant during a Glimepiride treatment you should instantly inform your doctor.

 

Breast-feeding

Glimepiride may pass into breast milk.

Glimepiride should not be taken during breast feeding.

 

Driving and using machines

Your ability to concentrate or react may be impaired if your blood sugar is lowered (hypoglycaemia), or raised (hyperglycaemia) or if you develop visual problems as a result of such conditions. Bear in mind that you could endanger yourself or others (e.g. when driving a car or using machines). Please ask your doctor whether you can drive a car if you:

• Have frequent episodes of hypoglycaemia.

• Have fewer or no warning signals of hypoglycaemia.

 

Glimepiride contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

 

3 How to take Glimepiride

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

 

Dosage

The dose is fixed by the doctor, depending on your blood and urine sugar levels.

Change in external factors (e.g. weight reduction, change in life style, stress) or improvements in the disease may require changed Glimepiride doses.

The recommended starting dose for adults is 1 mg of Glimepiride per day. If good blood sugar control is achieved the dosage should be used for maintenance therapy. Doses of more than 4 mg of Glimepiride per day give better results only in exceptional cases. The maximum recommended dose is 6 mg Glimepiride per day.

A combination therapy of Glimepiride plus metformin, or of Glimepiride plus insulin may be initiated. In such a case your doctor will determine the proper doses of Glimepiride, metformin or insulin individually for you.

Glimepiride must be swallowed with at least half a glass of water. Usually the entire daily dose is taken all at once directly before or during a substantial breakfast. If you do not have breakfast you should take the product on schedule as prescribed by your doctor. It is important not to leave out any meal when you are on Glimepiride.

 

Use in children

Glimepiride is not recommended for use in children.

Please speak with your doctor or pharmacist if you have the impression that Glimepiride is acting too strongly or not strongly enough.

 

If you take more Glimepiride than you should

If you happen to have taken too much Glimepiride or an additional dose there is a danger of low sugar levels, (for signs of hypoglycaemia see section 2) and therefore you should instantly consume enough sugar (e.g. a small bar of grape sugar cubes, sugar cubes, sweet juice, sweetened tea) and inform a doctor immediately. The same should be done if somebody, e.g. a child, has taken the product unintentionally.

Persons in a state of unconsciousness must not be given food or drink.

Since the state of low sugar levels may last for some time it is very important that the patient is carefully monitored until there is no more danger. Admission into hospital may be necessary, also as a measure of precaution. Severe cases of low blood sugar accompanied by loss of consciousness and severe neurological failure are cases of medical emergency requiring immediate medical treatment and admission into hospital.

It should be ensured that there is always a pre-informed person that can call a doctor in case of emergency.

 

If you forget to take Glimepiride

If you forget to take a dose, do not take the missed dose, just take the next dose on time.

Do not take a double dose to make up for a forgotten dose.

 

If you stop taking Glimepiride

If you interrupt or stop the treatment you should be aware that the desired blood sugar lowering effect is not achieved or that the disease will deteriorate again. If any change is necessary it is absolutely important for you to contact your doctor first.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

 

4 Possible side effects

Like all medicines, Glimepiride can cause side effects, although not everybody gets them.

 

Tell your doctor immediately if you experience any of the following symptoms

• Allergic reactions (including inflammation of blood vessels, often with skin rash) which may develop into serious reactions with difficulty in breathing, fall in blood pressure and sometimes progressing to shock.

• Abnormal liver function including yellowing of the skin and eyes (jaundice), problems with the bile flow (cholestasis), inflammation of the liver (hepatitis) or liver failure.

• Allergy (hypersensitivity) of the skin such as itching, rash, hives and increased sensitivity to sun.

Some mild allergic reactions may develop into serious reactions.

• Severe hypoglycaemia including loss of consciousness, seizures or coma.

• Severe decrease in the number of blood platelets (thrombocytopenia) and unusual bleeding or bruising under the skin (thrombocytopenic-purpura).

Some patients experienced the following side effects whilst taking Glimepiride:

 

Rare side effects (may affect up to 1 in 1,000 people)

• Lower blood sugar than normal (hypoglycaemia) (See Section 2 – Warnings and precautions).

• Decrease in the number of blood cells:

• Blood platelets (which increases risk of bleeding or bruising).

• White blood cells (which makes infections more likely).

• Red blood cells (which can make the skin pale and cause weakness or breathlessness).

These problems generally get better after you stop taking Glimepiride.

 

Very rare side effects (may affect up to 1 in 10,000 people)

• Allergic reactions (including inflammation of blood vessels, often with skin rash) which may develop into serious reactions with difficulty in breathing, fall in blood pressure and sometimes progressing to shock. If you experience any of these symptoms, tell your doctor immediately.

• Abnormal liver function including yellowing of the skin and eyes (jaundice), impairment of the bile flow (cholestasis), inflammation of the liver (hepatitis) or liver failure. If you experience any of these symptoms, tell your doctor immediately.

• Feeling or being sick, diarrhoea, feeling full or bloated, and abdominal pain.

• Decrease in the amount of sodium level in your blood (shown by blood tests).

 

Not known (frequency cannot be estimated from the available data)

• Allergy (hypersensitivity) of the skin may occur such as itching, rash, hives and increased sensitivity to sun.

Some mild allergic reactions may develop into serious reactions with swallowing or breathing problems, swelling of your lips, throat or tongue. Therefore in the event of one of these side effects, tell your doctor immediately.

• Allergic reactions with sulfonylureas, sulfonamides, or related drugs may occur.

• Problems with your sight may occur when beginning treatment with Glimepiride. This is due to changes in blood sugar levels and should soon improve.

• Increased liver enzymes.

• Severe decrease in the number of blood platelets (thrombocytopenia) and unusual bleeding or bruising under the skin (thrombocytopenic purpura).

 

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

By reporting side effects you can help provide more information on the safety of this medicine.

 

5 How to store Glimepiride

Keep this medicine out of the sight and reach of children. Do not store above 25°C. Do not use Glimepiride after the expiry date which is stated on the outer packaging. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

 

6 Contents of the pack and other information

What Glimepiride 1, 2, 3 & 4 mg Tablets contain

• The active substance is glimepiride. Each tablet contains either 1, 2, 3 or 4 mg of glimepiride.

• The other ingredients are lactose monohydrate, sodium starch glycolate, povidone, microcrystalline cellulose, magnesium stearate and the following colouring agents:

• 1 mg tablets – red iron oxide (E172).

• 2 mg tablets – yellow iron oxide (E172) and indigo carmine (E 132).

• 3 mg tablets – yellow iron oxide (E172).

• 4 mg tablets – indigo carmine (E 132).

 

What Glimepiride Tablets looks like and contents of the pack

• Glimepiride 1 mg Tablets are mottled pink, round tablets, bisected on both sides. One side of the tablet is debossed with “9” on one side of the score and “3” on the other. The other side of the tablet debossed with “72” on one side of the score and “54” on the other.

• Glimepiride 2 mg Tablets are mottled green, round tablets, bisected on both sides. One side of the tablet is debossed with “9” on one side of the score and “3” on the other. The other side of the tablet is debossed with “72” on one side of the score and “55” on the other.

• Glimepiride 3 mg Tablets are light yellow to yellow, round tablets, bisected on both sides. One side of the tablet is debossed with “G” on one side of the score and “3” on the other.

• Glimepiride 4 mg Tablets are mottled light blue, round tablets, bisected on both sides. One side of the tablet is debossed with “9” on one side of the score and “3” on the other. The other side of the tablet is debossed with “72” on one side of the score and “56” on the other.

• Glimepiride is available in pack sizes of 20, 28, 30, 50, 60, 90, 120 and 200 tablets. Not all pack sizes may be marketed.

 

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation holder and company responsible for manufacture:

TEVA UK Limited, Eastbourne, BN22 9AG.

 

This leaflet was last revised

March 2015

 

PL 00289/0943

PL 00289/0944

PL 00289/0945

PL 00289/0946

Tecral Carbamazepine Tablets

Tecral

(Carbamazepine)

Antiepileptic, neurotropic and psychotropic agent

 

COMPOSITION AND PHARMACEUTICAL FORM

Active substance: 5H-dibenzo [b,f] azepine-5-carboxamide

Tablets: 200 mg carbamazepine.

 

INDICATIONS

• Epilepsy

Complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization.

Generalized tonic-clonic seizures. Mixed forms of seizures.

Tecral is suitable for both monotherapy and combination therapy.

Tecral is usually not effective in absences (petit mal) and myoclonic seizures (see section SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

• Acute mania and maintenance treatment of bipolar affective disorders to prevent or attenuate recurrence.

• Alcohol withdrawal syndrome.

• Idiopathic trigeminal neuralgia and trigeminal neuralgia due to multiple sclerosis (either typical or atypical). Idiopathic giossopharyngeal neuralgia.

• Painful diabetic neuropathy

• Diabetes insipidus centralis. Polyuria and polydipsia of neurohormonal orgin.

 

DOSAGE AND ADMINISTRATION

The tablets may be taken during, after or between meals, Tablets should be taken with a little liquid, and possible remnants of the chewable tablets should be washed down with a little liquid. Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Tecral should be selected with caution on elderly patients.

 

Epilepsy

When possible. Tecral should be prescribed as monotherapy.

Treatment should be initiated with a low daily dosage, to be slowly increased until an optimal effect is obtained. Determination of plasma levels may help in establishing the optimum dosage (see section SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

When TECRAL is added to existing antiepileptic therapy, this should be done gradually while maintaining, or if necessary, adapting the dosage of the other antiepileptic(s) (see section INTERACTIONS)

Adults

Oral forms

Initially, 100 to 200 mg once or twice daily; the dosage should be slowly raised until – generally at 400 mg 2 to 3 times daily – an optimum response is obtained. In some patients 1600 mg or even 2000 mg daily may be appropriate.

Children

Oral forms

For children aged 4 years or less, a starting dose of 20 to 60 mg/day, increasing by 20 to 60 mg every second day, is recommended. For children over the age of 4 years, therapy may begin with 100 mg/day, increasing at weekly intervals by 100 mg.

Maintenance dosage: 10 to 20 mg/kg body weight daily in divided doses. e.g.

• Up to 1 year of age 100 to 200 mg daily

• 1 to 5 years of age 200 to 400 mg daily

• 6 to 10 years of age 400 to 600 mg daily

• 11 to 15 years of age 600 to 1000mg daily

 

Acute mania and maintenance treatment of bipolar affective disorders

Dosage range: about 400 to 1600 mg daily, the usual dosage being 400 to 600 mg daily given in 2 to 3 divided doses. In acute mania, the dosage should be increased rather quickly, whereas small dosage increments are recommended for maintenance therapy of bipolar disorders in order to ensure optimal tolerability.

 

Alcohol-withdrawal syndrome

Average dosage 200 mg 3 times daily in severe cases, it can be raised during the first few days (e.g. to 400 mg 3 times daily). At the start of treatment for severe withdrawal manifestations. Tecral should be given in combination with sedative-hypnotic drugs (e.g. clomethiazole, chlordiazepoxide). After the acute stage has abated. Tecral can be continued as monotherapy.

 

Trigeminal neuralgia

The initial dosage of 200 to 400 mg should be slowly raised daily until freedom from pain is achieved (normally all 200 mg 3 to 4 times daily). The dosage should then be gradually reduced to the lowest possible maintenance level. In elderly patients an initial dose of 100 mg twice daily is recommended.

 

Painful diabetic neuropathy

Average dosage: 200 mg 2 to 4 times daily.

 

Diabetes insipidus centralis

Average dosage for adults: 200 mg 2 to 3 times daily, in children the dosage should be reduced proportionally to the child’s age and body weight.

 

CONTRAINDICATIONS

• Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation

• Patients with atrioventricular block

• Patients with a history of bone-marrow depression

• Patients with a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda)

• The use of Tecral is not recommended in combination with monoamine-oxidase inhibitors (MAO/s) (See, section INTERACTIONS).

 

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Tecral should be given only under medical supervision. Tecral should be prescribed only after a critical benefit-risk appraisal and under close monitoring in patients with a history of cardiac, hepatic or renal damage, adverse haematological reactions to other drugs, or interrupted courses of therapy with Tecral.

 

Haematological effects

Agranulocytosis and aplastic anaemia have been associated with Tecral; however, due to the very low incidence of these conditions, meaningful risk estimates for Tecral are difficult to obtain. The overall risk in the general untreated population has been estimated at 4.7 persons per million per year for agranulocytosis and 2.0 persons per million per year for aplastic anaemia.

Transient or persistent decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of Tecral. However, in the majority of cases these effects prove transient and are unlikely to signal the onset of either aplastic anaemia or agranulocytosis. Nonetheless, complete pretreatment blood counts, including platelets (and possibly reticulocytes and serum iron), should be obtained at baseline, and periodically thereafter. If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the complete blood count should be closely monitored. Tecral should be discontinued if any evidence of significant bone-marrow depression appears. Patients should be made aware of early toxic signs and symptoms of a potential haematological problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage appear, the patient should be advised to consult his physician immediately.

 

Serious dermatologic reactions

Serious dermatologic reactions, including toxic epidermal necrolysis (TEN; also known as Lyell’s syndrome) and Stevens-Johnson syndrome (SJS), have been reported very rarely with Tecral. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and may be fatal. Most of the SJS/TEN cases appear in the first few months of treatment with Tecral. If signs and symptoms suggestive of severe skin reactions (e.g. SJS, Lyell’s syndrome/TEN) appear, Tecral should be withdrawn at once and alternative therapy should be considered. There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.

 

Association with HLA-A *3101

Human Leukocyte Antigen (HLA)3A 3101 may be a risk factor for the development of cutaneous adverse drug reactions such as SJS, TEN, DRESS. AGEP and maculopapular rash. Retrospective genome-wide studies in Japanese and Northern European populations reported association between severe skin reactions (SJS. TEN, DRESS. AGEP and maculopapular rash) associated with carbamazepine use and the presence of the HLAA*3101 allele in these patients.

The frequency of the HLAA*3101 allele varies widely between ethnic, populations. The frequency of this allele is estimated less than 5% in the majority of European, Australian, Asian, African and North American populations with some exceptions within 5-12%. Prevalence above 15% has been estimated in some ethnic groups in South America (Argentina and Brazil), North America (US Navajo and Sioux, and Mexico Sonora Seri) and Southern India (Tamil Nadu) and between 10%-15% in other native ethnicities in these same regions.

Testing for the presence of HLAA*3101 allele should be considered in patients with ancestry in genetically at-risk populations (for example, patients of the Japanese and Caucasian populations, patients who belong to the indigenous populations of the Americas. Hispanic populations, people of southern India, and people of Arabic descent), prior to initiating treatment with Tecral (see section information for Healthcare professionals). The use of Tecral should be avoided in patients who are found to be positive for HLAA*3101: unless the benefits clearly outweigh the risks. Screening is generally not recommended for any current Tecral users as the risk of SJS/TEN, AGEP. DRESS and maculopapular risk is largely confined to the first few, months of therapy, regardless of HLAA*3101 status.

 

Association with HLA-B*1502

Retrospective studies in patients of Han Chinese ancestry found a strong correlation between SJS/TEN skin reactions associated with carbamazepine and the presence in these patients of the Human Leukocyte Antigene (HLA)B*1502 allele. Higher reporting rates of SJS (rare rather than very rare) are reported in some countries in Asia (e.g. Taiwan, Malaysia and the Philippines) in which there is a higher prevalence of the HLA-B*1502 allele in the population. The prevalence of carriers of this allele in Asian populations is above 15% in the Philippines. Thailand, Hong Kong and Malaysia around 10% in Taiwan around 4% ,in North China around 2 to 4% in South Asia including Indians, and less than 1% in Japan and Korea. The prevalence of the HLAB*1502 allele is negligible in Caucasian, African, indigenous peoples of the Americas and Hispanic populations sampled.

Testing for the presence of HLAB* 1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with Tecral (see section information for Healthcare professionals). The use of Tecral should be avoided in tested patients who are found to be positive for HLAB*1502 unless the benefits clearly outweigh the risks. HLAB* 1502 may be a risk factor for the development of SJS/TEN in Chinese patients taking other anti-epileptic drugs (AED) associated with SJS/TEN. Consideration should therefore be given to avoiding use of other drugs associated with SJS/TEN in HLAB*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which, the prevalence of HLAB*1502 is low. Screening is generally not recommended for any current Tecral users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLAB*1502 status.

The identifications of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in those subjects has been shown to decrease the incidence of carbamazepine-induced SJS/TEN.

 

Limitation of genetic screening

Genetic screening results must never substitute for appropriate clinical vigilance and patient management. Many Asian patients positive for HLAB*1502 and treated with Tecral will not develop SJS/TEN and patients negative for HLAB*1502 of any ethnicity can still develop SJS/TEN. Similarly many patients positive for HLA-A*3101 and treated with Tecral will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA-A*3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of and morbidity from, these severe cutaneous adverse reactions, such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.

 

Other dermatologic reactions

Mild skin reactions, e.g. isolated macular or maculopapular exanthema, can also occur and are mostly transient and not hazardous. They usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with continued use. The HLA-A*3101 allele has been found to be associated with less severe adverse cutaneous reactions from carbamazepine and may predict the risk of these reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption). However, the HLA-B*1502 allele has not been found to predict the risk of these alone mentioned skin reactions.

 

Hypersensitivity

Tecral may trigger hypersensitivity reactions, including multi-organ hypersensitivity reactions, which can affect the skin, liver, (including intrahepatic bile ducts) haematopoietic organs and lymphatic system or other organs, either individually or together in the context of a systemic reaction (see section UNDESIRABLE EFFECTS). The HLA-A*3101 allele has been found to be associated with the occurrence of hypersensitivity syndrome, including maculopapular rash.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25 to 30 % of these patients may experience hypersensitivity reactions with oxcarbazepine.

Cross-hypersensitivity can occur between carbamazepine and phenytoin. In general if signs and symptoms suggestive of hypersensitivity reactions occur, Tecral should be withdrawn immediately.

 

Seizures

Tecral should be used with caution in patients with mixed seizures which includes absences, either typical or atypical all these conditions. Tecral may exacerbate seizures. In the event of exacerbation of seizures, Tecral should be discontinued.

 

Hepatic function

Baseline and periodic evaluations of hepatic function must be performed during treatment with Tecral particularly patients with a history of liver disease and in elderly patients. The drug should be withdrawn immediately in cases of aggravated liver dysfunction or active liver disease.

 

Renal function

Baseline and periodic complete urinalysis and BUN determinations are recommended.

 

Anticholinergic effects

Tecral has shown mild anticholinergic activity. Patients with increased intraocular pressure should therefore be closely observed during therapy (see section UNDESIRABLE EFFECTS).

 

Psychiatric effects

The possibility of activation of a latent psychosis and in elderly patients of confusion or agitation should be borne in mind.

 

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic drugs has shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known.

Therefore patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

 

Endocrinological effects

Breakthrough bleeding has been reported in women taking Tecral while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by Tecral and women of childbearing age should be advised to consider using alternative forms of birth control while taking Tecral. Due to enzyme induction, Tecral may cause failure of the therapeutic effect of drugs containing oestrogen and/or progesterone (e.g. failure of contraception).

 

Monitoring of plasma levels

Although correlations between dosage and plasma levels of carbamazepine and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following situations, dramatic increase in seizure frequency/verification of patient compliance during pregnancy when treating children or adolescents; in suspected absorption disorders, in suspected toxicity when more than one drug is being used see section INTERACTIONS).

 

Dose reduction and withdrawal

Abrupt withdrawal of Tecral may precipitate seizures. If treatment with Tecral has to be withdrawn abruptly in a patient with epilepsy the switch to the new antiepileptic compound should be made under cover of a suitable drug (e.g. diazepam i.v., rectal; or phenytoin i.v.).

 

INTERACTIONS

Cytochrome P450 3A4 (CYP 3A4) is the main enzyme catalyzing formation of the active metabolite carbamazepine 10, 11 epoxide. Coadministration of inhibitors of CYP3A4 may result in increased carbarmazepine plasma concentrations which could induce adverse reaction. Coadministration of CYP3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to a potential decrease in the carbamazepine serum level and potential decrease in the therapeutic effect. Similarly discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine plasma levels. Carbamazepine is a potent inducer of CYP3A4 and other phase I and Phase II enzyme systems in the liver, and may therefore reduce plasma concentrations of comedications mainly metabolized by CYP3A4 by induction of their metabolism. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10.11-transdiol derivative from carbamazepine 10.11 epoxide. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine 10.11 epoxide plasma concentrations.

 

Agents that may raise carbamazepine plasma levels

Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Tecral should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with Analgesics, anti-inflammatory drugs: dextropropoxyphene, iburofen, Androgens: danazol, Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin, ciprofloxacin), Antidepressants: possibly desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine: trazodone, viloxazine, Antiepileptics stinpentol, vigabatrin, Antifungais: azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole), Anthistamines loratadine terfenadine. Antipsychotics olanzapine, Antituberculosis isoniazid, Antivirals protease inhibitors for HIV treatment (e.g. ritonavir). Carbonic anhydrase inhibitors acetazolamide. Cardiovascular drugs diltiazem, verapamil, Gastrointestinal drugs possibly cimetidine omeprazole, Muscle relaxants oxybutynin, dantrolene. Platelet aggregation inhibitors ticlopidine, Other interactions grapefruit juice, nicotinamide (in adults only in high dosage).

 

Agents that may raise the active metabolite carbamazepine – 10.11 epoxide plasma levels

Since raised plasma carbamazepine 10.11 epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia) the dosage of Tecral should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with Loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.

 

Agents that may decrease carbamazepine plasma levels

The dose of Tecral may have to be adjusted when used concomitantly with Antiepileptics felbamate, methsuximide, oxcarbazepine, phenobarbitone, phensuximide, phenytoin and fosphenytoin, primidone, and although the data are partly contradictory, possibly also clonazepam, Antineoplastics cisplatin or doxorubicin, Antituberculosis, rifampicin, Bronchodilators or anti-asthma drugs, theophylline, aminophylline, Dermatological drugs isotretinoin. Other interactions, herbal preparations containing St. John’s wort (Hypericum perforatum).

 

Effect of Tecral on plasma levels of concomitant agents

Carbamazepine may lower the plasma level or diminish – or even abolish – the activity of certain drugs. The dosage of these drugs may have to be adjusted to clinical requirements. Analgesics, anti-inflammatory agents, methadone, paracetamol, phenazone (antipyrine), tramadol. Antibiotics doxycycline, Anticoagulants oral anticoagulants (e.g. warfarin, phenprocoumon, dicoumarol and acenocoumarol). Antidepressants, bupropion, citalopram, nefazodone, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine). The use of Tecral is not recommended in combination with monoamine-oxidase inhibitors (MAOIs), before administering Tecral MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.

Antiemetics: Aprepitant, Antiepileptics clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate valproic acid, zonisa mide. Plasma phenytoin levels have been reported both to be raised and to be lowered by carbamazepine and there have been rare reports of an increase in plasma mephenytoin levels. Antifungáls itraconazole, Anthelmintics praziquantel, albendazole, Antineoplastics imatinib cyclophosphamide, lapatinib, temsirolimus. Antipsychotics clozapine, haloperidol and bromperidol, olanzapine quetiapine risperidone ziprasidone aripiprazole, paliperidone. Antivirals protease inhibitors for HIV treatment (e.g. indinavir, ritonavir saquinavir). Anxiolytics, alprazolam, midazolam Bronchodilators or anti-asthma drugs theophylline. Contraceptives hormonal contraceptives (alternative contraceptive methods should be considered). Cardiovascular drugs calcium channel blockers (dihydropyridine group) e.g. felodipine, digoxin, Corticosteroids corticosteroids (e.g. prednisolone dexamethasone), Drugs used in erectile dysfunction. Tadalafil, immunosuppressants ciclosporin, everolimus, tacrolimus, sirolimus. Thyroid agents Ievothyroxine, other drug interactions products containing oestrogens and/or progesterones.

 

Combinations that require specific consideration

Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity. Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity. Combined use of carbamazepine and lithium or metoclopramide on the one hand and carbamazepine and neuroleptics (haloperidol, thioridazine) on the other may lead to increased neurological adverse reactions (with the latter combination even in the presence of therapeutic plasma levels).

Concomitant medication with Tecral and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraomia. Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g. pancuronium). Their dosage may need to be raised and patients should be monitored closely for more rapid recover from neuromuscular blockade than expected.

Carbamazepine like other psychoactive drugs may reduce alcohol tolerance. It is therefore advisable for the patient to abstain from alcohol.

 

PREGNANCY AND LACTATION

Pregnancy

In animals (mice, rats, rabbits) oral administration of carbamazepine during organogenesis led to increased embryonic mortality at daily doses which caused maternal toxicity (above 200 mg/kg body weight daily, i.e. 10 to 20 times the usual human dosage). In the rat there was also some evidence of abortion at 300 mg/kg body weight daily. Near term rat fetuses showed growth retardation, again at maternally toxic doses. There was no evidence of teratogenic potential in the three animal species tested, but in one study using mice, carbamazepine (40 to 240 mg/kg body weight daily, orally) caused defects (mainly dilatation of cerebral ventricles) in 4.7% of exposed fetuses as compared with 1.3% in controls. Offspring of epileptic mothers are known to be more prone to developmental disorders, including malformations. The possibility that carbamazepine, like all major antiepileptic drugs, increases this risk has been reported, although conclusive evidence from controlled studies with carbamazepine monotherapy is lacking. However, developmental disorders and malformations, including spina bifida and also other congenital anomalies, e.g. craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems, have been reported in association with Tecral.

Taking these data into consideration:

• Pregnant women with epilepsy should be treated with special care.

• If women receiving Tecral become pregnant or plan to become pregnant, or if the problem of initiating treatment with Tecral arises during pregnancy the drug’s potential benefits must be carefully weighed against its possible hazards, particularly in the first 3 months of pregnancy.

• In women of childbearing age Tecral should wherever possible be prescribed as monotherapy, because the incidence of congenital abnormalities in the offspring of women treated with a combination of antiepileptic drugs is greater than in those of mothers receiving the individual drugs as monotherapy.

• Minimum effective doses should be given and monitoring of plasma levels is recommended.

• Patients should be counseled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.

• During pregnancy an effective antiepileptic treatment must not be interrupted since the aggravation of the illness is detrimental to both the mother and the fetus.

 

Monitoring and prevention

Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate folic acid deficiency. This deficiency may contribute to the increased incidence of birth defects in the offspring of treated epileptic women. Folic acid supplementation has therefore been recommended before and during pregnancy.

 

In the neonate

In order to prevent bleeding disorders in the offspring, it has also been recommended that vitamin K1 be given to the mother during the last weeks of pregnancy as well as to the neonate.

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

 

Lactation

Carbamazepine passes into the breast milk (about 25 to 60% of plasma concentrations). The benefits of breast feeding should be weighed against the remote possibility of adverse effects occurring in the infants. Mothers taking Tecral may breast feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, allergic skin reaction).

 

Fertility

There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

 

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

The patient’s ability to react may be impaired by dizziness and drowsiness caused by Tecral, especially at the start of treatment or in connection with dose adjustments, patients should therefore exercise due caution when driving a vehicle or operating machinery.

 

UNDESIRABLE EFFECTS

Particularly at the start of treatment with Tecral or if the initial dosage is too high, or when treating elderly patients, certain types of adverse reaction occur very commonly or commonly, e.g. CNS adverse reactions (dizziness, headache, ataxia, drowsiness, fatigue, diplopia); gastrointestinal disturbances (nausea vomiting and allergic skin reactions.

The dose related adverse reactions usually abate within a few days, either spontaneously or after a transient dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor plasma levels.

Adverse reactions (Table 1) are ranked under heading of frequency the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, <1/1000); very rare (< 1/10,000), including isolated reports.

 

Blood and lymphatic system disorders

Very common: leukopenia

Common: thrombocytopenia, eosinophilia

Rare: leukocytosis, lymphadenopathy, folic acid deficiency

Very rate: agranulocytosis, aplastic anaemia, pancytopenia, pure red cell aplasia, anaemia, megaloblastic anaemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda, reticulocytosis, and possibly haemolytic anaemia.

 

Immune system disorders

Rare: a delayed multiorgan hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophillia, hepato-splenomegaly and abnormal liver function tests, occurring in various combinations. Other organs may also be affected (e.g. lungs, kidney, pancreas, myocardium, colon).

Very rare: aseptic meningitis, with myoclonus and peripheral eosinophilia, anaphylactic reaction angioneurotic oedema.

 

Endocrine disorders

Common: oedema, fluid retention, weight increase, hyponatraemia and blood osmolarity decreased due to an antidiuretic hormone (ADH)-like effect leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confusional state, neurological disorders.

Very rare: Blood prolactin increased with or without clinical manifestations such as galactorrhoea, gynecomastia, abnormal thyroid function tests, decreased L-Thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulation hormone, usually without clinical manifestations, bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol), leading to osteomalacia/osteoporosis, increased blood cholesterol, including HDL cholesterol, and triglycerides.

 

Psychiatric disorders

Rare: hallucinations (visual or auditory), depression, anorexia, restlessness, aggression, agitation, confusional state.

Very rare: activation of psychosis.

 

Nervous system disorders

Very common: dizziness, ataxia, drowsiness, fatigue.

Common: headache, diplopia, accommodation disorders (e.g. blurred vision).

Uncommon: abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics); nystagmus.

Rare: orofacial dyskinesia, eye movement disturbances, speech disorders (e.g. dysarthria, slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, and paresis.

Very rare: taste disturbances, neuroleptic malignant syndrome.

 

Eye disorders

Very rare: intraocular opacities, conjunctivities, intraocular pressure increased.

 

Ear and labyrinth disorders

Very rare: hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.

 

Cardiac disorders

Rare: cardiac conduction disorders; hypertension or hypotension.

Very rare: bradycardia, arrythmia, atrioventricular block with syncope, circulatory collapse, congestive heart failure, aggravation of coronary artery disease, thrombophlebitis, thromboembolism (e.g. pulmonary embolism).

 

Respiratory, thoracic and madiastinal disorders

Very rare: pulmonary hypersensitivity characterized e.g. by fever, dyspnoea, pneumonitis or penumonia.

 

Gastrointestinal disorders

Very common: nausea, vomiting.

Common: dry mouth: with suppositories, rectal irritation may occur.

Uncommon: diarrhoea, constipation.

Rare: abdominal pain

Very rare: glossitis, stomatitis, pancreatitis

 

Hepatobillary disorders

Very common: increased gamma-GT (due to hepatic enzyme induction), usually not clinically relevant.

Common: increased blood alkaline phosphatase.

Uncommon: increased transaminases.

Rare: hepatitis of cholestatic, parenchyma (hepatocellular) or mixed type, jaundice.

Very rare: granulomatous hepatitis, hepatic failure.

 

Skin and subcutaneous tissue disorders

Very common: dermatitis allergic, urticaria which may be severe.

Uncommon: exfoliative dermatitis and erythroderma.

Rare: systemic lupus erythematosus, pruritus.

Very rare: toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme and nodosum alterations in skin pigmentation, purpura, acne, hyperhydrosis, hair loss, hirsutism.

 

Musculoskeletal, connective tissue and bone disorders

Rare: muscular weakness.

Very rare: arthralgia, muscle pain, muscle spasms.

 

Renal and urinary disorders

Very rare: interstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria, and blood urea increased/azotemia), urinary frequency, urinary retention.

 

Reproductive system

Very rare: sexual dysfunction/impotence, spermatogenesis abnormal (with decreased sperm count and/or motility).

 

Investigations

Very rare: hypogammaglobulinaemia.

* In some Asian countries also reported as rare. See also section SPECIAL WARNINGS AND PRECAUTIONS FOR USE.

 

Adverse drug reactions from spontaneous reports and literature cases (frequency not known)

The following adverse drug reactions have been derived from post-marketing experience with Tecral via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

 

Immune system disorders

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

 

Skin and subscutaneous tissue disorders

Acute Generalized Exanthematous Pustulosis (AGEP).

 

OVERDOSE

Signs and symptoms

The presenting signs and symptoms of overdosage usually involve the central nervous, cardiovascular and respiratory systems.

 

Central nervous system

CNS depression: disorientation, somnolence, agitation, hallucination, coma: blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyper-reflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothemia, mydriases.

 

Respiratory system

Respiratory depression, pulmonary oedema.

 

Cardiovascular system

Tachycardia, hypotension at times hypertension, conduction disturbance with widening of QRS complex, syncope in association with cardiac arrest.

 

Gastrointestinal system

Vomiting, delayed gastric emptying, reduced bowel motility.

 

Renal function

Retention of urine, oliguria or anuria: fluid retention, water intoxication due to an ADH-Iike effect of carbamazepine.

 

Laboratory findings

Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased muscle creatine phosphokinase.

 

Management

There is no specific antidote.

Management could initially be guided by the patient’s clinical condition, admission to hospital. Measurement of the plasma level to confirm carbamazepine poisoning and to ascertain the size of the overdose. Evacuation of the stomach, gastric lavage, and administration of activated charcoal. Delay in evacuating the stomach may result in delayed absorption leading to relapse during recovery from intoxication. Supportive medical care in an intensive care until with cardiac monitoring and careful correction of electrolyte imbalance.

 

Special recommendations

Hypotension: administer dopamine or dobutamine i.v.

Disturbances of cardiac rhythm: to be handled on an individual basis.

Convulsions, administer a benzodiazepine (e.g. diazepam) or another antiepileptic, e.g. phenobarbitone (with caution because of increased respiratory depression), or paraldehyde.

Hyponatraemia (water intoxication): fluid restriction and slow and careful NaCI 0.9% infusion i.v. These measures may be useful in preventing brain damage.

Charcoal hemoperfusion has been recommended. Forced diuresis, haemodialysis, and peritoneal dialysis have been reported to be not effective.

Relapse and aggravation of symptomatology on the 2nd and 3rd day after overdose, due to delayed absorption, should be anticipated.

 

PHARMACODYNAMICS

Dibenzazepine derivative

As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and without secondary generalization: generalized tonic-clonic seizures, as well as combinations of these types of seizures. In clinical studies Tecral given as monotherapy to patients with epilepsy – in particular children and adolescents – has been reported to exert a psychotropic action, including a positive effect on symptoms of anxiety and depression as well as a decrease in irritability and aggressiveness. As regards cognitive and psychomotor performance, in some studies equivocal or negative effects, depending also upon dosages administered, were reported in other studies, a beneficial effect on attentiveness, cognitive performance/memory was observed.

As a neurotropic agent Tecral is clinically effective in a number of neurological disorders, e.g. it prevents paroxysmal attacks of pain in idopathic and secondary trigeminal neuralgia: In addition, it is used for the relief of neurogenic pain in a variety of conditions, including labes forsalls, post-traumatic paresthesia and post-herpetic rteuralgia: in alcohol-withdrawal syndrome it raises the lowered convulsion threshold and improves withdrawal symptoms (e.g hyperexcitability, tremor, impaired gait): in diabetes insipidus centralis, Tecral reduces the urinary volume and relieves the feeling of thirst.

As a psychotropic agent Tecral proved to have clinical efficacy in affective disorders i.e. as treatment for acute mania as well as for maintenance treatment of (manic-depressive) bipolar affective disorders, when given either, as monotherapy or in combination with neuroleptics, antidepressants or lithium in excited schizo-affective disorder and excited mania in combination with other neuroleptics, and in rapid cycling episodes. The mechanism of action of carbamazepine, the active substance of Tecral, has only been partially elucidated. Carbamazepine stabilizes hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of sodium-dependent action potentials in depolarized neurons via use and voltage-dependent blockade of sodium channels may be its main mechanism of action.

Whereas reduction of glutamate release and stabilization of neuronal membranes may account mainly for the antiepileptic, effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of carbamazepine.

 

PHARMACOKINETICS

Absorption

Carbamazepine is absorbed almost completely but relatively slowly from the tablets. The conventional tablets and the chewable tablets yield mean peak plasma concentrations of the unchanged substance within 12 and 6 hours, respectively, following single oral doses.
Steady-state plasma concentrations of carbamazepine are attained within about 1 to 2 weeks, depending individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-including drugs, as well as on pretreatment status, dosage, and duration, of treatment.

The steady-state plasma concentrations of carbamazepine considered as therapeutic range vary considerably interindividually for the majority of patients a range between 4 to 12 micrograms/mL corresponding to 17 to 50 micromol/L has been reported. Concentrations of carbamazepine-10,11-epoxide (pharmacologically active metabolite) about 30% of carbamazepine levels.

Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of Tecral.

 

Distribution

Assurring complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg. Carbamazepine crosses the placental barrier. Carbamazepine is bound to serum proteins to the extent of 70 to 80%. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in the plasma (20 to 30%). Concentrations in breast milk were found to be equivalent to 25 to 80% of the corresponding plasma levels.

 

Biotransformation

Carbamazepine is metabolized in the liver, where the epoxide pathway of biotransformation is the most important one, yielding the 10,11-transdiol derivative and its glucuronide as the main metabolites. Cytochrome P450 3A4 has been identified as the major isoform responsible for the formation of the pharmacologically active carbamazepne 10,11 epoxide from carbamazepirie. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11 -transdiol derivative from carbamazepine 10,11 epoxide. 9-Hydroxy-methyl- 10-carbamoyl acridan is a minor metabolite related to this pathway. After a single oral dose of carbamazepine about 30% appears in the urine as end-products of the epoxide pathway. Other important biotransformation pathways for carbamazepine lead to various monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine produced by UGT2B7.

 

Elimination

The elimination half-life of unchanged carbamazepine averages approx. 36 hours following a single oral dose, whereas after repeated administration it averages only 16 to 24 hours (auto-induction of the hepatic mono-oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment with other liver enzyme inducing drugs (e.g. phenytoin, phenobarbitone), half-life values averaging 9 to 10 hours have been found. The mean elimination half-life of the 10,11 epoxide metabolite in the plasma is about 6 hours following single oral doses of the epoxide itself.

After administration a single oral dose of 400 mg carbamazepine, 72% is excreted in the urine and 28% in the faeces. In the urine about 2% of the dose is recovered as unchanged drug and about 1% as the phamacologically active 10,11-epoxide metabolite.

 

Characteristics in patients

Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg) than adults. There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.

No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.

 

PRECLINICAL SAFETY DATA

In rats treated with carbamazepine for 2 years, the incidence of tumors of the liver was found to be increased. The significance of these finding relative to the use of carbamazepine in humans is unknown at present. Bacterial and mammalian mutagenicity studies yielded negative results.

 

STORAGE

Tablet: Protect from heat, light and moisture.

 

INSTRUCTIONS FOR HANDLING

Tecral must be kept out of the reach and sight of children.

If you have any questions about the medicinal product please contact your doctor.

 

Manufactured by

ROCK PHARMACEUTICALS (PVT) LTD.

134-B & 135-B Nowshera

Industrial Estate Risalpur Pakistan.