vonoprazan/amoxicillin/clarithromycin (Rx)

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%)

Postmarketing Reports

Vonoprazan

• Immune system disorders: Anaphylactic shock, urticaria, drug eruption
• Hepatobiliary disorders: Hepatic injury, hepatic failure, jaundice
• Skin and subcutaneous tissue disorders: Erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

Amoxicillin

• Infections and infestations: Mucocutaneous candidiasis
• Gastrointestinal: Black hairy tongue, and hemorrhagic/pseudomembranous colitis; onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment
• Hypersensitivity reactions: Anaphylaxis, serum sickness–like reactions, erythematous maculopapular rashes, erythema multiforme, exfoliative dermatitis, hypersensitivity vasculitis, and urticaria
• Renal: Crystalluria
• Hemic and lymphatic systems: Hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, and agranulocytosis; reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena
• Central nervous system: Reversible hyperactivity, agitation, confusion, convulsions, aseptic meningitis, and behavioral changes
• Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) reported; most occurred in pediatric patients; discoloration reduced or eliminated with brushing or dental cleaning in most cases
• Skin and subcutaneous tissue disorders: TEN, SJS, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP)

Clarithromycin

• Blood and lymphatic system: Thrombocytopenia, agranulocytosis
• Cardiac: Ventricular arrhythmia, torsades de pointes
• Ear and labyrinth: Deafness, reported chiefly in elderly women and was usually reversible
• Gastrointestinal: Pancreatitis acute, tongue discoloration; tooth discoloration reported and was usually reversible with professional cleaning upon discontinuation
• Hepatobiliary: Hepatic failure, jaundice hepatocellular
• Infections and infestations: Pseudomembranous colitis
• Immune system: Anaphylactic reactions, angioedema
• Investigations: Prothrombin time prolonged, white blood cell count decreased, INR increased; abnormal urine color reported, associated with hepatic failure
• Metabolism and nutrition: Hypoglycemia reported in patients taking oral hypoglycemic agents or insulin
• Musculoskeletal and connective tissue: Myopathy rhabdomyolysis reported; in some of the reports, clarithromycin was coadministered with statins, fibrates, colchicine, or allopurinol
• Nervous system: Parosmia, anosmia, paresthesia, and convulsions
• Psychiatric: Abnormal behavior, confusional state, depersonalization, disorientation, hallucination, manic behavior, abnormal dream, psychotic disorder; these usually resolve upon discontinuation
• Renal and urinary: Renal failure
• Skin and subcutaneous tissue disorders: TEN, SJS, DRESS, AGEP, Henoch-Schonlein purpura, acne
• Vascular: Hemorrhage

Contraindications

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

Contraindications specific to clarithromycin component

• Drug interactions

  • 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

• Cholestatic jaundice and hepatic dysfunction

  • History of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin

Cautions

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

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity; increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors; assess CgA levels at least 14 days after treatment, and consider repeating test if initial CgA levels are high

Glucose tests: High urine concentrations of amoxicillin may cause false-positive results when using glucose tests based on the Benedict copper reduction reaction that determines the amount of reducing substances, like glucose, in the urine; use enzymatic glucose oxidase reactions instead while taking amoxicillin

Clarithromycin only

• QT prolongation: Avoid in patients with prolongation of QT interval, ventricular cardiac arrhythmia, including torsades de pointes; patients receiving drugs known to prolong QT interval; patients with ongoing proarrhythmic conditions (eg, uncorrected hypokalemia or hypomagnesemia; clinically significant bradycardia; Class IA [eg, quinidine, procainamide, disopyramide] or Class III [dofetilide, amiodarone, sotalol] antiarrhythmic agents)
• Elderly patients may be more susceptible to drug-associated effects on QT interval
• Hepatic dysfunction, including increased liver enzymes and hepatocellular and/or cholestatic hepatitis (with or without jaundice) reported; in some instances, reported hepatic failure with fatal outcome 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 immediately if symptoms occur
• Not recommended for use in pregnant females, except in clinical circumstances where no alternative therapy is appropriate
• Exacerbation of myasthenia gravis and new onset of symptoms of myasthenic syndrome; monitor for symptoms

• Clarithromycin drug interactions

  • CYP3A4 substrates: Resulting serious effects may occur if coadministered with certain CYP3A4 substrates (examples follow)
  • Colchicine: May result in colchicine toxicity; if coadministration necessary in patients with normal renal and hepatic function, reduce dose of colchicine
  • Lomitapide: Markedly increased transaminases; if treatment cannot be avoided, therapy with lomitapide must be suspended during course of treatment
  • Statins: Rhabdomyolysis; if treatment cannot be avoided, therapy with lovastatin or simvastatin must be suspended during course of treatment; exercise caution when prescribing with atorvastatin or pravastatin
  • Hypoglycemic agents/insulin: Increased risk for hypoglycemia; carefully monitor glucose levels when these drugs are used concomitantly
  • Disopyramide, amiodarone, dofetilide, procainamide, sotalol, quinidine: QT prolongation resulting in cardiac arrhythmias (eg, torsades de pointes)
  • Quetiapine: Somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation; refer to quetiapine prescribing information for recommended dosage reduction if coadministration necessary
  • Pimozide: Contraindicated
  • Warfarin: Hemorrhage
  • Benzodiazepines: Prolonged sedation and CNS depression; closely monitor patients for signs or symptoms of increased or prolonged CNS effects when benzodiazepines such as triazolam or midazolam are used concomitantly with clarithromycin
  • Calcium-channel blockers: Hypotension and acute kidney injury (especially in aged >65 yr)
  • Tolterodine (patients deficient in CYP2D6 activity): Reduce tolterodine dose, owing to secondary CYP3A4 metabolic pathway

Drug interaction overview

Vonoprazan: CYP3A substrate; weak CYP3A inhibitor; CYP2C19 inhibitor

Clarithromycin: CYP3A substrate; strong CYP3A inhibitor

• Strong or moderate CYP3A inducers

  • Avoid coadministration
  • Strong or moderate CYP3A inducers may decrease exposure of vonoprazan and clarithromycin, which may reduce the effectiveness

• Probenecid

  • Closely monitor
  • Amoxicillin undergoes tubular secretion; probenecid may increase amoxicillin systemic exposure by blocking renal tubular secretion, which may increase risk of adverse reactions

• Allopurinol

  • Discontinue if skin rash occurs
  • Increase incidence of rashes reported with coadministration of allopurinol and amoxicillin

• Omeprazole

  • Avoid coadministration
  • Clarithromycin concentrations in gastric tissue and mucus increased by omeprazole

• Itraconazole

  • Monitor closely
  • Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bidirectional drug interaction when administered concomitantly
• Antivirals
  • Saquinavir (CYP3A substrate and inhibitor): Use with caution
  • Maraviroc (CYP3A substrate): Dose reduction may be needed
  • Ritonavir (CYP3A inhibitor): Not recommended in patients with decreased renal function
  • Etravirine (CYP3A inducer): Avoid coadministration
  • Clarithromycin is a CYP3A4 substrate and inhibitor; use with antivirals that are CYP3A substrates, inducers, or CYP3A inhibitors may potentially lead to bidirectional drug interactions leading to alterations in exposure of clarithromycin and/or CYP3A substrates, which may increase risk of adverse reactions or loss of effectiveness

• Drugs dependent on gastric pH for absorption

  • Rilpivirine: Contraindicated
  • Atazanavir, nelfinavir: Avoid
  • Other antiretroviral drugs: See prescribing for reliance on gastric pH for absorption
  • Other drugs (eg, iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole); check prescribing information for modifying time of dosage or avoidance
  • Vonoprazan reduces intragastric acidity, which may alter absorption of certain drugs

• Sensitive CYP3A4 substrates

  • See prescribing information for sensitive CYP3A substrates
  • Tacrolimus, cyclosporine: Dosage modification (dose reduction) may be needed; monitor closely
  • Clarithromycin (a strong CYP3A inhibitor) and vonoprazan (a weak CYP3A inhibitor) may increase exposure of CYP3A4 substrates, which may increase risk of adverse reactions related to these substrates

• CYP2C19 substrates

  • Clopidogrel: Carefully monitor the efficacy of clopidogrel, and consider alternative anti-platelet therapy
  • Citaprolam, cilostazol: Carefully monitor for adverse reactions
  • Vonoprazan is a CYP2C19 inhibitor; may reduce plasma concentration of the active metabolite of clopidogrel, resulting in reduced platelet inhibition; may increase exposure of CYP2C19 substrate drugs

• Oral anticoagulants

  • Monitor INR, and adjust dose accordingly
  • Abnormal prolongation of prothrombin time (increased INR) reported in patients receiving amoxicillin and oral anticoagulants

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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

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

Pharmacokinetics

Vonoprazan

• Absorption

  • Onset of antisecretory activity: 2-3 hr; elevated Absorptionintragastric pH maintained for >24 hr
  • Steady-state achieved: 3-4 days
  • Peak plasma time: 2.5 hr (single-dose); 3 hr (steady-state)
  • Peak plasma concentration: 25.2 ng/mL (single-dose); 37.8 ng/mL (steady-state)
  • AUC: 154.8 ng⋅hr/mL (single-dose); 272.5 ng⋅hr/mL (steady-state)

• Distribution

  • Vd: 1001 L (single-dose); 782.7 L (steady-state)
  • Protein bound: 85-88%

• Metabolism

  • Metabolized to inactive metabolites via multiple pathways by combination of CYP450 isoforms (CYP3A4/5, CYP2B6, CYP2C19, CYP2C9 and CYP2D6) along with sulfo- and glucuronosyl-transferases

• Elimination

  • Half-life: 7.1 hr (single-dose); 6.8 hr (steady-state)
  • Clearance: 97.3 L/hr (single-dose); 81.3 L/hr (steady-state)
  • Excretion: 67% urine (8% unchanged); 31% feces (1.4% unchanged)

Amoxicillin

• Half-life: 1.02 hr
• Absorption: 74-92%
• Distribution: Most body fluids and bone, CSF<1%
• Peak plasma time: 1-2 hr
• Protein bound: 17-20%
• Metabolism: Hepatic
• Excretion: Urine (60%)

Clarithromycin

• Half-life: 3-7 hr
• Peak plasma time: 2-4 hr
• Absorption: Highly stable in presence of gastric acid (unlike erythromycin); food delays but does not affect extent of absorption
• Distribution: Widely into most body tissues except CNS
• Metabolism: Partially hepatic (P450 enzyme CYP3A4); converted to 14-OH clarithromycin (active metabolite)
• Renal clearance: Approximates normal GFR
• Excretion: Primarily urine

Oral Administration

May take with or without food

Missed dose

• Within 4 hr of missed dose: Take as soon as possible
• >4 hr of missed dose: Skip missed dose, and administer next dose at regularly scheduled time
• Continue with normal dosing schedule until medication is completed

Storage

Store at 20-25ºC (68-77ºF); brief exposure to 15-30ºC (59-86ºF) permitted

Protect from light