Amoxicillin and Clavulanate Potassium for Oral Suspension and Tablets.
For the use only of a Registered Medical Practitioner or a hospital or a Laboratory.
AMCLAVIN 156.25 Oral Suspension
Each 5mI of reconstituted suspension contains:
Amoxicillin Trihydrate BP
equivalent to Amoxicillin 125 mg
Diluted Potassium Clavulanate BP
equivalent to Clavulanic Acid 31.25 mg
In a flavoured syrupy base.
AMCLAVIN – 375 Tablets
Each film coated tablet contains:
Amoxicillin Trihydrate USP equivalent to Amoxicillin 250mg
Diluted Potassium Clavulanate BP
equivalent to Clavulanic Acid 125mg
Colour: Titanium Dioxide BP
AMCLAVIN – 312.5 Oral suspension
Each 5ml of reconstituted suspension contains:
Amoxicillin Trihydrate BP equivalent to Amoxicillin 250 mg Diluted Potassium Clavulanate BP
equivalent to Clavulanic Acid 62.5 mg
In a flavoured syrupy base.
AMCLAVIN 625 Tablets
Each film coated tablet contains:
Amoxicillin Trihydrate USP equivalent to Amoxicillin 500 mg Diluted Potassium
Clavulanate BP equivalent to Clavulanic Acid 125 mg
Colour: Titanium Dioxide BP
Amclavin is an oral antibacterial combination consisting of the semisynthetic antibiotic Amoxicillin and the beta-lactamase inhibitor potassium Clavulanate providing a broad spectrum of antibacterial activity against beta-lactamase producing bacteria. Amoxicillin is chemically designated as (6R)-6-(ᾳ-4- hydroxypheny-D-glycylamino) penicillanic acid trihydrate. Its molecular formula is C16H19N3O5S.3H2O and its molecular weight is 419.45.
Clavulanate Potassium is chemically designated as Potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1azabicyclo[3.20] heptane-2-carboxylate. Its molecular formula is C8H8KNO5 and its molecular weight is 237.25.
Mechanism of Action
Amoxicillin acts through inhibition of biosynthesis of the bacterial cell wall mucopeptide. Antibacterial Spectrum Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative micro-oganisms.
Amoxicillin is, however, susceptible to degradation by β-lactamase and, therefore the spectrum of activity does not include organisms, which produce these enzymes.
Clavulanic acid is a β-lactam, structurally related to the Penicillins, which possesses the ability to inactivate a wide range of (β-lactamase enzymes commonly found in a micro-organisms resistant to Penicillins and cephas.
In particular, it has good activity against the clinically important plasmid mediated β-lactamases frequently responsible for transferred drug resistance.
The formulation of Amoxicillin and Clavulanic acid in Amclavin protects Amoxicillin from degradation by B-lactamase enzymes and effectively extends the antibiotic spectrum of Amoxicillin to include many bacteria normally resistant to Amoxicillin and other β-lactam antibiotics. Thus, co-amoxiclav possesses the properties of a broad-spectrum antibiotic and a β-lactamase inhibitor. Amoxicillin/Clavulanic acid has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections (see INDICATIONS).
Staphylococcus aureus (β-lactamase and non β-lactamase producing).
Staphylococci, which are resistant to Methicillln/Oxacillin must be considered resistant to Amoxicillin/Clavulanic acid.
Enterobacter species (Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with Amclavin in urinary tract infections caused by these organisms.) Escherichia coli (β-lactamase and non-a β lactamase producing) Haemophilus influenzae (β -lactamase and non- β -lactamase producing).
Klebsiella species (All known strains are β -Iactamase producing).
Moraxella catarrhalis (β -lactamase and non- β-lactamase producing).
The following in vitro data are available. But their clinical significance is unknown.
Amoxicillin/Clavulanic acid exhibits in vitro minimal inhibitory concentrations (MICs) of 2µg/ml or less against most (≥90%) strains of Streptococcus pneumoniae, MICs of 0.06 mg/ml or less against most (≥90%) strains of Neisseria gonorrhoeae; MICs of 4µg/ml or less against most (≥90%) strains of staphylococci and anaerobic bacteria; and MIC’s of 8µg/ml or less against most (≥90%) strains of other listed organisms. However, with the exception of organisms shown to respond to Amoxicillin alone. The safety and effectiveness of Amoxicillin/Clavulanic acid in treating clinical infections due to these micro-organisms have not been established in adequate and well-controlled clinical trials.
Because Amoxicillin has greater in vitro activity against Streptococcus pneumoniae than does Ampicillin or Penicillin, the majority of S. Pneumoniae strains with intermediate susceptibility to Ampicillin or Penicillin are fully susceptible to Amoxicillin.
GRAM POSITIVE AEROBES
Enterococcus faecalis, Staphylococcus epidermidis (β-lactamase and non-β-lactamase producing)Staphylococcus saprophyticus (β-lactamase and non-β-lactamase producing) Streptococcus pneumoniae, Streptococcus pyogenes viridans group Streptococcus.
GRAM NEGATIVE AEROBES
Eikenella corrodens (β-lactamase and non-β-lactamase producing) Neisseria gonorrhoeae (β-lactamase and non-β-lactamase producing) Proteus mirabilis (β-lactamase and non-β-lactamase producing).
ANAEROBIC BACTERIA Bacteroidos species including Bacteroides fragilis (β-lactamase and non β-lactamase producing) Fusobacterium species (β-lactamase and non-β-lactamase producing) Peptostreptococcus species. Adequate and well-controlled clinical trials have established the effectiveness of Amoxicillin alone in treating certain clinical infections due to these organisms.
These are non-β-lactamase-producing organism and, therefore, are susceptible to Amoxicillin alone.
Amoxicillin and Clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Amclavin. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of Amoxicillin. While Amclavin can be given without regard to meals, absorption of Clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of Clavulanate was reduced when Amclavin was dosed at 30 and 150 minutes after the start of a high fat breakfast.
The safety and efficacy of Amclavin have been established in clinical trials where Amclavin was taken without regard to meals. Amoxicillin serum concentrations achieved with Amclavin are similar to those produced by the oral administration of equivalent doses of Amoxicillin alone. The half-life of Amoxicillin after the oral administration of Amclavin is 1.3 hours and that of clavulanic acid is 1.0 hour.
Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like Amoxicillin, is well distributed in body tissues. Neither component in Amclavin is highly protein-bound; clavulanic acid has been found to be approximately 25% found to human serum and Amoxicillin approximately 18% found. Approximately 50% to 70% of the Amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single Amclavin 625 or Amclavin 375 tablet.
Amclavin is indicated for the treatment of following Infections caused by susceptible pathogens:
Lower respiratory tract infections (e.g., Pneumonia, bronchitis)
Acute otitis media
Urinary tract Infections
Skin and soft tissue infections
Bone and joint infections
DOSAGE AND ADMINISTRATION: (As directed by the physician)
While Amclavin Is indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to Amclavin treatment due to its Amoxicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and β-lactamase-producing organisms susceptible to Amclavin should not require the addition of another antibiotic. Because Amoxicillin has greater in vitro activity against Streptococcus pneumoniae than does Ampicillin or Penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to Ampicillin or Penicillin are fully susceptible to Amoxicillin and Amclavin (see Antibacterial Spectrum).
Bacteriological studies, to determine the causative organisms and their susceptibility to Amclavin, should be performed together with any indicated surgical procedures. Therapy may be instituted prior to obtaining the results from bacteriological and susceptibility studies to determine the causative organisms and their susceptibility to Amclavin when there is reason to believe the infection may involve any of the β-lactamase-producing organisms listed above. Once the results are known, therapy should be adjusted, if appropriate.
Pediatric Patients: Based on the Amoxicillin component, Amclavin should be dosed as follows:
Neonates and Infants aged < 12weeks (3 months):
Due to incompletely developed renal function affecting elimination of Amoxicillin in this age group, the recommended dose of Amclavin is 30mg/kg/day divided q 12th based on the Amoxicillin component. Clavulanate elimination is unaltered in this age group.
Premature: No dosage recommendations can be made for this category.
Children 3-9 months: 1.25mL of AMCLAVIN 156.25 Oral Suspension three times a day.
Children 9 months – 2 years: 2.5mL of AMCLAVIN 156.25 Oral Suspension three times a day.
Children 2-6 years: 5mL of AMCLAVIN 156.25 Oral Suspension three times a day. In severe infections this may be increased to 10mI AMCLAVIN 156.25 Oral Suspension three times a day.
Children 7-12 years: 5mL of AMCLAVIN 312.5 Oral Suspension three times daily. In severe infections this may be increased to 10mL of AMCLAVIN 312.5 Suspension three times a day.
Adults: Adult who have difficulty in swallowing may be given the Amclavin 156.25 or Amclavin 312.5 Oral Suspension in place of the Amclavin 625 tablet.
Since both AMCLAVIN 375 & AMCLAVIN 625 tablets contain the same amount of Clavulanic acid (125 mg, as the potassium salt), two tablets of AMCLAVIN 375 are not equivalent to one tablet of AMCLAVIN 625; therefore, two tablets of AMCLAVIN 375 should not be substituted for one tablet of AMCLAVIN 625.
Adults: The usual adult dose is one tablet of AMCLAVIN 625 every 12 hours or one tablet of AMCLAVIN 375 every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one tablet of AMCLAVIN 625 every 8 hours.
Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Severely impaired patients with a glomerular filtration rate of <30 mL/min should not receive the 875 mg tablet. Patients with a glomerular filtration rate of 10 to 30 mL/min should receive AMCLAVIN 625 or AMCLAVIN 375 every 12 hours, depending on the severity of the infection. Patients with a less than 10 mL/min glomerular filtration rate should receive AMCLAVIN 625 or AMCLAVIN 375 every 24 hours, depending on severity of the infection.
Hemodialysis patients should receive AMCLAVIN 625 or AMCLAVIN 375 every 24 hours, depending on severity of the Infection. They should receive an additional dose both during and at the end of dialysis.
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals. (See WARNINGS).
Pediatric Patients: Pediatric patients weighing 40 kg or more should be dosed according to the adult recommendations, due to the different Amoxicillin to clavulanic acid ratios in the 375 mg tablet of AMCLAVIN (250/125), it should not be used until the pediatric patient weighs at least 40 kg or more.
Administration: AMCLAVIN may be taken without regard to meals; however, absorption of Clavulanate potassium is enhanced when AMCLAVIN is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, AMCLAVIN should be taken at the start of a meal.
DIRECTIONS FOR USE
Do not chew, swallow with Water.
While Amclavin possesses the characteristic low toxicity of the Penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic and hematopoietic function, is advisable during prolonged therapy. A high percentage of patients with mononucleosis who receive Ampicillin develop an erythematous skin rash. Thus, Ampicillin class antibiotics should not be administered to patients with infectious mononucleosis.
The possibility of super-infections with mycotic or bacterial pathogens should be kept in mind during therapy. If super-infections occur (usually involving Pseudomonas or Candida), the drug should be discontinued and appropriate therapy instituted.
Serious and occasionally fatal hypersensitivity (Anaphylactic) reactions have been reported in patients Penicillin therapy. 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 Amclavin, careful inquiry should be made concerning previous hypersensitivity reactions to Penicillins, Cephalosporins or other allergens. If an allergic reaction occurs, Amclavin should be discontinued and appropriate therapy instituted.
Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, Intravenous steroids and airway management, including intubation, should also be administered as indicated.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Amclavin, and has ranged in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic associated colitis.
After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
Amclavin should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of Amclavin is usually reversible. On rare occasions, deaths have been reported (less than 4 death reported per estimated 4 million prescriptions worldwide). These have been generally cases associated with serious underlying diseases or concomitant medications (see contraindications and Adverse Reactions).
Amclavin is contraindicated in patients with a history of allergic reactions to any Penicillin. It is also contraindicated in patients with a previous history of Amclavin -associated cholestatic jaundice/hepatic dysfunction.
Carcinogenicity/Mutagenicity//Impairment of Fertility
Long-term carcinogenicity studies in animals have not been performed to evaluate carcinogenic potential.
The mutagenic potential of Amoxicillin and Clavulanate potassium combination was investigated in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All were negative apart from the in vitro mouse lymphoma assay where weak activity was found at very high, cytotoxic concentrations.
Amclavin at oral doses of up to 1200mg/kg/day (5.7 times the maximum human dose. 1480 mg/m2/day, based on body surface area) was found to have no effect on fertility and reproductive performance in rates, dosed with a 2:1 ration formulation of Amoxicillin: Clavulanate.
There are not adequate and well-controlled studies in pregnant women. Reproduction studies performed in pregnant rats and mice given Amclavin at oral dosages up to 1200mg/kg/day, equivalent to 7200 and 4080 mg/m2/day, respectively (4.9 and 2.8 times the maximum human oral dose based on body surface area) revealed no evidence of harm to the fetus due to Amclavin. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery
The use of Amclavin in humans during labor or delivery has immediate or delayed adverse effects on the foetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary. In a single study in women with premature rupture of fatal membranes, it was reported that prophylactic treatment with Amclavin may be associated with an increased risk of necrotizing enterocolitis in neonates.
Amclavin are excreted in the milk; therefore, caution should be exercised when Amclavin is administered to a nursing woman.
Pediatric patients above 12 years of age should be dosed according to adult recommendation (see DOSAGE & ADMINISTRATION).
Amclavin have been used in geriatric patients and no geriatrics-specific problems have been documented to date. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment in dosage in patients receiving Amclavin.
Probenecid decreases the renal tubular secretion of Amoxicillin. Concurrent use with Amclavin may result in increased and prolonged blood levels of Amoxicillin. Co-administration of Probenecid cannot be recommended. There are no data with Amclavin and Allopurinol administered concurrently.
In common with other broad-spectrum antibiotics, Amclavin may reduce the efficacy of oral contraceptives.
Drug/Laboratory Test interactions
Oral administration of Amclavin will result in high urine concentrations of Amoxicillin. High urine concentrations of Amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using a standardized self-heating method for quantitative determination of urine sugar by copper reduction, or Benedict’s Solution or Fehlirig’s Solution. Since this effect occurs with Amoxicillin and therefore Amclavin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
Following administration of Amoxicillin to pregnant women may cause transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone and estradiol . This effect may occurs with Amoxicillin and therefore Amclavin.
Amclavin is generally well tolerated. The majority of side effects observed in clinical trials were of a mild and transient nature and >3% of patients discontinued therapy because of drug-related side effects. The most frequently reported adverse effects were diarrhea/ loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). The overall incidence of side effects, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported reactions include: abdominal discomfort, flatulence and headache.
The following adverse reactions have been reported for Amoxicillin class antibiotics: Gastrointestinal: Diarrhea, nausea, vomiting, 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).
Skin rashes, pruritius, urticaria, angioedema, serum sickness- like reactions (urticaria or skin rash accompanied by arthritis, arthraigia, myalgia and frequently fever), erythema multiforme (rarely Stevens-Johnson syndrome), acute generalized exanthematous pustulosis and an occasional case of exfoliative dermatitis (Including toxic epidermal necrolysis) have been reported. These reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, the drug should be discontinued, unless the opinion of the physician dictates otherwise serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with oral Penicillin (see Warnings).
Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin class antibiotics but the significance of these findings is unknown. Hepatic dysfunction, including increases in serum transaminases (AST and/or ALT), serum bilirubin and/or alkaline phosphatase, has been infrequently reported with Amclavin. It has been reported more commonly in the elderly, in males, or in patients or 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. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications.
Renal: Interstitial nephritis and hematuria have been reported rarely.
Hemic and Lymphatic Systems
Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopania and agranulocytosis have been reported during therapy with Penicillins. These reactions are usually reversible on discontinuations of therapy and are believed to be hypersensitivity phenomena. A slight thrombocytosis was noted in less than 1% of the patients treated with Amclavin. There have been reports of increased prothrombin time in patients receiving and anticoagulant therapy concomitantly.
Central Nervous System
Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported rarely.
Tooth discoloration has been reported very rarely in children. Good hygiene may help to prevent tooth discoloration as it can usually be removed by brushing.
Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients. In the case of overdosage, discontinue Amclavin, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison center suggested that overdosages of less than 250 mg/kg of Amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying. Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with Amoxicillin. 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 both Amoxicillin and Clavulanate.
Both Amoxicillin and Clavulanate are removed from the circulation by hemodialysis (see DOSAGE AND ADMINISTRATION).
AMCLAVIN ORAL SUSPENSION: Store in a cool and dry place, below 25°C. Protect from light.
AMCLAVIN TABLETS: Store in a cool and dry place, below 25°C. Protect from light.
Keep all medicines away from Children.
AMCLAVIN 312.5 Oral Suspension
AMCLAVIN 156.25 Oral Suspension
AMCLAVIN 625 Tablets
AMCLAVIN 375 Tablets
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