Amoxicillin and Clavulanate Potassium (Page 3 of 7)
6.2 Postmarketing Experience
In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of Amoxicillin and Clavulanate Potassium. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Amoxicillin and Clavulanate Potassium.
Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. [see Warnings and Precautions (5.3) ]
Hypersensitivity Reactions: Pruritus, angioedema, serum sickness–like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens‑Johnson syndrome, acute generalized exanthematouspustulosis, hypersensitivity vasculitis, and cases of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. [see Warnings and Precautions (5.1) ]
Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with Amoxicillin and Clavulanate Potassium. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic‑hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported. [see Contraindications (4.2), Warnings and Precautions (5.2) ]
Renal: Interstitial nephritis, hematuria, and crystalluria have been reported. [see Overdosage (10) ]
Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosishave been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with Amoxicillin and Clavulanate Potassium. There have been reports of increased prothrombin time in patients receiving Amoxicillin and Clavulanate Potassium and anticoagulant therapy concomitantly. [see Drug Interactions (7.2) ]
Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported.
Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.
7 DRUG INTERACTIONS
Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with Amoxicillin and Clavulanate Potassium may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended.
7.2 Oral Anticoagulants
Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with Amoxicillin and Clavulanate Potassium. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.
The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.
7.4 Oral Contraceptives
Amoxicillin and Clavulanate Potassium may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.
7.5 Effects on Laboratory Tests
High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST® , Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with Amoxicillin and Clavulanate Potassium, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.
8 USE IN SPECIFIC POPULATIONS
Teratogenic Effects:Pregnancy Category B. Reproduction studies performed in pregnant rats and mice given Amoxicillin and Clavulanate Potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to Amoxicillin and Clavulanate Potassium. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
8.2 Labor and Delivery
Oral ampicillin‑class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin/clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention.
8.3 Nursing Mothers
Amoxicillin has been shown to be excreted in human milk. Amoxicillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin/clavulanate potassium is administered to a nursing woman.
8.4 Pediatric Use
The safety and effectiveness of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets have been established in pediatric patients. Use of Amoxicillin and Clavulanate Potassium in pediatric patients is supported by evidence from studies of Amoxicillin and Clavulanate Potassium Tablets in adults with additional data from a study of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension in pediatric patients aged 2 months to 12 years with acute otitis media. [see Clinical Studies (14.2)]
Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of Amoxicillin and Clavulanate Potassium should be modified in pediatric patients aged <12 weeks (<3 months). [see Dosage and Administration (2.2) ]
8.5 Geriatric Use
Of the 3,119 patients in an analysis of clinical studies of Amoxicillin and Clavulanate Potassium, 32% were ≥65 years old, and 14% were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but 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 adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
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