VOQUEZNA TRIPLE PAK contains vonoprazan tablets, 20 mg, amoxicillin capsules, 500 mg, and clarithromycin tablets, 500 mg for oral administration. VOQUEZNA DUAL PAK contains vonoprazan tablets, 20 mg and amoxicillin capsules, 500 mg for oral administration. Vonoprazan Tablets Vonoprazan (as the fumarate), is a potassium-competitive acid blocker (PCAB). Chemically, it is 1 H -pyrrole-3-methanamine, 5-(2-fluorophenyl)- N -methyl-1-(3-pyridinylsulfonyl)-, (2 E )-2-butenedioate (1:1). Its empirical formula is C 17 H 16 FN 3 O 2 S∙C 4 H 4 O 4 with a molecular weight of 461.5. Vonoprazan has the following structure: Vonoprazan fumarate is white to nearly white crystals or crystalline powder which melts at 194.8°C. Vonoprazan fumarate is soluble in dimethyl sulfoxide; sparingly soluble in N,N –dimethylacetamide, slightly soluble in N,N -dimethylformamide, methanol, and water; very slightly soluble in ethanol; and practically insoluble in 2-propanol, acetone, 1-octanol, and acetonitrile. Each film-coated tablet contains 20 mg of vonoprazan, present as 26.72 mg of vonoprazan fumarate and the following inactive ingredients: ascorbic acid, croscarmellose sodium, ferric oxide red, fumaric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol 8000, and titanium dioxide. Chemical structure Amoxicillin Capsules Amoxicillin is a penicillin class antibacterial, with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically it is (2 S , 5 R , 6 R )-6-[( R )-(-)-2-amino-2-( p- hydroxyphenyl) acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid trihydrate. The molecular formula is C 16 H 19 N 3 O 5 S ∙ 3H 2 O and the molecular weight is 419.45. Amoxicillin has the following structure: Each amoxicillin capsule, with yellow opaque cap and body, contains 500 mg amoxicillin as the trihydrate. Inactive ingredients: Capsule shells – ammonium hydroxide, black ferric oxide, gelatin, potassium hydroxide, propylene glycol, shellac, titanium dioxide, and yellow ferric oxide; Capsule contents – magnesium stearate and microcrystalline cellulose. Meets USP Dissolution Test 2. Chemical structure Clarithromycin Tablets Clarithromycin is a semi-synthetic macrolide antimicrobial for oral use. Chemically, it is 6- O -methylerythromycin. The molecular formula is C 38 H 69 NO 13 , and the molecular weight is 747.96. Clarithromycin has the following structure: Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water. Each clarithromycin tablet contains 500 mg of clarithromycin and the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, talc, and titanium dioxide. Chemical structure

VOQUEZNA TRIPLE PAK, is a co-packaged product containing vonoprazan, a potassium-competitive acid blocker (PCAB), amoxicillin, a penicillin class antibacterial, and clarithromycin, a macrolide antimicrobial, indicated for the treatment of Helicobacter pylori (H. pylori) infection in adults. VOQUEZNA DUAL PAK, is a co-packaged product containing vonoprazan, a PCAB, and amoxicillin, a penicillin class antibacterial, indicated for the treatment of H. pylori infection in adults. To reduce the development of drug-resistant bacteria and maintain the effectiveness of VOQUEZNA TRIPLE PAK, VOQUEZNA DUAL PAK and other antibacterial drugs, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria

Helicobacter pylori Infection VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK are indicated for the treatment of Helicobacter pylori ( H. pylori ) infection in adults

Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of VOQUEZNA TRIPLE PAK, VOQUEZNA DUAL PAK and other antibacterial drugs, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

VOQUEZNA TRIPLE PAK : Carton of 14 daily administration packs for morning and evening dosing, each containing the following three drug products: Tablets: Vonoprazan 20 mg Capsules: Amoxicillin 500 mg Tablets: Clarithromycin 500 mg VOQUEZNA DUAL PAK : Carton of 14 daily administration packs for morning, mid-day, and evening dosing, each containing the following two drug products: Tablets: Vonoprazan 20 mg Capsules: Amoxicillin 500 mg 3.1 VOQUEZNA TRIPLE PAK VOQUEZNA TRIPLE PAK is a co-package consisting of 14 administration packs for morning and evening dosing. Each administration pack contains the following three drug products: Vonoprazan Tablets, 20 mg: pale red, oval, film-coated tablets debossed V20 on one side and plain on the other side. Amoxicillin Capsules, 500 mg: yellow, opaque, hard gelatin capsules imprinted with AMOX 500 on one side and GG 849 on the other side. Clarithromycin Tablets, 500 mg: white, oval, film-coated debossed GG C9 on one side and plain on the other side

VOQUEZNA DUAL PAK VOQUEZNA DUAL PAK is a co-package consisting of 14 administration packs for morning, mid-day, and evening dosing. Each administration pack contains the following two drug products: Vonoprazan Tablets, 20 mg: pale red, oval, film-coated tablets debossed V20 on one side and plain on the other side. Amoxicillin Capsules, 500 mg: yellow, opaque, hard gelatin capsules imprinted with AMOX 500 on one side and GG 849 on the other side.

VOQUEZNA TRIPLE PAK : The recommended dosage is vonoprazan 20 mg plus amoxicillin 1,000 mg plus clarithromycin 500 mg, each given twice daily (morning and evening, 12 hours apart), with or without food, for 14 days. VOQUEZNA DUAL PAK : The recommended dosage is vonoprazan 20 mg twice daily (morning and evening) plus amoxicillin 1,000 mg, three times a day (morning, mid-day, and evening), with or without food, for 14 days. See full prescribing information for the recommended dosage for patients with renal or hepatic impairment

Recommended Dosage for VOQUEZNA TRIPLE PAK VOQUEZNA TRIPLE PAK is a co-packaged product containing vonoprazan tablets, amoxicillin capsules, and clarithromycin tablets each given twice daily (in the morning and evening, 12 hours apart) with or without food, for 14 days . The recommended adult oral dosage of VOQUEZNA TRIPLE PAK is the following: In the morning, take 20 mg of vonoprazan (one oval pale red tablet), 1,000 mg of amoxicillin (two yellow capsules), and 500 mg of clarithromycin (one oval white tablet) In the evening, take 20 mg of vonoprazan (one oval pale red tablet), and 1,000 mg of amoxicillin (two yellow capsules), and 500 mg of clarithromycin (one oval white tablet) 2.2 Recommended Dosage for VOQUEZNA DUAL PAK VOQUEZNA DUAL PAK is a co-packaged product containing vonoprazan tablets and amoxicillin capsules given with or without food, for 14 days . The recommended adult oral dosage of VOQUEZNA DUAL PAK is the following: In the morning, take 20 mg of vonoprazan (one oval pale red tablet) and 1,000 mg of amoxicillin (two yellow capsules) Mid-day, take 1,000 mg of amoxicillin (two yellow capsules) In the evening, take 20 mg of vonoprazan (one oval pale red tablet) and 1,000 mg of amoxicillin (two yellow capsules) 2.3 Recommended Dosage in Patients with Renal Impairment The recommended dosage of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in adult patients with renal impairment is described in Table 1 . Table 1: Recommended Dosage of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in Patients with Renal Impairment Estimated GFR Recommended Dosage VOQUEZNA TRIPLE PAK VOQUEZNA DUAL PAK 30 mL/minute or greater 20 mg vonoprazan twice daily 1,000 mg amoxicillin twice daily 500 mg clarithromycin twice daily 20 mg vonoprazan twice daily 1,000 mg amoxicillin three times daily Less than 30 mL/minute Use is not recommended 2.4 Recommended Dosage in Patients with Hepatic Impairment The recommended dosage of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in adult patients with hepatic impairment is described in Table 2 . Table 2: Recommended Dosage of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in Patients with Hepatic Impairment Classification Recommended Dosage VOQUEZNA TRIPLE PAK VOQUEZNA DUAL PAK Child-Pugh Class A 20 mg vonoprazan twice daily 1,000 mg amoxicillin twice daily 500 mg clarithromycin twice daily 20 mg vonoprazan twice daily 1,000 mg amoxicillin three times daily Child-Pugh Class B Use is not recommended Child-Pugh Class C Use is not recommended 2.5 Missed Doses If a dose is missed, administer VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK as soon as possible, within 4 hours after the missed dose. If more than 4 hours have passed, skip the missed dose and administer the next dose on the regularly scheduled time. Patients should continue the normal dosing schedule until the medication is completed.

VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK : Hypersensitivity Reactions : Serious and occasionally fatal reactions (e.g., anaphylaxis) have been reported with components of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK. If hypersensitivity reactions occur, discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK and institute immediate therapy (e.g., anaphylaxis management). Acute Tubulointerstitial Nephritis : Discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK and evaluate patients. Severe Cutaneous Adverse Reactions (SCAR) : Discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK at the first signs or symptoms of SCAR or other signs of hypersensitivity and consider further evaluation. Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK. If this occurs, discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK and institute appropriate therapy. Clostridioides difficile -associated diarrhea (CDAD) : Evaluate if diarrhea occurs with VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK. VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component : QT Prolongation : Avoid VOQUEZNA TRIPLE PAK in patients with known QT prolongation or receiving drugs known to prolong the QT interval, ventricular arrhythmia ( torsades de pointes ), hypokalemia/hypomagnesemia, significant bradycardia, or taking Class IA or III antiarrhythmics. Hepatotoxicity : Discontinue if signs and symptoms of hepatitis occur with VOQUEZNA TRIPLE PAK. Serious Adverse Reactions Due to Concomitant Use with Other Drugs : Serious adverse reactions can occur with VOQUEZNA TRIPLE PAK due to drug interactions of clarithromycin with colchicine, some lipid lowering agents, some calcium channel blockers, and other drugs. Embryo-Fetal Toxicity : Based on the findings from animal studies and human observational studies in pregnant women treated with clarithromycin, VOQUEZNA TRIPLE PAK is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. Myasthenia Gravis : Exacerbation of myasthenia gravis can occur with VOQUEZNA TRIPLE PAK since it has been reported in patients receiving clarithromycin tablets. 5.1 Warnings and Precautions for VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity reactions (e.g., anaphylaxis, anaphylactic shock, rash, erythema multiforme, and Henoch-Schonlein purpura) have been reported with components of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK . Before initiating therapy with VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, macrolide antibacterial drugs or other allergens. Discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK immediately and institute appropriate treatment if hypersensitivity occurs. Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been reported with vonoprazan, a component of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK . If suspected, discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK and evaluate patients with suspected acute TIN. Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the components of VOQUEZNA TRIPLE PAK: vonoprazan, amoxicillin, and clarithromycin and VOQUEZNA DUAL PAK: vonoprazan and amoxicillin . In addition, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with amoxicillin and clarithromycin. Discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK at the first signs or symptoms of SCAR or other signs of hypersensitivity and consider further evaluation. Drug-Induced Enterocolitis Syndrome Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK , with most cases occurring in pediatric patients ≤18 years of age. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK and institute appropriate therapy. Clostridioides difficile -Associated Diarrhea Clostridioides difficile- associated diarrhea (CDAD) has been reported with use of acid suppressing therapies and nearly all antibacterial agents, including amoxicillin (component of VOQUEZNA DUAL PAK and TRIPLE PAK) and clarithromycin (component of VOQUEZNA TRIPLE PAK), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of Clostridioides difficile (C. difficile) . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is confirmed, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK should be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin (a component of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK) develop an erythematous skin rash. Avoid use of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in patients with mononucleosis. Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at least 4 weeks after VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK treatment and consider repeating the test if initial CgA levels are high . Development of Drug-Resistant Bacteria Prescribing VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient, and increases the risk of the development of drug-resistant bacteria

Additional Warnings and Precautions for VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component QT Prolongation Clarithromycin (a component of VOQUEZNA TRIPLE PAK) has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported. Avoid VOQUEZNA TRIPLE PAK in the following patients: Patients with known prolongation of QT interval, ventricular cardiac arrhythmia, including torsades de pointes. Patients receiving drugs known to prolong the QT interval (e.g., pimozide). Patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia and in patients receiving Class IA (e.g., quinidine, procainamide, disopyramide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval . Hepatotoxicity Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin (a component of VOQUEZNA TRIPLE PAK). This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue VOQUEZNA TRIPLE PAK immediately if signs and symptoms of hepatitis occur. Serious Adverse Reactions Due to Concomitant Use of Clarithromycin with Other Drugs Drugs metabolized by CYP3A4 Serious adverse reactions have been reported in patients taking clarithromycin (a component of VOQUEZNA TRIPLE PAK) concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; markedly increased transaminases with lomitapide; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia and cardiac arrhythmias (e.g., torsades de pointes ) with disopyramide; and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older . Colchicine Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin (a component of VOQUEZNA TRIPLE PAK) and colchicine. If co-administration of VOQUEZNA TRIPLE PAK and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant administration of VOQUEZNA TRIPLE PAK and colchicine is contraindicated in patients with renal or hepatic impairment . Lomitapide Concomitant use of VOQUEZNA TRIPLE PAK with lomitapide may increase the risk of elevation in transaminases due to the clarithromycin component. Concomitant use of VOQUEZNA TRIPLE PAK with lomitapide is contraindicated . If treatment with VOQUEZNA TRIPLE PAK cannot be avoided, therapy with lomitapide must be suspended during the course of treatment. HMG-CoA Reductase Inhibitors (statins) Concomitant use of VOQUEZNA TRIPLE PAK with lovastatin or simvastatin may increase these drug's plasma concentrations due to the clarithromycin component, which may increase the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients treated concomitantly with clarithromycin (a component of VOQUEZNA TRIPLE PAK) and lovastatin or simvastatin. Concomitant use of VOQUEZNA TRIPLE PAK with lovastatin or simvastatin is contraindicated . If treatment with VOQUEZNA TRIPLE PAK cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment. Exercise caution when prescribing VOQUEZNA TRIPLE PAK with atorvastatin or pravastatin . Hypoglycemic Agents/Insulin Concomitant use of VOQUEZNA TRIPLE PAK, and hypoglycemic agents (such as nateglinide, pioglitazone, repaglinide, or rosiglitazone) and/or insulin can result in significant hypoglycemia due to the clarithromycin component. Carefully monitor glucose levels when these drugs are used concomitantly with VOQUEZNA TRIPLE PAK . Quetiapine Concomitant use of VOQUEZNA TRIPLE PAK with quetiapine could result in somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation due to the clarithromycin component. Refer to quetiapine prescribing information for recommended dosage reduction if co-administered with VOQUEZNA TRIPLE PAK . Warfarin There is a risk of serious hemorrhage and significant elevations in the international normalized ratio (INR) and prothrombin time when clarithromycin (a component of VOQUEZNA TRIPLE PAK) is used concomitantly with warfarin. Monitor INR and prothrombin times frequently when warfarin is used concomitantly with VOQUEZNA TRIPLE PAK . Benzodiazepines Increased sedation and prolongation of sedation have been reported with concomitant administration when clarithromycin (a component of VOQUEZNA TRIPLE PAK), and triazolobenzodiazepines, such as triazolam and midazolam. Closely monitor patients for signs or symptoms of increased or prolonged central nervous system effects when benzodiazepines such astriazolam or midazolam are used concomitantly with VOQUEZNA TRIPLE PAK . Embryo-Fetal Toxicity with Use of VOQUEZNA TRIPLE PAK Based on findings from animal studies and human observational studies in pregnant women with use of clarithromycin, VOQUEZNA TRIPLE PAK is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If VOQUEZNA TRIPLE PAK is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, advise the patient of the potential risk to the fetus. Clarithromycin demonstrated adverse effects on pregnancy outcome and/or embryo-fetal development, in pregnant animals administered oral clarithromycin. Observational studies in pregnant women also demonstrated adverse effects on pregnancy outcomes, including an increased risk of miscarriage and in some studies an increased incidence of fetal malformations . Exacerbation of Myasthenia Gravis Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy (a component of VOQUEZNA TRIPLE PAK). Monitor patients for symptoms.

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 . 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 , 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 . 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 . 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 , 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 , 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 , 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 . 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 . 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 , 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 . Glucose Tests Clinical Effect Amoxicillin is primarily excreted in the urine . High urine concentrations of ampicillin or amoxicillin may cause false-positive results when using glucose tests based on the Benedict's copper reduction reaction that determines the amount of reducing substances like glucose in the urine. Prevention or Management Use a test based on enzymatic glucose oxidase reactions when testing for glucose in the urine of patients treated with VOQUEZNA TRIPLE PAK. 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. Antiarrhythmics Clinical Effect Clarithromycin is a strong CYP3A inhibitor. Clarithromycin may increase exposure of antiarrhythmic drugs that are CYP3A substrates, which may increase the risk of adverse reactions related to these substrates including cardiac arrhythmias (e.g., torsades de pointes ). There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Prevention or Management Disopyramide Avoid concomitant use with VOQUEZNA TRIPLE PAK. If concomitant use is unavoidable, monitor patients for QTc prolongation and changes in blood glucose levels. Amiodarone Avoid concomitant use with VOQUEZNA TRIPLE PAK. If concomitant use is unavoidable, monitor patients for QTc prolongation. Dofetilide Procainamide Sotalol Quinidine Colchicine Clinical Effect Clarithromycin is an inhibitor of CYP3A and the efflux transporter, P-glycoprotein (P-gp). Colchicine is a substrate of CYP3A and P-gp. Clarithromycin increases exposure of colchicine , which may increase the risk of adverse reactions related to colchicine. Prevention or Management Concomitant use of colchicine with VOQUEZNA TRIPLE PAK is contraindicated in patients with renal or hepatic impairment. If co-administration of VOQUEZNA TRIPLE PAK and colchicine is necessary in patients with normal renal or hepatic function, carefully monitor patients for clinical symptoms of colchicine toxicity and refer to the colchicine prescribing information for recommendations on dosage reduction. Antipsychotics Clinical Effect Clarithromycin is a strong CYP3A inhibitor. Clarithromycin may increase exposure of antipsychotic drugs that are CYP3A substrates, which may increase the risk of adverse reactions related to these substrates including the risk of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, or cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes ). Prevention or Management Pimozide Concomitant use with VOQUEZNA TRIPLE PAK is contraindicated. Lurasidone Concomitant use with VOQUEZNA TRIPLE PAK is contraindicated. Quetiapine Refer to quetiapine prescribing information for recommendations on dosage reduction if co-administered with CYP3A4 inhibitors such as clarithromycin. Tolterodine (patients deficient in CYP2D6 activity) Clinical Effect Clarithromycin is a strong CYP3A inhibitor. The primary route of metabolism for tolterodine is via CYP2D6. Clarithromycin may increase tolterodine exposure and the risk of adverse reactions related to tolterodine in patients deficient in CYP2D6 activity because tolterodine is metabolized via CYP3A in this subset of population. Prevention or Management Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with strong CYP3A4 inhibitors such as 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 . 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. Maraviroc (CYP3A substrate) Use VOQUEZNA TRIPLE PAK with caution. See the prescribing information of maraviroc for dosage recommendation when given with strong CYP3A inhibitors such as clarithromycin. Zidovudine Administration of VOQUEZNA TRIPLE PAK and zidovudine should be separated by at least two hours. Benzodiazepines Clinical Effect Clarithromycin is a strong CYP3A inhibitor. Clarithromycin may increase exposure of benzodiazepines that are CYP3A substrates, which may increase the risk of adverse reactions related to these substrates . Prevention or Management Midazolam Closely monitor patients for signs or symptoms of increased or prolonged central nervous system effects (e.g., somnolence and confusion) and refer to the CYP3A substrate prescribing information for dosage adjustments when used concomitantly with VOQUEZNA TRIPLE PAK. Alprazolam Triazolam Calcium Channel Blockers Clinical Effect Clarithromycin is a strong CYP3A inhibitor. Clarithromycin may increase exposure of calcium channel blockers that are CYP3A substrates, which may increase the risk of adverse reactions related to these substrates including hypotension, acute kidney injury, bradyarrhythmias, lactic acidosis, or peripheral edema. Prevention or Management Verapamil Use VOQUEZNA TRIPLE PAK with caution. Amlodipine Diltiazem Nifedipine Ergot Alkaloids Clinical Effect Clarithromycin is a strong CYP3A inhibitor. Clarithromycin may increase exposure of ergot alkaloids that are CYP3A substrates, which may increase the risk of vasospasm and ischemia of the extremities and other tissues including the central nervous system . Prevention or Management Ergotamine Concomitant use with VOQUEZNA TRIPLE PAK is contraindicated. Dihydroergotamine Hypoglycemic Agents Clinical Effect Clarithromycin is a strong CYP3A inhibitor. Clarithromycin may increase exposure of hypoglycemic agents that are CYP3A substrates, which may increase the risk of hypoglycemia . Prevention or Management Nateglinide Closely monitor glucose levels when used concomitantly with VOQUEZNA TRIPLE PAK. Pioglitazone Repaglinide Rosiglitazone Insulin Lipid-lowering Agents Clinical Effect Clarithromycin is a strong CYP3A inhibitor. Clarithromycin may increase exposure of lipid-lowering drugs that are CYP3A substrates, thereby increasing the risk of toxicities from these drugs . Prevention or Management Lomitapide Concomitant use with VOQUEZNA TRIPLE PAK is contraindicated. Lovastatin Simvastatin Atorvastatin Use VOQUEZNA TRIPLE PAK with caution. In situations where the concomitant use of VOQUEZNA TRIPLE PAK with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Pravastatin Fluvastatin Use of a statin that is not dependent on CYP3A metabolism (e.g., fluvastatin) can be considered. It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided. Phosphodiesterase Inhibitors Clinical Effect Clarithromycin is a strong CYP3A inhibitor. Clarithromycin may increase exposure of phosphodiesterase inhibitors that are CYP3A substrates, which may increase the risk of adverse reactions related to these substrates. Prevention or Management Sildenafil Avoid concomitant use with VOQUEZNA TRIPLE PAK. If concomitant use is unavoidable, see the prescribing information of the respective phosphodiesterase inhibitors for dosage recommendation when given with strong CYP3A inhibitors such as clarithromycin. Tadalafil Vardenafil Other CYP3A Based Interactions Clinical Effect Clarithromycin is a substrate and strong inhibitor of CYP3A4. Clarithromycin increases exposure of CYP3A substrates , which may increase the risk of adverse reactions related to these substrates . Strong or moderate CYP3A inducers may decrease exposure of clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John's Wort. Prevention or Management Use VOQUEZNA TRIPLE PAK with caution. P-glycoprotein (P-gp) Substrates: Digoxin Clinical Effect Clarithromycin is a P-gp inhibitor. Clarithromycin may increase exposure of P-gp substrates, which may increase the risk of adverse reactions related to these substrates, including potentially fatal arrhythmias. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Prevention or Management Digoxin Carefully monitor serum concentrations and refer to the digoxin prescribing information for dosage adjustments when used concomitantly with VOQUEZNA TRIPLE PAK. Drugs Metabolized by CYP450 Isoforms Other than CYP3A Clinical Effect Clarithromycin may increase exposure of drugs that are metabolized by CYP450 isoforms other than CYP3A by inhibiting their metabolism. There have been post-marketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A. Prevention or Management Hexobarbital Use VOQUEZNA TRIPLE PAK with caution. Phenytoin Valproate Theophylline Clinical Effect Clarithromycin may increase exposure of theophylline (a xanthine derivative drug) , which may increase the risk of adverse reactions related to theophylline. Prevention or Management Closely monitor serum theophylline concentrations in patients receiving high dosages of theophylline or with baseline concentrations in the upper therapeutic range when used concomitantly with VOQUEZNA TRIPLE PAK. Table 7: Effects of VOQUEZNA DUAL PAK on Other Drugs Drugs Dependent on Gastric pH for Absorption Antiretrovirals Clinical Effect Vonoprazan reduces intragastric acidity , 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 DUAL PAK is contraindicated . Atazanavir Avoid concomitant use with VOQUEZNA DUAL 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 DUAL PAK. Other Drugs (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Effect Vonoprazan reduces intragastric acidity , 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 Vonoprazan is a weak CYP3A inhibitor . Vonoprazan may increase exposure of CYP3A4 substrates, which may increase the risk of adverse reactions related to these substrates. Prevention or Management Immunosuppressants: Tacrolimus, cyclosporine Frequent monitoring for concentrations and/or adverse reactions related to the substrate drugs when used with VOQUEZNA DUAL PAK. Dosage reduction of substrate drugs may be needed. See prescribing information for the relevant substrate drugs. 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. CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol) Clinical Effect Vonoprazan is a CYP2C19 inhibitor . 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. CgA Test for Neuroendocrine Tumors Clinical Effect Vonoprazan reduces intragastric acidity , which increases 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 DUAL 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 DUAL PAK to allow gastrin levels to return to normal . Glucose Tests Clinical Effect Amoxicillin is primarily excreted in the urine . High urine concentrations of ampicillin or amoxicillin may cause false-positive results when using glucose tests based on the Benedict's copper reduction reaction that determines the amount of reducing substances like glucose in the urine. Prevention or Management Use a test based on enzymatic glucose oxidase reactions when testing for glucose in the urine of patients treated with VOQUEZNA DUAL PAK. Components of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK have the potential for clinically important drug interactions. See Full Prescribing Information for important drug interactions with VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK. ( 4 , 5.2 , 7 )