DRUG INTERACTIONS-

 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.

BRIEF SUMMARY-

VONOPRAZAN-(March 2022)

Indn- To treat Helicobacterial Pylori Infection                                                                     

Dosage-  The recommended dosage regimen is vonoprazan 20 mg plus amoxicillin 1,000 mg plus clarithromycin 500 mg, each given twice daily (morning and evening, 12 hours apart), with or without food, for 14 days

ADR- Most common adverse reactions (= 2%) were dysgeusia, diarrhea, vulvovaginal candidiasis, headache, abdominal pain, and hypertension.                                              

CI- Known hypersensitivity to vonoprazan, amoxicillin or any other betalactams, clarithromycin or any other macrolide antimicrobial or any component.

Pat Inform

Advise the patient to call their healthcare provider immediately if they develop a new rash, urticaria, drug eruptions, swelling of the face, difficulty in breathing   other symptoms of allergic reactions

 Severe Cutaneous Adverse Reactions-                                                                     Advise patients about the signs and symptoms of serious skin manifestations.

Instruct patients to stop taking  immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity 

=================================================================

U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 13

Name of the Drug-   VOQUEZNA

Active Ingredient -   Vonoprazan, Amoxicilin and Clarithromycin

Pharmacological Classification- To treat Helicobacterial Pylori Infection                                                                                                                                                     

Date of Approval-         5/3/22       

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                       VOQUEZNATM TRIPLE PAKTM and VOQUEZNATM DUAL PAKTM safely and effectively.

See full prescribing information for VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK. VOQUEZNA TRIPLE PAK (vonoprazan tablets; amoxicillin capsules; clarithromycin tablets), co-packaged for oral use VOQUEZNA DUAL PAK (vonoprazan tablets; amoxicillin capsules) co-packaged for oral use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE-

 VOQUEZNA TRIPLE PAK, is a co-packaged product containing vonoprazan, a potassium-competitive acid blocker (PCAB), amoxicillin, a penicillin class antibacterial, and clarithromycin, a macrolide antimicrobial, indicated for the treatment of Helicobacter pylori (H. pylori) infection in adults.

 VOQUEZNA DUAL PAK, is a co-packaged product containing vonoprazan, a PCAB, and amoxicillin, a penicillin class antibacterial, indicated for the treatment of H. pylori infection in adults

 To reduce the development of drug-resistant bacteria and maintain the effectiveness of VOQUEZNA TRIPLE PAK, VOQUEZNA DUAL PAK and other antibacterial drugs, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 

 DOSAGE AND ADMINISTRATION- -

 VOQUEZNA TRIPLE PAK: The recommended dosage regimen is vonoprazan 20 mg plus amoxicillin 1,000 mg plus clarithromycin 500 mg, each given twice daily (morning and evening, 12 hours apart), with or without food, for 14 days

VOQUEZNA DUAL PAK: The recommended dosage regimen is vonoprazan 20 mg twice daily (morning and evening) plus amoxicillin 1,000 mg, three times a day (morning, mid-day, and evening), with or without food, for 14 days.

 DOSAGE FORMS AND STRENGTHS-

 VOQUEZNA TRIPLE PAK: Carton of 14 daily administration packs for morning and evening dosing, each containing the following three drug products

 • Tablets: Vonoprazan 20 mg • Tablets: Clarithromycin 500 mg • Capsules: Amoxicillin 500 mg VOQUEZNA DUAL PAK: Carton of 14 daily administration packs for morning, mid-day and evening dosing, each containing the following two drug products

 • Tablets: Vonoprazan 20 mg • Capsules: Amoxicillin 500 mg

CONTRAINDICATIONS-

 VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK:

• Known hypersensitivity to vonoprazan, amoxicillin or any other betalactams, clarithromycin or any other macrolide antimicrobial or any component of VOQUEZNA TRIPLE PAK.

 • Known hypersensitivity to vonoprazan, amoxicillin or any other betalactams or any component of VOQUEZNA DUAL PAK.

 • Rilpivirine-containing products. VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component:

• Pimozide.  • Lomitapide, lovastatin, and simvastatin.  • Ergot alkaloids (ergotamine or dihydroergotamine). • Colchicine in renal or hepatic impairment. ( • History of cholestatic jaundice/hepatic dysfunction with use of clarithromycin. 

-- ADVERSE REACTIONS :

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 1-800-775-PHAT (7428) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CONTRAINDICATIONS-

 VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK:

• Known hypersensitivity to vonoprazan, amoxicillin or any other betalactams, clarithromycin or any other macrolide antimicrobial or any component of VOQUEZNA TRIPLE PAK.

 • Known hypersensitivity to vonoprazan, amoxicillin or any other betalactams or any component of VOQUEZNA DUAL PAK.

 • Rilpivirine-containing products. VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component:

• Pimozide.  • Lomitapide, lovastatin, and simvastatin.  • Ergot alkaloids (ergotamine or dihydroergotamine). • Colchicine in renal or hepatic impairment. ( • History of cholestatic jaundice/hepatic dysfunction with 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).

 • 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

 • 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.

 • Hepatotoxicity:                                                                                                    Discontinue if signs and symptoms of hepatitis occur with VOQUEZNA TRIPLE PAK.

 • Serious adverse reactions due to concomitant use with other drugs:                       Serious adverse reactions can occur with VOQUEZNA TRIPLE PAK due to drug interactions of clarithromycin with colchicine, some lipid lowering agents, some calcium channel blockers, and other drugs.

 • Embryo-Fetal Toxicity:                                                                                           Based on the findings from animal studies and human observational studies in pregnant women treated with clarithromycin, VOQUEZNA TRIPLE PAK is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate.

 • Myasthenia Gravis:                                                                                              Exacerbation of myasthenia gravis can occur with VOQUEZNA TRIPLE PAK since it has been reported in patients receiving clarithromycin tablets. (5.2) ----------------------------

-- ADVERSE REACTIONS ------------------------------ 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 1-800-775-PHAT (7428) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------DRUG INTERACTIONS-------------------------------- Components of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK have the potential for clinically important drug interactions. See Full Prescribing Information for important drug interactions with VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK. (4, 5.2, 7) ------

--------------------USE IN SPECIFIC POPULATIONS--------------------- • Lactation: Breastfeeding not recommended during treatment, but a lactating woman can pump and discard breast milk during treatment and for 2 days after VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK administration. (8.2) • Geriatrics: VOQUEZNA TRIPLE PAK increased risk of torsades de pointes due to the clarithromycin component. (8.5) • Renal Impairment: Avoid use in severe renal impairment. (8.6) • Hepatic Impairment: Avoid use in moderate and severe hepatic impairment. (8.7) See 17 for PATIENT COUNSELING INFORMATION R

DOSAGE AND ADMINISTRATION- -

 VOQUEZNA TRIPLE PAK: The recommended dosage regimen is vonoprazan 20 mg plus amoxicillin 1,000 mg plus clarithromycin 500 mg, each given twice daily (morning and evening, 12 hours apart), with or without food, for 14 days

VOQUEZNA DUAL PAK: The recommended dosage regimen is vonoprazan 20 mg twice daily (morning and evening) plus amoxicillin 1,000 mg, three times a day (morning, mid-day, and evening), with or without food, for 14 days.

 DOSAGE FORMS AND STRENGTHS-

 VOQUEZNA TRIPLE PAK: Carton of 14 daily administration packs for morning and evening dosing, each containing the following three drug products

 • Tablets: Vonoprazan 20 mg • Tablets: Clarithromycin 500 mg • Capsules: Amoxicillin 500 mg VOQUEZNA DUAL PAK: Carton of 14 daily administration packs for morning, mid-day and evening dosing, each containing the following two drug products

 • Tablets: Vonoprazan 20 mg • Capsules: Amoxicillin 500 mg

PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions -

Patients should be aware that VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK can cause allergic reactions in some individuals.

Advise the patient to call their healthcare provider immediately if they develop a new rash, urticaria, drug eruptions, swelling of the face, difficulty in breathing   other symptoms of allergic reactions

 Severe Cutaneous Adverse-

Reactions Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity 

 Drug Interactions-

Advise patients that VOQUEZNA TRIPLE PAK or the individual components of VOQUEZNA TRIPLE PAK may interact with some drugs; therefore, advise patients to report to their healthcare provider the use of any other medications including natural substitutes and nutritional supplements.

Diarrhea -                                                                                                                        Advise patients that diarrhea is a common problem caused by antibacterials including amoxicillin and clarithromycin, and it usually ends when the drugs are stopped. However, rarely after receiving treatment with VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose.

If this occurs, instruct patients to contact their healthcare provider as soon as possible 

Embryo-Fetal Toxicity -                                                                                                    Advise pregnant patients and females of reproductive potential that if pregnancy occurs while taking VOQUEZNA TRIPLE PAK, there is a potential risk to the fetus to

 Lactation -                                                                                                                Advise the lactating women to pump and discard their milk during treatment with VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK and for 2 days after the therapy ends [see Use in Specific Populations (8.2)].

Infertility-                                                                                                                          Advise males of reproductive potential that VOQUEZNA TRIPLE PAK may impair fertility [see Use in Specific Populations (8.3)]

 Potential for Dizziness, Vertigo and Confusion There are no data on the effect of VOQUEZNA TRIPLE PAK on the ability to drive or use machines. However, counsel patients regarding the potential for dizziness, vertigo, confusion and disorientation, which may occur with clarithromycin, a component of VOQUEZNA TRIPLE PAK.

VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK are distributed by Phathom Pharmaceuticals, Inc., Buffalo Grove, IL, 60089, U.S.A. Vonoprazan Tablets are manufactured for Phathom Pharmaceuticals, Inc., Buffalo Grove, IL 60089, U.S.A.

Amoxicillin Capsules and Clarithromycin Tablets are manufactured for Sandoz Inc., Princeton, NJ 08540, U.S.A. VOQUEZNA, VOQUEZNA TRIPLE PAK, VOQUEZNA DUAL PAK and the VOQUEZNA logo are trademarks, and Phathom Pharmaceuticals is a registered trademark, of Phathom Pharmaceuticals, Inc. © 2022 Phathom Pharmaceuticals, Inc. All rights reserved. VOQ221 V

CLINICAL PHARMACOLOGY

12.1. Mechanism of Action Vonoprazan suppresses basal and stimulated gastric acid secretion at the secretory surface of the gastric parietal cell through inhibition of the H+, K+-ATPase enzyme system in a potassium competitive manner. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, vonoprazan has been characterized as a type of gastric proton-pump inhibitor, in that it blocks the final step of acid production. Vonoprazan does not require activation by acid. Vonoprazan may selectively concentrate in the parietal cells in both the resting and stimulated states. Vonoprazan binds to the active proton pumps in a noncovalent and reversible manner. Amoxicillin is an antibacterial drug. Clarithromycin is a macrolide antimicrobial drug [see Microbiology (12.4)]. Acid suppression enhances the replication of H. pylori bacteria and the stability and effectiveness of antimicrobials in the treatment of H. pylori infection. 12.2. Pharmacodynamics 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 6.0 (1.5) 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 Reference ID: 4978225 Page 31 of 42 At a dose 6 times the maximum recommended dose, vonoprazan does not prolong the QT interval to any clinically relevant extent. 12.3. Pharmacokinetics 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 6. Table 6: Mean (%CV) Pharmacokinetic Parameters for Vonoprazan Following a Single Dose or at Steady State Following Twice Daily Dosing PK Parameter Single Dose (N=10) Steady State (N=32) Tmax (h), median (range) 2.5 (1.0-4.0) 3.0 (1.0-6.0) Cmax (ng/mL) 25.2 (39.7) 37.8 (36.1) AUC0-12h (ng*hr/mL) 154.8 (25.2) 272.5 (30.5) t1/2 (h) 7.1 (10.1) 6.8 (22.7) CL/F (L/h) 97.3 (36.3) 81.3 (35.7) Vz/F (L) 1001 (39.6) 782.7 (34.4) Cmax = Maximum plasma concentration; AUC0-12h =Area under the plasma concentration-time curve from time 0 to the end of the 12-hour dosing interval; Tmax = Time to reach Cmax; t1/2 = Elimination half-life, CL/F = Apparent oral clearance, Vz/F = Apparent oral volume of distribution. 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, Cmax and AUC values for vonoprazan increased in an approximately dose-proportional manner. Steady state mean plasma exposure of vonoprazan following 20 mg twice daily dosing (AUC0-12h = 273 hr*ng/mL, N=10) was approximately 1.8-fold higher compared to Day 1 (AUC0-12h = 155 hr*ng/mL, N=10). 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 Cmax, a 15% increase in AUC, and a delay in median Tmax of 2 hours. These changes are not considered to be clinically significant. 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: Reference ID: 4978225 Page 32 of 42 Vonoprazan is metabolized to inactive metabolites via multiple pathways by a combination of cytochrome P450 (CYP) isoforms (CYP3A4/5, CYP2B6, CYP2C19, CYP2C9 and CYP2D6) 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 (AUC8) was 1.7-, 1.3- and 2.4- times greater in patients with mild, moderate, and severe renal impairment, respectively. In subjects requiring dialysis (N=8), AUC8 estimates were 1.3-fold greater compared to estimates from subjects with normal renal function. Protein binding of vonoprazan is not affected by impaired renal function. In patients requiring dialysis, vonoprazan was present in the dialysate and represented 0.94% of the dose administered. 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 (AUC8) of vonoprazan was 1.2-, 2.4- and 2.6-times greater in patients with mild, moderate, and severe hepatic impairment, respectively. Protein binding of vonoprazan is not affected by impaired hepatic function. Drug Interaction Studies In vitro studies: Cytochrome P450 (CYP450) Enzymes: In vitro studies have shown that vonoprazan directly and time-dependently inhibits CYP2B6, CYP2C19, and CYP3A4/5. 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: Reference ID: 4978225 Page 33 of 42 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 Cmax and AUC0-12h increased by 87% and 85%, respectively, and clarithromycin, Cmax and AUC0-12h increased by 64% and 45%, respectively, compared to administration of each component alone. 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 AUC8 increased 93% compared to administration of midazolam alone. 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 AUC8 increased 58% compared to administration of vonoprazan alone. 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% proteinbound. 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 61.3 minutes. 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 2.5 hours. 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 Reference ID: 4978225 Page 34 of 42 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 Cmin and AUC increased 33% and 18%, respectively. Clarithromycin exposures were increased and steady-state concentrations of 14-OH clarithromycin were not significantly affected by concomitant administration of fluconazole. Colchicine: When a single dose of colchicine 0.6 mg was administered with clarithromycin 250 mg twice daily for 7 days, the colchicine Cmax increased 197% and the AUC0-8 increased 239% compared to administration of colchicine alone. Atazanavir: Reference ID: 4978225 Page 35 of 42 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 Cmax increased 177% and 187% respectively compared to administration of saquinavir alone. Clarithromycin AUC and Cmax increased 45% and 39% respectively, whereas the 14-OH clarithromycin AUC and Cmax decreased 24% and 34% respectively, compared to administration with clarithromycin alone. 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 Cmax increased 100% whereas the AUC was unaffected (N=24). 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 (Cmax, AUC0-24, and t½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The plasma levels of clarithromycin and 14-OH clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-OH clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole. Table 7: Clarithromycin Tissue Concentrations 2 hours after Dose (mcg/mL)/(mcg/g) Treatment N Antrum Fundus N Mucus Clarithromycin 5 10.48 ± 2.01 20.81 ± 7.64 4 4.15 ± 7.74 Clarithromycin + Omeprazole 5 19.96 ± 4.71 24.25 ± 6.37 4 39.29 ± 32.79 Theophylline: In two studies in which theophylline was administered with clarithromycin (a theophylline sustainedrelease formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h Reference ID: 4978225 Page 36 of 42 clarithromycin), the steady-state levels of Cmax, Cmin, and the AUC of theophylline increased about 20%. 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.

12.4. Microbiology 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 lea

USE IN SPECIFIC POPULATIONS 8.1. Pregnancy 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 wellcontrolled 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. Reference ID: 4978225 Page 23 of 42 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 US 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 1-800-775- PHAT (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 nonlive 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 Reference ID: 4978225 Page 24 of 42 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 embryofetal effects were observed at the 100 mg/kg/day. Reference ID: 4978225 Page 25 of 42 Pregnant rabbits were orally administered vonoprazan at doses of 3, 10, or 30 mg/kg/day (0.04, 1.5, 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 (0.01, 0.18, 1.1, 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)]. The clinical relevance of the liver findings is uncertain. 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 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). There was no evidence of harm to the fetus due to amoxicillin. 8.2. Lactation 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). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential risk of adverse liver effects shown in animal studies with vonoprazan, a woman should pump and discard human milk for the duration of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK therapy, and for 2 days after therapy ends, and feed her infant stored human milk (collected prior to therapy) or formula. 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). In a separate observational study of lactating women exposed to clarithromycin, reported adverse effects on breast-fed children (rash, diarrhea, loss of appetite, somnolence) were comparable to amoxicillin. No data are available to assess the effects of clarithromycin or 14-OH clarithromycin on milk production. Reference ID: 4978225 Page 26 of 42 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. 8.3. Females and Males of Reproductive Potential 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)]. Reference ID: 4978225 Page 27 of 42 8.4. Pediatric Use Safety and effectiveness of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK in pediatric patients have not been established. 8.5. Geriatric Use 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 infection [see Clinical Studies (14)]. Of the total number of vonoprazan-treated subjects (N=694), there were 153 (22.0%) patients aged 65 years and older and 18 (2.6%) patients were aged 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger adult patients. 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 arrhythmias than younger patients [see Warnings and Precautions (5.2)]. Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., 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) and Warnings and Precautions (5.2)]. Reference ID: 4978225 Page 28 of 42 8.6. Renal Impairment 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). Avoid the use of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK in patients with severe renal impairment (eGFR < 30 mL/min) [see Clinical Pharmacology (12.3)]. 8.7. Hepatic Impairment No dosage adjustment of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK is recommended in patients with mild hepatic impairment (Child-Pugh A). Avoid the use of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK in patients with moderate to severe hepatic impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3)]. 10. 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. Reference ID: 4978225 Page 29 of 42

11. DESCRIPTION VOQUEZNA TRIPLE PAK contains vonoprazan tablets, 20 mg, amoxicillin capsules, 500 mg and clarithromycin tablets, 500 mg for oral administration. VOQUEZNA DUAL PAK contains vonoprazan tablets, 20 mg and amoxicillin capsules, 500 mg for oral administration. Vonoprazan Tablets Vonoprazan (as the fumarate), is a potas