Clavam 375

Clavam 375 is a medicine used to treat infections and contains a combination of Amoxicillin 250mg+ clavulanic acid 125mg. It is an Antibiotic belonging to the Penicillin Derivatives /Beta-lactamase inhibitors. It is sold by Alkem Laboratories Ltd.

The combination of amoxicillin and clavulanic acid is used to treat certain infections caused by bacteria, including infections of the ears, lungs, sinus, skin, and urinary tract. Amoxicillin is in a class of medications called penicillin-like antibiotics. It works by stopping the growth of bacteria. Clavulanic acid is in a class of medications called beta-lactamase inhibitors.

Amoxicillin: It is rapidly and well absorbed from the gastrointestinal tract. Increased absorption and decreased gastrointestinal upset with food. The Bioavailability is approximately 70%. The Time to peak plasma concentration is about 1-2 hours. Via IV, Amoxicillin readily distributed into body tissues and fluids (e.g. gall bladder, abdominal or muscle tissues, skin, fat, synovial and peritoneal fluids, bile, pus) except the brain and CSF. It crosses placenta and enters breast milk. The Volume of distribution is approximately 0.3-0.4 L/kg. The Plasma protein binding is approximately 18%. It is Metabolised to a limited extent to form inactive penicilloic acid. Amoxicillin: It is excreted mainly via urine (approx 60-80% as unchanged drug). The Elimination half-life is approximately 1.3 hours.

Clavulanic acid: It is rapidly and well absorbed from the gastrointestinal tract. Decreased absorption with high-fat meals. The Bioavailability is approximately 70%. The Time to peak plasma concentration is about 1.5 hours. Via IV, Clavulanic acid is well distributed into body tissues and fluids (e.g., gall bladder, abdominal or muscle tissues, skin, fat, synovial and peritoneal fluids, bile, pus). Crosses placenta and enters breast milk. Volume of distribution: Approx 0.2 L/kg. Plasma protein binding: Approx 25%. It is extensively metabolised. It is excreted via urine (approx 25-40% as unchanged drug); faeces; expired air. The Elimination half-life is approximately 1 hour.

Clavam 375 shows common side effects like Diarrhea, upset stomach, vomiting, mild skin rash.

Clavam 375 is available in the form of Oral Tablet and Reconstituted Suspension.

Amoxicillin + clavulanic acid is available in India, US, UK, Singapore, Italy, France, Spain, Canada, China, Japan and Australia.

Clavam 375 (Amoxicillin 250mg+ clavulanic acid 125mg) is approved for use in the following clinical indications:

Adult indication

• Bite wound infection, prophylaxis or treatment
• Chronic obstructive pulmonary disease, acute exacerbation
• Diabetic foot infection
• Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure
• Neutropenic fever, low-risk cancer patients
• Odontogenic infection
• Otitis media, acute
• Peritonsillar cellulitis or abscess
• Pneumonia
• Rhinosinusitis, acute bacterial
• Streptococcus, chronic carriage
• Urinary tract infection

Pediatric indication

• Impetigo
• Otitis media, acute
• Pneumonia, community-acquired
• Rhinosinusitis, acute bacterial
• Streptococcus, group A; chronic carriage
• Urinary tract infections

Adult Dose

Clavam 375mg (Amoxicillin 250mg+ clavulanic acid 125mg) in adults and children ≥ 40 kg are recommended one tablet three times daily depending on the severity of the disease.

• Bite wound infection, prophylaxis, or treatment

Oral: Immediate release: 375 mg every 8 hours.

• Chronic obstructive pulmonary disease, acute exacerbation

Oral: Immediate release: 375 mg every 8 hours

Diabetic foot infection

Oral: Immediate release: 375 mg every 8 hours. Duration of therapy should be tailored to individual clinical circumstances; most patients with infection limited to skin and soft tissue respond to 1 to 2 weeks of therapy.

• Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure

Immediate release: Oral: 375 mg every 8 hours.

• Neutropenic fever, low-risk cancer patients

Oral: Immediate release: 375 mg every 8 hours.

Combine either dosing regimen with oral ciprofloxacin; continue until resolution of fever and neutropenia.

• Odontogenic infection

Oral: Immediate release: 375 mg every 8 hours

• Otitis media, acute

Immediate release: 375 mg every 8 hours.

Duration: 5 to 7 days for mild to moderate infection and 10 days for severe infection.

• Peritonsillar cellulitis or abscess

Oral: Immediate release: 375 mg every 8 hours to complete a total of 14 days of therapy.

• Pneumonia

Aspiration pneumonia (community-acquired [mild]):

Immediate release: Oral: 375 mg thrice daily.

Duration of therapy: Generally, 5 days.

Community-acquired pneumonia:

Immediate release: Oral: 375 mg 3 times daily as part of an appropriate combination regimen.

• Rhinosinusitis, acute bacterial

Standard dose: Oral: Immediate release: 375 mg every 8 hours for 5 to 7 days.

• Streptococcus, chronic carriage

Oral: Immediate release: 40 mg/kg/day in divided doses (eg, 375 mg every 8 hours) for 10 days.

• Urinary tract infection

Cystitis, acute uncomplicated or acute simple cystitis (infection limited to the bladder without signs/symptoms of upper tract, prostate, or systemic infection) : Oral: Immediate release: 375 mg thrice daily for 5 to 7 days.

Urinary tract infection, complicated (including pyelonephritis) : Oral: Immediate release: 375 mg thrice daily for 10 to 14 days; for patients with symptomatic improvement within the first 48 to 72 hours of therapy, some experts recommend shorter courses of 7 to 10 days.

Pediatric Dose

Children weighing < 40 kg: Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations. 20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day given in three divided doses.

Children may be treated with Clavam tablets, suspensions, or pediatric sachets.

Children weighing less than 25 kg must not be treated with Clavam tablets, as tablets cannot be divided.

The recommended dose of Clavam is 30 mg/kg/day divided every 12 hours. Children aged 6 years and below or weighing less than 25 kg should preferably be treated with Clavam suspension or pediatric sachets (200 mg/5 mL and 400 mg/5 mL).

Clavam 375 (Amoxicillin 250mg+ clavulanic acid 125mg) is available in the form of Oral tablet and Reconstituted Suspension.

• Dosage Adjustment in Kidney Patient

Oral:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl 10 to <30 mL/minute: 250 to 500 mg every 12 hours.

CrCl <10 mL/minute: 250 to 500 mg every 12 to 24 hours.

IV:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl 10 to 30 mL/minute: Initial: 1 g followed by 500 mg every 12 hours.

CrCl <10 mL/minute: Initial: 1 g followed by 500 mg every 12 to 24 hours.

Clavam 375 (Amoxicillin 250mg+ clavulanic acid 125mg) is contraindicated in patients with:

• Serious Hypersensitivity Reactions

Clavam 375 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).

• Cholestatic Jaundice/Hepatic Dysfunction

Clavam 375 is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Clavam 375.

• Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including Clavam 375. These Clavam 375 PLR Master 8 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 Clavam 375 careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, Clavam 375 should be discontinued, and appropriate therapy instituted.

• Hepatic Dysfunction

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of Clavam 375. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.

• Clostridium difficile Associated Diarrhea (CDAD)

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Clavam 375, 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 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. 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.

• Skin Rash in Patients with Mononucleosis

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, Clavam 375 should not be administered to patients with mononucleosis.

• Potential for Microbial Overgrowth

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin/clavulanate potassium should be discontinued and appropriate therapy instituted.

• Phenylketonurics

Clavam 375 Chewable tablets and Clavam 375 Powder for Oral Solution contain aspartame which contains phenylalanine. Each 200-mg chewable tablet of Clavam 375 contains 2.1 mg phenylalanine; each 400-mg chewable tablet contains 4.2 mg phenylalanine; each 5 mL of either the 200 mg/5 mL or 400 mg/5 mL oral suspension contains 7 mg phenylalanine. The other formulations of Clavam 375 does not contain phenylalanine.

• Development of Drug-Resistant Bacteria

Prescribing Clavam 375 in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

• Common

Diarrhea, Candidal diaper rash, diaper rash, skin rash, urticaria, Nausea, vomiting, Vaginal mycosis, vaginitis, Candidiasis.

• Rare

Abdominal distress, flatulence, Thrombocytosis, Headache.

Probenecid

Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with Clavam 375 may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended.

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 Clavam 375. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

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

Oral Contraceptives Clavam 375 may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

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 Clavam 375, 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.

The common side effects of Clavam 375include the following:

• Common side effects

Diarrhea, upset stomach, vomiting, mild skin rash.

• Rare side effects

Severe skin rash, itching, hives, difficulty breathing or swallowing, wheezing, vaginal itching and discharge, and yellowing of the skin or eyes.

• Pregnancy

Pregnancy Category B

Teratogenic Effects

Reproduction studies performed in pregnant rats and mice given Clavam 375 (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 Clavam 375. 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.

• 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.

• Pediatric Use

The safety and effectiveness of Clavam 375 Powder for Oral Suspension and Chewable Tablets have been established in pediatric patients. Use of Clavam 375 in pediatric patients is supported by evidence from studies of Clavam 375Tablets in adults with additional data from a study of Clavam 375Powder for Oral Suspension in pediatric patients aged 2 months to 12 years with acute otitis media. 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 Clavam 375 should be modified in pediatric patients aged <12 weeks (<3 months).

• Geriatric Use

Of the 3,119 patients in an analysis of clinical studies of Clavam 375, 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.

Symptoms: Gastrointestinal effects (e.g. stomach or abdominal pain, vomiting, and diarrhea), rash, hyperactivity, drowsiness, fluid and electrolyte imbalance, crystalluria resulting in renal failure, and convulsions (in patients with renal impairment).

Management: Symptomatic and supportive treatment. Focus on water/electrolyte balance.

Pharmacodynamic

Amoxicillin, a semi-synthetic penicillin, inhibits bacterial cell wall synthesis by binding to 1 or more of the penicillin-binding proteins (PBPs), thereby blocking the final transpeptidation step of peptidoglycan synthesis in the bacterial cell walls. It is susceptible to degradation by β-lactamases which are produced by certain resistant bacteria.

Clavulanic acid, a β-lactam structurally related to penicillin, binds, and inhibits β-lactamases, thereby preventing amoxicillin inactivation and expands the amoxicillin spectrum of activity. It does not exert clinically significant antibacterial effect alone.

Pharmacokinetics

• Absorption

Amoxicillin: It is rapidly and well absorbed from the gastrointestinal tract. Increased absorption and decreased gastrointestinal upset with food. The Bioavailability is approximately 70%. The Time to peak plasma concentration is about 1-2 hours.

Clavulanic acid: It is rapidly and well absorbed from the gastrointestinal tract. Decreased absorption with high-fat meals. The Bioavailability is approximately 70%. The Time to peak plasma concentration is about 1.5 hours.

• Distribution

Amoxicillin: Via IV, Amoxicillin readily distributed into body tissues and fluids (e.g. gall bladder, abdominal or muscle tissues, skin, fat, synovial and peritoneal fluids, bile, pus) except the brain and CSF. It crosses placenta and enters breast milk. The Volume of distribution is approximately 0.3-0.4 L/kg. The Plasma protein binding is approximately 18%.

Clavulanic acid: Via IV, Clavulanic acid is well distributed into body tissues and fluids (e.g., gall bladder, abdominal or muscle tissues, skin, fat, synovial and peritoneal fluids, bile, pus). Crosses placenta and enters breast milk. Volume of distribution: Approx 0.2 L/kg. Plasma protein binding: Approx 25%.

• Metabolism

Amoxicillin: Metabolized to a limited extent to form inactive penicilloic acid.

Clavulanic acid: It is extensively metabolized.

• Excretion

Amoxicillin: It is excreted mainly via urine (approx 60-80% as unchanged drug). The Elimination half-life is approximately 1.3 hours.

Clavulanic acid: It is excreted via urine (approx 25-40% as unchanged drug); faeces; expired air. The Elimination half-life is approximately 1 hour.

Therapeutic benefits of Amoxicillin + clavulanic acid Combination

Clavam 375 is a combination of Amoxicillin and Clavulanic acid. Clavam 375 belongs to the group of medicines called antibiotics. Clavam 375 is used to treat bacterial infections of the ear, nose, throat, skin, bone, soft tissue, joints, urinary tract, and respiratory tract. Amoxicillin works by preventing the formation of bacterial cell covering, which is necessary for the survival of the bacteria. Thereby, kills the bacteria. Clavulanic acid works by decreasing bacterial resistance and enhancing the activity of amoxicillin against the bacteria. Together, Clavam 375 helps in treating bacterial infections. Clavam 375 is a broad-spectrum antibiotic that is effective against both gram-positive and gram-negative bacteria.

Clavam 375 is a combination of Amoxicillin and Clavulanic acid. Amoxicillin works by preventing the formation of bacterial cell covering, which is necessary for the survival of the bacteria. Thereby, it kills the bacteria. Clavulanic acid works by decreasing bacterial resistance and enhancing the activity of amoxicillin against the bacteria. Together, Clavam 375 helps in treating bacterial infections.