Introduction

Vonoprazan, clarithromycin, and amoxicillin (vonoprazan/clarithromycin/amoxicillin) is a fixed combination of vonoprazan fumarate, a potassium-competitive acid blocker (PCAB), clarithromycin, a semi-synthetic macrolide antimicrobial, and amoxicillin trihydrate, a penicillin class antibacterial with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms.

Uses for Vonoprazan, Clarithromycin, and Amoxicillin

Vonoprazan, clarithromycin, and amoxicillin has the following uses:

Vonoprazan/clarithromycin/amoxicillin is indicated for the treatment of Helicobacter pylori (H. pylori) infection in adults.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of vonoprazan/clarithromycin/amoxicillin and other antibacterial drugs, the fixed-combination preparation should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Vonoprazan, Clarithromycin, and Amoxicillin Dosage and Administration

General

The fixed combination of vonoprazan/clarithromycin/amoxicillin is available in the following dosage form(s) and strength(s):

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

• Vonoprazan 20 mg tablets

• Clarithromycin 500 mg tablets

• Amoxicillin 500 mg capsules

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

The recommended dosage regimen of vonoprazan/clarithromycin/amoxicillin 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.

Contraindications

• Known hypersensitivity to vonoprazan, amoxicillin or any other beta-lactams, clarithromycin or any other macrolide antimicrobials, or any component of the formulations.

• Concomitant use with rilpivirine-containing products.

• Concomitant use with pimozide due to the clarithromycin component.

• Concomitant use with lomitapide, lovastatin, or simvastatin due to the clarithromycin component.

• Concomitant use with alkaloids (ergotamine or dihydroergotamine) due to the clarithromycin component.

• Concomitant use with colchicine in patients with renal or hepatic impairment due to the clarithromycin component.

• History of cholestatic jaundice/hepatic dysfunction with use of clarithromycin.

Warnings/Precautions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions (e.g., anaphylaxis, anaphylactic shock, rash, erythema multiforme, and Henoch-Schonlein purpura) have been reported with components of vonoprazan/clarithromycin/amoxicillin.

Before initiating therapy with vonoprazan/clarithromycin/amoxicillin, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, macrolide antibacterial drugs or other allergens. Discontinue the fixed-combination preparation immediately and institute appropriate treatment if hypersensitivity occurs.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the components of vonoprazan/clarithromycin/amoxicillin. In addition, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with amoxicillin and clarithromycin.

Discontinue vonoprazan/clarithromycin/amoxicillin at the first signs or symptoms of SCAR or other signs of hypersensitivity and consider further evaluation.

Clostridioides Difficile-associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of acid suppressing therapies and nearly all antibacterial agents, including amoxicillin and clarithromycin, components of the fixed-combination preparation, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of Clostridioides difficile (C. difficile).

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is confirmed, vonoprazan/clarithromycin/amoxicillin should be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Rash in Patients with Mononucleosis

A high percentage of patients with mononucleosis who receive amoxicillin, a component of the fixed-combination preparation develop an erythematous skin rash. Avoid use of vonoprazan/clarithromycin/amoxicillin in patients with mononucleosis.

Interactions with Diagnostic Investigations for Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at least 14 days after vonoprazan/clarithromycin/amoxicillin treatment and consider repeating the test if initial CgA levels are high.

Development of Drug-Resistant Bacteria

Prescribing vonoprazan/clarithromycin/amoxicillin in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient, and increases the risk of the development of drug-resistant bacteria.

QT Prolongation

Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported. Avoid vonoprazan/clarithromycin/amoxicillin in the following patients:

• Patients with known prolongation of QT interval, ventricular cardiac arrhythmia, including torsades de pointes.

• Patients receiving drugs known to prolong the QT interval (e.g., pimozide).

• Patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and patients receiving Class IA (e.g., quinidine, procainamide, disopyramide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.

Elderly patients may be more susceptible to drug-associated effects on the QT interval.

Hepatotoxicity

Hepatic dysfunction, including increased liver enzymes and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin, a component of the fixed-combination preparation. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Discontinue vonoprazan/clarithromycin/amoxicillin immediately if signs and symptoms of hepatitis occur.

Serious Adverse Reactions Due to Concomitant Use of Clarithromycin with Other Drugs

Drugs metabolized by CYP3A4: Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; markedly increased transaminases with lomitapide; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia and cardiac arrhythmias (e.g., torsades de pointes) with disopyramide; and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older

Colchicine: Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin. If co-administration of vonoprazan/clarithromycin/amoxicillin and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant administration of vonoprazan/clarithromycin/amoxicillin and colchicine is contraindicated in patients with renal or hepatic impairment.

Lomitapide: Concomitant use of vonoprazan/clarithromycin/amoxicillin with lomitapide may increase the risk of elevation in transaminases due to the clarithromycin component. Concomitant use of the fixed-combination preparation with lomitapide is contraindicated. If treatment with vonoprazan/clarithromycin/amoxicillin cannot be avoided, therapy with lomitapide must be suspended during the course of treatment.

HMG-CoA Reductase Inhibitors (statins): Concomitant use of vonoprazan/clarithromycin/amoxicillin with lovastatin or simvastatin may increase these drug's plasma concentrations due to the clarithromycin component, which may increase the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients treated concomitantly with clarithromycin and lovastatin or simvastatin. Concomitant use of vonoprazan/clarithromycin/amoxicillin with lovastatin or simvastatin is contraindicated. If treatment with the fixed-combination preparation cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment. Exercise caution when prescribing vonoprazan/clarithromycin/amoxicillin with atorvastatin or pravastatin.

Hypoglycemic Agents/Insulin: Concomitant use of vonoprazan/clarithromycin/amoxicillin and hypoglycemic agents (such as nateglinide, pioglitazone, repaglinide and rosiglitazone) and/or insulin can result in significant hypoglycemia due to the clarithromycin component. Carefully monitor glucose levels when these drugs are used concomitantly with the fixed-combination preparation.

Quetiapine: Concomitant use of vonoprazan/clarithromycin/amoxicillin with quetiapine could result in somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation due to the clarithromycin component. Refer to quetiapine prescribing information for recommended dosage reduction if co-administered with the fixed-combination preparation.

Warfarin: There is a risk of serious hemorrhage and significant elevations in the international normalized ratio (INR) and prothrombin time when clarithromycin is used concomitantly with warfarin. Monitor INR and prothrombin times frequently when warfarin is used concomitantly with vonoprazan/clarithromycin/amoxicillin.

Benzodiazepines: Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam and midazolam. Closely monitor patients for signs or symptoms of increased or prolonged central nervous system effects when benzodiazepines such as triazolam or midazolam are used concomitantly with vonoprazan/clarithromycin/amoxicillin.

Embryo-Fetal Toxicity

Based on findings from animal studies and human observational studies in pregnant women with use of clarithromycin, use of vonoprazan/clarithromycin/amoxicillin is not recommended in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If the fixed-combination preparation is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, advise the patient of the potential risk to the fetus. Clarithromycin demonstrated adverse effects on pregnancy outcome and/or embryo fetal development, in pregnant animals administered oral clarithromycin. Observational studies in pregnant women also demonstrated adverse effects on pregnancy outcomes, including an increased risk of miscarriage and in some studies an increased incidence of fetal malformations.

Exacerbation of Myasthenia Gravis

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy. Monitor patients for symptoms.

Specific Populations

Pregnancy

Based on findings from animal studies and observational studies in pregnant women with use of clarithromycin, use of vonoprazan/clarithromycin/amoxicillin 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 the fixed-combination preparation in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. If vonoprazan/clarithromycin/amoxicillin 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.

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. 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.

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. 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.

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 1-888-775-PHAT (7428).

Lactation

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. 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 vonoprazan/clarithromycin/amoxicillin treatment, 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. 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.

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.

Females and Males of Reproductive Potential

Based on animal fertility study findings for clarithromycin, vonoprazan/clarithromycin/amoxicillin may impair fertility in males of reproductive potential.

Pediatric Use

Safety and effectiveness of vonoprazan/clarithromycin/amoxicillin in pediatric patients have not been established.

Geriatric Use

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.

Vonoprazan: There were 218 patients aged 65 years and older in the clinical study of vonoprazan/clarithromycin/amoxicillin for the treatment of H. pylori infection. 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, 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 AUCs 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 pointe arrhythmias than younger patients. Most reports of acute kidney injury with concomitant use of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older. 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.

Renal Impairment

No dosage adjustment of vonoprazan/clarithromycin/amoxicillin is recommended in patients with mild to moderate renal impairment (eGFR 30 to 89 mL/min). Avoid use of the fixed-combination preparation in patients with severe renal impairment (eGFR < 30 mL/min).

Hepatic Impairment

No dosage adjustment of vonoprazan/clarithromycin/amoxicillin is recommended in patients with mild hepatic impairment (Child-Pugh A). Avoid use of the fixed-combination preparation in patients with moderate to severe hepatic impairment (Child-Pugh B or C).

Common Adverse Effects

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

General

The fixed combination of vonoprazan/clarithromycin/amoxicillin is available in the following dosage form(s) and strength(s):

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

• Vonoprazan 20 mg tablets

• Clarithromycin 500 mg tablets

• Amoxicillin 500 mg capsules

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

The recommended dosage regimen of vonoprazan/clarithromycin/amoxicillin 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.

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Components of vonoprazan/clarithromycin/amoxicillin have the potential for clinically important drug interactions. See Full Prescribing Information for important drug interactions with the fixed-combination preparation.