Vonoprazan + Amoxicillin + Clarithromycin

Vonoprazan + Amoxicillin + Clarithromycin is used for: Helicobacter pylori Infection

Oral Indicated for treatment of Helicobacter pylori (H pylori) infection Vonoprazan 20 mg plus Amoxicillin 1000 mg plus Clarithromycin 500 mg 1 strip twice daily for 14 days Hepatic impairment Mild (Child-Pugh A): No dosage adjustment required Moderate-to-severe (Child-Pugh B-C): Avoid

Renal impairment Mild-to-moderate (eGFR 30-89 mL/min): No dosage adjustment required Severe (eGFR <30 mL/min): Avoid

Known hypersensitivity to any component – vonoprazan, amoxicillin (or other beta-lactam antibacterials [eg, penicillins, cephalosporins]), or clarithromycin (or other macrolide antibacterial drugs [eg, erythromycin]) Rilpivirine-containing products, owing to inhibition of gastric pH by vonoprazan Cholestatic jaundice and hepatic dysfunction History of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin

Serious and occasionally fatal hypersensitivity reactions (eg, anaphylaxis, anaphylactic shock, rash, erythema multiforme, and Henoch-Schonlein purpura) reported with components; discontinue immediately and institute appropriate treatment if hypersensitivity occurs Severe cutaneous adverse reactions (SCAR), including SJS and TEN reported with all components; additionally, DRESS and AGEP have been reported with amoxicillin and clarithromycin; discontinue at first signs of SCAR Clostridioides difficile–associated diarrhea (CDAD) reported with acid-suppressing therapies and nearly all antibacterial agents; CDAD must be considered in all patients who present with diarrhea following antibacterial use; careful medical history necessary since CDAD reported to occur over 2 months after administration of antibacterial agents; if CDAD confirmed, discontinue, and implement appropriate management High percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash; avoid in patients with mononucleosis Prescribing this regimen in absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit, and increases risk for drug-resistant bacteria

Pregnancy On the basis of animal studies and observational studies in pregnant females with use of clarithromycin, use is not recommended in pregnant females, except in clinical circumstances where no alternative therapy is appropriate Clarithromycin: Observational studies in pregnant females demonstrated adverse effects on pregnancy outcomes, including an increased risk of miscarriage, and in some studies, an increased incidence of fetal malformations Report pregnancies to the Phathom Pharmaceuticals, Inc. Adverse Event reporting line at 1-800-775- PHAT (7428) Animal studies Vonoprazan: Pups from dams orally administered vonoprazan during organogenesis and through lactation, exhibited liver discoloration that was associated with necrosis, fibrosis, and hemorrhage at a dose ~22x the maximum recommended human dose (MRHD) Amoxicillin: No evidence of harm to the fetus found Clarithromycin Oral administration to pregnant mice, rats, rabbits, and monkeys during organogenesis produced malformations in rats (cardiovascular anomalies) and mice (cleft palate) at clinically relevant doses Fetal effects in mice, rats, and monkeys (eg, reduced fetal survival, reduced body weight, body weight gain) and implantation losses in rabbits were generally considered to be secondary to maternal toxicity Infertility Clarithromycin in males: On the basis of animal fertility study findings for clarithromycin, may impair fertility in males of reproductive potential Lactation Vonoprazan 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 Amoxicillin Data from published clinical lactation study indicate that amoxicillin is present in human milk There are no data on the effects of amoxicillin on milk production Clarithromycin Observational study of lactating women exposed to clarithromycin, reported adverse effects on breastfed children (rash, diarrhea, loss of appetite, somnolence) that were comparable with amoxicillin

Pimozide: Postmarketing reports of drug interactions resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes), most likely due to inhibition of metabolism of these drugs by clarithromycin; fatalities reported Lipid-lowering agents: Lomitapide, simvastatin, and lovastatin Ergot alkaloids: Ergotamine or dihydroergotamine Colchicine in patients with renal or hepatic impairment

Side effects of Vonoprazan + Amoxicillin + Clarithromycin : 1-10% Dysgeusia (4.6%) Diarrhea (4%) Vulvovaginal candidiasis (3.2%) Headache (2.6%) Abdominal pain (2.3%) Hypertension (2%) <2% Blood and lymphatic system disorders: Anemia, leukocytosis, leukopenia, neutropenia Cardiac disorders: QT prolongation, tachycardia Eye disorders: Orbital edema Gastrointestinal disorders: Abdominal distention, constipation, dry mouth, duodenal polyp, duodenal ulcer, dyspepsia, flatulence, gastric ulcer, gastroesophageal reflux disease, hematochezia, large intestine polyp, nausea, rectal polyp, stomatitis, tongue discomfort, vomiting General disorders and administration site conditions: Fatigue, pyrexia Immune system disorders: Drug hypersensitivity Infections and infestations: Anal fungal infection, gastrointestinal viral infection, oral fungal infection, pneumonia, tongue fungal infection, upper respiratory tract infection, urinary tract infection, viral infection Investigations: Liver function test abnormal Metabolism and nutrition disorders: Decreased appetite Musculoskeletal system: Bone fracture Nervous system disorders: Ageusia, dizziness, tension headache Psychiatric disorders: Anxiety, depression, insomnia Renal and urinary disorders: Renal hypertrophy, tubulointerstitial nephritis Reproductive system and breast disorders: Vaginal discharge Respiratory, thoracic, and mediastinal disorders: Cough, nasal polyps, oropharyngeal pain Skin and subcutaneous tissue disorders: Dermatitis, dry skin, rash <1% Nasopharyngitis (0.3%)

Vonoprazan Potassium-competitive acid blocker (PCAB) Suppresses basal and stimulated gastric acid secretion at secretory surface of 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, as it blocks the final step of acid production Does not require activation by acid; may selectively concentrate in parietal cells in both resting and stimulated states Binds to active proton pumps in noncovalent and reversible manner Amoxicillin Ampicillin derivative; elicits antibacterial effect by binding to penicillin-binding proteins and inhibiting biosynthesis of cell wall Clarithromycin Macrolide antimicrobial; reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition