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. ( 1.1 ) 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.
( 1.1 ) 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. ( 1.2 )
1.1 Helicobacter pylori Infection VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK are indicated for the treatment of Helicobacter pylori ( H. pylori ) infection in adults [see Clinical Studies (14) ].
1.2Usage
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.
Contraindications
VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK : Known hypersensitivity to vonoprazan, amoxicillin or any other beta-lactams, clarithromycin or any other macrolide antimicrobial or any component of VOQUEZNA TRIPLE PAK. ( 4.1 ) Known hypersensitivity to vonoprazan, amoxicillin or any other beta-lactams or any component of VOQUEZNA DUAL PAK. ( 4.1 ) Rilpivirine-containing products. ( 4.1 ) VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component : Pimozide.
( 4.2 ) Lomitapide, lovastatin, and simvastatin. ( 4.2 ) Ergot alkaloids (ergotamine or dihydroergotamine). ( 4.2 ) Colchicine in renal or hepatic impairment. ( 4.2 ) History of cholestatic jaundice/hepatic dysfunction with use of clarithromycin. ( 4.2 ) Lurasidone. ( 4.2 )
VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK Hypersensitivity Reactions VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK are contraindicated in patients with a known hypersensitivity to any component of VOQUEZNA TRIPLE PAK: vonoprazan, amoxicillin (or other β-lactam antibacterials, e.g., penicillins and cephalosporins), or clarithromycin (or other macrolide antibacterial drugs, e.g., erythromycin) or VOQUEZNA DUAL PAK: vonoprazan or amoxicillin (or other β-lactam antibacterials, e.g., penicillins and cephalosporins) [see Warnings and Precautions (5.1) ].
Rilpivirine-containing Products VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK are contraindicated with rilpivirine-containing products [see Drug Interactions (7) ].
4.2Additional Contraindications to
VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component Serious Adverse Reactions/Risks Due to Drug Interactions Because of the clarithromycin component, VOQUEZNA TRIPLE PAK is contraindicated with concomitant use of: Pimozide: There have been postmarketing reports of drug interactions when clarithromycin is co-administered with pimozide, resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes ) most likely due to inhibition of metabolism of these drugs by clarithromycin.
Fatalities have been reported [see Warnings and Precautions (5.2) and Drug Interactions (7) ]. Lipid-lowering Agents: Lomitapide, simvastatin, and lovastatin [see Warnings and Precautions (5.2) and Drug Interactions (7) ] Ergot Alkaloids: Ergotamine or dihydroergotamine [see Drug Interactions (7) ] Colchicine in patients with renal or hepatic impairment [see Warnings and Precautions (5.2) and Drug Interactions (7) ] Lurasidone: Coadministration of clarithromycin and lurasidone may lead to an increase in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions (7) ] .
Cholestatic Jaundice/Hepatic Dysfunction VOQUEZNA TRIPLE PAK is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin.
Warnings and precautions
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). ( 5.1 ) Acute Tubulointerstitial Nephritis : Discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK and evaluate patients.
( 5.1 ) 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. ( 5.1 ) 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.
( 5.1 ) Clostridioides difficile -associated diarrhea (CDAD) : Evaluate if diarrhea occurs with VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK. ( 5.1 ) 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.
( 5.2 ) Hepatotoxicity : Discontinue if signs and symptoms of hepatitis occur with VOQUEZNA TRIPLE PAK. ( 5.2 ) 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. ( 5.2 ) 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.
( 5.2 ) Myasthenia Gravis : Exacerbation of myasthenia gravis can occur with VOQUEZNA TRIPLE PAK since it has been reported in patients receiving clarithromycin tablets. ( 5.2 )
5.1Warnings 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 [see Contraindications (4.1) ]. 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 [see Adverse Reactions (6.1) ] . 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 [see Adverse Reactions (6.2) ] . 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 [see Adverse Reactions (6.2) ] , 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 [see Drug Interactions (7) and Clinical Pharmacology (12.2) ].
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.
5.2Additional 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.,
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Interactions
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
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Pregnancy and breastfeeding
8.1Pregnancy 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 orally administered vonoprazan during organogenesis and through lactation, exhibited liver discoloration, which in follow-up mechanistic animal studies was associated with necrosis, fibrosis, and hemorrhage at a dose approximately 22 times the MRHD based on AUC comparisons which were likely attributable to exposure during lactation [see Use in Specific Populations (8.2) ] .
These effects were not observed at the next lower dose in this study, which was approximately equal to the MRHD based on AUC comparison, however they were seen at clinically relevant exposures in dose range finding studies in rats (see Data ) . Amoxicillin: Available data from published epidemiologic studies and pharmacovigilance case reports over several decades with amoxicillin use have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Reproduction studies with amoxicillin have been performed in mice and rats (5 and 10 times the human dose 2 g human dose for mice and rats, respectively, 3 and 6 times the 3 g human dose for mice and rats, respectively). There was no evidence of harm to the fetus due to amoxicillin. The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Clarithromycin: Available data from prospective and retrospective observational studies with clarithromycin use in pregnant women demonstrate an increased risk of miscarriage. Data from these same studies regarding major congenital malformations are inconsistent, with some studies reporting an increased risk (atrioventricular septal defects, genital malformations, orofacial clefts) and others finding no difference between those exposed to clarithromycin and those exposed to nonteratogenic controls.
Available studies have methodologic limitations, including small sample size, under-capture of non-live births, exposure misclassification and inconsistent comparator groups. Animal Data Clarithromycin: Animal reproduction studies were conducted in mice, rats, rabbits, and monkeys with oral and intravenously administered clarithromycin. In pregnant mice, clarithromycin was administered during organogenesis (gestation day [GD] 6 to 15) at oral doses of 15, 60, 250, 500, or 1000 mg/kg/day.
Reduced body weight observed in dams at 1000 mg/kg/day (3 times the MRHD based on BSA comparison) resulted in reduced survival and body weight of the fetuses. At ≥ 500 mg/kg/day, increases in the incidence of post-implantation loss and cleft palate in the fetuses were observed. No adverse developmental effects were observed in mice at ≤ 250 mg/kg/day (≤ 1 times MRHD based on BSA comparison). In pregnant Sprague Dawley rats, clarithromycin was administered during organogenesis (GD 6 to 15) at oral doses of 15, 50, or 150 mg/kg/day.
Reductions in body weight and food consumption was observed in dams at 150 mg/kg/day. Increased resorptions and reduced body weight of the fetuses at this dose were considered secondary to maternal toxicity. Additionally, at 150 mg/kg/day (1 times MRHD based on BSA comparison), a low incidence of cardiovascular anomalies (complete situs inversus, undivided truncus, IV septal defect) was observed in the fetuses. Clarithromycin did not cause adverse developmental effects in rats at 50 mg/kg/day (0.3 times MRHD based on BSA comparison).
Intravenous dosing of clarithromycin during organogenesis in rats (GD 6 to 15) at 15, 50, or 160 mg/kg/day was associated with maternal toxicity (reduced body weight, body-weight gain, and food consumption) at 160 mg/kg/day but no evidence of adverse developmental effects at any dose (≤ 1 times MRHD based on BSA comparison). In pregnant Wistar rats, clarithromycin was administered during organogenesis (GD 7 to 17) at oral doses of 10, 40, or 160 mg/kg/day.
Reduced body weight and food consumption were observed in dams at 160 mg/kg/day but there was no evidence of adverse developmental effects at any dose (≤ 1 times MRHD based on surface BSA comparison). In pregnant rabbits, clarithromycin administered during organogenesis (GD 6 to 18) at oral doses of 10, 35, or 125 mg/kg/day resulted in reduced maternal food consumption and decreased body weight at the highest dose, with no evidence of any adverse developmental effects at any dose (≤ 2 times MRHD based on BSA comparison).
Intravenously administered clarithromycin to pregnant rabbits during organogenesis (GD 6 to 18) in rabbits at 20, 40, 80, or 160 mg/kg/day (≥ 0.3 times MRHD based on BSA comparison) resulted in maternal toxicity and implantation losses at all doses. In pregnant monkeys, clarithromycin was administered (GD 20 to 50) at oral doses of 35 or 70 mg/kg/day. Dose-dependent emesis, poor appetite, fecal changes, and reduced body weight were observed in dams at all doses (≥ 0.5 times MRHD based on BSA comparison).
Growth retardation in 1 fetus at 70 mg/kg/day was considered secondary to maternal toxicity. There was no evidence of primary drug related adverse developmental effects at any dose tested. In a reproductive toxicology study in rats administered oral clarith
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Adverse reactions
The following serious adverse reactions are described below and elsewhere in labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions (5.1) ] Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.1) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.1) ] QT Prolongation [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Serious Adverse Reactions Due to Concomitant Use with Other Drugs [see Warnings and Precautions (5.2) ] Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.2) ] VOQUEZNA TRIPLE PAK : Most common adverse reactions (≥ 2%) were dysgeusia, diarrhea, vulvovaginal candidiasis, headache, abdominal pain, and hypertension.
( 6.1 ) VOQUEZNA DUAL PAK : Most common adverse reactions (≥ 2%) were diarrhea, abdominal pain, vulvovaginal candidiasis, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Phathom Pharmaceuticals, Inc. at toll-free phone 1-888-775-7428 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ) .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions with VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK The safety of VOQUEZNA TRIPLE PAK was evaluated in 675 adult patients (aged 20 to 82 years) in clinical trials in the United States, Europe and Japan and VOQUEZNA DUAL PAK was evaluated in 348 adult patients (aged 20 to 80 years) in a clinical trial in the United States and Europe.
All the patients were screened and found to be positive for H. pylori infection. The safety of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK was evaluated in a randomized, controlled, double-blind triple therapy/open-label dual therapy study conducted in the United States and Europe in treatment-naïve H. pylori -positive adult patients. Patients were randomized 1:1:1 to vonoprazan 20 mg twice daily plus amoxicillin 1,000 mg twice daily plus clarithromycin 500 mg twice daily (VOQUEZNA TRIPLE PAK) or vonoprazan 20 mg twice daily plus amoxicillin 1,000 mg three times daily (VOQUEZNA DUAL PAK) or lansoprazole 30 mg twice daily plus amoxicillin 1,000 mg twice daily plus clarithromycin 500 mg twice daily (LAC) administered for 14 consecutive days.
A total of 346 patients received VOQUEZNA TRIPLE PAK in the study, 348 received VOQUEZNA DUAL PAK and 345 received LAC. These patients had a mean age of 51 years (range 20 to 87 years); 62.2% were female, 89.3% were White, 7.4% Black or African American, 1.5% were Asian and 1.8% were others with 72.5% non-Hispanic or Latino. Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 2.3% (8/346) of the VOQUEZNA TRIPLE PAK-treated patients, 0.9% (3/348) of the VOQUEZNA DUAL PAK-treated patients and 1.2% (4/345) of the LAC-treated patients.
The most common adverse reactions leading to discontinuation of VOQUEZNA TRIPLE PAK were diarrhea (0.6%) and hypertension (0.6%) and the most common adverse reaction leading to discontinuation of VOQUEZNA DUAL PAK was rash (0.6%). Most Common Adverse Reactions The adverse reactions occurring in ≥2% of patients are described in Table 3. Table 3: Adverse Reactions Occurring in ≥2% of Adult Patients Receiving VOQUEZNA DUAL PAK or VOQUEZNA TRIPLE PAK Adverse Reactions VOQUEZNA DUAL PAK VOQUEZNA TRIPLE PAK LAC (N=348) n (%) (N=346) n (%) (N=345) n (%) Diarrhea 18 (5.2) 14 (4.0) 33 (9.6) Dysgeusia Dysgeusia also includes taste disorder. 2 (0.6) 16 (4.6) 21 (6.1) Vulvovaginal candidiasis Vulvovaginal candidiasis includes: urogenital infection fungal, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginal pruritus, pruritus genital, genital infection fungal. 7 (2.0) 11 (3.2) 5 (1.4) Abdominal pain Abdominal pain includes: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper. 9 (2.6) 8 (2.3) 10 (2.9) Headache 5 (1.4) 9 (2.6) 5 (1.4) Hypertension Hypertension also includes blood pressure increased. 4 (1.1) 7 (2.0) 3 (0.9) Nasopharyngitis 7 (2.0) 1 (0.3) 3 (0.9) This study was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the VOQUEZNA DUAL PAK, VOQUEZNA TRIPLE PAK, and LAC treatment groups.
Other Adverse Reactions Other adverse reactions occurring in <2% of patients with VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK are listed below by body system: Blood and lymphatic system disorders: anemia, leukocytosis, leukopenia, neutropenia . Cardiac disorders: QT prolongation, tachycardia. Eye disorders: orbital edema. Gastrointestinal disorders: abdominal distension, constipation, dry mouth, duodenal polyp, duodenal ulcer, dyspepsia, flatulence, gastric ulcer, gastroesophageal reflux disease, hematochezia, large intestine polyp, nausea, rectal polyp, stomatitis, tongue discomfort, vomiting.
General disorders and administration site conditions: fatigue, pyrexia . Immune system disorders: drug hypersensitivity. Infections and infestations: anal fungal infection, gastrointestinal viral infection, oral fungal infection, pneumonia, tongue fungal infection, upper respiratory tract infection, urinary tract infection, viral infection. Investigations: increased liver function test. Metabolism and nutrition disorders: decreased appetite.
Musculoskeletal system: bone fracture. Nervous system disorders: ageusia, dizziness, tension headache. Psychiatric disorders: anxiety, depression, insomnia. Renal and urinary disorders: renal hypertrophy, tubulointerstitial nephritis . Reproductive system and breast disorders: vaginal discharge. Respiratory, thoracic and mediastinal disorders: cough, nasal polyps, oropharyngeal pain. Skin and subcutaneous tissue disorders: dermatitis, dry skin, rash.
6.2Postmarketing Experience with Components of
VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK The following adverse reactions have been identified during post-approval use of vonoprazan (outside of the United States), amoxicillin, or clarithromycin (all used separately). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Vonoprazan Blood and lymphatic system disorders: thrombocytopenia. Immune system disorders: anaphylactic shock, urticaria [see Contraindications (4.1) ]. Infections and Infestations: C. difficile (with concomitant antibacterials) . Investigation: hypomagnesemia, hypokalemia, hypocalcemia, vitamin B12 deficiency. Hepatobiliary disorders: hepatic injury, hepatic failure, jaundice. Skin and subcutaneous tissue disorders: drug eruption, erythema multiforme, SJS, TEN.
Amoxicillin Infections and infestations: mucocutaneous candidiasis. Gastrointestinal: Drug-induced enterocolitis syndrome (DIES), black hairy tongue, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment . Hypersensitivity reactions: anaphylaxis [see Contraindications (4.1) ]. Serum sickness–like reactions, erythematous maculopapular rashes, erythema multiforme, exfoliative dermatitis, hypersensitivity vasculitis, and urticaria have been reported.
Renal: crystalluria has been reported [see Overdosage (10) ]. Hemic and lymphatic systems: hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Central nervous system: reversible hyperactivity, agitation, confusion, convulsions, aseptic meningitis, and behavioral changes have
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
AMOXICILLIN 500MG; CLARITHROMYCIN 500MG; VONOPRAZAN FUMARATE EQ 20MG BASE
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA215152.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
