PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION APO-CLOBAZAM Clobazam Tablets, 10 mg Apotex Standard Prescribed Antiepileptic Apotex Inc. DATE OF REVISION: 150 Signet Drive June 29, 2017 Toronto, Ontario M9L 1T9 Control #: 205755 1 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION.................................................................... 3 SUMMARY PRODUCT INFORMATION ..................................................................................... 3 INDICATIONS AND CLINICAL USE ........................................................................................... 3 CONTRAINDICATIONS .............................................................................................................. 3 WARNINGS AND PRECAUTIONS ............................................................................................. 3 ADVERSE REACTIONS ............................................................................................................. 8 DRUG INTERACTIONS ............................................................................................................ 11 DOSAGE AND ADMINISTRATION ........................................................................................... 13 OVERDOSAGE ......................................................................................................................... 14 ACTION AND CLINICAL PHARMACOLOGY ........................................................................... 15 STORAGE AND STABILITY ..................................................................................................... 17 SPECIAL HANDLING INSTRUCTIONS ................................................................................... 17 DOSAGE FORMS, COMPOSITION AND PACKAGING .......................................................... 17 PART II: SCIENTIFIC INFORMATION ......................................................................................... 18 PHARMCEUTICAL INFORMATION ......................................................................................... 18 CLINICAL TRIALS ..................................................................................................................... 18 DETAILED PHARMACOLOGY ................................................................................................. 19 TOXICOLOGY ........................................................................................................................... 23 REFERENCES .......................................................................................................................... 26 PATIENT MEDICATION INFORMATION ..................................................................................... 28 2 APO-CLOBAZAM Clobazam Tablets 10 mg PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength All Non-medicinal Ingredients Oral Tablet - 10 mg colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate (spray-dried), magnesium stearate, microcrystalline cellulose (PH 102). INDICATIONS AND CLINICAL USE APO-CLOBAZAM (clobazam) is indicated for: adjunctive therapy in patients with epilepsy who are not adequately stabilized with their current anticonvulsant therapy. Geriatrics (> 65 years of age): The efficacy of clobazam in adults aged 65 and over has not been established (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY sections). CONTRAINDICATIONS Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. These reactions may not be limited to rash, urticaria, and hypotension. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. myasthenia gravis (risk of aggravation of muscle weakness) narrow angle glaucoma any history of drug or alcohol dependence (increased risk of development of dependence); severe respiratory insufficiency sleep apnoea syndrome (risk of deterioration) severe impairment of liver function (risk of precipitating encephalopathy) during first trimester of pregnancy and breast-feeding (see WARNINGS AND PRECAUTIONS section). WARNINGS AND PRECAUTIONS General Clobazam can cause muscle weakness. Clobazam is contraindicated in patients with myasthenia gravis. In patients with pre-existing muscle weakness or with spinal or cerebellar ataxia, special observation is required and a dose reduction may be necessary (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION sections). 3 Additive effects are to be expected if clobazam is combined with alcohol or drugs with central nervous system depressant effects. Moreover, concomitant consumption of alcohol can increase the serum levels of clobazam by 50%. Patients should therefore be advised against consumption of alcohol during treatment with clobazam due to an increased risk of sedation and other adverse effects (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS sections). Clobazam possesses a mild central nervous system depressant effect. Under experimental conditions, impairment of alertness has been observed to be less pronounced after therapeutic doses of clobazam than after other benzodiazepines. Nevertheless, even when used as directed, clobazam may alter reactivity to such an extent as to impair driving performance or the ability to operate machinery, especially when it is taken in conjunction with alcohol. Therefore patients should be cautioned against driving, operating dangerous machinery or engaging in other hazardous activities, particularly in the dose adjustment period, or until it has been established that they do not become drowsy, dizzy or develop muscle weakness. Dependence/Tolerance Physical and psychological dependence are known to occur in persons taking benzodiazepines. Clobazam should not be administered to individuals prone to drug abuse. Caution should be observed in all patients who are considered to have potential for psychological dependence. The risk of dependence increases with the dose and duration of treatment. However, this risk is present even with daily intake of clobazam over periods of only a few weeks, and applies not only to possible abuse with particularly high doses but also to the therapeutic dose range. The risk of dependence is increased in patients with a history of alcohol or drug abuse. As with other benzodiazepines, the therapeutic benefit must be balanced against the risk of habituation and dependence during prolonged use. These patients or those who may increase the dose on their own initiative must be closely monitored. On withdrawal of benzodiazepines, especially if abrupt, a rebound phenomenon or a withdrawal syndrome may occur. A withdrawal syndrome may also occur when abruptly changing over from a benzodiazepine with a long duration of action (for example, clobazam) to one with a short duration of action. The rebound phenomenon is characterized by a recurrence in enhanced form of the symptoms which originally led to clobazam treatment (i.e. seizures). This may be accompanied by other reactions including mood changes, anxiety, or sleep disturbances and restlessness. Once physical dependence has developed, abrupt termination of clobazam treatment will lead to withdrawal symptoms. These may include headaches, insomnia, sleep disturbances, increased dreaming, restlessness, tension, mental impairment, confusion, extreme anxiety, excitability, irritability, nervousness, agitation, derealization, depersonalization, hallucinations and symptomatic psychoses (e.g. withdrawal delirium), numbness and tingling sensations in the extremities, muscle pain, tremors, sweating, diarrhea, abdominal cramps, vomiting, nausea, hyperacusis, hypersensitivity to light, noise and physical contact, convulsions, as well as epileptic seizures. As with other benzodiazepines, clobazam should be withdrawn gradually (see WARNINGS AND PRECAUTIONS section). 4 Loss of part or all of the anticonvulsant effectiveness of clobazam has been described in patients who have been receiving the drug for some time. There is no absolute or universal definition for the phenomenon and reports vary widely on its development. The reported success of clobazam in intermittent therapy in catamenial epilepsy implies that tolerance may be minimized by intermittent treatment but long-term follow-up is unreported. No studies have identified or predicted which patients are likely to develop tolerance or precisely when this might occur. Hepatic/Biliary/Pancreatic Clobazam is contraindicated in patients with severe liver dysfunction. In patients with a lesser degree of liver dysfunction (mild to moderate hepatic impairment), responsiveness to clobazam and susceptibility to adverse effects are increased. These patients require low initial doses and gradual dose increments under careful observation (see CONTRAINDICATIONS, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY sections). In long-term treatment, hepatic function must be checked regularly. Neurologic In clinical trials, somnolence or sedation was reported at all effective doses, especially at the beginning of treatment with clobazam and when higher doses are used. Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants. Patients should be advised that sedation can occur, particularly early in treatment or with dose increases. Prescribers should caution patients against engaging in hazardous activities requiring mental