Amoxicillin for bacterial infection

The most common adverse reactions (> 1%) observed in clinical trials of AMOXIL capsules, tablets or oral suspension were diarrhea, rash, vomiting, and nausea.

Triple therapy : The most frequently reported adverse events for patients who received triple therapy (amoxicillin/clarithromycin/ lansoprazole) were diarrhea (7%), headache (6%), and taste perversion (5%).

Dual therapy : The most frequently reported adverse events for patients who received double therapy amoxicillin/lansoprazole were diarrhea (8%) and headache (7%). For more information on adverse reactions with clarithromycin or lansoprazole, refer to the Adverse Reactions section of their package inserts. In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of penicillins. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

These

events

Gastrointestinal : Black hairy tongue, and hemorrhagic/pseudomembranous colitis.

Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see WARNINGS AND PRECAUTIONS ].

Hypersensitivity Reactions : Anaphylaxis [see WARNINGS AND PRECAUTIONS ].

Serum sickness-like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and urticaria have been reported. Liver : A moderate rise in AST and/or ALT has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported.

Renal : Crystalluria has been reported [see OVERDOSAGE ]. Hemic and Lymphatic Systems : Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported.

These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.

Central Nervous System : Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness have been reported Miscellaneous :

Tooth

It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.

AMOXIL may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin.

This has been demonstrated in vitro ; however, the clinical significance of this interaction is not well documented. High urine concentrations of ampicillin may result in false-positive reactions when

testing

Although

anaphylaxis

These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with AMOXIL, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AMOXIL, 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 C. difficile produces toxins A and B which contribute to the development of CDAD. 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 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

Prescribing AMOXIL in the absence of a proven or strongly suspected bacterial infection is unlikely to

provide

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash.

Thus amoxicillin should not be administered to patients with mononucleosis. Amoxil chewable tablets contain aspartame which contains phenylalanine.

Each 200 mg chewable tablet contains 1.82 mg phenylalanine; each 400 mg chewable tablet contains 3.64 mg phenylalanine.

The oral suspensions of Amoxil do not contain

phenylalanine

Carcinogenesis, Mutagenesis, Impairment Of Fertility.

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate (AUGMENTIN).

AUGMENTIN was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. AUGMENTIN was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. AUGMENTIN was negative in the mouse micronucleus test and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 2 times the 3 g human dose based on body surface area). Reproduction studies have been performed in mice and rats at doses up to 2000 mg/kg (3 and 6 times the 3 g human dose, based on body surface area). There was no evidence of harm to the fetus due to amoxicillin.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, amoxicillin

should

It is not known whether use of amoxicillin 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.

Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants.

Caution should be exercised when amoxicillin is administered to a nursing woman. Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed.

Dosing of AMOXIL should be modified in pediatric patients 12 weeks or younger ( ? 3 months). An analysis of clinical studies of AMOXIL 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, care should be taken in

dose

Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms. Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin 1 . Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients.

In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria.

Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin.

Amoxicillin may be removed from circulation by hemodialysis.

AMOXIL is contraindicated in patients who have experienced a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to AMOXIL or to other ?-lactam antibiotics (e.g., penicillins and cephalosporins).

Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. The effect of food on the absorption of amoxicillin from the tablets and suspension of AMOXIL has been partially investigated; 400-mg and 875-mg formulations have been studied only when administered at the start of a light meal.

Orally administered doses of 250-mg and 500-mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 3.5 mcg/mL to 5.0 mcg/mL and 5.5 mcg/mL to 7.5 mcg/mL, respectively.

Mean amoxicillin pharmacokinetic parameters from an open, two-part, single-dose crossover bioequivalence study in 27 adults comparing 875 mg of AMOXIL with 875 mg of AUGMENTIN® (amoxicillin/clavulanate potassium) showed that the 875-mg tablet of AMOXIL produces an AUC0-? of 35.4 ± 8.1 mcg•hr/mL and a Cmax of 13.8 ± 4.1 mcg/mL.

Dosing was at the start of a light meal following an overnight fast. Orally administered doses of amoxicillin suspension, 125 mg/5 mL and 250 mg/5 mL, result in average peak blood levels 1 to 2 hours after administration in the range of 1.5 mcg/mL to 3.0 mcg/mL and 3.5 mcg/mL to 5.0 mcg/mL, respectively. Oral administration of single doses of 400-mg chewable tablets and 400 mg/5 mL suspension of AMOXIL to 24 adult volunteers yielded comparable pharmacokinetic data: Table 3: Mean Pharmacokinetic Parameters of Amoxicillin (400 mg chewable tablets and 400 mg/5 mL suspension) in Healthy Adults Dose* AUC0-? (mcg•hr/mL) Cmax (mcg/mL)† Amoxicillin Amoxicillin (±S.D.) Amoxicillin (±S.D.) 400 mg (5 mL of suspension) 17.1 (3.1) 5.92 (1.62) 400 mg (1 chewable tablet) 17.9 (2.4) 5.18 (1.64) * Administered at the start of a light meal.

Peak concentrations occurred approximately 1 hour after the dose. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. In blood serum, amoxicillin is approximately 20% protein-bound.

Following a 1-gram dose and utilizing a special skin window technique to determine levels of the antibiotic, it was noted that therapeutic levels were found in the interstitial fluid.

Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Since most of the amoxicillin is excreted unchanged in the urine, its excretion can be delayed by concurrent administration of probenecid [see DRUG INTERACTIONS ]. Amoxicillin is similar to penicillin in its bactericidal action against susceptible bacteria during the stage of active multiplication.

It acts through the inhibition of cell wall biosynthesis that leads to the death of the bacteria.

Resistance to amoxicillin is mediated primarily through enzymes called beta-lactamases that cleave the beta-lactam ring of amoxicillin, rendering it inactive.

Amoxicillin has been shown to be active against most isolates of the bacteria listed below, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Escherichia coli Haemophilus influenzae Helicobacter pylori Proteus mirabilis. When available, the clinical microbiology laboratory should provide cumulative in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques : Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs).

These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method -(broth or agar) 2,4 .

The MIC values should be interpreted according to the criteria in Table 4. Diffusion Techniques : Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds 3,4 . The zone size should be determined using a standardized test method 3 . Susceptibility to amoxicillin of Enterococcus spp., Enterobacteriaceae , and H. influenzae, may be inferred by testing ampicillin 4 .

Susceptibility to amoxicillin of Staphylococcus spp., and beta-hemolytic Streptococcus spp., may be inferred by testing penicillin 4 .

that are resistant to ampicillin or amoxicillin produce a TEM-type beta-lactamase. A beta-lactamase test can provide a rapid means of determining resistance to ampicillin and amoxicillin 4 . Susceptibility to amoxicillin of Streptococcus pneumoniae (non-meningitis isolates) may be inferred by testing penicillin or oxacillin 4 . pneumoniae to amoxicillin are provided in Table 4 4 . Table 4: Susceptibility Interpretive Criteria for Amoxicillin Minimum Inhibitory Concentration (mcg/mL) Disk Diffusion (

zone

Isolates with oxacillin zone sizes of ? 20 mm are susceptible to amoxicillin.

An amoxicillin

MIC

and

clinical

for

Standardized susceptibility test procedures 2,3,4 require use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test control. Standard amoxicillin powder should provide the following range of MIC values provided in Table 5 4 . For the diffusion technique the criteria provided in Table 5 should be achieved.