APO-CARBAMAZEPINE CR

Apotex Inc. is only authorized for APO-CARBAMAZEPINE (carbamazepine tablets, 200 mg) and APO-CARBAMAZEPINE CR (controlled release tablets, 200 mg and 400 mg). Please refer to a product monograph for a carbamazepine oral suspension formulation when needed.

Since a given dose of carbamazepine oral suspension produces higher peak carbamazepine levels than the same dose in tablet form, it is advisable to start with low doses and to increase slowly to avoid adverse reactions. , BID carbamazepine tablets to TID carbamazepine oral suspension).

1 Dosing Considerations Geriatrics: Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of APO-CARBAMAZEPINE should be selected with caution in elderly patients. 2 APO-CARBAMAZEPINE and APO-CARBAMAZEPINE CR Page 8 of 52 Recommended Dose and Dosage Adjustment), reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease.

3 Pharmacokinetics, Special Populations and Conditions. 2 Recommended Dose and Dosage Adjustment Use in Epilepsy APO-CARBAMAZEPINE (carbamazepine) may be used alone or with other anticonvulsants. A low initial daily dosage of APO-CARBAMAZEPINE with a gradual increase in dosage is advised.

To achieve adequate control of seizures, dosage should be adjusted to the needs of the individual patient. Determination of plasma levels may help in establishing the optimum dosage. In the treatment of epilepsy, the dose of carbamazepine should be adjusted to maintain steady state plasma concentration of about 4 to 10 mcg/mL.

See 10 CLINICAL PHARMACOLOGY. APO- CARBAMAZEPINE should be taken with meals whenever possible. APO-CARBAMAZEPINE tablets should be taken in 2 to 4 divided doses daily. The controlled release characteristics of APO-CARBAMAZEPINE CR (controlled-release tablets) reduce the daily fluctuations of plasma carbamazepine.

APO-CARBAMAZEPINE CR tablets (either whole or, if so prescribed, only half a tablet) should be swallowed unchewed with a little liquid during or after a meal. These controlled release tablets should be prescribed as a twice - daily dosage.

If necessary, three divided doses may be prescribed. Some patients have been reported to require a dosage increase when switching from APO-CARBAMAZEPINE (tablets) to APO-CARBAMAZEPINE CR (controlled-release tablets). Dosage adjustments should be individualized based on clinical response and, if necessary, plasma carbamazepine levels.

Adults and Children Over 12 Years of Age Initially, 100 to 200 mg once or twice a day depending on the severity of the case and previous therapeutic history. The initial dosage is progressively increased, in divided doses, until the best response is obtained.

The usual optimal dosage is 800 to 1200 mg daily. In rare instances some adult patients have received 1600 mg. As soon as disappearance of seizures has been o btained and maintained, dosage should be reduced very gradually until a minimum effective dose is reached.

Children 6 to 12 Years of Age Initially, 100 mg in 2 to 4 divided doses on the first day. Increase gradually by adding 100 mg per day until the best response is obtained. Dosage should generally not exceed 1000 mg daily. As soon as disappearance of seizures has been obtained and maintained, dosage should be reduced very gradually until a minimum effective dose is reached.

APO-CARBAMAZEPINE and APO-CARBAMAZEPINE CR Page 9 of 52 Combination Therapy When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except for phenytoin, which may be increased.

1 WARNINGS AND PRECAUTIONS, Special Populations: Pregnant Women and 9 DRUG INTERACTIONS. Use in Trigeminal Neuralgia The initial daily dosage should be small; 200 mg taken in 2 doses of 100 mg each is recommended. The total daily dosage can be increased by 200 mg/day until relief of pain is obtained.

This is usually achieved at dosage between 200 and 800 mg daily, but occasionally up to 1200 mg/day may be necessary. Maximum recommended dose is 1200 mg/day. As soon as relief of pain has been obtained and maintained, progressive reduction in dosage should be attempted until a minimal effective dosage is reached.

Because trigeminal neuralgia is characterized by periods of remission, attempts should be made to reduce or discontinue the use of APO-CARBAMAZEPINE at intervals of not more than 3 months, depending upon the individual clinical course.

Prophylactic use of the drug in trigeminal neuralgia is not recommended. Use in Mania and Bipolar (Manic-Depressive) Disorders The initial daily dosage should be low, 200 to 400 mg/day, administered in divided doses, although higher starting doses of 400 to 600 mg/day may be used in acute mania.

This dose may be gradually increased until patient symptomatology is controlled or a total daily dose of 1600 mg is achieved. Increments in dosage should be adjusted to ensure optimal patient tolerability. The usual dose range is 400 to 1200 mg/day administered in divided doses.

Doses used to achieve optimal acute responses and tolerability should be continued during maintenance treatment. When given in combination with lithium and neuroleptics, the initial dosage should be low, 100 mg to 200 mg daily, and then increased gradually.

A dose higher than 800 mg/day is rarely required when given in combination with neuroleptics and lithium, or with other psychotropic drugs such as benzodiazepines. Plasma levels are probably not helpful for guiding therapy in bipolar disorders.

5 Missed Dose If a scheduled dose is missed, APO-CARBAMAZEPINE and APO-CARBAMAZEPINE CR […]

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

Central Nervous System:

CNS depression, disorientation, depressed level of consciousness, tremor, restlessness, somnolence, agitation, hallucination, coma, blurred vision, nystagmus, mydriasis, slurred speech, dysarthria, ataxia, dyskinesia, abnormal reflexes (slowed/hyperactive), convulsions, psychomotor disturbances, myoclonus, opisthotonia, hypothermia/ hyperthermia, flushed skin/cyanosis, EEG changes.

Respiratory System: respiratory depression, pulmonary edema. Cardiovascular System: tachycardia, hypotension/hypertension, conduction disturbance with widening of QRS complex, syncope in association with cardiac arrest. Gastrointestinal System: nausea, vomiting, delayed gastric emptying, reduced bowel motility.

Musculoskeletal System:

There have been some cases which reported rhabdomyolysis in association with carbamazepine toxicity. Renal Function: urinary retention, oliguria or anuria; fluid retention, and water intoxication. Laboratory Findings: hyponatremia, hypokalemia, leukocytosis, reduced white cell count, metabolic acidosis, hyperglycemia, glycosuria, acetonuria, increased muscle creatine phosphokinase.

Treatment of Overdosage There is no known specific antidote to APO-CARBAMAZEPINE (carbamazepine). Evacuate the stomach, with an emetic or by gastric lavage and then administer activated charcoal. Delay in evacuating the stomach may result in delayed absorption, leading to relapse during recovery from intoxication.

Hemodialysis is the effective treatment modality in the management of the carbamazepine overdose. Vital signs, including electrocardiogram to detect any cardiac arrhythmias or conduction defects, should be watched and symptomatic treatment should be administered as required.

Hyperirritability or convulsions should be appropriately managed by standard medical care. APO-CARBAMAZEPINE and APO-CARBAMAZEPINE CR Page 11 of 52 Hyponatremia should be appropriately managed by standard medical care. Shock (circulatory collapse) should be treated with supportive measures, including intravenous fluids, oxygen, and corticosteroids.

Charcoal hemoperfusion has been recommended. For management of a suspected drug overdose, contact your regional poison control centre. 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING Table 1 – Dosage Forms, Strengths, Composition and Packaging.

Availability of Dosage Forms APO-CARBAMAZEPINE 200 mg:

Each round, white, flat-faced tablet, one side cross-scored, the other side engraved “APO” over “200”, contains 200 mg carbamazepine. Available in bottles of 100 and 500, unit dose packages of 100.

APO-CARBAMAZEPINE CR 200 mg:

Each light orange, capsule-shaped, film-coated tablet, scored and engraved “APO” bisect “200” on one side, plain with bisect on the other side, contains 200 mg carbamazepine. Available in bottles of 100 and 500, unit dose packages of 30 (aluminum blister 3 x 10), 60 (aluminum blister 6 x 10) and 100 (aluminum blister 10 x 10).

APO-CARBAMAZEPINE CR 400 mg:

Each capsule-shaped, dark orange, film-coated tablet, scored and engraved “APO” bisect “400” on one side, plain with bisect on the other side, contains 400 mg carbamazepine. Available in bottles of 100 and 500, unit dose packages of 30 (aluminum blister 3 x 10), 60 (aluminum blister 6 x 10) and 100 (aluminum blister 10 x 10).

7 WARNINGS AND PRECAUTIONS Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX. Route of Administration Dosage Form / Strength/Composition All Non-medicinal Ingredients Oral Tablets; 200 mg colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and microcrystalline cellulose.

Oral Controlled Release Tablets; 200 mg and 400 mg crospovidone, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, methylcellulose, polyethylene glycol, red ferric oxide, titanium dioxide and yellow ferric oxide APO-CARBAMAZEPINE and APO-CARBAMAZEPINE CR Page 12 of 52 Pharmacogenomics There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.

Ancestry and Allelic Variation in the HLA-A Gene The frequency of the HLA-A*3101 allele, an inherited allelic variant of the HLA-A gene, varies widely between ethnic populations and its frequency is about 2 to 5% in European populations and about 10% in the Japanese population.

The frequency of this allele is estimated to be less than 5% in the majority of Australian, Asian, African and North American populations with some exceptions within 5 to 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% to 15% in other native ethnicities in these same regions.

Testing for the presence of HLA-A*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 APO-CARBAMAZEPINE (see 7 WARNINGS AND PRECAUTIONS, Important Limitations of HLA-A and HLA-B Genotyping).

The use of APO-CARBAMAZEPINE should be avoided in patients who are found to be positive for HLA-A*3101, unless the benefits clearly outweigh the risks. Screening is generally not recommended for any current APO- CARBAMAZEPINE users, as the risk of SJS/TEN, AGEP, DRESS and maculopapular rash is largely confined to the first few months of therapy, regardless of HLA-A*3101 status.

See 7 WARNINGS AND PRECAUTIONS, Important Limitations of HLA-A and HLA-B Genotyping. Ancestry and Allelic Variation in the HLA-B Gene In studies that included small samples of carbamazepine-treated patients of Han Chinese and Thai origin, a […]

1 Dosing Considerations, Geriatrics. 2 CONTRAINDICATIONS APO-CARBAMAZEPINE (carbamazepine) is contraindicated in:  Patients who are hypersensitive to carbamazepine or to any of the components of the tablets or suspension. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

g. amitriptyline, trimipramine, imipramine, or their analogues or metabolites). APO-CARBAMAZEPINE and APO-CARBAMAZEPINE CR Page 6 of 52  Patients with hepatic disease, a history of bone-marrow depression, a history of hepatic porphyria (acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda), or serious blood disorder.

 Conjunction with, or immediately after a monoamine oxidase (MAO) inhibitor. See 9 DRUG INTERACTIONS.  Conjunction with itraconazole and voriconazole. See 9 DRUG INTERACTIONS.  Patients presenting atrioventricular heart block. See 7 WARNINGS AND PRECAUTIONS, Cardiovascular.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX HEMATOLOGIC: Although reported infrequently, serious adverse effects have been observed during the use of APO-CARBAMAZEPINE (carbamazepine). Agranulocytosis and aplastic anemia, with a fatal outcome, have occurred very rarely.

Leucopenia, thrombocytopenia, hepatocellular and cholestatic jaundice, and hepatitis have also been reported. However, in the majority of cases, leucopenia and thrombocytopenia were transient and did not signal the onset of either aplastic anemia or agranulocytosis.

It is important that APO-CARBAMAZEPINE (carbamazepine) be used carefully and close clinical and frequent laboratory supervision should be maintained throughout treatment in order to detect as early as possible signs and symptoms of a possible blood dyscrasia.

AP O- CARBAMAZEPINE should be discontinued if any evidence of significant bone marrow depression appears. see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, Bone marrow function.

DERMATOLOGIC:

Steven’s-Johnson Syndrome and Toxic Epidermal Necrolysis: Serious and sometimes fatal dermatologic reactions, including Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), have been reported with carbamazepine. , Taiwan, Malaysia and the Philippines) the risk is estimated to be about 10 times higher.

Human Leukocyte Antigens (HLA)-A*3101 and HLA-B*1502 may be risk factors for the development of serious cutaneous adverse drug reactions. Retrospective genome -wide studies in Japanese and Northern European populations reported an association between severe skin reactions (SJS, TEN, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Acute Generalized Exanthematous Pustulosis (AGEP) and maculopapular rash) associated with carbamazepine use and the presence of the HLA-A*3101 allele in these patients.

Similarly, in studies that included small samples of patients of HanRash Chinese ancestry, a strong association was found between the risk of developing SJS/TEN and the presence of the HLA-B*1502 allele. The HLA-B*1502 allele is found almost exclusively in individuals with ancestry across broad areas of Asia (This provides a rough estimate of the frequency of HLA-B*1502 allele in various populations: from 2 to 12% in Han Chinese APO-CARBAMAZEPINE and APO-CARBAMAZEPINE CR Page 7 of 52 populations, about 8% in Thai populations, and above 15% in the Philippines and some Malaysian populations.

Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in persons from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations sampled and in Japanese (< 1%).

The estimated frequencies have limitations due to the wide variation in allele frequencies that exist within ethnic groups, the difficulties in ascertaining ethnic ancestry and the likelihood of mixed ancestry). It is, therefore, recommended that physicians consider HLA- A*3101 and HLA-B*1502 genotyping as a screening tool in genetically at-risk populations.

See 7 WARNINGS AND PRECAUTIONS, Ancestry and Allelic Variations in the HLA-A Gene and Ancestry and Allelic Variations in the HLA-B Gene. Until further information is available, the use of APO-CARBAMAZEPINE and other anti-epileptic drugs associated with SJS/TEN should be avoided in patients who test positive for the HLA-A*3101 or HLA-B*1502 alleles (see 7WARNINGS AND PRECAUTIONS, Ancestry and Allelic Variations in the HLA-A Gene; Ancestry and Allelic Variation in the HLA-B Gene; Important Limitations of HLA-A and HLA-B Genotyping).

Treatment recommendations for dermatological reactions:

APO-CARBAMAZEPINE should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

The use of other anti-epileptic drugs associated with SJS/TEN should be avoided in patients who have shown severe dermatological reactions during APO - CARBAMAZEPINE treatment.

CARCINOGENICITY:

Long-term toxicity studies in rats indicated a potential carcinogenic risk. See 16 NON-CLINICAL TOXICOLOGY. Therefore, the possible risk of the drug must be weighed against the potential benefits before prescribing APO-CARBAMAZEPINE to individual patients.

4 DOSAGE AND ADMINISTRATION Apotex Inc. is only authorized for APO-CARBAMAZEPINE (carbamazepine tablets, 200 mg) and APO-CARBAMAZEPINE CR (controlled release tablets, 200 mg and 400 mg). Please refer to a product monograph for a carbamazepine oral suspension formulation when needed.

Since a given dose of carbamazepine oral suspension produces higher peak carbamazepine levels than the same […]

APO-CARBAMAZEPINE (carbamazepine) is contraindicated in:  Patients who are hypersensitive to carbamazepine or to any of the components of the tablets or suspension. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

g. amitriptyline, trimipramine, imipramine, or their analogues or metabolites). APO-CARBAMAZEPINE and APO-CARBAMAZEPINE CR Page 6 of 52  Patients with hepatic disease, a history of bone-marrow depression, a history of hepatic porphyria (acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda), or serious blood disorder.

 Conjunction with, or immediately after a monoamine oxidase (MAO) inhibitor. See 9 DRUG INTERACTIONS.  Conjunction with itraconazole and voriconazole. See 9 DRUG INTERACTIONS.  Patients presenting atrioventricular heart block. See 7 WARNINGS AND PRECAUTIONS, Cardiovascular.