Amoxicillin: prescribing information – dosing, contraindications, interactions, side effects

Adults and Pediatric Patients

• Upper Respiratory Tract Infections of the Ear, Nose, and Throat:Amoxicillin for oral suspension is indicated in the treatment of infections due to susceptible (ONLY β-lactamase–negative) isolates of Streptococcusspecies. (α- and β- hemolytic isolates only), Streptococcus pneumoniae, Staphylococcusspp., or Haemophilus influenzae.
• Infections of the Genitourinary Tract:Amoxicillin for oral suspension is indicated in the treatment of infections due to susceptible (ONLY β-lactamase–negative) isolates of Escherichia coli, Proteus mirabilis, or Enterococcus faecalis.
• Infections of the Skin and Skin Structure:Amoxicillin for oral suspension is indicated in the treatment of infections due to susceptible (ONLY β-lactamase–negative) isolates of Streptococcusspp. (α- and β-hemolytic isolates only), Staphylococcusspp., or E. coli.
• Infections of the Lower Respiratory Tract:Amoxicillin for oral suspension is indicated in the treatment of infections due to susceptible (ONLY β-lactamase–negative) isolates of Streptococcusspp. (α- and β-hemolytic isolates only), S. pneumoniae, Staphylococcusspp., or H. influenzae.

Adult Patients only

• Helicobacter pyloriInfection and Duodenal Ulcer Disease:

Triple therapy for Helicobacter pylori (H. pylori)with clarithromycin and lansoprazole :

Amoxicillin for oral suspension, in combination with clarithromycin plus lansoprazole as triple therapy, is indicated for the treatment of patients with H. pyloriinfection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylorihas been shown to reduce the risk of duodenal ulcer recurrence.

Dual therapy for H. pyloriwith lansoprazole :

Amoxicillin for oral suspension, in combination with lansoprazole delayed-release capsules as dual therapy, is indicated for the treatment of patients with H. pyloriinfection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) who are either allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected. (See the clarithromycin package insert, MICROBIOLOGY.) Eradication of H. pylorihas been shown to reduce the risk of duodenal ulcer recurrence.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and other antibacterial drugs, amoxicillin for oral suspension should be used only to treat infections that are proven or strongly suspected to be caused by 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.

2.1 Important Administration Instructions

To minimize the potential for gastrointestinal intolerance, amoxicillin for oral suspension should be taken at the start of a meal.

2.2 Dosage for Adults and Pediatric Patients Aged 3 Months (12 weeks) and Older

• Treatment should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic, or evidence of bacterial eradication has been obtained.
• It is recommended that there be at least 10 days’ treatment for any infection caused by Streptococcus pyogenesto prevent the occurrence of acute rheumatic fever.
• In some infections, therapy may be required for several weeks. It may be necessary to continue clinical and/or bacteriological follow-up for several months after cessation of therapy.

Table 1. Dosage Recommendations for Adult and Pediatric Patients Aged 3 Months (12 weeks) and Older

Infection | Severity a | Recommended Dosage for Adults and Pediatric Patients Aged 3 Months and Older and Weight Greater than 40 kg | Recommended Dosage for Pediatric Patients Aged 3 Months and Older and Weight Less than 40 kg
Ear/Nose/Throat Skin/Skin Structure Genitourinary Tract | Mild/Moderate | 500 mg every 12 hours or 250 mg every 8 hours | 25 mg/kg/day in divided doses every 12 hours or 20 mg/kg/day in divided doses every 8 hours
Severe | 875 mg every 12 hours or 500 mg every 8 hours | 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours
Lower Respiratory Tract | Mild/Moderate or Severe | 875 mg every 12 hours or 500 mg every 8 hours | 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours

aDosage for infections caused by bacteria that are intermediate in their susceptibility to amoxicillin should follow the recommendations for severe infections.

2.3 Dosage in Pediatric Patients Aged Less than 12 Weeks (3 months)

• It is recommended that there be at least 10 days’ treatment for any infection caused by Streptococcus pyogenesto prevent the occurrence of acute rheumatic fever.
• Due to incompletely developed renal function affecting elimination of amoxicillin in this age group, the recommended upper dose of amoxicillin for oral suspension is 30 mg/kg/day divided every 12 hours. There are currently no dosing recommendations for pediatric patients with impaired renal function.
• Treatment should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic, or evidence of bacterial eradication has been obtained.

2.4 Dosage for H. pyloriInfection in Adults

Triple therapy:The recommended adult oral dose is 1 gram amoxicillin for oral suspension, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (every 12 hours) for 14 days.

Dual therapy:The recommended adult oral dose is 1 gram amoxicillin for oral suspension and 30 mg lansoprazole, each given three times daily (every 8 hours) for 14 days.

Please refer to clarithromycin and lansoprazole full prescribing information.

2.5 Dosage in Renal Impairment for Adults and Pediatric Patients Aged 3 Months and Older and Weight Greater than 40 kg

• Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of less than 30 mL/min should NOTreceive the 875 mg dose. See dosage regimens in patients with severe renal impairment provided in Table 2.

Table 2. Dosing in Patients with Severe Renal Impairment

Patients with Renal Impairment | Dosage Regimen
GFR 10 to 30 mL/min | 500 mg or 250 mg every 12 hours, depending on the severity of the infection
GFR less than 10 mL/min | 500 mg or 250 mg every 24 hours, depending on severity of the infection
Hemodialysis | 500 mg or 250 mg every 24 hours, depending on severity of the infection Administer an additional dose both during and at the end of dialysis

2.6 Directions for Mixing Oral Suspension

Prepare a suspension at time of dispensing as follows: Tap bottle until all powder flows freely. Measure the total amount of water (see Table 3). Add approximately 1/3 of the water to powder. Replace cap and shake vigorouslyto wet powder. Add remaining water. Replace cap and shake vigorously.

Table 3. Amount of Water for Mixing For Oral Suspension

Strength | Bottle Size | Total Amount of Water Required for Reconstitution
For Oral Suspension 400 mg/5 mL | 100 mL | 65 mL

After reconstitution, the required amount of suspension should be placed directly on the child’s tongue for swallowing. Alternate means of administration are to add the required amount of suspension to formula, milk, fruit juice, water, ginger ale, or cold drinks. These preparations should then be taken immediately.

SHAKE ORAL SUSPENSION WELL BEFORE USING. Keep bottle tightly closed. Any unused portion of the reconstituted suspension must be discarded after 14 days. Refrigeration is preferable, but not required.

Amoxicillin for Oral Suspension, USP 400 mg/5 mL. Each 5 mL of reconstituted pink, bubble gum flavored suspension contains 400 mg amoxicillin as the trihydrate.

Amoxicillin for oral suspension is contraindicated in patients who have experienced a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin or to other β-lactam antibacterial drugs (e.g., penicillins and cephalosporins).

The following are discussed in more detail in other sections of the labeling:

• Anaphylactic reactions [see Warnings and Precautions (5.1)]
• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
• Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions (5.3)]
• Clostridioides difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions (greater than 1%) observed in clinical trials of amoxicillin for oral suspension 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.

6.2 Postmarketing Experience

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 have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin for oral suspension.

• Infections and Infestations:Mucocutaneous candidiasis.
• Gastrointestinal:Drug-induced enterocolitis syndrome (DIES), black hairy tongue, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.4)] .
• Immune: Hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), hypersensitivity vasculitis [see Warnings and Precautions (5.1)].
• Skin and Appendages:Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS, AGEP, exfoliative dermatitis, and linear IgA bullous dermatosis.
• 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 (10)] .
• 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, aseptic meningitis, and/or dizziness 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.

5.1 Anaphylactic Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy including amoxicillin. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. 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 amoxicillin for oral suspension, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin for oral suspension should be discontinued, and appropriate therapy instituted.

5.2 Severe Cutaneous Adverse Reactions

Amoxicillin for oral suspension may cause severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). If patients develop skin rash they should be monitored closely, and amoxicillin for oral suspension discontinued if lesions progress.

5.3 Drug-Induced Enterocolitis Syndrome (DIES)

Drug-induced enterocolitis syndrome (DIES) has been reported with amoxicillin use [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 amoxicillin for oral suspension and institute appropriate therapy.

5.4 Clostridioides difficile-Associated Diarrhea (CDAD)

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin for oral suspension, 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.

C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficilecause 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 antibacterial use not directed against C. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Development of Drug-Resistant Bacteria

Prescribing amoxicillin for oral suspension 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.

5.6 Skin Rash in Patients with Mononucleosis

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin for oral suspension should not be administered to patients with mononucleosis.

5.7 Phenylketonurics

Amoxicillin for oral suspension does not contain phenylalanine and can be used by phenylketonurics.

7.1 Probenecid

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin.

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. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

7.3 Allopurinol

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 rashes is due to allopurinol or the hyperuricemia present in these patients.

7.4 Oral Contraceptives

Amoxicillin for oral suspension may affect the intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

7.5 Other Antibacterials

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.

7.6 Effects on Laboratory Tests

High urine concentrations of ampicillin 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 for oral suspension , it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX ®) be used.

Following administration of ampicillin or amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.

8.1 Pregnancy

Teratogenic Effects:Pregnancy Category B. 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 be used during pregnancy only if clearly needed.

8.2 Labor and Delivery

Oral ampicillin is poorly absorbed during labor. 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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

The safety and effectiveness of amoxicillin for oral suspension for the treatment of upper respiratory tract infections, and infections of the genitourinary tract, skin and skin structure and lower respiratory tract have been established in pediatric patients.

The safety and effectiveness of amoxicillin for oral suspension for the treatment of H.Pyloriinfection have not been established in pediatric patients.

Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Dosing of amoxicillin for oral suspension should be modified in pediatric patients 12 weeks or younger (3 months or younger) [see Dosage and Administration (2.3)].

8.5 Geriatric Use

An analysis of clinical studies of amoxicillin for oral suspension 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 selection, and it may be useful to monitor renal function.

8.6 Dosing in Renal Impairment

Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR less than 30 mL/min). See Dosing in Renal Impairment (2.5) for specific recommendations in patients with renal impairment.

In case of overdosage, discontinue amoxicillin for oral suspension, 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 amoxicillin¹.

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.

12.1 Mechanism of Action

Amoxicillin is an antibacterial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption: 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 amoxicillin 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 amoxicillin with 875 mg of amoxicillin/clavulanate potassiumshowed that the 875-mg tablet of amoxicillin produces an AUC 0-∞of 35.4 ± 8.1 mcg·hr/mL and a C maxof 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 amoxicillin to 24 adult volunteers yielded comparable pharmacokinetic data:

Table 4: Mean Pharmacokinetic Parameters of amoxicillin (400 mg chewable tablets and 400 mg/5 mL suspension) in Healthy Adults

Dose * Amoxicillin | AUC 0-∞(mcg±hr/mL) Amoxicillin (±S.D.) | C max(mcg/mL) † 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.
†Mean values of 24 normal volunteers. Peak concentrations occurred approximately 1 hour after the dose.

Distribution: amoxicillin for oral suspension 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.

Metabolism and Excretion: The half-life of amoxicillin is 61.3 minutes. 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 (7.1)].

12.4 Microbiology

Mechanism of Action