Is there any known risk of interaction between oral contraceptives and modafinil, amphetamine or cl

Fråga: Is there any known risk of interaction between oral contraceptives and modafinil, amphetamine or clonazepam?

Sammanfattning: There are no clinical reports of drug interactions of oral contraceptives and modafinil, amphetamine or clonazepam published in the literature. Impaired contraceptive effect upon concomitant use of modafinil is possible due to a metabolic drug interaction, although the risk is probably low. Clinically important interactions between oral contraceptives and amphetamine or clonazepam are not expected to occur.

Svar: In a thorough literature search, including Drugline, Medline, Embase and other pharmacological sources, no clinical reports on drug interactions between oral contraceptive agents and the patients other medications have been found.

Oral contraceptive agents are metabolised by cytochrome P-450 isoenzyme CYP3A4 and through glucuronidation (1).

Modafinil is metabolised presumably in the liver, but it is not clear which enzymes are involved in the metabolism (2). However, in vitro studies have shown that modafinil can induce CYP3A4 (2-4), but is not metabolised by cytochrome enzymes (3). The induction of CYP3A4 can last for two weeks after withdrawal of modafinil (3). Pharmacokinetic parameters of ethinylestradiol and triazolam during concomitant use of modafinil have been followed in a placebo controlled single blind study (5). Forty-one female subjects, who were on long-term treatment with oral contraceptives (ethinylestradiol 35 ug and norgestimate 180-250 ug), received a single oral dose of triazolam 125 ug one day before initiation of treatment with modafinil 200 mg for seven days followed by 400 mg for 21 days or placebo during 28 days. A second dose of triazolam was administered with the final dose of modafinil. The pharmacokinetic profile showed a marked decrease in maximum plasma concentration and area under the plasma concentration time curve for triazolam but a much smaller decrease for ethinylestradiol. The plasma half-life of triazolam was decreased, but the half-life of ethinylestradiol did not appear to be affected by modafinil. It is therefore suggested that this metabolic drug interaction appears to be more gastrointestinal than hepatic in nature and drug interactions are more likely to occur with compounds that undergo significant gastrointestinal CYP3A4 mediated first pass-metabolism. The risk for a metabolic interaction is therefore probably low. However, there is a single case report describing an organ transplant recipient who experienced a 50% reduction in her cyclosporine blood levels following one month of therapy with modafinil 200 mg daily (6). Whether the patient was treated with other influencing drugs is not mentioned. Thus, impaired contraceptive effect upon concomitant use of modafinil cannot be ruled out. According to the SPC (summary products characteristics) another anticonceptional method than oral contraceptives is recommended if modafinil treatment is initiated (8).

Clonazepam can possibly potentitate other centrally acting agents such as amphetamine (3). Clonazepam is completely metabolised, but by which enzymes is not known (3,9). Theoretically there is no obvious risk for a metabolic interaction between clonazepam and oral contraceptives. A few case reports of contraceptive failure after concomitant medication with oral contraceptives and antiepileptic agents that strongly induce CYP3A4 are documented in the literature (7,10). However, clonazepam is not known to induce CYP3A4 and a risk of a clinical important metabolic drug interaction is not expected. It has been suggested that oral contraceptive agents could increase sensitivity to bensodiazepines due to increased plasma concentration of benzodiazepines (8,10-12). The mechanism as well as the clinical relevance of this is unclear.

Amphetamine is excreted both metabolised and unchanged in the urine (13). Studies have indicated that more than one enzyme (e.g. CYP2D6, CYP2C9) are involved in its metabolism. Metabolic interactions between amphetamine and oral contraceptives, if there are any, should be of minor significance.

There is no theoretical ground for a pharmacodynamic interaction between oral contraceptives and modafinil, amphetamine or clonazepam of receptor or transduction levels. 1 Shenfield GM. Oral contraceptives. Are drug interactions of clinical significance? Drug Saf 1993;9:21-37. 2 Drugline 17564 (year 2000) 3 FASS 2002 (The Swedish catalogue of approved medical products) 4 Robertson P, Decory HH, Madan A, Parkinson A. In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug Metab Disp 2000;28:664-71. 5 Robertson P Jr, Hellriegel ET, Arora S, Nelson M. Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers. Clin Pharmacol Ther 2002;71:46-56.

6 Cyclosporine. Drugdex(R) System; Micromedex, Inc., Englewood, Colorado (edition expires (9/2002)
7 Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002;16:263-72.
8 SPC, Summary products characteristics: modafinil.
9 Drugline no 13111 (year 1996)

10 Sjöqvist F. Interaktion mellan läkemedel. In: FASS 2002 (The Swedish catalogue of approved medical products). p. 1481-1556 11 Karalliedde L, Henry J, editors. Handbook of drug interactions. London: Arnold Publishers; 1998 12 Stoehr GP, Kroboth PD, Juhl RP, Wender DB, Phillips JP, Smith RB. Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics. Clin Pharmacol Ther 1984;36:683-90. 13 Drugline no 17826 (year 2001)