Amoxicillin / clarithromycin / vonoprazan Pregnancy and Breastfeeding Warnings

Brand names: Voquezna Triple Pak

Medically reviewed by Drugs.com. Last updated on Nov 16, 2022.

Amoxicillin / clarithromycin / vonoprazan Pregnancy Warnings

This product is not recommended unless there are no alternatives.

US FDA pregnancy category: Not assigned.

Risk summary: No data available on use of this product in pregnant women to inform a drug-related risk; observational studies in pregnant women have shown adverse effects on pregnancy outcomes with use of clarithromycin.

Comments:
-If this product is used during pregnancy, the patient should be apprised of the potential harm to the fetus.
-Pregnancies should be reported to Phathom Pharmaceuticals at 1-888-775-7428.

Animal studies with this product have not been reported. There are no controlled data in human pregnancy.

AMOXICILLIN: Animal studies have failed to reveal evidence of fetal harm; studies were performed in mice and rats at doses up to 2000 mg/kg (5 and 10 times the 2 g human dose, respectively, and 3 and 6 times the 3 g human dose, respectively, based on body surface area [BSA] comparison). There are no controlled data in human pregnancy.

CLARITHROMYCIN: Animal studies have revealed evidence of teratogenicity, fetotoxicity, and implantation losses. After oral dosing to pregnant mice during organogenesis (gestation day [GD] 6 to 15), reduced maternal body weight at 1000 mg/kg/day (3 times the maximum recommended human dose [MRHD] based on BSA comparison) resulted in reduced fetal survival and body weight; at doses at least 500 mg/kg/day, increased incidences of postimplantation loss and cleft palate in fetuses were observed, but no adverse developmental effects were seen in mice at doses up to 250 mg/kg/day (up to 1 times MRHD based on BSA comparison). After oral dosing to pregnant Sprague Dawley rats during organogenesis (GD 6 to 15), increased resorptions and reduced body weight of fetuses were considered secondary to maternal toxicity (reduced body weight and food intake) at 150 mg/kg/day; also, at this dose (1 times MRHD based on BSA comparison), a low incidence of cardiovascular anomalies was seen in fetuses, but no adverse developmental effects were observed in rats at 50 mg/kg/day (0.3 times MRHD based on BSA comparison). After oral dosing to pregnant Wistar rats during organogenesis (GD 7 to 17), reduced maternal body weight and food intake were seen at 160 mg/kg/day (1 times MRHD based on surface BSA comparison) but no adverse developmental effects were observed at any dose (up to 160 mg/kg/day). After oral dosing to pregnant rabbits during organogenesis (GD 6 to 18), reduced maternal food intake and decreased body weight were seen at the highest dose (125 mg/kg/day), with no evidence of any adverse developmental effects at any dose (up to 2 times MRHD based on BSA comparison); IV dosing (at doses at least 0.3 times MRHD based on BSA comparison) resulted in maternal toxicity and implantation losses at all doses. After oral dosing to pregnant monkeys (GD 20 to 50), dose-dependent emesis, poor appetite, fecal changes, and reduced body weight were seen in dams at all doses (at least 0.5 times MRHD based on BSA comparison); while growth retardation (considered secondary to maternal toxicity) was observed in 1 fetus at 70 mg/kg/day, there was no evidence of primary drug-related adverse developmental effects at any dose tested. There are limited controlled data in human pregnancy.
-Available data from prospective and retrospective observational studies with clarithromycin use in pregnant women showed an increased risk of miscarriage; data regarding major congenital malformations were inconsistent in these studies, with some reporting an increased risk (atrioventricular septal defects, genital malformations, orofacial clefts) and others finding no difference between clarithromycin and nonteratogenic controls. Available studies have methodologic limitations (including small sample size, under-capture of non-live births, exposure misclassification, inconsistent comparator groups).

VONOPRAZAN: Animal studies have revealed evidence of embryofetal toxicity, teratogenicity, and embryofetal mortality at exposures higher than MRHD based on AUC comparison. After oral dosing to pregnant rats at doses of 30, 100, or 300 mg/kg/day (7, 27, 130 times MRHD based on AUC comparison at the same doses from unmated female rats from separate studies) during organogenesis (GB 6 to 17), 1 high-dose female died and decreased body weight and food intake occurred at the middle and highest doses; no embryofetal lethality and no adverse embryofetal effects were observed in the highest dose group and at 100 mg/kg/day, respectively, but decreased fetal body weight was seen in the highest dose group and fetal abnormalities were limited to the 300 mg/kg/day dose group. After oral dosing to pregnant rabbits at doses of 3, 10, or 30 mg/kg/day (0.04, 1.5, 10 times MRHD based on AUC comparison) during organogenesis (GD 6 to 18), 2 animals aborted at the highest dose and decreased body weight and food intake; no embryofetal mortality or toxicity occurred and there were no external, visceral, or skeletal abnormalities. There are no controlled data in human pregnancy.

Based on animal studies for clarithromycin, this product may impair fertility in males of reproductive potential.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

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Amoxicillin / clarithromycin / vonoprazan Breastfeeding Warnings

Breastfeeding is not recommended during use of this product and for 2 days after the last dose.

Excreted into human milk: Yes (amoxicillin, clarithromycin); Unknown (vonoprazan)
Excreted into animal milk: Yes (vonoprazan)

Comments:
-No information is available on the clinical use of vonoprazan during breastfeeding; an alternate drug may be preferred.
-Due to the potential risk of adverse liver effects shown in animal studies with vonoprazan, women should pump and discard human milk during therapy and for 2 days after the last dose; infants should be fed stored human milk (collected before therapy) or formula.
-Amoxicillin and clarithromycin are considered acceptable in nursing mothers.

AMOXICILLIN:
Limited information indicates amoxicillin produces low levels in milk that are not expected to cause harmful effects in breastfed infants. Rash and disruption of infant's gastrointestinal flora (resulting in diarrhea or thrush) have been reported occasionally; such effects have not been adequately evaluated.

After a single 1 g oral dose in 6 women, peak amoxicillin milk levels occurred at 4 to 5 hours after dosing; milk levels averaged 0.69 mg/L (range: 0.46 to 0.88 mg/L) at 4 hours and 0.81 mg/L (range: 0.39 to 1.3 mg/L) at 5 hours after dosing. From this data, it is expected that an exclusively breastfed infant would receive a maximum of about 0.1 mg/kg/day with a maternal dose of 500 mg 3 times a day (about 0.25% to 0.5% of a typical infant amoxicillin dose).

In a telephone follow-up study, 25 nursing mothers reported taking amoxicillin (dosage not provided); while 3 mothers reported diarrhea in their infants, no rashes or candidiasis were reported in the exposed infants. A prospective, controlled study asked mothers who called an information service about adverse reactions experienced by their breastfed infants; of 40 infants exposed to amoxicillin in breast milk, 2 developed diarrhea and 1 developed a rash.

A study compared breastfed infants of mothers taking amoxicillin to those taking a macrolide antibiotic. Adverse reactions occurred in 8.3% of the infants exposed to amoxicillin, which was similar to the rate in macrolide-exposed infants; reactions included rash and somnolence.

CLARITHROMYCIN:
The low levels of clarithromycin in breast milk are unlikely to cause harmful effects in the nursing infant. The infant should be monitored for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (thrush, diaper rash). According to unconfirmed epidemiologic evidence, maternal macrolide use during the first 2 weeks of breastfeeding may increase the risk of hypertrophic pyloric stenosis in infants, but others have questioned this relationship; 2 meta-analyses failed to demonstrate a relationship between maternal macrolide use during breastfeeding and infantile hypertrophic pyloric stenosis.

Clarithromycin 250 mg orally twice a day was given to 12 mothers for puerperal infections; clarithromycin and its active metabolite (14-hydroxyclarithromycin) were found in milk. Peak milk levels were 0.85 mg/L for clarithromycin and 0.63 mg/L for 14-hydroxyclarithromycin at 2.2 and 2.8 hours after dosing, respectively; trough levels were 0.21 and 0.36 mg/L, respectively. The half-lives of the drug and metabolite were 4.3 and 9 hours, respectively. Using the milk level data from this study, an exclusively breastfed infant would receive about 136 mcg/kg/day (estimated average) of drug plus metabolite with a maternal dosage of 500 mg/day; this dosage is less than 1% of the recommend pediatric (less than 6 months) dosage, and is about 1.7% of the maternal weight-adjusted dosage.

A study comparing breastfed infants of mothers taking amoxicillin to those taking a macrolide antibiotic found no cases of pyloric stenosis; however, only 6 of the 55 infants exposed to a macrolide were exposed to clarithromycin. Adverse reactions occurred in 12.7% of the infants exposed to macrolides, which was similar to the rate in amoxicillin-exposed infants; reactions included rash, diarrhea, loss of appetite, and somnolence.

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Further information

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