CLOBAZEM
ESLICARBAZEPINE
EZOGABINE
FELBAMATE
GABAPENTIN
LACOSAMIDE
LAMOTRIGINE
LEVITERACETAM
OXCARBAZEPINE
PREGABALIN
PERMPANEL
RUFINAMIDE
TOPIRAMATE
VIGABATRIN
- Cytochrome P450 enzyme substrate: CYP3A4, CYP2C19, and CYP2B6
- Action to be taken: Caution with close monitoring for side effects.Potential dose reduction
- Rationale: Extrapolation from pharmacogenomics data found that clobazam with moderate or potent inhibitors of CYP2C19 resulted in 5-fold increase in exposure to N-desmethylclobazam. In vitro study has shown that CBD may be a potent inhibitor of CYP2C19. Therefore based on available data, adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. A dosage reduction of clobazam may be necessary.
ESLICARBAZEPINE
- Cytochrome P450 enzyme substrate: CYP3A4 and CYP2C19
- Action to be taken: Caution with close monitoring for side effects.Potential dose reduction
- Rationale:In vitro studies in human liver microsomes, eslicarbazepine had no clinically relevant inhibitory effect on
the activity of CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, and CYP3A4, and only a moderate inhibitory effect on CYP2C19. APTIOM can inhibit CYP2C19, which can cause increased plasma concentrations of drugs that are metabolized by this isoenzyme. In vivo studies suggest that APTIOM can induce CYP3A4, decreasing plasma concentrations of drugs that are metabolized by this isoenzyme. In vitro studies show that cannabis is extensively metabolized by CYP3A4 and CYP2C19. Furthermore it was shown that CBD is a potent inhibitor of CYP2C19. Therefore based on available data, cannabis and eslicarbazepine may exhibit drug -drug interactions.
EZOGABINE
- Action to be taken: No action needed
- Rationale: Ezogabine is extensively metabolized primarily via glucuronidation and acetylation in humans. A substantial fraction of the ezogabine dose is converted to inactive N-glucuronides, the predominant circulating metabolites in humans. In vitro studies showed no evidence of oxidative metabolism of ezogabine or NAMR by cytochrome P450 enzymes. Coadministration of ezogabine with medications that are inhibitors or inducers of cytochrome P450 enzymes is therefore unlikely to affect the pharmacokinetics of ezogabine.
FELBAMATE
- Cytochrome P450 enzyme substrate: CYP3A4 and CYP2E1
- Action to be taken: Caution
- Rationale: In vitro studies show that felbamate is a substrate for CYP3A4 and CYP2E1. Compounds which induce CYP3A4 (e.g. carbamazepine, phenytoin and phenobarbital) increase felbamate clearance. However, the CYP3A4 inhibitors gestodene, ethinyl estradiol and erythromycin have little or no effect on felbamate trough plasma concentrations, consistent with the fact that the pathway is relatively minor for felbamate under normal (non-induced) conditions. In vitro studies show that cannabis is extensively metabolized by CYP3A4 and CYP2C19. Furthermore cannabis and its components weakly inhibit these enzymes. However cannabis has not shown to induce the activity of CYP3A4 or CYP2E1. Therefore based on available data, its unlikely that felbamate and cannabis will interact with each other. However caution is adivsed since both of these drugs are substrates of CYP450 enzymes.
GABAPENTIN
- Cytochrome P450 enzyme substrate: CYP2A6
- Action to be taken: Interaction unlikely
- Rationale:Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective markersubstrates and human liver microsomal preparations. Only at the highest concentration tested was a slight degree of inhibition (14%-30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed. Based on available data its unlikely that marijuana will interact with gabapentin
LACOSAMIDE
- Cytochrome P450 enzyme substrate: CYP3A4, CYP2C9, and CYP2C19
- Action to be taken: Caution with close monitoring, particularly patients with renal or hepatic impairment. Possible dose reduction.
- Rationale: Lacosamide is a CYP3A4 substrate. Patients with renal or hepatic impairment may have significantly exposure to lacosamide if co-administered with a strong CYP3A4 inhibitor. In vitro studies show that cannabis is extensively metabolized by CYP3A4 and CYP2C19 and may be a weak inhibitor of these enzymes. A dosage reduction of lacosamide may be necessary in patients with renal or hepatic impairment.
LAMOTRIGINE
- Action to be taken: Caution, monitor CNS effects
- Rationale: Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that induce or inhibit
glucuronidation may affect the apparent clearance of lamotrigine. The most commonly observed adverse experiences seen in association with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Cannabis does not have an effect on glocuronidation however it can cause similar side effects as lamictal. Therefore concomitant administration should be used in caution as additive CNS effects may impair ability to drive and use machines and increase risk off falls.
LEVITERACETAM
- Action to be taken: No action needed, interaction unlikely
- Rationale: Levetiracetam is not extensively meta bolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models.Levetiracetam and its major metabolite, at concentrations well above C max levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms. The most common side effects seen in people who take KEPPRA include sleepiness, weakness, dizziness, infection. Cannabis can cause similar side effects as leviteracetam. Therefore concomitant administration should be used in caution as additive CNS effects may impair ability to drive and use machines and increase risk off falls.
OXCARBAZEPINE
- Cytochrome P450 enzyme substrate: CYP3A4 and CYP2C19
- Action to be taken: Caution with monitor for side effects.Potential dose reduction
- Rationale: Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs.The data demonstrates that oxcarbazepine and its pharmacologically active metabolite have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by oxcarbazepine did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine can cause increased plasma concentrations of drugs that are substrates of CYP2C19. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine. In vitro studies have shown that cannabis undergoes metabolism by CYP3A4 and CYP2D6. Therefore based on available data, cannabis concentration may be increased when used in combination with oxcarbazepine
PREGABALIN
- Action to be taken: Caution with monitor for side effects.Potential dose reduction
- Rationale: Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. Pregabalin, at concentrations that were, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates or CYP3A4 substrates is not anticipated. Lyrica, and cannabis may cause dizziness and somnolence. Inform patients that these additive side effects may impair their ability to perform tasks such as driving or operating machinery and increase the risk of falls.
PERMPANEL
- Cytochrome P450 enzyme substrate: CYP3A4, CYP3A5, CYP1A2, and CYP2B6
- Action to be taken: Caution with monitoring for side effects; potential dose reduction
- Rationale: In vitro studies have shown that cannabis is a weak inhibitor of CYP3A4. Ketoconazole, a potent CYP3A4 inhibitor, has been shown to prolong half-life and decrease perampanel metabolism. Patients taking cannabis and perampanel are advised to be closely monitored for adverse effects; perampanel dosage adjustment may be necessary.
RUFINAMIDE
- Cytochrome P450 enzyme substrate: CYP3A4, CYP2E1
- Action to be taken: Caution with monitoring for side effects; potential dose reduction
- Rationale: Rufinamide is a weak inhibitor of CYP2E1. It did not show significant inhibition of other CYP enzymes. Rufinamide is a weak inducer of CYP3A4 enzymes.Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital, appear to increase the clearance of Banzel. However given that the majority of clearance of Banzel is via a non-CYP -dependent route, the observed decreases in blood levels seen with carbamazepine, phenytoin, phenobarbital, and primidone are unlikely to be entirely attributable to induction of a P450 enzyme. In vitro studies have shown that cannabis undergoes metabolism by CYP3A4 and CYP2D6. Therefore based on available data, cannabis concentration may be increased when used in combination with rufinamide.
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Caution with close monitoring
- Rationale: Tiagabine is a substrate of CYP3A4.Reduced metabolism of tiagabine may occur when inhibitors of CYP3A4 isoenzyme are administered concomitantly. Cannabis is a weak inhibitor of CYP3A4 and may reduce metabolism of tiagabine. The clinical significance of potential interactions are not known.
TOPIRAMATE
- Action to be taken: Caution with close monitoring
- Rationale:Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine. In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, topiramate should be used with extreme caution if used in combination with CNS depressants.
VIGABATRIN
- Cytochrome P450 enzyme substrate: CYP2C9
- Action to be taken: Caution, monitor CNS side effects
- Rationale: Vigabatrin induces CYP2C9, but does not induce other hepatic cytochrome P450 enzyme systems. Adverse reactions associated with the use of SABRIL in combination with other AEDs were headache, somnolence, fatigue, dizziness. Certain cannabinoids undergo metabolism by CYP2C9, thus their concentration may be reduced when combined with vigabatrin. Additionally cannabis has potential to cause CNS depression, therefore vigabatrin and cannabis should be used in caution as the additive side effects may impair patients' ability to perform tasks such as driving or operating machinery and increase the risk of falls.
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Caution, monitor CNS side effects
- Rationale: Reduction of zonisamide to its metabolite is mediated by cytochrome P450 isozyme 3A4 . Zonisamide
did not inhibit mixed-function liver oxidase enzymes (cytochrome P450), as measured in human liver microsomal preparations, in vitro. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. Concurrent medication with drugs that either induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. In vitro studies show that cannabis is a weak inhibitor of CYP3A4 and may therefore increase serum concentrations of zonisamide. Additionally zonisamide and cannabis have potential to cause CNS depression. Therefore combination of these medications should be used in caution as the additive side effects may impair patients' ability to perform tasks such as driving or operating machinery and increase the risk of falls.
References
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