Amoxicillin and clavulanate: uses, appearance and warnings

Amoxicillin and clavulanate potassium for oral suspension is a combination of amoxicillin, a penicillin-class antibacterial and clavulanate potassium, a beta-lactamase inhibitor, indicated for the treatment of infections caused by designated susceptible (confirmed or suspected) beta-lactamase-producing microorganisms ( 1 ): Lower Respiratory Tract Infections ( 1.1 ) Amoxicillin and Clavulanate Potassium for Oral Suspension: pediatric patients weighing less than 40 kg, and in adult and pediatric patients who cannot swallow tablets Acute Bacterial Sinusitis ( 1.3 ) Amoxicillin and Clavulanate Potassium for Oral Suspension: pediatric patients weighing less than 40 kg, and in adult and pediatric patients who cannot swallow tablets Acute Bacterial Otitis Media ( 1.4 ) Amoxicillin and Clavulanate Potassium for Oral Suspension: pediatric patients weighing less than 40 kg, and in adult and pediatric patients who cannot swallow tablets Skin and Skin Structure Infections ( 1.6 ) Amoxicillin and Clavulanate Potassium for Oral Suspension: pediatric patients weighing less than 40 kg, and in adult and pediatric patients who cannot swallow tablets Urinary Tract Infections ( 1.7 ) Amoxicillin and Clavulanate Potassium for Oral Suspension: pediatric patients weighing less than 40 kg, and in adult and pediatric patients who cannot swallow tablets Limitations of Use ( 1.8 ) Therapy may be initiated before bacteriological results are available when beta-lactamase-producing pathogens are suspected. When results show susceptibility to amoxicillin alone, amoxicillin and clavulanate potassium for oral suspension should not be used. Usage to Reduce Development of Drug-Resistant Bacteria ( 1.9 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium for oral suspension and other antibacterial drugs, amoxicillin and clavulanate potassium for oral suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. 1.1 Lower Respiratory Tract Infections Amoxicillin and clavulanate potassium for oral suspension is indicated for the treatment of lower respiratory tract infection due to confirmed or suspected beta-lactamase producing Haemophilus influenzae and Moraxella catarrhalis as follows [see Clinical Pharmacology (12.4) , Clinical Studies (14.1) ] : Amoxicillin and Clavulanate Pot assi um for Oral Suspension: pediatric patients weighing less than 40 kg, and in adult and pediatric patients who cannot swallow tablets 1.3 Acute Bacterial Sinusitis Amoxicillin and clavulanate potassium for oral suspension are indicated for the treatment of acute bacterial sinusitis due to confirmed or suspected beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis as follows [see Clinical Pharmacology (12.4) , Clinical Studies (14.4) ]: Amoxicillin and Clavulanate Po tassi um for Oral Suspension: pediatric patients weighing less than 40 kg, and in adult and pediatric patients who cannot swallow tablets 1.4 Acute Bacterial Otitis Media Amoxicillin and clavulanate potassium for oral suspension is indicated for the treatment of acute bacterial otitis media due to confirmed or suspected beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis as follows [see Use in Specific Populations (8.4) , Clinical Studies (14.5) ] : Amoxicillin and Clavulanate Pot assi um for Oral Suspension: pediatric patients weighing less than 40 kg, and in adult and pediatric patients who cannot swallow tablets 1.6 Skin and Skin Structure Infections Amoxicillin and clavulanate potassium for oral suspension is indicated for the treatment of skin and skin structure infections due to confirmed or suspected beta-lactamase-producing S. …

125 mg/31.25 mg per 5 mL : White to off-white granular powder – Each 5 mL of reconstituted white to pale yellow, orange flavored suspension contains 125 mg of amoxicillin (as amoxicillin trihydrate) and 31.25 mg of clavulanic acid as the potassium salt. 250 mg/62.5 mg per 5 mL: White to off-white granular powder – Each 5 mL of reconstituted white to pale yellow, orange flavored suspension contains 250 mg of amoxicillin (as amoxicillin trihydrate) and 62.5 mg of clavulanic acid as the potassium salt. For Oral Suspension: 125 mg/31.25 mg per 5 mL and 250 mg/62.5 mg per 5 mL ( 3 )

How Supplied Amoxicillin and Clavulanate Potassium for Oral Suspension USP, 125 mg/31.25 mg per 5 mL is a white to off-white granular powder – Each 5 mL of reconstituted white to pale yellow, orange flavored suspension contains 125 mg of amoxicillin as the trihydrate and 31.25 mg of clavulanic acid as the potassium salt (equivalent to 37.23 mg of clavulanate potassium). Bottles of 75 mL NDC 59651-025-75 Bottles of 100 mL NDC 59651-025-01 Bottles of 150 mL NDC 59651-025-55 Amoxicillin and Clavulanate Potassium for Oral Suspension USP, 250 mg/62.5 mg per 5 mL is a white to off-white granular powder – Each 5 mL of reconstituted white to pale yellow, orange flavored suspension contains 250 mg of amoxicillin as the trihydrate and 62.5 mg of clavulanic acid as the potassium salt (equivalent to 74.5 mg of clavulanate potassium). Bottles of 75 mL NDC 59651-026-75 Bottles of 100 mL NDC 59651-026-01 Bottles of 150 mL NDC 59651-026-55 Storage Powder for Oral Suspension Store dry powder at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.] Reconstituted Oral Suspension Store reconstituted amoxicillin and clavulanate potassium for oral suspension in the original container under refrigeration. Discard unused reconstituted suspension after 10 days. A slight color change during storage is normal. [see Dosage and Administration (2.7) ] .

History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium or to other beta-lactams (e.g., penicillins and cephalosporins). ( 4.1 ) History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. ( 4.2 ) 4.1 Serious Hypersensitivity Reactions Amoxicillin and clavulanate potassium for oral suspension is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins). 4.2 Cholestatic Jaundice/Hepatic Dysfunction Amoxicillin and clavulanate potassium for oral suspension is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin/clavulanate potassium.

Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium for oral suspension if a reaction occurs and institute appropriate therapy. ( 5.1 ) Severe cutaneous adverse reactions (SCAR): Monitor closely. Discontinue if rash progresses. ( 5.2 ) Drug-induced enterocolitis syndrome (DIES) : Discontinue if DIES occurs and institute appropriate therapy. ( 5.3 ) Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. ( 5.4 ) Clostridioides difficile -associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. ( 5.5 ) Patients with mononucleosis: Increased risk of skin rash. Avoid amoxicillin and clavulanate potassium use in these patients. ( 5.6 ) 5.1 Serious Allergic Reactions, including Anaphylaxis Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. Amoxicillin and clavulanate potassium is contraindicated in patients with a history of serious hypersensitivity reactions to amoxicillin, clavulanate, or to other beta-lactam antibacterial drugs [see Contraindications (4.1) ] . If an allergic reaction occurs, discontinue amoxicillin and clavulanate potassium and institute appropriate therapy. 5.2 Severe Cutaneous Adverse Reactions (SCAR) Amoxicillin and clavulanate potassium 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 a skin rash, they should be monitored closely, and amoxicillin and clavulanate potassium discontinued if lesions progress. 5.3 Drug-Induced Enterocolitis Syndrome (DIES) Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of amoxicillin and clavulanate potassium for oral suspension [see Adverse Reactions (6.2) ] , with most cases occurring in pediatric patients . 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 and clavulanate potassium and institute appropriate therapy. 5.4 Hepatic Dysfunction Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and clavulanate potassium. Hepatotoxicity is usually reversible; however, deaths have been reported. These cases have generally been associated with serious underlying diseases or concomitant medications. Amoxicillin and clavulanate potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin and clavulanate potassium [see Contraindications (4.2) , Use in Specific Populations (8.7), Adverse Reactions (6.2) ] . 5.5 Clostridioides difficile -Associated Diarrhea (CDAD) Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, 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. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. 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 drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may 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. 5.6 Skin Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Avoid amoxicillin and clavulanate potassium use in patients with mononucleosis [see Adverse Reactions (6.2) ] . 5.7 Potential for Microbial Overgrowth The possibility of superinfections with mycotic or bacterial pathogens should be considered during therapy. If superinfections occur (commonly involving Pseudomonas spp. or Candida spp.), discontinue amoxicillin and clavulanate potassium and institute appropriate therapy. 5.8 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). Amoxicillin and clavulanate potassium for oral suspension contain aspartame which contains phenylalanine. Each 5 mL of the 125 mg/31.25 mg per 5 mL oral suspension contains 3.16 mg phenylalanine and each 5 mL of the 250 mg/62.5 mg per 5 mL oral suspension contains 6.31 mg phenylalanine. Before prescribing the amoxicillin and clavulanate potassium oral suspension to patients with PKU, consider the combined daily amount of phenylalanine from all sources, including amoxicillin and clavulanate potassium. …

The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Allergic Reactions, including Anaphylaxis [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) ] Hepatic Dysfunction [see Warnings and Precautions (5.4) ] Clostridioides difficile -associated diarrhea (CDAD) [see Warnings and Precautions (5.5) ] Skin Rash in Patients with Mononucleosis [see Warnings and Precautions (5.6) ] The most frequently reported adverse reactions with amoxicillin and clavulanate potassium for oral suspension were (incidence ≥3%) diarrhea/loose stools, nausea, skin rash, and urticaria. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. …

Concomitant use with probenecid is not recommended. ( 7.1 ) Concomitant use with oral anticoagulants may increase the prolongation of prothrombin time. ( 7.2 ) Concomitant use with allopurinol increases the risk of rash. ( 7.3 ) 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin and clavulanate potassium may result in increased and prolonged blood levels of amoxicillin. Co-administration 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. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. …