Based on varenicline pharmacokinetic characteristics, and clinical experience to date, it appears unlikely that CHAMPIX would produce or be subject to clinically meaningful drug interactions.
Drug interaction studies were performed with varenicline and: cimetidine, metformin, digoxin, warfarin, transdermal nicotine and bupropion.
No clinically meaningful pharmacokinetic drug interactions have been identified, other than potential for interaction with cimetidine in patients with severe renal impairment (see Cimetidine, below).
Drugs cleared by, or which affect, cytochrome P450 enzymes
In vitro studies demonstrated that varenicline does not inhibit cytochrome P450 enzymes (IC50 >6400 ng/mL). The P450 enzymes tested for inhibition were: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline did not induce the activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline is unlikely to alter the pharmacokinetics of compounds that are primarily metabolized by cytochrome P450 enzymes.
Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHAMPIX (see ACTION AND CLINICAL PHARMACOLOGY: Pharmacokinetics) and therefore a dose adjustment of CHAMPIX should not be required for these types of drugs.
Drugs cleared by, or which affect, renal secretion
In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (eg, metformin - see below) are unlikely to be affected by varenicline.
In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter, hOCT2. In patients with normal renal function coadministration with inhibitors of hOCT2 does not require a dose adjustment of CHAMPIX as the increase in systemic exposure to CHAMPIX is not expected to be clinically meaningful except in cases of severe renal impairment (see Cimetidine, and Other Inhibitors of hOCT2 below).
Patients should be advised that alcohol intake may increase the risk of experiencing psychiatric adverse events during treatment with CHAMPIX (See WARNINGS and PRECAUTIONS, Psychiatric Symptoms in Patients with and without Pre-existing Psychiatric Disorder or Symptoms ; see also Patient Counselling Information).
Drug-drug interaction studies were limited to approximately two-week studies in healthy young adult volunteers who smoked.
Single dosing for one of the two drugs:
Cimetidine: Co-administration of varenicline (2 mg single dose) with an hOCT2 inhibitor, cimetidine (300 mg four times daily (QID) at steady-state) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance. No dosage adjustment is recommended based on concomitant cimetidine administration in subjects with normal renal function or in patients with mild to moderate renal impairment. In patients with severe renal impairment, the concomitant use of cimetidine and varenicline should be avoided (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment: Special Populations, Patients with Impaired Renal Function).
Other inhibitors of hOCT2: Other inhibitors of hOCT2 have not been directly studied. Cimetidine causes greater in vivo drug interactions with renally cleared compounds than other inhibitors of hOCT2. Consequently, co-administration of other inhibitors of hOCT2 with varenicline would not require dosage adjustment in patients with normal renal function or moderate renal impairment. In patients with severe renal impairment, the concomitant use of varenicline and other inhibitors of hOCT2, such as trimethoprim, ranitidine or levofloxacin should be avoided (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment: Special Populations, Patients with Impaired Renal Function).
Co-administration with Other Drugs Eliminated via hOCT2: Based on the lack of interaction between varenicline and metformin, interactions between varenicline and other cationic drugs eliminated via hOCT2 are unlikely.
Warfarin: Varenicline (1 mg BID steady-state) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by CHAMPIX. Smoking-cessation itself may result in changes to warfarin pharmacokinetics (see WARNINGS AND PRECAUTIONS).
Multiple dosing for both drugs:
Metformin: When co-administered to 30 smokers, varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of metformin (500 mg BID), which is a substrate of hOCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.
Digoxin: Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose in 18 smokers. Steady-state pharmacokinetics of varenicline remained unchanged by digoxin co-administration.
Use with other therapies for smoking-cessation:
Safety and efficacy of varenicline in combination with other smoking-cessation therapies, such as bupropion or nicotine replacement therapy, have not been studied.
Bupropion: Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of bupropion (150 mg BID) in 46 smokers. Steady-state pharmacokinetics of varenicline remained unchanged by bupropion co-administration.
Nicotine replacement therapy (NRT): When varenicline (1 mg BID) and NRT (transdermal, 21 mg/day) were co-administered to 24 smokers for 12 days, there was a statistically significant decrease in average systolic blood pressure (mean 2.6 mmHg) measured on the final day of the study. In this study, the incidence of nausea, headache, vomiting, dizziness, dyspepsia and fatigue were greater for the combination of varenicline and NRT than for NRT alone. Due to the partial agonist nicotinic activity of varenicline, it is not anticipated that co-administration with NRT would confer additional benefits compared with CHAMPIX alone, and may result in increased side effects (see WARNINGS AND PRECAUTIONS).
Oral bioavailability of CHAMPIX is unaffected by food.
CHAMPIX has no known drug-herb interactions.
CHAMPIX has no known drug-laboratory test interactions.