Amoxicillin and Clavulanate Potassium (Pregnancy and Lactation, In-Depth)

Disclaimer

With each pregnancy, there is a risk of birth defect, loss, or other adverse outcome regardless of drug exposure. While Lexicomp and its third party providers have taken great care to ensure the accuracy of the information and recommendations presented, application of the information in this monograph to a specific patient is the responsibility of the health care provider. This information is not a substitute for individual patient assessment and consideration of factors unique to the patient by a health care provider. Health care providers and their patients should not use the information as a substitute for actual medical care. Use of this information is subject to Lexicomp’s Terms & Conditions and Disclaimer, which are available on the Lexicomp Online home page.

Brand Names: U.S.

Augmentin; Augmentin ES-600; Augmentin XR [DSC]

Pharmacologic Class

Antibiotic, Penicillin

Index Terms

Amoxicillin and Clavulanate Potassium; Amoxicillin and Clavulanic Acid; Amoxicillin-Clavulanate; Amoxicillin/Clavulanate; Amoxicillin/Clavulanate K; Amoxicillin/Potassium Clav; Amoxycillin and Clavulanate Potassium; Amoxycillin and Clavulanic Acid; Clavulanic Acid and Amoxicillin; Clavulanic Acid and Amoxycillin; Co-Amoxiclav

Use

Otitis media, acute:

Immediate-release tablets, chewable tablets, oral suspension (400/57 mg per 5 mL, 250/62.5 mg per 5 mL, 200/28.5 mg per 5 mL, and 125/31.25 mg per 5 mL only): Treatment of otitis media caused by beta-lactamase-producing strains of H. influenzae and M. catarrhalis.

Oral suspension (600/42.9 mg per 5 mL concentration): Treatment of acute otitis media, recurrent or persistent, caused by S. pneumoniae (penicillin MIC = 2 mcg/mL or less), H. influenzae (including beta-lactamase-producing strains), and M. catarrhalis (including beta-lactamase-producing strains) in pediatric patients with a history of antibiotic exposure for acute otitis media in the preceding 3 months and who are either 2 years or younger or attend day care.

Pneumonia:

Extended-release tablets only: Treatment of patients with community-acquired pneumonia (CAP) caused by confirmed or suspected beta-lactamase-producing pathogens (ie, Haemophilus influenzaeMoraxella catarrhalisHaemophilus parainfluenzaeKlebsiella pneumoniae, methicillin-susceptible Staphylococcus aureus) and Streptococcus pneumoniae with reduced susceptibility to penicillin (penicillin minimum inhibitory concentration [MIC] = 2 mcg/mL).

Limitations of use: Augmentin XR is not indicated for the treatment of infections caused by S. pneumoniae with penicillin MIC of 4 mcg/mL or greater (limited data).

Immediate-release tablets, chewable tablets, oral suspension (400/57 mg per 5 mL, 250/62.5 mg per 5 mL, 200/28.5 mg per 5 mL, and 125/31.25 mg per 5 mL only): Treatment of lower respiratory tract infection caused by beta-lactamase-producing strains of H. influenzae and M. catarrhalis.

Rhinosinusitis, acute bacterial:

Extended-release tablets: Treatment of patients with acute bacterial sinusitis caused by confirmed or suspected beta-lactamase-producing pathogens (ie, H. influenzaeM. catarrhalisH. parainfluenzaeK. pneumoniae, methicillin-susceptible S. aureus) and S. pneumoniae with reduced susceptibility to penicillin (penicillin MIC = 2 mcg/mL).

Limitations of use: Augmentin XR is not indicated for the treatment of infections caused by S. pneumoniae with penicillin MIC of 4 mcg/mL or greater (limited data).

Immediate-release tablets, chewable tablets, oral suspension (400/57 mg per 5 mL, 250/62.5 mg per 5 mL, 200/28.5 mg per 5 mL, and 125/31.25 mg per 5 mL only): Treatment of sinusitis caused by beta-lactamase-producing strains of H. influenzae and M. catarrhalis.

Skin and skin structure infections: Immediate-release tablets, chewable tablets, oral suspension (400/57 mg per 5 mL, 250/62.5 mg per 5 mL, 200/28.5 mg per 5 mL, and 125/31.25 mg per 5 mL only): Treatment of skin and skin structure infections caused by beta-lactamase-producing strains of S. aureusEscherichia coli, and Klebsiella spp.

Urinary tract infections: Immediate-release tablets, chewable tablets, oral suspension (400/57 mg per 5 mL, 250/62.5 mg per 5 mL, 200/28.5 mg per 5 mL, and 125/31.25 mg per 5 mL only): Treatment of urinary tract infections caused by beta-lactamase-producing strains of E. coliKlebsiella spp, and Enterobacter spp.

Use: Off-Label
  Bite wound, prophylaxis or treatment (animal or human bite)Level of Evidence [G]
  Bronchiectasis, acute exacerbationLevel of Evidence [C]
  Chronic obstructive pulmonary disease (COPD), exacerbationLevel of Evidence [A, G]
  Diabetic foot infectionLevel of Evidence [C, G]
  Intraabdominal infectionLevel of Evidence [B, G]
  Neutropenic fever, low-risk cancer patients (empiric therapy)Level of Evidence [G]
  Odontogenic infectionLevel of Evidence [B]
  Peritonsillar cellulitis or abscessLevel of Evidence [C]
  Streptococcus (group A), chronic carriageLevel of Evidence [G]
Level of Evidence Definitions
  Level of Evidence Scale
Pregnancy Risk Factor

B

Pregnancy Considerations – Summary

Both amoxicillin and clavulanic acid cross the placenta (Weber 1984). Oral ampicillin-class antibiotics are poorly absorbed during labor.

Pregnancy Considerations – Issues Related to Fetus/Infant

Both amoxicillin and clavulanic acid cross the placenta (Weber 1984).

• Although the intravenous route is not available in the United States, amoxicillin was shown to cross the placenta following IV administration. Women in labor received amoxicillin 2 g IV over 30 minutes, followed by amoxicillin 1 g IV over 15 minutes, 4 hours after the first dose (n=44). Treatment was for the prevention of group B streptococcal disease (GBS) in women with known or suspected Streptococcus agalactiae carriage. Two women with suspected amniotic infection received amoxicillin 1 g and clavulanic acid 200 mg IV every 8 hours, over 15 minutes. All women delivered between 30 to 42.4 weeks’ gestation. Amoxicillin concentrations in the umbilical cord serum were 1 to 16.8 mcg/mL (arterial) and 1.1 to 18 mcg/mL (venous). Peak concentrations in the venous cord serum were 18% of the maternal peak concentrations and were reached 3.3 minutes after the maternal peak. Samples were also obtained from 13 neonates. The peak neonatal serum concentration was 8 mcg/mL 1.1 hours after the maternal 2 g dose. Although the venous cord concentrations were initially higher, the neonatal serum concentrations exceeded the cord concentrations as the dosing interval progressed. The volume of distribution (Vd) for amoxicillin was calculated to be 3.4 L in the venous cord serum and 11.9 L in the neonate. The authors conducted a simulation and calculated the serum concentrations of amoxicillin IV to be above the MIC for >90% of the dosing interval in the maternal, venous cord, and neonatal serum (Muller 2009).

Maternal use of amoxicillin/clavulanate has generally not resulted in an increased risk of birth defects.

• The safety of intrauterine exposure to amoxicillin/clavulanate during the first trimester of pregnancy was evaluated in a prospective study. Pregnant women taking amoxicillin/clavulanate (n=191) were matched (based on age, smoking, and alcohol use) with pregnant women taking amoxicillin for similar medical conditions (n=191). The mean daily dose of amoxicillin/clavulanate was 1,500 mg (range: 500 to 3,000 mg) for 8 days (range: 2 to 28 days). The mean daily dose of amoxicillin was 1,500 mg (range: 500 to 3,000 mg) for 7 days (range: 2 to 14 days). The rate of major malformations in the amoxicillin/clavulanate group was 1.9%, which did not differ significantly from the amoxicillin group (3%, P=0.49, RR=0.62, 95% CI: 0.15 to 2.55) (Berkovitch 2004).

• An epidemiologic study to investigate the possible teratogenic effects of amoxicillin/clavulanate was conducted using the Hungarian Case-Control Surveillance of Congenital Abnormalities dataset. Included in the study were a population-control group of women who had newborns with no birth defects (n=10,238) and a case group of women who had fetuses or newborns with congenital abnormalities (n=6,935). Data was collected from medical documents and a patient questionnaire. This study evaluated amoxicillin/clavulanate use at any time during pregnancy. Maternal amoxicillin/clavulanate was most frequently given in oral doses of 250 to 500 mg 3 times/day for 7 days. Amoxicillin/clavulanate was used by 0.55% of the mothers in the control group compared to 0.75% of the mothers in the case group and was not significantly different between groups (crude OR 1.4, 95% CI: 0.9 to 2.0). When medication use was specifically examined in the second or third trimesters of pregnancy, there were no specific congenital abnormalities associated with use of amoxicillin/clavulanate (Czeizel 2001).

• An increase in most types of birth defects was not found following first trimester exposure to penicillins in a National Birth Defects Prevention Study (NBDPS); however, an increased risk of intercalary limb deficiency was observed. The NBDPS is a population-based, case-control study that obtains data from 10 centers in the United States. Children born between 1997 and 2003 were eligible for this analysis. Cases were mothers of infants (liveborn, stillborn, or induced abortion) with ≥1 specific malformation within >30 categories of birth defects (n=13,155). Infants with chromosomal abnormalities or single-gene conditions were excluded. Controls were mothers of infants randomly selected from live births without malformations (n=4,941). Case and control mothers were contacted by telephone following the birth of their infant for information related to antibiotic use from 1 month prior to conception until the end of the first trimester of pregnancy. Penicillins were the most common class of antibiotics used (cases 5.5%; control 5.9%). The overall safety profile of penicillin use in pregnancy was confirmed. There was only one birth defect associated following first trimester use of a penicillin (specific agents not noted): Intercalary limb deficiency (four exposed cases; adjusted OR 3.1, 95% CI: 1.0 to 9.4) (Crider 2009).

• Amoxicillin exposure was found to be potentially teratogenic in two comparative studies; however, the majority of malformations were considered to be minor. One study gathered data from pregnant women for 1 month from four hospitals in Zagreb, Croatia (n=893; 859 used medications) and the second study obtained data for 1 year from a single center in Novi-Sad, Serbia (n=6,099; 2,013 used medications). In both studies, pregnant women were interviewed prior to delivery by trained physicians who obtained information related to maternal age, education, obstetrical history, medication, use of contraception, number of ultrasounds; alcohol, caffeine, nicotine, and narcotic use, as well as x-ray exposure. The studies focused on women who used beta-lactam antibiotics during pregnancy (Croatia n=231; Serbia n=296). Following beta-lactam use, malformations were detected in eight cases from Croatia and 14 cases from Serbia (one major). Amoxicillin was used by 47 women in Croatia and 81 women in Serbia. Five infants were born with malformations and the majority were considered to be minor (see the Amoxicillin monograph for details). The study also included 38 women in Croatia and 12 women in Serbia who took amoxicillin/clavulanic acid during pregnancy. One baby was born with a malformation following first trimester exposure (additional details not provided) (Erić 2012).

Maternal use of penicillins during the second or third trimesters of pregnancy does not increase the risk of delivering an infant small for gestation age (SGA). A case-control study was conducted using the Quebec Pregnancy Registry. The registry used administrative databases to collect information related to maternal medications, diagnosis (based on ICD-9 codes), hospitalizations, and pregnancy outcomes. Women were eligible for the study if they were between 15 to 45 years of age, enrolled in the Quebec Public Insurance Plan for at least 1 year prior to pregnancy, and gave birth to a liveborn singleton infant between 1998 and 2003. Cases were infants born SGA, defined as less than the tenth percentile for weight based on the Canadian reference curves (n=8,192). Control infants weighed greater than or equal to the tenth percentile (n=55,146). Maternal medical conditions (eg, diabetes, hypertension, infections), use of other medications, and maternal socioeconomic variables were considered in the analysis of data. The mean age of all mothers was 27 years and the mean gestational age at delivery was 39.1 weeks (cases) and 38.8 weeks (controls). The use of any antibiotic during the second or third trimester of pregnancy was not associated with SGA (adjusted OR 0.97, 95% CI: 0.91 to 1.04). The use of penicillins as a class (AHFS system 8:12:16) was also not associated with an increased risk of SGA (adjusted OR 0.94, 95% CI: 0.87 to 1.01). Factors not considered in the study included maternal smoking, and illicit substance, alcohol, or caffeine use (Santos 2011).

A possible increased risk of necrotizing enterocolitis in neonates or bowel disorders in children exposed to amoxicillin/clavulanate in utero has been observed.

• A possible increased risk of necrotizing enterocolitis in neonates exposed in utero to amoxicillin/clavulanate at the end of pregnancy has been identified. The ORACLE I and the ORACLE II trials were large, randomized, multicenter trials that studied the effect of erythromycin and/or amoxicillin/clavulanate compared to placebo for patients with preterm labor (<37 weeks’ gestation). In both studies, patients were randomized to receive either erythromycin 250 mg plus placebo, amoxicillin/clavulanic acid 250 mg/125 mg plus placebo, both antibiotics, or two placebos 4 times/day for 10 days or until delivery. The authors of ORACLE I and ORACLE II concluded that amoxicillin/clavulanate should not be routinely prescribed for women in spontaneous preterm labor without evidence of infection or for preterm premature rupture of membranes (PPROM).

° ORACLE I focused on patients who had PPROM. Women at <37 weeks’ gestation with PPROM were eligible for the study if the need to prescribe antibiotics was uncertain. Women were excluded if antibiotics were already prescribed, if there was a documented infection, or if there was any reason that an antibiotic would not normally be administered. Women were randomized into the following groups: Erythromycin (n=1,190), amoxicillin/clavulanic acid (n=1,205), both antibiotics (n=1,189), or placebo (n=1,225). The median gestational age at study entry was 223 days in women assigned to amoxicillin/clavulanate and this did not differ significantly between treatment groups. Use of amoxicillin/clavulanate alone or in combination with erythromycin was associated with prolongation of pregnancy. Amoxicillin/clavulanate was associated with a significantly higher rate of proven necrotizing enterocolitis (Amoxicillin/clavulanate alone 1.9%, placebo 0.5%, p=0.001; amoxicillin/clavulanate + erythromycin 1.7%, placebo 0.5%, p=0.005) (Kenyon ORACLE I 2001).

° ORACLE II focused on patients with spontaneous preterm labor with intact membranes and no evidence of clinical infection. Other entry criteria were the same as in ORACLE I. Women were randomized into the following groups: Erythromycin (n=1,600), amoxicillin/clavulanic acid (n=1,534), both antibiotics (n=1,551), or placebo (n=1,556). The median gestational age at study entry was 219 days in women assigned to amoxicillin/clavulanate and this did not differ significantly between treatment groups. Neither of the trial antibiotics was found to prolong pregnancy in comparison to placebo. There was a higher, but not statistically significant, incidence of proven necrotizing enterocolitis noted in the newborns receiving amoxicillin/clavulanate alone (0.6%, placebo 0.3%; p=0.16) or with amoxicillin/clavulanate + erythromycin (0.7%, p=0.07) (Kenyon ORACLE II, 2001).

• The ORACLE Children Study (OCS) followed up with children born to women in the ORACLE studies in order to determine if perinatal use of erythromycin or amoxicillin/clavulanic acid led to functional or educational disabilities. Information was collected on children born to women who completed ORACLE I (OCS I) or ORACLE II (OCS II) at 7 years of age. Data were collected via a parental questionnaire, a phone interview with the parents, and/or the child’s physician. Information was not collected on children who were subsequently adopted, moved out of the country, or who were in foster care. The primary outcome was the presence of functional impairment (mild, moderate, or severe), including ambulation, cognition, dexterity, emotion, hearing, pain, speech, or vision. For all OCS children who resided in England, results from the national curriculum tests which are administered at 7 years of age were also obtained. Following maternal use of amoxicillin/clavulanic acid, OCS I showed a possible increase of bowel disorders in children at 7 years of age, and OCS II showed an increased risk of cerebral palsy (although the overall risk was low).

° OCS I collected information from 75% of children born to women in ORACLE I. There was not an increased risk of functional impairment between children exposed to amoxicillin/clavulanic acid (n=1,587) and children not exposed to amoxicillin/clavulanic acid (n=1,584; OR 1.11, 95% CI: 0.96 to 1.28). Academic achievement, as determined by the national curriculum tests, was not different between children exposed to erythromycin or amoxicillin/clavulanic acid; however, children in the study had lower scores overall, which is what is normally observed with preterm children. Specifically, the percentage of children expected to be less than the level achieved by 60% to 70% of the population would be 15% for reading, 18% for writing, or 11% for math. In children exposed to amoxicillin/clavulanic acid, the percentages of children who achieved scores less than the majority of the population were 22% for reading, 25% for writing, and 15% for math. There was not an increased risk of bowel disorders overall in children exposed to amoxicillin/clavulanic acid; however, more exposed children reported hospital admissions for constipation, diarrhea, stomach problems, or bowel problems requiring physician care (exposure to any amoxicillin/clavulanic acid 2.7%, exposure to no amoxicillin/clavulanic acid 1.6%; OR 1.71; 95% CI:1.05 to 2.79). The authors of the study note that they did not adjust for these comparisons and the results should be interpreted with caution (Kenyon ORACLE I, 2008).

° OCS II collected information from 71% of children born to women in ORACLE II. In this study, there was not an increased risk of functional impairment between children exposed to amoxicillin/clavulanic acid (n=1,532) and children not exposed to amoxicillin/clavulanic acid (n=1,520) (OR 1.03, 95% CI: 0.89 to 1.19). Unexpectedly, there was an increased risk of cerebral palsy in children of women who took either erythromycin or amoxicillin/clavulanic acid. For amoxicillin/clavulanic acid specifically, the incidence of cerebral palsy was 3.2% in comparison to 1.9% with no maternal amoxicillin/clavulanic acid use (OR 1.69, 95% CI: 1.07 to 2.67). Upon additional analysis, children who developed cerebral palsy were more often born to mothers assigned to take both antibiotics (n=35), in comparison to erythromycin alone (n=18), amoxicillin/clavulanic acid alone (n=15), or placebo (n=12). In addition, children who developed cerebral palsy were exposed to treatment at an earlier gestational age and born closer to enrollment of the mother into the study. The results of OCS II did not show an associated risk of functional impairment in children at 7 years of age following maternal use of amoxicillin/clavulanic acid and the overall risk of cerebral palsy is low (Kenyon ORACLE II, 2008).

• The ORACLE Children Study (OCS) continued following children until 11 years of age to evaluate their educational status. In this part of the follow-up study, results from universal standardized testing was obtained from the Department of Education in England; the tests are independently scored and results are unmodified. Information was available for children exposed to amoxicillin/clavulanic acid (n=1,523) and children not exposed to amoxicillin/clavulanic acid (n=1,517) who were part of the preterm PROM group and for children exposed to amoxicillin/clavulanic acid (n=1,498) and children not exposed to amoxicillin/clavulanic acid (n=1,549) who were part of the spontaneous preterm labor group. A child with score of level 4 or above is considered to be making appropriate progress at school. The number of children who scored less than level 4 in math, science, or English was not statistically different between those who were exposed and those who were not, regardless of their original study group. Results were also compared to national outcomes. In England, level 4 is achieved for 80% of children in English and 79% in math; among all children in the study, 75% achieved a level 4 for English, and 74% for math. The lower scores in children who were part of the OCS may, in part, be explained by the large number of children in the study who were born premature. Overall, the antibiotic intervention was not shown to influence test scores among children in this study (Marlow 2017).

Pregnancy Considerations – Issues Related to Mother

Oral ampicillin-class antibiotics are poorly absorbed during labor (Amoxicillin and clavulanate potassium prescribing information 2015).

• Amoxicillin/clavulanate may be used to treat melioidosis in pregnant women. It is used in place of cotrimoxazole which has a relative contraindication for use during pregnancy (Cheng 2008).

Amoxicillin/clavulanate is not recommended for use in the management of preterm prelabor rupture of membranes (PROM).

• Antibiotics are used in the management of PROM to prolong pregnancy and reduce the risk of infection; however, due to the increased risk of necrotizing enterocolitis in neonates exposed in utero to amoxicillin/clavulanate, this combination is not recommended. The ACOG recommended regimen for the management of PROM in patients of 24 to 33 weeks’ gestation who have no contraindications is a 7-day course of parenteral and oral therapy with ampicillin or amoxicillin and erythromycin (ACOG 188 2018). The ACOG does not recommend use of an antibiotic to prolong pregnancy in women with preterm labor and intact membranes in the absence of a documented infection (ACOG 199 2018).

When used during pregnancy, pharmacokinetic changes have been observed with amoxicillin alone (refer to the Amoxicillin monograph for details).

Pregnancy Considerations – Animal Data

Adverse events were not observed in animal reproduction studies when rats were administered amoxicillin/clavulanate in doses up to ~4 times the human dose of amoxicillin and ~9 times the human dose of clavulanate based on body surface area (BSA). Adverse events were not observed in mice with doses up to ~2 of amoxicillin and ~4 times the human dose of clavulanate based on BSA (Amoxicillin and clavulanate potassium prescribing information 2015).

Breast-Feeding Considerations – Summary

Amoxicillin is present in breast milk following administration amoxicillin/clavulanate (Weber 1984).

The relative infant dose (RID) of amoxicillin following administration of amoxicillin/clavulanate is 0.02% to 0.07% when calculated using the highest average breast milk concentration located and compared to an infant therapeutic dose of 25 to 90 mg/kg/day. In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).

Using the highest average milk concentration (0.12 mcg/mL), the estimated daily infant dose via breast milk is 0.018 mg/kg/day. This milk concentration was obtained 4 to 6 hours following maternal administration of oral amoxicillin/clavulanate 250 mg/125 mg (Takase 1982).

Constipation, diarrhea, restlessness, and rash have been reported in breastfeeding infants exposed to amoxicillin and clavulanate; reversible elevations in AST and ALT have been noted in one infant (Benyamini 2005). The manufacturer warns of the potential for allergic sensitization in the infant. In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush and diarrhea (WHO 2002).

Although the manufacturer recommends that caution be exercised when administering amoxicillin and clavulanate to breastfeeding women, amoxicillin/clavulanate is considered compatible with breastfeeding when used in usual recommended doses (WHO 2002).

Breast-Feeding Considerations – Issues Related to Infant

Amoxicillin is present in breast milk.

• Following a dose of amoxicillin/clavulanate 250 mg/125 mg, amoxicillin was found in breast milk in low levels. Clavulanic acid was not detected (Weber 1984). Milk samples were obtained from 1 to 6 hours after administration of oral amoxicillin/clavulanate 250 mg/125 mg to three women. Concentrations of amoxicillin in breast milk ranged from a trace (<0.04 mcg/mL) to 0.12 mcg/mL. Clavulanate was not detected (Takase 1982). Using a milk concentration of 0.12 mcg/mL, the estimated exposure to the breastfeeding infant would be 0.018 mg/kg/day (0.02% to 0.07% of a therapeutic infant dose of 25 to 90 mg/kg/day [based on the amoxicillin component]).

Adverse events have been reported in breastfeeding infants exposed to amoxicillin with or without clavulanate.

• The safety of maternal use of amoxicillin/clavulanate (n=67) was compared to amoxicillin (n=40) during breastfeeding. Information was obtained using a questionnaire prior to treatment and by phone interview after treatment was completed. The women taking amoxicillin/clavulanate reported adverse events in 22% of their infants. These included constipation, diarrhea, irritability, and rash. Elevated AST and ALT were noted in one infant; these values returned to normal within 10 days after amoxicillin/clavulanate was discontinued. Adverse events were reported in only 7.5% of the infants of mothers taking amoxicillin. The difference in the overall rate of adverse events between groups was statistically significant (p=0.046, RR=2.99, 95% CI: 0.92 to 9.68). When further analyzed, it was noted that the higher the maternal dose of amoxicillin/clavulanate, the higher the rate of adverse events in their infants (p=0.0139). When looking at the risk of each adverse event individually, there was not a significant difference between groups. The authors of the study concluded that amoxicillin/clavulanate poses only minimal risk to the breastfed infant (Benyamini 2005).

The manufacturer warns of the potential for allergic sensitization in the infant (Amoxicillin and clavulanate potassium prescribing information 2015).

In general, antibiotics that are present in breast milk may cause nondose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush or diarrhea. Breastfeeding may continue when otherwise appropriate; however, discontinuing the antibiotic or changing to an alternate maternal therapy may be needed (WHO 2002).

• Although the manufacturer recommends caution if administering amoxicillin/clavulanate to a breastfeeding mother (Amoxicillin and clavulanate potassium prescribing information 2015), amoxicillin/clavulanate is considered compatible with breastfeeding when used in usual recommended doses (WHO 2002).

Protein Binding

Clavulanic acid: ~25%

Half-life, Elimination

Clavulanic acid: 1 hour

Time to Peak

Clavulanic acid: Serum: 1.5 hours

Excretion

Clavulanic acid: Urine (25% to 40% as unchanged drug)

Pharmacokinetic Note

Refer to the individual Amoxicillin monograph for pharmacokinetics. Amoxicillin pharmacokinetics are not affected by clavulanic acid.

Pharmacokinetic Pregnancy Considerations

Both amoxicillin and clavulanic acid cross the placenta. Low concentrations of amoxicillin are found in breast milk; clavulanate has not been detected. When used during pregnancy, pharmacokinetic changes have been observed with amoxicillin alone (refer to the Amoxicillin monograph for details).

Molecular Weight

Amoxicillin: 419.46

Clavulanate potassium: 237.25

Selected Readings

American College of Obstetricians and Gynecologists (ACOG), Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin no. 188: prelabor rupture of membranes. Obstet Gynecol. 2018;131(1):e1-e14.[PubMed 29266075]

American College of Obstetricians and Gynecologists (ACOG), Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin no. 199: use of Prophylactic antibiotics in labor and delivery. Obstet Gynecol. 2018;132(3):e103-e119.[PubMed 30134425]

References

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Kenyon SL, Taylor DJ, Tarnow-Mordi W, et al, “Broad-Spectrum Antibiotics for Preterm, Prelabour Rupture of Fetal Membranes: The ORACLE I Randomised Trial. ORACLE Collaborative Group,” Lancet, 2001, 357(9261):979-88.[PubMed 11293640]

Kenyon SL, Taylor DJ, Tarnow-Mordi W, et al, “Broad-Spectrum Antibiotics for Spontaneous Preterm Labour: The ORACLE II Randomised Trial. ORACLE Collaborative Group,” Lancet, 2001, 357(9261):989-94.[PubMed 11293641]

Marlow N, Bower H, Jones D, et al. The ORACLE children study: educational outcomes at 11 years of age following antenatal prescription of erythromycin or co-amoxiclav. Arch Dis Child Fetal Neonatal Ed. 2017;102(2):F131-F135.[PubMed 27515985]

Muller AE, Oostvogel PM, DeJongh J, “Pharmacokinetics of Amoxicillin in Maternal, Umbilical Cord, and Neonatal Sera,” Antimicrob Agents Chemother, 2009, 53(4):1574-80.[PubMed 19164154]

Santos F, Sheehy O, Perreault S, et al, “Exposure to Anti-infective Drugs During Pregnancy and the Risk of Small-for-Gestational-Age Newborns: A Case-Control Study,” BJOG, 2011, 118(11):1374-82.[PubMed 21749628]

Takase Z, Shirafuji H, Uchida M. Clinical and Laboratory Studies on BRL25000 (Clavulanic acid-amoxicillin) in the field of obstetrics and gynecology. Japanese Journal of Chemotherapy 1982;30(Suppl 2):579-586.

Weber DJ, Tolkoff-Rubin NE, and Rubin RH, “Amoxicillin and Potassium Clavulanate: An Antibiotic Combination. Mechanism of Action, Pharmacokinetics, Antimicrobial Spectrum, Clinical Efficacy and Adverse Effects,” Pharmacotherapy, 1984, 4(3):122-36.[PubMed 6739312]

World Health Organization (WHO). Breastfeeding and maternal medication, recommendations for drugs in the Eleventh WHO Model List of Essential Drugs. 2002. Available at http://www.who.int/maternal_child_adolescent/documents/55732/en/[PubMed 23215911]

Amoxicillin and Clavulanate (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(a moks i SIL in & klav yoo LAN ate)

Brand Names: US

Augmentin; Augmentin ES-600; Augmentin XR [DSC]

Brand Names: Canada

Amoxi-Clav; Clavulin

What is this drug used for?
  • It is used to treat bacterial infections.
What do I need to tell my doctor BEFORE I take this drug?
  • If you have an allergy to amoxicillin, clavulanate potassium, any penicillin, or any other part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have kidney disease.
  • If you have turned yellow or had liver side effects with this drug before.
  • If you have mono.
  • If you are taking probenecid.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • All products:
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Very bad and sometimes deadly allergic side effects have rarely happened. Talk with your doctor.
  • Have your blood work checked if you are on this drug for a long time. Talk with your doctor.
  • This drug may affect certain lab tests. Tell all of your health care providers and lab workers that you take this drug.
  • If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this drug.
  • If you have high blood sugar (diabetes), do not use Clinitest®. Use some other urine glucose testing like Clinistix® or Tes-Tape®.
  • Do not use longer than you have been told. A second infection may happen.
  • Birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Use some other kind of birth control also like a condom when taking this drug.
  • Tell your doctor if you are pregnant, plan on getting pregnant, or are breast-feeding. You will need to talk about the benefits and risks to you and the baby.
  • Chewable tablets and liquid (suspension):
  • If you have phenylketonuria (PKU), talk with your doctor. Some products have phenylalanine.
What are some side effects that I need to call my doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Vaginal irritation.
  • It is common to have diarrhea when taking antibiotics. Rarely, a severe form of diarrhea called C diff–associated diarrhea (CDAD) may happen. Sometimes, this has led to a deadly bowel problem (colitis). CDAD may happen while you are taking an antibiotic or within a few months after you stop taking it. Call your doctor right away if you have stomach pain or cramps, very loose or watery stools, or bloody stools. Do not try to treat diarrhea without first checking with your doctor.
  • A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
  • For all patients taking this drug:
  • Diarrhea.
  • Upset stomach or throwing up.
  • Children:
  • Diaper rash.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • All products:
  • To gain the most benefit, do not miss doses.
  • Keep using this drug as you have been told by your doctor or other health care provider, even if you feel well.
  • Extended-release tablets:
  • Take tablet with food.
  • Avoid taking this drug with high-fat meals.
  • Swallow whole. Do not chew or crush.
  • Some products may be broken in half. If you are not sure if you can break this product in half, talk with the doctor.
  • All other products:
  • Take with or without food. Take with food if it causes an upset stomach.
  • Chewable tablet:
  • Chew well before swallowing.
  • Liquid (suspension):
  • Shake well before use.
  • Measure liquid doses carefully. Use the measuring device that comes with this drug. If there is none, ask the pharmacist for a device to measure this drug.
What do I do if I miss a dose?
  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
How do I store and/or throw out this drug?
  • Liquid (suspension):
  • Store liquid (suspension) in a refrigerator. Do not freeze. Throw away any part not used after 10 days.
  • All other products:
  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • All products:
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Amoxicillin and Clavulanate (Patient Education – Pediatric Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(a moks i SIL in & klav yoo LAN ate)

Brand Names: US

Augmentin; Augmentin ES-600; Augmentin XR [DSC]

Brand Names: Canada

Amoxi-Clav; Clavulin

What is this drug used for?
  • It is used to treat bacterial infections.
What do I need to tell the doctor BEFORE my child takes this drug?
  • If your child has an allergy to any part of this drug.
  • If your child is allergic to any drugs like this one or any other drugs, foods, or other substances. Tell the doctor about the allergy and what signs your child had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If your child has kidney disease.
  • If your child has turned yellow or has had liver side effects with this drug before.
  • If your child has mono.
  • If your child is taking probenecid.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell the doctor and pharmacist about all of your child’s drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for your child to take this drug with all of his/her drugs and health problems. Do not start, stop, or change the dose of any drug your child takes without checking with the doctor.
What are some things I need to know or do while my child takes this drug?
  • All products:
  • Tell all of your child’s health care providers that your child is taking this drug. This includes your child’s doctors, nurses, pharmacists, and dentists.
  • Very bad and sometimes deadly allergic side effects have rarely happened. Talk with your child’s doctor.
  • Have your child’s blood work checked if he/she is on this drug for a long time. Talk with your child’s doctor.
  • This drug may affect certain lab tests. Tell all of your child’s health care providers and lab workers that your child takes this drug.
  • If your child is taking warfarin, talk with the doctor. Your child may need to have blood work checked more closely while taking it with this drug.
  • If your child has high blood sugar (diabetes), do not use Clinitest®. Use some other urine glucose testing like Clinistix® or Tes-Tape®.
  • Do not give to your child longer than you have been told. A second infection may happen.
  • If your child is or may be sexually active:
  • Birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Be sure your child uses some other kind of birth control also, like a condom, when taking this drug.
  • If your child is pregnant or breast-feeding a baby:
  • Talk with the doctor if your child is pregnant, becomes pregnant, or is breast-feeding a baby. You will need to talk about the benefits and risks to your child and the baby.
  • Chewable tablets and liquid (suspension):
  • If your child has phenylketonuria (PKU), talk with your child’s doctor. Some products have phenylalanine.
What are some side effects that I need to call my child’s doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your child’s doctor or get medical help right away if your child has any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Vaginal irritation.
  • It is common to have diarrhea when taking antibiotics. Rarely, a severe form of diarrhea called C diff-associated diarrhea (CDAD) may happen. Sometimes, this has led to a deadly bowel problem (colitis). CDAD may happen while your child is taking an antibiotic or within a few months after he/she stops taking it. Call your child’s doctor right away if your child has stomach pain or cramps, very loose or watery stools, or bloody stools. Do not try to treat diarrhea without first checking with the doctor.
  • A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if your child has signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in the mouth, throat, nose, or eyes.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your child’s doctor or get medical help if any of these side effects or any other side effects bother your child or do not go away:
  • Diarrhea.
  • Upset stomach or throwing up.
  • Diaper rash.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your child’s doctor. Call your child’s doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best given?
  • Give this drug as ordered by your child’s doctor. Read all information given to you. Follow all instructions closely.
  • All products:
  • To gain the most benefit, do not miss giving your child doses.
  • Keep giving this drug to your child as you have been told by your child’s doctor or other health care provider, even if your child feels well.
  • Extended-release tablets:
  • Give this drug with food.
  • Avoid giving this drug with high-fat meals.
  • Have your child swallow whole. Do not let your child chew or crush.
  • Some products may be broken in half. If you are not sure if you can break this product in half, talk with the doctor.
  • All other products:
  • Give this drug with or without food. Give with food if it causes an upset stomach.
  • Chewable tablet:
  • Have your child chew well before swallowing.
  • Liquid (suspension):
  • Shake well before use.
  • Measure liquid doses carefully. Use the measuring device that comes with this drug. If there is none, ask the pharmacist for a device to measure this drug.
What do I do if my child misses a dose?
  • Give a missed dose as soon as you think about it.
  • If it is close to the time for your child’s next dose, skip the missed dose and go back to your child’s normal time.
  • Do not give 2 doses at the same time or extra doses.
How do I store and/or throw out this drug?
  • Liquid (suspension):
  • Store liquid (suspension) in a refrigerator. Do not freeze. Throw away any part not used after 10 days.
  • All other products:
  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • All products:
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your child’s symptoms or health problems do not get better or if they become worse, call your child’s doctor.
  • Do not share your child’s drug with others and do not give anyone else’s drug to your child.
  • Keep a list of all your child’s drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your child’s doctor.
  • Talk with your child’s doctor before giving your child any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your child’s doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.