Voquenza
(clarithromycin, vonoprazan, amoxicillin)Dosage & Administration
VOQUEZNA TRIPLE PAK: The recommended dosage 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 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.
See full prescribing information for the recommended dosage for patients with renal or hepatic impairment.
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Voquenza Prescribing Information
Helicobacter pylori Infection
VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK are indicated for the treatment of Helicobacter pylori (H. pylori) infection in adults [see Clinical Studies (14)].
Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of VOQUEZNA TRIPLE PAK, VOQUEZNA DUAL PAK and other antibacterial drugs, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Recommended Dosage for VOQUEZNA TRIPLE PAK
VOQUEZNA TRIPLE PAK is a co-packaged product containing vonoprazan tablets, amoxicillin capsules, and clarithromycin tablets each given twice daily (in the morning and evening, 12 hours apart) with or without food, for 14 days [see Clinical Pharmacology (12.3)]. The recommended adult oral dosage of VOQUEZNA TRIPLE PAK is the following:
- In the morning, take 20 mg of vonoprazan (one oval pale red tablet), 1,000 mg of amoxicillin (two yellow capsules), and 500 mg of clarithromycin (one oval white tablet)
- In the evening, take 20 mg of vonoprazan (one oval pale red tablet), and 1,000 mg of amoxicillin (two yellow capsules), and 500 mg of clarithromycin (one oval white tablet)
Recommended Dosage for VOQUEZNA DUAL PAK
VOQUEZNA DUAL PAK is a co-packaged product containing vonoprazan tablets and amoxicillin capsules given with or without food, for 14 days [see Clinical Pharmacology (12.3)]. The recommended adult oral dosage of VOQUEZNA DUAL PAK is the following:
- In the morning, take 20 mg of vonoprazan (one oval pale red tablet) and 1,000 mg of amoxicillin (two yellow capsules)
- Mid-day, take 1,000 mg of amoxicillin (two yellow capsules)
- In the evening, take 20 mg of vonoprazan (one oval pale red tablet) and 1,000 mg of amoxicillin (two yellow capsules)
Recommended Dosage in Patients with Renal Impairment
The recommended dosage of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in adult patients with renal impairment is described in Table 1 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
| Estimated GFR | Recommended Dosage | |
|---|---|---|
| VOQUEZNA TRIPLE PAK | VOQUEZNA DUAL PAK | |
| 30 mL/minute or greater | 20 mg vonoprazan twice daily 1,000 mg amoxicillin twice daily 500 mg clarithromycin twice daily | 20 mg vonoprazan twice daily 1,000 mg amoxicillin three times daily |
| Less than 30 mL/minute | Use is not recommended | |
Recommended Dosage in Patients with Hepatic Impairment
The recommended dosage of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK in adult patients with hepatic impairment is described in Table 2 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
| Classification | Recommended Dosage | |
|---|---|---|
| VOQUEZNA TRIPLE PAK | VOQUEZNA DUAL PAK | |
| Child-Pugh Class A | 20 mg vonoprazan twice daily 1,000 mg amoxicillin twice daily 500 mg clarithromycin twice daily | 20 mg vonoprazan twice daily 1,000 mg amoxicillin three times daily |
| Child-Pugh Class B | Use is not recommended | |
| Child-Pugh Class C | Use is not recommended | |
Missed Doses
If a dose is missed, administer VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK as soon as possible, within 4 hours after the missed dose. If more than 4 hours have passed, skip the missed dose and administer the next dose on the regularly scheduled time. Patients should continue the normal dosing schedule until the medication is completed.
VOQUEZNA TRIPLE PAK
VOQUEZNA TRIPLE PAK is a co-package consisting of 14 administration packs for morning and evening dosing. Each administration pack contains the following three drug products:
- Vonoprazan Tablets, 20 mg: pale red, oval, film-coated tablets debossed V20 on one side and plain on the other side.
- Amoxicillin Capsules, 500 mg: yellow, opaque, hard gelatin capsules imprinted with AMOX 500 on one side and GG 849 on the other side.
- Clarithromycin Tablets, 500 mg: white, oval, film-coated debossed GG C9 on one side and plain on the other side.
VOQUEZNA DUAL PAK
VOQUEZNA DUAL PAK is a co-package consisting of 14 administration packs for morning, mid-day, and evening dosing. Each administration pack contains the following two drug products:
- Vonoprazan Tablets, 20 mg: pale red, oval, film-coated tablets debossed V20 on one side and plain on the other side.
- Amoxicillin Capsules, 500 mg: yellow, opaque, hard gelatin capsules imprinted with AMOX 500 on one side and GG 849 on the other side.
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 well-controlled studies of VOQUEZNA TRIPLE PAK in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. If VOQUEZNA TRIPLE PAK is used during pregnancy, advise pregnant women of the potential risk to a fetus.
No reproductive and developmental toxicity studies with the combination of vonoprazan, amoxicillin, and/or clarithromycin were conducted.
VOQUEZNA DUAL PAK
There are no adequate and well-controlled studies of VOQUEZNA DUAL PAK in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
Individual Components of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK
Clarithromycin:
Published observational studies in pregnant women have demonstrated adverse effects on pregnancy outcomes, including an increased risk of miscarriage and in some studies an increased incidence of fetal malformations (see Data). 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.
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 United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Report pregnancies to the Phathom Pharmaceuticals, Inc. Adverse Event reporting line at 1-888-775-7428.
Data
Human Data
Clarithromycin:
Available data from prospective and retrospective observational studies with clarithromycin use in pregnant women demonstrate an increased risk of miscarriage. Data from these same studies regarding major congenital malformations are inconsistent, with some studies reporting an increased risk (atrioventricular septal defects, genital malformations, orofacial clefts) and others finding no difference between those exposed to clarithromycin and those exposed to nonteratogenic controls. Available studies have methodologic limitations, including small sample size, under-capture of non-live births, exposure misclassification and inconsistent comparator groups.
Animal Data
Clarithromycin:
Animal reproduction studies were conducted in mice, rats, rabbits, and monkeys with oral and intravenously administered clarithromycin. In pregnant mice, clarithromycin was administered during organogenesis (gestation day [GD] 6 to 15) at oral doses of 15, 60, 250, 500, or 1000 mg/kg/day. Reduced body weight observed in dams at 1000 mg/kg/day (3 times the MRHD based on BSA comparison) resulted in reduced survival and body weight of the fetuses. At ≥ 500 mg/kg/day, increases in the incidence of post-implantation loss and cleft palate in the fetuses were observed. No adverse developmental effects were observed in mice at ≤ 250 mg/kg/day (≤ 1 times MRHD based on BSA comparison).
In pregnant Sprague Dawley rats, clarithromycin was administered during organogenesis (GD 6 to 15) at oral doses of 15, 50, or 150 mg/kg/day. Reductions in body weight and food consumption was observed in dams at 150 mg/kg/day. Increased resorptions and reduced body weight of the fetuses at this dose were considered secondary to maternal toxicity. Additionally, at 150 mg/kg/day (1 times MRHD based on BSA comparison), a low incidence of cardiovascular anomalies (complete situs inversus, undivided truncus, IV septal defect) was observed in the fetuses. Clarithromycin did not cause adverse developmental effects in rats at 50 mg/kg/day (0.3 times MRHD based on BSA comparison). Intravenous dosing of clarithromycin during organogenesis in rats (GD 6 to 15) at 15, 50, or 160 mg/kg/day was associated with maternal toxicity (reduced body weight, body-weight gain, and food consumption) at 160 mg/kg/day but no evidence of adverse developmental effects at any dose (≤ 1 times MRHD based on BSA comparison).
In pregnant Wistar rats, clarithromycin was administered during organogenesis (GD 7 to 17) at oral doses of 10, 40, or 160 mg/kg/day. Reduced body weight and food consumption were observed in dams at 160 mg/kg/day but there was no evidence of adverse developmental effects at any dose (≤ 1 times MRHD based on surface BSA comparison).
In pregnant rabbits, clarithromycin administered during organogenesis (GD 6 to 18) at oral doses of 10, 35, or 125 mg/kg/day resulted in reduced maternal food consumption and decreased body weight at the highest dose, with no evidence of any adverse developmental effects at any dose (≤ 2 times MRHD based on BSA comparison). Intravenously administered clarithromycin to pregnant rabbits during organogenesis (GD 6 to 18) in rabbits at 20, 40, 80, or 160 mg/kg/day (≥ 0.3 times MRHD based on BSA comparison) resulted in maternal toxicity and implantation losses at all doses.
In pregnant monkeys, clarithromycin was administered (GD 20 to 50) at oral doses of 35 or 70 mg/kg/day. Dose-dependent emesis, poor appetite, fecal changes, and reduced body weight were observed in dams at all doses (≥ 0.5 times MRHD based on BSA comparison). Growth retardation in 1 fetus at 70 mg/kg/day was considered secondary to maternal toxicity. There was no evidence of primary drug related adverse developmental effects at any dose tested.
In a reproductive toxicology study in rats administered oral clarithromycin late in gestation through lactation (GD 17 to post-natal day 21) at doses of 10, 40, or 160 mg/kg/day (≤ 1 times MRHD based on BSA comparison), reductions in maternal body weight and food consumption were observed at 160 mg/kg/day. Reduced body-weight gain observed in offspring at 160 mg/kg/day was considered secondary to maternal toxicity. No adverse developmental effects were observed with clarithromycin at any dose tested.
Vonoprazan:
Pregnant rats were orally administered vonoprazan at doses of 30, 100, or 300 mg/kg/day (7, 27, 130 times the MRHD based on AUC comparison at the same doses from unmated female rats from separate studies) during the period of organogenesis from gestation Day 6 to 17. During maternal dosing, one high-dose female died and decreased body weight and food consumption occurred at the middle and highest doses. No embryo-fetal lethality was observed but decreased fetal body weight was observed in the highest dose group. Fetal abnormalities were limited to the 300 mg/kg/day dose group and included ventricular septal defect and mal-positioned subclavian artery in fetuses in a majority (15/19) of litters, as well as tail abnormalities, and small anal opening. No adverse embryo-fetal effects were observed at the 100 mg/kg/day.
Pregnant rabbits were orally administered vonoprazan at doses of 3, 10, or 30 mg/kg/day (0.04, 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 to 2,000 mg/kg (5 and 10 times the 2 g human dose for mice and rats, respectively, 3 and 6 times the 3 g human dose for mice and rats, respectively, based on BSA comparison). There was no evidence of harm to the fetus due to amoxicillin.
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.
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.
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)].
Pediatric Use
Safety and effectiveness of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK in pediatric patients have not been established.
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)].
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). Use of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK is not recommended in patients with severe renal impairment (eGFR < 30 mL/min) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
Hepatic Impairment
No dosage adjustment of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK is recommended in patients with mild hepatic impairment (Child-Pugh A). Use of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
Contraindications to VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK
Hypersensitivity Reactions
VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK are contraindicated in patients with a known hypersensitivity to any component of VOQUEZNA TRIPLE PAK: vonoprazan, amoxicillin (or other β-lactam antibacterials, e.g., penicillins and cephalosporins), or clarithromycin (or other macrolide antibacterial drugs, e.g., erythromycin) or VOQUEZNA DUAL PAK: vonoprazan or amoxicillin (or other β-lactam antibacterials, e.g., penicillins and cephalosporins) [see Warnings and Precautions (5.1)].
Rilpivirine-containing Products
VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK are contraindicated with rilpivirine-containing products [see Drug Interactions (7)].
Additional Contraindications to VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component
Serious Adverse Reactions/Risks Due to Drug Interactions
Because of the clarithromycin component, VOQUEZNA TRIPLE PAK is contraindicated with concomitant use of:
- Pimozide: There have been postmarketing reports of drug interactions when clarithromycin is co-administered with pimozide, resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these drugs by clarithromycin. Fatalities have been reported [see Warnings and Precautions (5.2) and Drug Interactions (7)].
- Lipid-lowering Agents: Lomitapide, simvastatin, and lovastatin [see Warnings and Precautions (5.2) and Drug Interactions (7)]
- Ergot Alkaloids: Ergotamine or dihydroergotamine [see Drug Interactions (7)]
- Colchicine in patients with renal or hepatic impairment [see Warnings and Precautions (5.2) and Drug Interactions (7)]
- Lurasidone: Coadministration of clarithromycin and lurasidone may lead to an increase in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions (7)].
Cholestatic Jaundice/Hepatic Dysfunction
VOQUEZNA TRIPLE PAK is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin.
Warnings and Precautions for VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK
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 VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK [see Contraindications (4.1)].
Before initiating therapy with VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, macrolide antibacterial drugs or other allergens. Discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK immediately and institute appropriate treatment if hypersensitivity occurs.
Acute Tubulointerstitial Nephritis
Acute tubulointerstitial nephritis (TIN) has been reported with vonoprazan, a component of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK [see Adverse Reactions (6.1)]. If suspected, discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK and evaluate patients with suspected acute TIN.
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 VOQUEZNA TRIPLE PAK: vonoprazan, amoxicillin, and clarithromycin and VOQUEZNA DUAL PAK: vonoprazan and amoxicillin [see Adverse Reactions (6.2)]. In addition, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with amoxicillin and clarithromycin.
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.
Drug-Induced Enterocolitis Syndrome
Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK [see Adverse Reactions (6.2)], with most cases occurring in pediatric patients ≤18 years of age. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK and institute appropriate therapy.
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 (component of VOQUEZNA DUAL PAK and TRIPLE PAK) and clarithromycin (component of VOQUEZNA TRIPLE PAK), 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, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK 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 VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK) develop an erythematous skin rash. Avoid use of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK 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 4 weeks after VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK treatment and consider repeating the test if initial CgA levels are high [see Drug Interactions (7) and Clinical Pharmacology (12.2)].
Development of Drug-Resistant Bacteria
Prescribing VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK 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.
Additional Warnings and Precautions for VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component
QT Prolongation
Clarithromycin (a component of VOQUEZNA TRIPLE PAK) 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 VOQUEZNA TRIPLE PAK 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 in 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 [see Use in Specific Populations (8.5)].
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 VOQUEZNA TRIPLE PAK). 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 VOQUEZNA TRIPLE PAK 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 (a component of VOQUEZNA TRIPLE PAK) 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 [see Contraindications (4.2) and Drug Interactions (7)].
Colchicine
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin (a component of VOQUEZNA TRIPLE PAK) and colchicine. If co-administration of VOQUEZNA TRIPLE PAK 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 VOQUEZNA TRIPLE PAK and colchicine is contraindicated in patients with renal or hepatic impairment [see Contraindications (4.2) and Drug Interactions (7)].
Lomitapide
Concomitant use of VOQUEZNA TRIPLE PAK with lomitapide may increase the risk of elevation in transaminases due to the clarithromycin component. Concomitant use of VOQUEZNA TRIPLE PAK with lomitapide is contraindicated [see Contraindications (4.2) and Drug Interactions (7)]. If treatment with VOQUEZNA TRIPLE PAK cannot be avoided, therapy with lomitapide must be suspended during the course of treatment.
HMG-CoA Reductase Inhibitors (statins)
Concomitant use of VOQUEZNA TRIPLE PAK 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 (a component of VOQUEZNA TRIPLE PAK) and lovastatin or simvastatin. Concomitant use of VOQUEZNA TRIPLE PAK with lovastatin or simvastatin is contraindicated [see Contraindications (4.2)]. If treatment with VOQUEZNA TRIPLE PAK cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment. Exercise caution when prescribing VOQUEZNA TRIPLE PAK with atorvastatin or pravastatin [see Drug Interactions (7)].
Hypoglycemic Agents/Insulin
Concomitant use of VOQUEZNA TRIPLE PAK, and hypoglycemic agents (such as nateglinide, pioglitazone, repaglinide, or 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 VOQUEZNA TRIPLE PAK [see Drug Interactions (7)].
Quetiapine
Concomitant use of VOQUEZNA TRIPLE PAK 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 VOQUEZNA TRIPLE PAK [see Drug Interactions (7)].
Warfarin
There is a risk of serious hemorrhage and significant elevations in the international normalized ratio (INR) and prothrombin time when clarithromycin (a component of VOQUEZNA TRIPLE PAK) is used concomitantly with warfarin. Monitor INR and prothrombin times frequently when warfarin is used concomitantly with VOQUEZNA TRIPLE PAK.
Benzodiazepines
Increased sedation and prolongation of sedation have been reported with concomitant administration when clarithromycin (a component of VOQUEZNA TRIPLE PAK), 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 astriazolam or midazolam are used concomitantly with VOQUEZNA TRIPLE PAK [see Drug Interactions (7)].
Embryo-Fetal Toxicity with Use of VOQUEZNA TRIPLE PAK
Based on findings from animal studies and human observational studies in pregnant women with use of clarithromycin, VOQUEZNA TRIPLE PAK is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If VOQUEZNA TRIPLE PAK 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 [see Use in Specific Populations (8.1)].
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 (a component of VOQUEZNA TRIPLE PAK). Monitor patients for symptoms.