Concomitant use of atazanavir or nelfinavir with proton pump inhibitors is not recommended.
Coadministration of atazanavir or nelfinavir with proton pump inhibitors is expected to substantially
decrease atazanavir or nelfinavir plasma concentrations and may result in a loss of therapeutic effect
and development of drug resistance.
There have been postmarketing reports of increased INR and prothrombin time in patients receiving
proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and
prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump
inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time.
Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically
important effect on exposure to the active metabolite of clopidogrel or clopidogrelinduced platelet
inhibition. No dose adjustment of clopidogrel is necessary when administered with an approved dose
of pantoprazole.
Pantoprazole causes long-lasting inhibition of gastric acid secretion. Therefore, pantoprazole may
interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability
(e.g., ketoconazole, ampicillin esters, and iron salts).
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in
patients receiving proton pump inhibitors. An alternative confirmatory method should be considered
to verify positive results.
Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that
concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and
prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal
drug interaction studies of methotrexate with PPIs have been conducted.
Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6, and 2C9.
In in vivo drug-drug interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4
substrate] and phenytoin [also a CYP3A4 inducer]), nifedipine, midazolam, and clarithromycin
(CYP3A4 substrates), metoprolol (a CYP2D6 substrate), diclofenac, naproxen and piroxicam
(CYP2C9 substrates), and theophylline (a CYP1A2 substrate) in healthy subjects, the
pharmacokinetics of pantoprazole were not significantly altered.
Clopidogrel is metabolized to its active metabolite in part by CYP2C19. In a crossover clinical study,
66 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day)
alone and with pantoprazole (80 mg at the same time as clopidogrel) for 5 days. On Day 5, the mean
AUC of the active metabolite of clopidogrel was reduced by approximately 14% (geometric mean
ratio was 86%, with 90% CI of 79 to 93%) when pantoprazole was coadministered with clopidogrel as
compared to clopidogrel administered alone. Pharmacodynamic parameters were also measured and
demonstrated that the change in inhibition of platelet aggregation (induced by 5 μM ADP) was
correlated with the change in the exposure to clopidogrel active metabolite. The clinical significance
of this finding is not clear.
In vivo studies also suggest that pantoprazole does not significantly affect the kinetics of the
following drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam],
phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen,
piroxicam, and oral contraceptives [levonorgestrel/ethinyl estradiol]). Dosage adjustment of these
drugs is not necessary when they are coadministered with pantoprazole. In other in vivo studies,
digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically
relevant interactions with pantoprazole.
Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage
adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine,
caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac,
naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl
estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or
amoxicillin.
There was also no interaction with concomitantly administered antacids.
Caution is advised when levosulpiride is taken concomitantly with other centrally acting drugs. It can
potentiate the cognitive and motor effects of alcohol.
The effect of levosulpiride on gastrointestinal motility can be antagonized by anti-cholinergic drugs,
narcotics and analgesic drugs.
