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Clinically Important Drug Interactions With Antiepileptic Drugs 

Clinically Important Drug Interactions With Antiepileptic Drugs
Chapter:
Clinically Important Drug Interactions With Antiepileptic Drugs
Author(s):

Ali A. Asadi-Pooya

and Michael R. Sperling

DOI:
10.1093/med/9780190214968.003.0006
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Drug interactions can occur whenever two or more drugs are administered simultaneously. Most clinically important antiepileptic drug (AED) interactions with other drugs result from induction or inhibition of drug metabolizing hepatic enzymes or significant protein binding properties. However, other mechanisms, including pharmacodynamic interactions, sometimes play a role. Unfortunately, many AEDs are substrates, inducers, or inhibitors of hepatic enzymes and have significant protein binding (Table 6.1). Therefore, drug interactions are common in patients with epilepsy (Patsalos et al., 2002; Anderson et al., 2004; Perucca, 2005; Patsalos 2013). Drug interactions that cause more than a 50% change in drug exposure (area under the plasma drug concentration-versus-time curve [AUC]) or plasma levels usually require dosage adjustments (Bialer, 2005). Typically, cytochrome P-450 enzyme inducers (e.g., carbamazepine, phenytoin, phenobarbital, oxcarbazepine, topiramate) take days to weeks to upregulate the target enzymes; however, enzyme inhibitors (e.g., valproate) have a more immediate effect. Therefore, for example, initiation of as little as 500 mg of valproate per day may necessitate an immediate 50% reduction of the dose of chronically used lamotrigine (Pollard & Delanty, 2007).

Table 6.1 Effects of Antiepileptic Drugs on Hepatic Enzymes and Enzymes Involved in Antiepileptic Drugs Metabolism

Antiepileptic Drug

Effect

Induces

Inhibits

Enzymes involved in metabolism

Acetazolamide

CYP3A4

Carbamazepine

CYP1A2, CYP2C, CYP3A4, UGTs

CYP1A2, CYP2C8, CYP3A4

Clonazepam

CYP3A4

Eslicarbazepine acetate

CYP3A4

CYP2C19

Esterases, Uridine diphosphate- glucuronosyltransferase

Ethosuximide

CYP3A4, CYP2B, CYP2E1

Ezogabine

uridine 5’-diphosphate (UDP)- glucuronyltransferases

Phenobarbital/primidone

CYP1A2, CYP2A6, CYP2B, CYP2C, CYP3A4, UGTs

CYP2C9, CYP2C19, CYP2E1

Phenytoin

CYP1A2, CYP2B, CYP2C, CYP3A4, UGTs

CYP2C8, CYP2C9, CYP2C19

Valproic acid

CYP2C9, UGTs, epoxide hydrolase

CYP2A6, CYP2C9, CYP2C19, UGTs, mitochondrial oxidases

Felbamate

CYP3 A4

CYP2C19, β‎-oxidation

CYP2E1, CYP3A4

Gabapentin

Lacosamide

CYP3A4, CYP2C9, and CYP2C19

Lamotrigine

UGTs (weak inducer)

UGTs

Levetiracetam

Oxcarbazepine

CYP3A4, UGTs

CYP2C19

UGTs

Perampanel

CYP2B6 and CYP3A4/5 and UGTs (weak inducer)

CYP2C8, CYP3A4 and UGTs (weak inhibitor)

CYP3A4 and/or CYP3A5

Pregabalin

Rufinamide

CYP 3A4 (weakly)

CYP 2E1 (weakly)

Carboxylesterases

Tiagabine

CYP3A4

Topiramate

CYP3A4,* β‎-oxidation

CYP2C19

Inducible CYP isoforms

Vigabatrin

Zonisamide

CYP3A4

CYP, cytochrome P-450 isozyme; UGT, UDP glucuronosyltransferase.

*Dose-dependent induction.

Lacosamide, levetiracetam, pregabalin, vigabatrin, and gabapentin do not usually produce clinically significant interactions with other drugs. Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 (e.g., valproate) may have a significant increase in exposure to lacosamide. Dose reduction may be necessary in these patients. Eslicarbazepine acetate, ezogabine, lamotrigine, perampanel, rufinamide, tiagabine, topiramate, and zonisamide have moderate drug interactions. Phenobarbital, phenytoin, carbamazepine, primidone, valproate, and felbamate have extensive and important interactions with many drugs.

Clinically Important Interactions Between Antiepileptic Drugs and Other Drugs

Interactions Resulting in Decreased Antiepileptic Drug Plasma Levels

Co-administration of the combined contraceptive pills causes a decrease in serum lamotrigine level by about 50%, which is likely due to the stimulation of uridine glucuronosyltransferase activity by the steroids. This interaction can result in reduced seizure control in some women. Other examples for a clinically important decrease in serum AED concentration due to drug interactions include the marked inhibition of the gastrointestinal absorption of phenytoin, carbamazepine, and phenobarbital given concurrently with antacids; the decrease in serum valproic acid concentration after addition of some antibiotics of the carbapenem class; the decrease in serum phenytoin levels after the addition of ciprofloxacin; the decrease in serum perampanel levels after the addition of rifampin; and decreased serum carbamazepine, perampanel, and phenytoin levels due to increase in their metabolism by St. John’s wort (an over-the-counter herb purported as possibly useful in mood stabilization and stress relief) (Novak et al., 2004; Perucca, 2005; Pollard and Delanty, 2007; Patsalos, 2013).

Interactions Resulting in Increased Antiepileptic Drug Plasma Levels

Interactions resulting in elevated serum AED concentrations have been reported mostly with carbamazepine, phenytoin, and phenobarbital. Clarithromycin and erythromycin can increase carbamazepine plasma levels and cause serious adverse effects by inhibiting metabolism of this agent. Similarly, fluoxetine, trazodone, fluconazole, ketoconazole, isoniazid, metronidazole, cimetidine, and verapamil can increase carbamazepine plasma levels. Omeprazole, cimetidine, allopurinol, amiodarone, ketoconazole, fluconazole, isoniazid, sertraline, fluoxetine, fluorouracil, and tamoxifen may increase phenytoin levels by inhibiting its metabolism, and sertraline and antiretroviral protease inhibitors may inhibit lamotrigine metabolism and increase its plasma concentrations (Novak et al., 2004; Perucca, 2005; Pollard and Delanty, 2007). Diltiazem, an inhibitor of CYP3A4, has been reported to increase plasma carbamazepine and phenytoin levels significantly, resulting in toxicity (Novak et al., 2004). Acetazolamide may increase plasma carbamazepine levels by a similar mechanism (Spina et al., 1996). Chloramphenicol may increase plasma phenobarbital levels, and cimetidine, isoniazid, and sertraline may increase plasma valproate levels (Pollard and Delanty, 2007).

Interactions Resulting in Decreased Plasma Levels of Other Drugs

Patients treated with enzyme-inducing AEDs are susceptible to important drug-drug interactions mediated by hepatic microsomal enzyme induction. The list of such interactions is extensive (Table 6.2). Because of practical difficulties in compensating for such interactions, effective use of some of these drugs may not be feasible in enzyme-induced patients (Novak et al., 2004). In some patients (e.g., patients with HIV/AIDS [Mullin et al., 2004; Romanelli et al., 2000] or those requiring anticancer therapy [Oberndorfer et al., 2005; Sperling and Ko, 2006]), the use of AEDs without enzyme-inducing properties is clearly preferred. AEDs that induce metabolism of at least one of the components of contraceptive pills include carbamazepine, eslicarbazepine acetate, felbamate, lamotrigine, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide, and topiramate (doses >200 mg/day). In patients taking both oral contraceptive pills and one of these AEDs, a double-barrier method or an IUD may be necessary for effective birth control (Pollard and Delanty, 2007).

Table 6.2 Drugs With Which Hepatic Enzyme Inducer Antiepileptic Drugs Have Clinically Important Interactions

Drug Category

Specific Drugs

Anticoagulant drugs

Dicoumarol, warfarin

Antidepressant drugs

Amitriptyline, amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine, mianserin, nortriptyline, protriptyline, trimipramine

Antiepileptic drugs

Carbamazepine, ethosuximide, felbamate, lamotrigine, phenytoin, tiagabine, topiramate, valproic acid, zonisamide

Anti-infectious agents

Albendazole, doxycycline, griseofulvin, itraconazole, ketoconazole, mebendazole, metronidazole, voriconazole

Antineoplastic agents

9-Aminocampthotecin, busulfan, cyclophosphamide, etoposide, ifosfamide, irinotecan, methotrexate, nitrosoureas, paclitaxel, procarbazine, tamoxifen, teniposide, thiotepa, topotecan, vinca alkaloids, vincristine

Antipsychotic agents

Chlorpromazine, clozapine, haloperidol, risperidone, quetiapine

Antivirals

Amprenavir, atazanavir, delavirdine, indinavir, nelfinavir, ritonavir, saquinavir, zidovudine

Benzodiazepines

Alprazolam, clonazepam, diazepam, lorazepam, midazolam

Calcium channel blockers

Amlodipine, bepridil, diltiazem, felodipine, isradipine, nisoldipine, nicardipine, nifedipine, nimodipine, nivaldipine, nitrendipine, verapamil

Cardiovascular drugs

Amiodarone, atorvastatin, digoxin, disopyramide, lovastatin, procainamide, propranolol, metoprolol, timolol, quinidine, simvastatin

Corticosteroids

Cortisone, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone

Immunosuppressants

Cyclosporine, sirolimus, tacrolimus

Oral contraceptives

Conjugated estrogens, ethinyl estradiol, levonorgestrel, norethindrone

Miscellaneous

Methadone, theophylline

Interactions Resulting in Increased Plasma Levels of Other Drugs

Valproic acid, due to its enzyme-inhibiting properties, may increase the plasma levels of a variety of drugs, including lorazepam, nimodipine, paroxetine, amitriptyline, nortriptyline, nitrosoureas, and etoposide. For some, such as amitriptyline and nortriptyline, and for some antineoplastic drugs, these interactions may cause toxicity (Perucca, 2005; Drug Facts and Comparisons, 2007). In addition, valproate is a highly protein-bound agent and may displace some drugs (e.g., warfarin) from their binding sites leading to an increased effect (Drug Facts and Comparisons, 2007). N-acetyl metabolite of ezogabine inhibited P-glycoprotein—mediated transport of digoxin in a concentration-dependent manner, indicating that this metabolite may inhibit renal clearance of digoxin. Serum levels of digoxin should be monitored when ezogabine is prescribed simultaneously.

Drug Interactions Between AEDs

Most clinically important antiepileptic drug (AED) interactions with other AEDs result from induction or inhibition of drug metabolizing hepatic enzymes. Because often the treatment of epilepsy is lifelong and patients are commonly prescribed polytherapy with other AEDs, interactions are an important consideration in the treatment of epilepsy. For new AEDs, their propensity to interact is particularly important because they are often prescribed as adjunctive polytherapy (Box 6.1) (Patsalos, 2013).

Adapted from: Patsalos PN. Clin Pharmacokinet. 2013; 52(11): 927–966.

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