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Utah Medicaid Pharmacy & Therapeutics Committee Utah Medicaid Pharmacy & Therapeutics Committee Drug Class Review: Older Anticonvulsants Barbiturates, Anticonvulsants 28:12.04 Primidone (Mysoline®) Hydantoins 28:12.12 Ethotoin (Peganone®) Phenytoin (Dilantin-125®, Dilantin®, Dilantin® Infatabs®, Dilantin® Kapseals®, Phenytek® and generics) Succinimides 28:12:20 Ethosuximide (Zarontin®, Zarontin® Syrup) Methsuximide (Celontin® Kapseals®) Anticonvulsants, Miscellaneous 28:12.92 Carbamazepine (Carbatrol®, Epitrol®, Tegretol®, Tegretol® XR) Valproate Sodium, Valproic Acid, Divalproex Sodium (Depacon®, Depakene®, Depakote®, Depakote® ER, Depakote® Sprinkle, Stavzor®) Anticonvulsants, Miscellaneous 28:12.92 and 54:40.12 Carbonic Anhydrase Inhibitor Acetazolamide (Diamox®) Barbiturates 28:24.04 Pentobarbital (Nembutal® Sodium Solution) Phenobarbital (Luminal® Sodium and generic) Final Report October 2016 Prepared by: Vicki Frydrych BS, PharmD, Clinical Pharmacist University of Utah College of Pharmacy Copyright © 2016 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved 1 Table of Contents Executive Summary ...................................................................................................................................................... 3 Introduction ................................................................................................................................................................... 8 Table 1: Product Comparison ................................................................................................................................. 10 Table 2: Anticonvulsant Labeled Indications ........................................................................................................ 23 Disease Overview ........................................................................................................................................................ 24 Epilepsy ................................................................................................................................................................... 24 Table 3: Classification of Seizures .................................................................................................................... 26 Table 4: Abbreviated Recommendations from Clinical Practice Guidelines ................................................. 29 Table 5: Clinical Practice Guidelines for the Treatment of Epilepsy .............................................................. 29 Bipolar Disorder ...................................................................................................................................................... 39 Table 6. Current Clinical Practice Guidelines for the Treatment of Bipolar Disorder................................... 41 Migraine Prophylaxis .............................................................................................................................................. 43 Pharmacology .............................................................................................................................................................. 44 Pharmacokinetics .................................................................................................................................................... 45 Table 7: Pharmacokinetics ................................................................................................................................. 47 Therapeutic Drug Monitoring and Generic Substitution ...................................................................................... 49 Special Populations ..................................................................................................................................................... 50 Table 8: Special Populations .................................................................................................................................. 54 Methods ....................................................................................................................................................................... 56 Clinical Evidence ........................................................................................................................................................ 56 Safety: .......................................................................................................................................................................... 63 Table 9: Adverse Events ......................................................................................................................................... 67 Table 10: Hepatic Enzyme Drug Interaction Table .............................................................................................. 75 Table 11: Drug Interactions Between Antiepileptic Drugs .................................................................................. 75 Table 12: Drug Interactions Between AEDs and Other Medications .................................................................. 76 Summary: ..................................................................................................................................................................... 77 Appendix I: Evidence.................................................................................................................................................. 79 References.................................................................................................................................................................... 95 2 Executive Summary Introduction Bromide was the first anticonvulsant used clinically in the 19th century followed by phenobarbital in the early 20th century. Further discovery led to the development of less sedating agents of which phenytoin was the earliest. This was followed by the ability to study of “brain waves” and ushered in the era of seizure threshold measurement determinations for antiepileptic activity. Anticonvulsant medications have been identified with various mechanism of action and pharmacologic class This report focuses on the earlier anticonvulsants, including the barbiturates, pentobarbital, phenobarbital, and primidone; the hydantoins ethotoin and phenytoin, the succinimides ethosuximide and methsuximide; and the miscellaneous anticonvulsant agents acetazolamide, carbamazepine, and valproic acid derivatives. Each of the ten agents are available in oral tablet or capsule formulations. Five of the ten agents are available for administration as oral liquid formulations; carbamazepine and phenytoin as suspensions, ethosuximide and valproic acid as syrups, and phenobarbital as an elixir. Divalproex is available in a sprinkle formulation. Carbamazepine and phenytoin are available as chewable tablets and extended release tablets. Divalproex is additionally formulated as a delayed- release tablet. Acetazolamide and carbamazepine are available as extended-release capsules and valproic acid and divalproex as delayed-release capsules. Four agents are available for injection: acetazolamide, pentobarbital, phenytoin, and valproate sodium. These medications are each FDA approved for use in at least one seizure disorder: epilepsy (unspecified) for acetazolamide and primidone; generalized, tonic-clonic seizures for phenytoin; status epilepticus for pentobarbital and phenytoin; complex-partial seizures for ethotoin, phenytoin, and valproic acid derivatives; absence seizures for ethosuximide and valproic acid derivatives; refractory absence seizures for methsuximide; grand mal seizures for ethotoin; partial, generalized and mixed epilepsies for carbamazepine; partial and generalized seizures for phenobarbital; and treatment and prophylaxis of seizures during and following neurosurgery for phenytoin. Additional indications for acetazolamide include the treatment of acute mountain sickness, edema, and as adjunct therapy in glaucoma. Additional indications for carbamazepine include bipolar I disorder with acute manic or mixed episodes and trigeminal neuralgia Additional indications for pentobarbital include adjunct therapy in anesthesia, short-term treatment of insomnia, and sedation. Additional indications for valproic acid and divalproex include bipolar I disorder with acute manic or mixed episodes as well as migraine prophylaxis. Finally, phenobarbital is additionally indicated for use in sedation. Treatment of epilepsy depends on the type of epilepsy of epilepsy syndrome identified. Pharmacotherapy may reduce the likelihood of recurrent seizures, associated morbidity and mortality, improve quality of life and reduce the risk of sudden unexpected death in epilepsy (SUDEP). According to Clinical Practice Guidelines, decision making concerning antiepileptic therapy should involve the patient, parent and caregivers; consider race, genetic variability, culture and specific needs; involve the development of a comprehensive care plan involving primary and 3 secondary practitioners and individualize treatment considering seizure type, syndrome, patient age, concomitant medications, comorbidity, patient lifestyle and preferences. Important safety issues in patients with epilepsy, include adverse events, bone health, psychological issues, pregnancy, idiosyncratic and hypersensitivity reactions. The newer antiepileptic medications have not been shown clinically superior to the older agent’s newer agents are considered to have a safety advantage. A summary of some of the first-line treatment recommendations are summarized below (agents
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