Vonoprazan, amoxicillin, and clarithromycin

Collated drug interaction information for the individual components in VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK is summarized below. Drug interaction studies with VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK have not been conducted. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy [see Clinical Pharmacology (12.3) ] . Clarithromycin (a component of VOQUEZNA TRIPLE PAK) is a strong CYP3A inhibitor.

Concomitant use of VOQUEZNA TRIPLE PAK with a drug(s) primarily metabolized by CYP3A may cause elevations in CYP3A substrate drug's concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Table 4: Effects of Other Drugs on VOQUEZNA TRIPLE PAK Strong or Moderate CYP3A Inducers Clinical Effect Vonoprazan and clarithromycin are CYP3A substrates. Strong or moderate CYP3A inducers may decrease exposure of vonoprazan and clarithromycin [see Clinical Pharmacology (12.3) ] , which may reduce the effectiveness of VOQUEZNA TRIPLE PAK. Prevention or Management Avoid concomitant use with VOQUEZNA TRIPLE PAK.

Probenecid Clinical Effect Amoxicillin undergoes tubular secretion. Probenecid may increase amoxicillin exposure by blocking its renal tubular secretion, which may increase the risk of VOQUEZNA TRIPLE PAK adverse reactions. Prevention or Management Closely monitor for signs or symptoms of increased or prolonged adverse reactions associated with amoxicillin when used with VOQUEZNA TRIPLE PAK. Allopurinol Clinical Effect Increase in the incidence of rashes is reported in patients receiving both allopurinol and amoxicillin together compared to patients receiving amoxicillin alone.

It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. Prevention or Management Discontinue allopurinol at the first appearance of skin rash when used concomitantly with VOQUEZNA TRIPLE PAK. Omeprazole Clinical Effect Clarithromycin concentrations in the gastric tissue and mucus were increased by concomitant administration of omeprazole [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid concomitant use of VOQUEZNA TRIPLE PAK with omeprazole.

Itraconazole Clinical Effect Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly. VOQUEZNA TRIPLE PAK's use with strong CYP3A4 inhibitors may lead to increases in clarithromycin exposure, which may increase the risk of VOQUEZNA TRIPLE PAK adverse reactions. Prevention or Management Patients taking itraconazole with VOQUEZNA TRIPLE PAK should be monitored closely for signs or symptoms of increased or prolonged adverse reactions associated with itraconazole and clarithromycin. Antivirals Clinical Effect Clarithromycin is a CYP3A4 substrate and inhibitor.

Use of VOQUEZNA TRIPLE PAK with antivirals that are CYP3A substrates, inducers, or CYP3A inhibitors may potentially lead to bi-directional drug interactions leading to alterations in exposure of clarithromycin and/or CYP3A substrates, which may increase the risk of adverse reactions or loss of effectiveness [see Clinical Pharmacology (12.3) ] . Prevention or Management Saquinavir (CYP3A substrate and inhibitor) Use VOQUEZNA TRIPLE PAK with caution. See saquinavir prescribing information for instructions when saquinavir (with or without ritonavir) is co-administered with clarithromycin.

Ritonavir (CYP3A inhibitor) Use of VOQUEZNA TRIPLE PAK with ritonavir is not recommended in patients with decreased renal function. Etravirine (CYP3A inducer) Avoid concomitant use with VOQUEZNA TRIPLE PAK. Table 5: Effects of Other Drugs on VOQUEZNA DUAL PAK Strong or Moderate CYP3A Inducers Clinical Effect Vonoprazan is a CYP3A substrate. Strong or moderate CYP3A inducers may decrease vonoprazan exposure [see Clinical Pharmacology (12.3) ] , which may reduce the effectiveness of VOQUEZNA DUAL PAK. Prevention or Management Avoid concomitant use with VOQUEZNA DUAL PAK. Probenecid Clinical Effect Amoxicillin undergoes tubular secretion.

Probenecid may increase amoxicillin exposure by blocking its renal tubular secretion, which may increase the risk of VOQUEZNA DUAL PAK adverse reactions. Prevention or Management Closely monitor for signs or symptoms of increased or prolonged adverse reactions associated with amoxicillin when used with VOQUEZNA DUAL PAK. Allopurinol Clinical Effect Increase in the incidence of rashes is reported in patients receiving both allopurinol and amoxicillin together compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.

Prevention or Management Discontinue allopurinol at the first appearance of skin rash when used concomitantly with VOQUEZNA DUAL PAK. Table 6: Effects of VOQUEZNA TRIPLE PAK on Other Drugs Drugs Dependent on Gastric pH for Absorption Antiretrovirals Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2) ] , which may alter the absorption of antiretroviral drugs leading to changes in their safety and/or effectiveness. Prevention or Management Rilpivirine-containing Products Concomitant use with VOQUEZNA TRIPLE PAK is contraindicated . Atazanavir Avoid concomitant use with VOQUEZNA TRIPLE PAK.

Nelfinavir Other Antiretroviral Drugs See the prescribing information of other antiretroviral drugs dependent on gastric pH for absorption prior to concomitant use with VOQUEZNA TRIPLE PAK. Other Drugs (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2) ] , which may decrease the absorption of drugs reducing their effectiveness. Prevention or Management See the prescribing information for other drugs dependent on gastric pH for absorption.

Certain CYP3A Substrates where minimal concentration changes may lead to serious toxicities Clinical Effect Clarithromycin is a strong CYP3A inhibitor. Vonoprazan is a weak CYP3A inhibitor [see Clinical Pharmacology (12.3) ] . Clarithromycin and vonoprazan may increase exposure of CYP3A4 substrates, which may increase the risk of adverse reactions related to these substrates. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus and cyclosporine.

Prevention or Management Immunosuppressants: Tacrolimus, cyclosporine Frequent monitoring for concentrations and/or adverse reactions related to the substrate drugs when used with VOQUEZNA TRIPLE PAK. Dosage reduction of substrate drugs may be needed. See prescribing information for the relevant substrate drugs. CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol) Clinical Effect Vonoprazan is a CYP2C19 inhibitor [see Clinical Pharmacology (12.3) ] . Vonoprazan may reduce plasma concentrations of the active metabolite of clopidogrel and may cause reduction in platelet inhibition. Vonoprazan may increase exposure of CYP2C19 substrate drugs (e.g., citalopram, cilostazol).

Prevention or Management Clopidogrel Carefully monitor the efficacy of clopidogrel and consider alternative anti-platelet therapy. Citalopram and Cilostazol Carefully monitor patients for adverse reactions associated with citalopram and cilostazol. See the prescribing information for dosage adjustments. Oral Anticoagulants Clinical Effect Abnormal prolongation of prothrombin time (increased INR) has been reported in patients receiving amoxicillin and oral anticoagulants. Prevention or Management Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently.

Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. Chromogranin A (CgA) Test for Neuroendocrine Tumors Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2) ], which increases chromogranin A (CgA) levels and may cause false positive results in diagnostic investigations for neuroendocrine tumors. Prevention or Management Assess CgA levels at least 4 weeks after VOQUEZNA TRIPLE PAK treatment and repeat the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), use the same commercial laboratory for testing, as reference ranges between tests may vary.

Interaction with Secretin Stimulation Test Clinical Effect Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. Prevention or Management Test should be performed at least 4 weeks after stopping VOQUEZNA TRIPLE PAK to allow gastrin levels to return to normal [see Clinical Pharmacology (12.2) ] . Glucose Tests Clinical Effect Amoxicillin is primarily…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK during pregnancy. Healthcare providers are encouraged to register patients by calling 1-866-609-1612 or visiting https://voqueznapregnancyregistry.com/ . Risk Summary VOQUEZNA TRIPLE PAK Based on findings from animal studies and observational studies in pregnant women with use of clarithromycin, use of VOQUEZNA TRIPLE PAK is not recommended in pregnant women except in clinical circumstances where no alternative therapy is appropriate.

There are no adequate and well-controlled studies of VOQUEZNA TRIPLE PAK in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. If VOQUEZNA TRIPLE PAK is used during pregnancy, advise pregnant women of the potential risk to a fetus. No reproductive and developmental toxicity studies with the combination of vonoprazan, amoxicillin, and/or clarithromycin were conducted. VOQUEZNA DUAL PAK There are no adequate and well-controlled studies of VOQUEZNA DUAL PAK in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Individual Components of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK Clarithromycin: Published observational studies in pregnant women have demonstrated adverse effects on pregnancy outcomes, including an increased risk of miscarriage and in some studies an increased incidence of fetal malformations (see Data ) . In animal reproduction studies, administration of oral clarithromycin to pregnant mice, rats, rabbits, and monkeys during the period of organogenesis produced malformations in rats (cardiovascular anomalies) and mice (cleft palate) at clinically relevant doses.

Fetal effects in mice, rats, and monkeys (e.g., reduced fetal survival, body weight, body weight gain) and implantation losses in rabbits were generally considered to be secondary to maternal toxicity (see Data ) . Vonoprazan: Available data from pharmacovigilance reports with vonoprazan use in pregnant women are not sufficient to evaluate for a drug-associated risk for major birth defects, miscarriage or other adverse maternal or fetal outcomes. In pregnant rats, no adverse effects were noted after oral administration of vonoprazan during organogenesis at approximately 27 times the maximum recommended human dose (MRHD) based on AUC exposure comparisons.

In a pre- and postnatal development (PPND) study, pups from dams…