VOQUEZNA DUAL PAK- vonoprazan fumarate and amoxicillin

Vonoprazan suppresses basal and stimulated gastric acid secretion at the secretory surface of the gastric parietal cell through inhibition of the H + + Amoxicillin is an antibacterial drug. Clarithromycin is a macrolide antimicrobial drug [see Microbiology (12. 4) Acid suppression enhances the replication of H. pylori Vonoprazan Antisecretory Activity Following a single 20 mg dose of vonoprazan, the onset of the antisecretory effect as measured by intragastric pH occurs within 2 to 3 hours. The elevated intragastric pH compared to placebo is maintained for over 24-hours after dosing. The inhibitory effect of vonoprazan on acid secretion increases with repeated daily dosing and antisecretory effect reached steady state by Day 4 with a mean (SD) 24-hour intragastric pH of 6. 5) following 20 mg once daily dose (not an approved recommended dosage). The antisecretory effect of vonoprazan decreases following drug discontinuation although intragastric pH remained elevated compared to placebo for 24 to 48 hours following the dose on Day 7. Cardiac Electrophysiology At a dose 6 times the maximum recommended dose, vonoprazan does not prolong the QT interval to any clinically relevant extent. Serum Gastrin Effects In clinical trials conducted in adult patients with erosive esophagitis, treatment with vonoprazan increased baseline serum gastrin concentrations. Mean gastrin levels remained elevated with the recommended daily dose of vonoprazan for the treatment of erosive esophagitis and the mean serum gastrin levels returned to normal within 4 weeks of discontinuation of treatment. Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum CgA levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5. 1) Drug Interactions (7) Pharmacokinetic (PK) parameters for vonoprazan 20 mg after a single dose (not an approved recommended dosage) and at steady state following twice daily administration are summarized in Table 8. Table 8: Mean (%CV) Pharmacokinetic Parameters for Vonoprazan Following a Single Dose or at Steady State Following Twice Daily Dosing PK Parameter Single Dose Steady State C max 0-12h max max 1/2 z T max 2. 0) C max 25. 1) AUC 0-12h 154. 7) CL/F (L/h) 97. 7) V z 1001 (39. 4) Vonoprazan Absorption Vonoprazan exhibits time independent pharmacokinetics and steady state concentrations are achieved by Day 3 to 4. After multiple doses of vonoprazan ranging from 10 mg (0. 5 times the lowest approved recommended single dosage) to 40 mg (2 times the highest approved recommended single dosage) once daily for 7 days in healthy subjects, C max Steady state mean plasma exposure of vonoprazan following 20 mg twice daily dosing (AUC 0-12h 0-12h Effect of Food: In a food effect study in healthy subjects (N=24) receiving vonoprazan 20 mg, a high-fat meal resulted in a 5% increase in C max max Distribution Plasma protein binding of vonoprazan ranged from 85 to 88% in healthy subjects and was independent of concentration from 0. 1 to 10 mcg/mL. Elimination Metabolism: Vonoprazan is metabolized to inactive metabolites via multiple pathways by a combination of cytochrome P450 (CYP) isoforms (predominantly CYP3A4/5, CYP2C19, CYP2D6, and CYP2B6) along with sulfo- and glucuronosyl-transferases. CYP2C19 polymorphisms have been evaluated in clinical studies and there were no considerable differences in the pharmacokinetics of vonoprazan based on CYP2C19 metabolizer status. Excretion: Following oral administration of radiolabeled vonoprazan, approximately 67% of the radiolabeled dose (8% as unchanged vonoprazan) was recovered in urine and 31% (1. 4% as unchanged vonoprazan) was recovered in feces. Specific Populations Sex, Race or Ethnicity: There were no clinically significant differences in the pharmacokinetics of vonoprazan based on sex or race/ethnicity. Patients with Renal Impairment The pharmacokinetics of vonoprazan administered as a single 20 mg dose in patients with mild (N=8), moderate (N=8), or severe (N=8) renal impairment were compared to those with normal renal function (N=13). Compared to subjects with normal renal function, systemic exposure (AUC infinity infinity [see Dosage and Administration (2. Patients with Hepatic Impairment The pharmacokinetics of vonoprazan administered as a single 20 mg dose in patients with mild [Child-Pugh Class A (N=8)], moderate [Child-Pugh Class B (N=8)], or severe [Child-Pugh Class C (N=6)] hepatic impairment were compared to those with normal hepatic function (N=12). Compared to subjects with normal hepatic function, systemic exposure (AUC infinity [see Dosage and Administration (2. Drug Interaction Studies In vitro studies: Cytochrome P450 (CYP450) Enzymes In vitro Transporter Systems Vonoprazan inhibits multidrug and toxin extrusion protein 1 (MATE1) and organic cation transporter 1 (OCT1), but only at concentrations higher than clinically relevant. Clinical Studies: Combination Therapy with Vonoprazan, Amoxicillin, and Clarithromycin When vonoprazan 20 mg, amoxicillin 750 mg, and clarithromycin 400 mg were co-administered twice daily for 7 days (N=11), there was no effect on pharmacokinetics of amoxicillin compared to administration of amoxicillin alone. However, vonoprazan C max 0-12h max 0-12h Effect of Vonoprazan on CYP3A4 Substrates When a single oral dose of midazolam 2 mg was administered following vonoprazan 20 mg twice daily for 7 days (N=20), midazolam AUC infinity Effect of CYP3A Inhibitors on Vonoprazan When a single 40 mg (2 times the highest approved recommended single dosage) dose of vonoprazan was administered with clarithromycin 500 mg twice daily for 7 days (N=16), vonoprazan AUC infinity Model-Informed Approaches: Effect of CYP3A Inducers on Vonoprazan Vonoprazan exposures are predicted to be 80% lower when co-administered with a strong CYP3A4 inducer such as rifampicin and 50% lower when co-administered with a moderate CYP3A4 inducer such as efavirenz. Amoxicillin Absorption Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. Orally administered doses of 500-mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 5. 5 mcg/mL to 7. 5 mcg/mL, respectively. Distribution Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. In blood serum, amoxicillin is approximately 20% protein-bound. Following a 1-gram dose and utilizing a special skin window technique to determine levels of the antibacterial, it was noted that therapeutic levels were found in the interstitial fluid. Metabolism and Excretion The half-life of amoxicillin is 61. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Since most of the amoxicillin is excreted unchanged in the urine, its excretion can be delayed by concurrent administration of probenecid. Clarithromycin Absorption For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately 2 to 2. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in AUC. Therefore, clarithromycin may be given without regard to food. In non-fasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Distribution Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intracellular concentrations, tissue concentrations are higher than serum concentrations. Metabolism and Elimination Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were 3 mcg/mL to 4 mcg/mL with a 500 mg dose administered every 8 hours to 12 hours. The elimination half-life of clarithromycin was 5 hours to 7 hours with 500 mg administered every 8 hours to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 500 mg administered every 8 hours to 12 hours. With a 500 mg every 8 hours to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 mcg/mL), and its elimination half-life is about 7 hours to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 days to 4 days. After a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is approximately 30%. The renal clearance of clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH clarithromycin, which accounts for an additional 10% to 15% of the dose with a 500 mg tablet administered every 12 hours. Patients with Hepatic Impairment The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects. Patients with Renal Impairment The pharmacokinetics of clarithromycin were also altered in subjects with impaired renal function. Drug Interaction Studies Fluconazole: Following administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers, the steady-state clarithromycin C min Colchicine: When a single dose of colchicine 0. 6 mg was administered with clarithromycin 250 mg twice daily for 7 days, the colchicine C max 0-infinity Atazanavir: Following administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), the clarithromycin AUC increased 94%, the 14-OH clarithromycin AUC decreased 70%, and the atazanavir AUC increased 28%. Ritonavir: Concomitant administration of clarithromycin and ritonavir (N=22) resulted in a 77% increase in clarithromycin AUC and a 100% decrease in the AUC of 14-OH clarithromycin. Saquinavir: Following administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers, the steady-state saquinavir AUC and C max max max Didanosine: Simultaneous administration of clarithromycin tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics. Zidovudine: Following administration of clarithromycin 500 mg tablets twice daily with zidovudine 100 mg every 4 hours, the steady-state zidovudine AUC decreased 12% compared to administration of zidovudine alone (N=4). Individual values ranged from a decrease of 34% to an increase of 14%. When clarithromycin tablets were administered two to four hours prior to zidovudine, the steady-state zidovudine C max Omeprazole: Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (C max 0-24 ½ The plasma levels of clarithromycin and 14-OH clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean C max min 0-8 max min 0-8 Table 9: Clarithromycin Tissue Concentrations 2 hours after Dose (mcg/mL)/(mcg/g) Treatment N Antrum Fundus N Mucus Clarithromycin 5 10. 74 Clarithromycin + Omeprazole 5 19. 79 Theophylline: In two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release formulation was dosed at either 6. 5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h clarithromycin), the steady-state levels of C max min Midazolam: When a single dose of midazolam was co-administered with clarithromycin tablets (500 mg twice daily for 7 days), midazolam AUC increased 174% after intravenous administration of midazolam and 600% after oral administration. Mechanism of Action Amoxicillin is similar to penicillin in its bactericidal action against susceptible bacteria during the stage of active multiplication. It acts through the inhibition of cell wall biosynthesis that leads to the death of the bacteria. Clarithromycin exerts its antibacterial activity by binding to the 50S ribosomal subunit of susceptible bacteria resulting in inhibition of protein synthesis. Resistance Resistance to amoxicillin is mediated primarily through enzymes called beta-lactamases that cleave the beta-lactam ring of amoxicillin, rendering it inactive. The major routes of clarithromycin resistance are modification of the 23S rRNA in the 50S ribosomal subunit to insensitivity or drug efflux pumps. Beta-lactamase production should have no effect on clarithromycin activity. pylori Antimicrobial Activity Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of H. pylori [see Clinical Studies (14) in vitro in vitro H. pylori Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www. Effects on Gastrointestinal Microbial Ecology Decreased gastric acidity due to any means, increases gastric counts of bacteria normally present in the gastrointestinal tract. Vonoprazan decreases gastric acidity, VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK may lead to a slightly increased risk of gastrointestinal infections due to pathogens such as Salmonella Campylobacter C.

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. 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. 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. 2 VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK are indicated for the treatment of Helicobacter pylori H. pylori [see Clinical Studies (14) 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 2. 1 VOQUEZNA DUAL PAK 2. 2 See full prescribing information for the recommended dosage for patients with renal or hepatic impairment. 4 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 [see Clinical Pharmacology (12. 3) 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) VOQUEZNA DUAL PAK is a co-packaged product containing vonoprazan tablets and amoxicillin capsules given with or without food, for 14 days [see Clinical Pharmacology (12. 3) 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) The recommended dosage of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in adult patients with renal impairment is described in Table 1 [see Use in Specific Populations (8. 6) Clinical Pharmacology (12. 3) 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 20 mg vonoprazan twice daily Less than 30 mL/minute Use is not recommended The recommended dosage of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in adult patients with hepatic impairment is described in Table 2 [see Use in Specific Populations (8. 7) Clinical Pharmacology (12. 3) 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 20 mg vonoprazan twice daily Child-Pugh Class B Use is not recommended Child-Pugh Class C Use is not recommended 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.

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 [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 6. 1 VOQUEZNA DUAL PAK 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. gov/medwatch. 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 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 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. 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=346) (N=345) Diarrhea 18 (5. 6) Dysgeusia Dysgeusia also includes taste disorder. 1) Vulvovaginal candidiasis Vulvovaginal candidiasis includes: urogenital infection fungal, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginal pruritus, pruritus genital, genital infection fungal. 4) Abdominal pain Abdominal pain includes: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper. 9) Headache 5 (1. 4) Hypertension Hypertension also includes blood pressure increased. 9) Nasopharyngitis 7 (2. 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:. Cardiac disorders: Eye disorders: Gastrointestinal disorders: General disorders and administration site conditions:. Immune system disorders: Infections and infestations: Investigations: Metabolism and nutrition disorders: Musculoskeletal system: Nervous system disorders: Psychiatric disorders: Renal and urinary disorders:. Reproductive system and breast disorders: Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders: 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: Immune system disorders: [see Contraindications (4. 1) Infections and Infestations: C. difficile [see Warnings and Precautions (5. 1) Investigation: Hepatobiliary disorders: Skin and subcutaneous tissue disorders: [see Warnings and Precautions (5. 1) Amoxicillin Infections and infestations: Gastrointestinal: [see Warnings and Precautions (5. 1) Hypersensitivity reactions: [see Contraindications (4. 1) Warnings and Precautions (5. 1) Renal: [see Overdosage (10) Hemic and lymphatic systems: Central nervous system: Miscellaneous: Skin and subcutaneous tissue disorders: Clarithromycin Blood and lymphatic system: Cardiac: torsades de pointes. Ear and labyrinth: Gastrointestinal: Hepatobiliary: [see Warnings and Precautions (5. 2) Infections and infestations: [see Warnings and Precautions (5. 2) Immune system: Investigations: Metabolism and nutrition: Musculoskeletal and connective tissue: [see Contraindications (4. 2) Warnings and Precautions (5. 2) Nervous system: Psychiatric: Renal and urinary: Skin and subcutaneous tissue disorders: [see Warnings and Precautions (5. 1) Vascular:.

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. 1 Known hypersensitivity to vonoprazan, amoxicillin or any other beta-lactams or any component of VOQUEZNA DUAL PAK. 1 Rilpivirine-containing products. 1 VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component Pimozide. 2 Lomitapide, lovastatin, and simvastatin. 2 Ergot alkaloids (ergotamine or dihydroergotamine). 2 Colchicine in renal or hepatic impairment. 2 History of cholestatic jaundice/hepatic dysfunction with use of clarithromycin. 2 Lurasidone. 2 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 beta-lactam antibacterials, e. , penicillins and cephalosporins), or clarithromycin (or other macrolide antibacterial drugs, e. , erythromycin) or VOQUEZNA DUAL PAK: vonoprazan or amoxicillin (or other beta-lactam antibacterials, e. , 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) 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 [see Warnings and Precautions (5. 2) Drug Interactions (7) Lipid-lowering Agents: Lomitapide, simvastatin, and lovastatin [see Warnings and Precautions (5. 2) 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) 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.

Lactation 8. 2 Geriatrics torsades de pointes 8. 5 Renal Impairment 8. 6 Hepatic Impairment 8. 7 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 (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) (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. Report pregnancies to the Phathom Pharmaceuticals, Inc. Adverse Event reporting line at 1-888-775-7428. 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 clarithromycin late in gestation through lactation (GD 17 to post-natal day 21) at doses of 10, 40, or 160 mg/kg/day (<= 1 times MRHD based on BSA comparison), reductions in maternal body weight and food consumption were observed at 160 mg/kg/day. Reduced body-weight gain observed in offspring at 160 mg/kg/day was considered secondary to maternal toxicity. No adverse developmental effects were observed with clarithromycin at any dose tested. Vonoprazan: Pregnant rats were orally administered vonoprazan at doses of 30, 100, or 300 mg/kg/day (7, 27, 130 times the MRHD based on AUC comparison at the same doses from unmated female rats from separate studies) during the period of organogenesis from gestation Day 6 to 17. During maternal dosing, one high-dose female died and decreased body weight and food consumption occurred at the middle and highest doses. No embryo-fetal lethality was observed but decreased fetal body weight was observed in the highest dose group. Fetal abnormalities were limited to the 300 mg/kg/day dose group and included ventricular septal defect and mal-positioned subclavian artery in fetuses in a majority (15/19) of litters, as well as tail abnormalities, and small anal opening. No adverse embryo-fetal effects were observed at the 100 mg/kg/day. Pregnant rabbits were orally administered vonoprazan at doses of 3, 10, or 30 mg/kg/day (0. 5, 10 times the MRHD based on AUC comparison) during the period of organogenesis from gestation Day 6 to 18. Two animals aborted at the highest dose and decreased body weight and food consumption occurred at the mid and high doses. No embryo-fetal mortality or toxicity occurred. There were no external, visceral or skeletal abnormalities. In a PPND study, pregnant female rats were orally administered vonoprazan at doses of 1, 3, 10, or 100 mg/kg/day (0. 1, 22 times the MRHD based on AUC comparison) from GD 6 to lactation day (LD) 21. Decreased body weight gain and food consumption were present in dams at the highest dose during lactation. Decreased body weight gain compared to controls was observed in offspring from dams in the high dose group. Liver discoloration occurred in offspring from the high dose group at LD 4 but was not present in animals examined after weaning. Similarly, in dose range finding studies in rats and follow-up mechanistic animal studies, the liver discoloration was observed and characterized as necrosis, fibrosis and hemorrhage at equal to or greater than clinically relevant exposures based on AUC comparisons. The mechanistic studies further demonstrated the effect was likely attributable to vonoprazan exposure during lactation [see Use in Specific Populations (8. 2) Exposure margins from vonoprazan between the animal and clinical studies for vonoprazan, amoxicillin, and clarithromycin used in combination may be lower due to increased vonoprazan exposure from concomitant use with clarithromycin in patients [see Clinical Pharmacology (12. 3) 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 other adverse maternal or fetal outcomes. Animal reproduction studies with amoxicillin have been performed in mice and rats, at doses up to 2,000 mg/kg (5 and 10 times the 2 g human dose for mice and rats, respectively, 3 and 6 times the 3 g human dose for mice and rats, respectively, based on BSA comparison). Risk Summary There are no data regarding the presence of vonoprazan in human milk, the effects on the breastfed infant, or the effects on milk production. Vonoprazan and its metabolites are present in rat milk. Liver injury occurred in offspring from pregnant and lactating rats administered oral vonoprazan at AUC exposures approximately equal to and greater than the MRHD (see Data K Based on data from a published lactation study, clarithromycin and its active metabolite 14-OH clarithromycin are present in human milk at less than 2% of the maternal weight-adjusted dose (see Data Data from published clinical lactation study reports that amoxicillin is present in human milk. There are no data on the effects of amoxicillin on milk production. Data Human Data Clarithromycin: Serum and milk samples were obtained after 3 days of treatment, at steady state, from one published study of 12 lactating women who were taking clarithromycin 250 mg orally twice daily. Based on data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk fed infant would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with this maternal dosage regimen. This is less than 2% of the maternal weight-adjusted dose (7. 8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than 6 months of age. A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibacterial (6 were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12. 7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence. Animal Data No studies with the combination of vonoprazan and amoxicillin, and/or clarithromycin were conducted to examine the effect of lactational exposure on animal offspring. Vonoprazan: In a PPND study in rats, in which the dams were administered oral vonoprazan during gestation and through lactation at up to 22-times the MRHD (based on a comparison of AUC), liver discoloration occurred in offspring from the high dose group [see Use in Specific Populations (8. 1) Liver discoloration associated with necrosis, fibrosis, and hemorrhage in the offspring of dosed rats was also seen in dose-range finding studies and limited, non-standard, follow-up, mechanistic studies, including offspring in lactation only studies. These effects were reported in pups on LD 4 at doses from 3 to 100 mg/kg/day (approximately 0. 2- to 22-fold the MRHD based on an AUC values extrapolated from the PPND study) and on LD 14 at doses from 10 to 100 mg/kg/day (approximately 1- to 22-fold the MRHD based on an extrapolated AUC comparisons). In mechanistic studies, liver effects were observed in offspring treated only during lactation but not in offspring from animals only treated during gestation. In some of these studies, this finding was associated with increased offspring stomach weights that was reversed along with liver discoloration by concomitant treatment with a gastrointestinal prokinetic agent. Infertility Males Clarithromycin: Based on animal fertility study findings for clarithromycin, VOQUEZNA TRIPLE PAK may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13. 1) Safety and effectiveness of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK in pediatric patients have not been established. Geriatric Use for the Individual Components of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK Amoxicillin and Clarithromycin Amoxicillin and clarithromycin are known to be substantially excreted by the kidney, and the risk of adverse reactions to these drugs may be greater in patients with impaired renal function and it may be useful to monitor renal function [see Use in Specific Populations (8. 6) Vonoprazan There were 218 patients aged 65 years and older in the clinical study of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK for the treatment of H. pylori [see Clinical Studies (14) Amoxicillin An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. These analyses have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, and it may be useful to monitor renal function. Clarithromycin In a steady-state study in which healthy elderly subjects (65 years to 81 years of age) were given 500 mg of clarithromycin every 12 hours, the maximum serum concentrations and area under the curves of clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse reactions when compared to younger patients. Elderly patients may be more susceptible to development of torsades de pointes [see Warnings and Precautions (5. 2) Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e. , verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older [see Warnings and Precautions (5. 2) Especially in elderly patients, there have been reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, some of which occurred in patients with renal insufficiency. Deaths have been reported in some patients [see Contraindications (4. 2) Warnings and Precautions (5. 2) No dosage adjustment of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK is recommended in patients with mild to moderate renal impairment (eGFR 30 to 89 mL/min). Use of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK is not recommended in patients with severe renal impairment (eGFR < 30 mL/min) [see Dosage and Administration (2. 3) Clinical Pharmacology (12. 3) No dosage adjustment of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK is recommended in patients with mild hepatic impairment (Child-Pugh A). Use of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) [see Dosage and Administration (2. 4) Clinical Pharmacology (12.

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) 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) Prevention or Management Avoid concomitant use with VOQUEZNA DUAL PAK. 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. 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) 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. , iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12. 2) 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. [see Clinical Pharmacology (12. 3) 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. CYP2C19 Substrates (e. , clopidogrel, citalopram, cilostazol) Clinical Effect Vonoprazan is a CYP2C19 inhibitor [see Clinical Pharmacology (12. 3) 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) 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. , 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 excreted in the urine [see Clinical Pharmacology (12. 3) 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. 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. , torsades de pointes 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 [see Clinical Pharmacology (12. 3) 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. 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 [see Warnings and Precautions (5. 2) Clinical Pharmacology (12. 3) Prevention or Management Midazolam Closely monitor patients for signs or symptoms of increased or prolonged central nervous system effects (e. , 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 [see Contraindications (4. 2) 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 [see Warnings and Precautions (5. 2) 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 [see Warnings and Precautions (5. 2) 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. , 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 [see Clinical Pharmacology (12. 3) [see Warnings and Precautions (5. 2) 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) [see Clinical Pharmacology (12. 3) 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 [see Clinical Pharmacology (12. 2) 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. Certain CYP3A Substrates where minimal concentration changes may lead to serious toxicities Clinical Effect Vonoprazan is a weak CYP3A inhibitor [see Clinical Pharmacology (12. 3) 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. CgA Test for Neuroendocrine Tumors Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12. 2) 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. Prevention or Management Test should be performed at least 4 weeks after stopping VOQUEZNA DUAL PAK to allow gastrin levels to return to normal [see Clinical Pharmacology (12. 3) 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.

OVERDOSAGE
No information is available on accidental overdosage of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK in humans. In case of an overdose, patients should contact a physician, poison control center, or emergency room. The available overdosage information for each of the individual components in VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK are summarized below: Vonoprazan There have been no reports of overdose with vonoprazan. In clinical studies, a single dose of 120 mg resulted in no serious adverse reactions. Vonoprazan is not removed from the circulation by hemodialysis. If overdose occurs, treatment should be symptomatic and supportive. Amoxicillin In case of amoxicillin overdosage, discontinue medication, treat symptomatically and institute supportive measures as needed. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms. Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin. Amoxicillin can be removed from circulation by hemodialysis. Clarithromycin Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea. Treat adverse reactions accompanying overdosage by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.
NONCLINICAL TOXICOLOGY
No adequate or well-controlled long-term studies have been performed to evaluate the effect of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK on carcinogenesis, mutagenesis, or impairment of fertility. Vonoprazan Carcinogenicity In a 24-month carcinogenicity study in mice, vonoprazan at daily oral doses of 6, 20, 60, and 200 mg/kg/day (approximately 0. 4, 4, 19, and 93 times the MRHD based on AUC) produced hyperplasia of neuroendocrine cells, gastropathy and benign and/or malignant neuroendocrine cell tumors (carcinoids) in the stomach at all doses in males and at 60 mg/kg/day and greater in females. In liver, increased incidences of hepatocellular adenoma and carcinomas were observed at doses of 20 mg/kg/day and greater in males and 60 mg/kg/day and greater in females. In a 24-month carcinogenicity study in Sprague-Dawley rats, vonoprazan at daily oral doses of 5, 15, 50, and 150 mg/kg/day (approximately 0. 6, 4, 19, and 65 times the MRHD based on AUC) produced benign and/or malignant neuroendocrine cell tumors in the stomach in both male and female rats at doses of 5 mg/kg/day or more. Increased incidence of hepatocellular adenoma and carcinomas and hepatocholangiocellular adenomas and carcinomas were observed at doses of 50 and 150 mg/kg/day. In both mice and rats, neuroendocrine tumors in the stomach occurred in association with neuroendocrine hyperplasia and gastropathy in the stomach and increased plasma gastrin concentrations that are consistent with inhibition of gastric acid secretion. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with proton pump inhibitors or high doses of H 2 Mutagenesis Vonoprazan was negative for mutagenicity in the in vitro in vitro in vivo Impairment of Fertility Vonoprazan at oral doses up to 300 mg/kg/day in rats (approximately 133 times the MRHD based on AUC from a separate study in nonpregnant animals administered the same dose) was found to have no effect on fertility and reproductive performance. Elongation of the estrous cycle was observed in rats at doses equivalent to 133 times the MRHD based on AUC. Amoxicillin Carcinogenicity Long-term studies in animals have not been performed to evaluate carcinogenic potential. Mutagenesis Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate. Amoxicillin and potassium clavulanate were non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and potassium clavulanate were weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and potassium clavulanate were negative in the mouse micronucleus test and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test and was negative in each of these assays. Impairment of Fertility In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 1. 6 times the human dose in mg/m 2 Clarithromycin Mutagenesis The following in vitro Salmonella Bacterial Induced Mutation Frequency Test In Vitro Rat Hepatocyte DNA Synthesis Assay Mouse Lymphoma Assay Mouse Dominant Lethal Study Mouse Micronucleus Test All tests had negative results except the in vitro Impairment of Fertility Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were twice the human serum levels. Testicular atrophy occurred in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8 times greater than the maximum human daily dose (on a BSA comparisons). Clarithromycin Corneal opacity occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose (on BSA comparisons). Lymphoid depletion occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose (on BSA comparisons).
CLINICAL STUDIES
The effectiveness and safety of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK were 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 H. pylori H. pylori 13 H. pylori 13 H. pylori VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK were shown to be noninferior to LAC in patients who did not have a clarithromycin or amoxicillin resistant strain of H. pylori H. pylori H. pylori Table 10: Eradication Rates of H. pylori in Patients Receiving VOQUEZNA TRIPLE PAK, VOQUEZNA DUAL PAK, or LAC at >=27 Days Post-therapy - mITT VOQUEZNA TRIPLE PAK VOQUEZNA DUAL PAK LAC % % % LAC = lansoprazole, amoxicillin, clarithromycin triple therapy regimen; CI = confidence interval calculated via the Miettinen and Nurminen method Modified intent to treat (mITT) population: Patients were included in the mITT analysis if they had documented H. pylori Patients with H. pylori Clarithromycin resistant strains of H. pylori 84.7 78.5 78.8 Treatment Difference from LAC 5.9 p<0.0001 for test of non-inferiority versus LAC. -0.3 p<0.01 for test of non-inferiority versus LAC. All randomized patients with H. pylori 80.8 77.2 68.5 Treatment Difference from LAC 12.3 p=0.0003 for test of superiority versus LAC. 8.7 p=0.01 for test of superiority versus LAC. Patients with H. pylori H. pylori 65.8 69.6 31.9 Treatment Difference from LAC 33.8 p<0.0001 for test of superiority versus LAC. 37.7

VOQUEZNA TRIPLE PAK- vonoprazan fumarate, amoxicillin and clarithromycin

VOQUEZNA DUAL PAK- vonoprazan fumarate and amoxicillin Product manual source documgent