Clavokor 457mg Dry Syrup/ 375 mg dispersible Tablet

Manufacturer

Medicef

Marketing in India

Koronis Pharmaceutical Private Limited

Contents

Co-amoxiclav: Amoxycillin and clavulanic acid.

Indications

See Microbiology under Actions for a comprehensive list of sensitive organisms.
Oral: For short-term treatment of bacterial infections at the following sites: Upper respiratory tract infections (including ENT) eg, recurrent tonsillitis, sinusitis, otitis media; lower respiratory tract infections eg, acute and chronic bronchitis (especially if considered severe), lobar and bronchopneumonia; genitourinary tract infections eg, cystitis (especially when recurrent or complicated, excluding prostatitis), urethritis, pyelonephritis; skin and soft tissue infections eg, boils, abscesses, cellulitis, wound infections, animal bites; bone and joint infections eg, osteomyelitis; dental infections eg, dentoalveolar abscess with spreading cellulitis; other infections eg, septic abortion, puerperal sepsis, intra-abdominal sepsis.
IV: Prophylaxis against infection which may be associated with major surgical procedures eg, gastrointestinal, pelvic, head and neck, cardiac, renal, joint replacement and biliary tract.
Mixed infections caused by amoxycillin-susceptible organisms in conjunction with Clavokor -susceptible β-lactamase-producing organisms may be treated with Clavokor 457-mg/5 mL suspension/ dry syrup. These infections should not require the addition of another antibiotic resistant to β-lactamases.

Dosage & Administration

Tablet: Usual Dosages for the Treatment of Infection: Adults and Children >12 years:Mild to Moderate Infections: One 375-mg tablet 3 times daily or one 625-mg tablet twice daily. Severe Infections: Two 375-mg tablet 3 times daily or one 1-g tablet twice daily.
Dental Infections (eg, dentoalveolar abscess): One 375-mg tablet 3 times daily or one 625-mg tablet 2 times a day for 5 days.
Renal Impairment: Adults: Clavokor 1-g tablet should only be used in patients with a glomerular filtration rate of >30 mL/min.
Mild Impairment [creatinine clearance (CrCl) >30 mL/min]: No change in dosage (ie, either one 625-mg tablet twice daily or one 1-g tablet twice daily).Moderate Impairment (CrCl 10-30 mL/min):One 625-mg tablet twice daily. The 1-g tablet should not be administered. Severe Impairment (CrCl <10 mL/min): Not more than one 375-mg tablet 12 hourly or one 625-mg tablet every 24 hrs.
Hepatic Impairment: Dose with caution; monitor hepatic function at regular intervals.
Each 375-mg tablet contains 0.63 mmol (25 mg) of potassium.
156-mg/5 mL Syrup: Usual Dosages for the Treatment of Infection: Usual Recommended Daily Dosage: 25 mg/kg/day* in divided doses every 8 hrs. Children 1-6 years (10-18 kg): 5 mL 3 times a day; <1 year: 25 mg/kg/day**, for example a 7.5-kg child would require 2 mL 3 times a day.
In more serious infections, the dosage may be increased up to 50 mg/kg/day in divided doses every 8 hrs.
Note: *Each 25-mg Clavokor provides amoxycillin 20 mg and clavulanic acid 5 mg.
457-mg/5 mL Suspension: Usual Recommended Daily Dosage: Mild to Moderate Infections (Upper Respiratory Tract Infections eg, Recurrent Tonsillitis, Lower Respiratory Infections and Skin and Soft Tissue Infections): 25/3.6 mg/kg/day. Children >2 years: 25/3.6 mg/kg/day: Children 7-12 years (22-40 kg): 5 mL twice daily; 2-6 years (13-21 kg): 2.5 mL twice daily.
More Serious Infections (upper respiratory tract infections eg, otitis media and sinusitis, lower respiratory tract infections eg, bronchopneumonia and urinary tract infections): 45/6.4 mg/kg/day.
Children 7-12 years: 10 mL twice daily; 2-6 years (13-21 kg): 5 mL twice daily.
Children 2 months to 2 years: Children <2 years should be dosed according to body weight.

There is insufficient experience with 457 mg/5 mL suspension to make dosage recommendations for children <2 months.
Infants with Immature Kidney Function: 457 mg/5 mL suspension is not recommended.
Renal Impairment: For children with GFR of >30 mL/min, no adjustment in dosage is required. For children with a GFR of <30 mL/min, 457 mg/5 mL suspension is not recommended.
Hepatic Impairment: Dose with caution; monitor hepatic function at regular intervals. There is, as yet, insufficient evidence on which to base a dosage recommendation.
Vial: Infection: Adults and Children >12 years: Usually 1.2 g 8 hourly. In more serious infections, increase frequency to 6-hourly intervals. Children 3 months-12 years: Usually 30 mg/kg* 8 hourly. In more serious infections, increase frequency to 6-hourly intervals; 0-3 months: 30 mg/kg* every 12 hrs in premature infants and in full-term infants during the perinatal period, increasing to 8 hrs thereafter.
Note: *Each 30-mg Clavokor contains amoxycillin 25 mg and clavulanic acid 5 mg.
Therapy can be started parenterally and continued with an oral preparation.
Surgical Prophylaxis: Adults: Usual Dose: 1.2 g given at the induction of anaesthesia. Operations where there is a high risk of infection eg, colorectal surgery may require 3, and up to 4, doses of 1.2 g in a 24-hr period. These doses are usually given at 0, 8, 16 (and 24) hrs. This regimen can be continued for several days if the procedure has a significantly increased risk of infection.
Clear clinical signs of infection at operation will require a normal course of IV or oral Clavokor therapy postoperatively.
Children: Similar reductions in dosage should be made.
Renal Impairment: Adults: Mild Impairment (creatinine clearance >30 mL/min): No change in dosage. Moderate Impairment (creatinine clearance 10-30 mL/min): 1.2 g IV immediately, followed by 600 mg IV 12 hourly. Severe Impairment (creatinine clearance <10 mL/min): 1.2 g IV immediately, followed by 600 mg IV 24 hourly. Dialysis decreases serum concentrations of Clavokor and an additional 600 mg IV dose may need to be given during dialysis and at the end of dialysis.
Hepatic Impairment: Dose with caution; monitor hepatic function at regular intervals.
Each 1.2-g vial contains 1 mmol of potassium and 3.1 mmol of sodium (approximately).
Administration: Tablet/Syrup : To minimise potential gastrointestinal intolerance, administer at the start of a meal. The absorption of Clavokor is optimised when taken at the start of a meal. Duration of therapy should be appropriate to the indication and should not exceed beyond 14 days without review. Therapy can be started parenterally and continued with an oral preparation.
Clavokor 1-g tablets should be swallowed whole without chewing. If required, tablets may be broken in half and swallowed without chewing.
Vial: Clavokor IV may be administered either by IV injection or by intermittent infusion. It is not suitable for IM administration.
Instructions for Use/Handling: 156 mg suspension: At time of dispensing, the dry powder should be reconstituted to 92 mL of water, added to the reconstitute to form a final volume of 100 mL reconstituted oral suspension.
Vial: To reconstitute 600-mg and 1.2-g vial, dissolve in 10- and 20- mL Water for Injections BP (final volume 10.5 and 20.9 mL), respectively.
A transient pink coloration may appear during reconstitution. Reconstituted solutions are normally, a pale, straw colour.
IV Injection: The stability of Clavokor IV solution is concentration-dependent, thus it should be used immediately upon reconstitution and given by slow IV injection over a period of 3-4 min. It should be used within 20 min of reconstitution. It may be injected directly into a vein or via a drip tube.
IV Infusion: Alternatively, Clavokor IV may be infused in water for injections BP or 0.9% w/v sodium chloride IV injection. Add, without delay (solutions should be made up to full infusion volume immediately after reconstitution), 600 mg reconstituted solution to 50 mL infusion fluid or 1.2 g reconstituted solution to 100 mL infusion fluid (eg, using a mini-bag or in-line burette). Infuse over 30-40 min and complete within 4 hrs of reconstitution. For other appropriate infusion fluids, see Cautions For Usage.
Any residual antibiotic solutions should be discarded.
Therapy can be started parenterally and continued with an oral preparation. Treatment should not be extended beyond 14 days without review.

Overdosage

Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Gastrointestinal symptoms may be treated symptomatically with attention to the water electrolyte balance.
Amoxycillin crystalluria, in some cases leading to renal failure, has been observed (see Precautions).
Clavokor can be removed from the circulation by haemodialysis.
375 mg tablet/156 mg syrup: Amoxycillin crystalluria, in some cases leading to renal failure, has been observed.
IV: Amoxycillin has been reported to precipitate in bladder catheters after intravenous administration of large doses. A regular check of patency should be maintained.

Contraindications

History of hypersensitivity to β-lactams eg, penicillins and cephalosporins.
Previous history of Clavokor-associated jaundice/hepatic dysfunction.

Special Precautions

Before initiating therapy with Clavokor, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.
Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity (see Contraindications).
Clavokor should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxycillin.
Prolonged use may also occasionally result in overgrowth of nonsusceptible organisms.
Prolongation of prothrombin time has been reported rarely in patients receiving Clavokor. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly.
Changes in liver function tests have been observed in some patients receiving Clavokor. The clinical significance of these changes is uncertain, but Clavokor should be used with caution in patients with evidence of hepatic dysfunction.
Cholestatic jaundice, which may be severe, but is usually reversible, has been reported rarely. Signs and symptoms may not become apparent for up to 6 weeks after treatment has ceased.
In patients with renal impairment, dosage should be adjusted as recommended under Dosage & Administration; 457-mg/5 mL suspension, however, is not recommended.
Clavokor 457-mg/5 mL suspension contains 12.5 mg aspartame per 5-mL dose and therefore care should be taken in patients with phenylketonuria.
Prolongation of bleeding time and prothrombin time have been reported in some patients receiving Clavokor. Clavokor should be used with care in patients on anti-coagulation therapy. In common with other broad-spectrum antibiotics, Clavokor may reduce the efficacy of oral contraceptives and patients should be warned accordingly.
If the parenteral administration of high doses is necessary, the sodium content must be taken into account in patients on sodium-restricted diet.
In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During administration of high doses of amoxycillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxycillin crystalluria (see Overdosage). The presence of clavulanic acid in Clavokor may cause a nonspecific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.
Effects on the Ability to Drive or Operate Machinery: Adverse effects on the ability to drive or operate machinery have not been observed.
Use in pregnancy & lactation: Reproduction studies in animals (mice and rats) with orally and parenterally administered Clavokor have shown no teratogenic effects. In a single study in women with preterm, premature rupture of the foetal membrane (pPROM), it was reported that prophylactic treatment with Clavokor may be associated with an increased risk of necrotising enterocolitis in neonates. As with all medicines, use should be avoided in pregnancy, especially during the 1st trimester, unless considered essential by the physician.
Clavokor may be administered during the period of lactation. With the exception of the risk of sensitisation associated with the excretion of trace quantities in breast milk, there are no detrimental effects for the infant.
Use in children: Clavokor tablet is not recommended in children ≤12 years.

Adverse Drug Reactions

Data from large clinical trials were used to determine the frequency of very common to rare adverse effects. The frequencies assigned to all other adverse effects (ie, those occurring at <1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency.
The following convention has been used for the classification of frequency: Very common (>1/10); common (>1/100 and <1/10); uncommon (>1/1000 and <1/100); rare (>1/10,000 and <1/1000); very rare (<1/10,000).
Infections and Infestations: Common: Mucocutaneous candidiasis.
Blood and Lymphatic System Disorders: Rare: Reversible leucopenia (including neutropenia) and thrombocytopenia. Very Rare: Reversible agranulocytosis and haemolytic anaemia. Prolongation of bleeding time and prothrombin time (see Precautions).
Immune System Disorders: Very Rare: Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis.
Nervous System Disorders: Uncommon: Dizziness, headache. Very Rare: Reversible hyperactivity and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.
Vascular Disorders: Rare: Thrombophlebitis at the site of injection.
Gastrointestinal Disorders: Suspension: Adults: Very Common: Diarrhoea. Common: Nausea, vomiting. Children: Common: Diarrhoea, nausea, vomiting. All Populations: Nausea is more often associated with higher oral dosages. If gastrointestinal reactions are evident, they may be reduced by taking Clavokor at the start of a meal. Uncommon: Indigestion. Very Rare: Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis). Black hairy tongue. Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. IV: Common: Diarrhoea. Uncommon: Nausea, vomiting, indigestion.
Hepatobiliary Disorders: Uncommon: A moderate rise in AST and/or ALT has been noted in patients treated with β-lactam class antibiotics, but the significance of these findings is unknown. Very Rare: Hepatitis and cholestatic jaundice. These events have been noted with other penicillins and cephalosporins.
Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children.
Signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects.
Skin and Subcutaneous Tissue Disorders: Uncommon: Skin rash, pruritus, urticaria. Rare: Erythema multiforme. Very Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative-dermatitis, acute generalised exanthemous pustulosis (AGEP).
If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued.
Renal and Urinary Disorders: Very Rare: Interstitial nephritis, crystalluria (see Overdosage).

Drug Interactions

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxycillin. Concomitant use with Clavokor may result in increased and prolonged blood levels of amoxycillin but not of clavulanate.
Concomitant use of allopurinol during treatment with amoxycillin can increase the likelihood of allergic skin reactions. There are no data on the concomitant use of Clavokor and allopurinol.
In common with other antibiotics, Clavokor may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

Pregnancy Category (US FDA)

Category B : Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1sttrimester (and there is no evidence of a risk in later trimesters).

Description

Each 375- and 625-mg, and 1-g tablet contains amoxycillin 250 mg, 500 mg and 875 mg, clavulanic acid 125 mg, respectively.
Each 5 mL of 156-mg syrup contains amoxycillin 125 mg, clavulanic acid 31.25 mg.
Each 5 mL of suspension contains amoxycillin 400 mg, clavulanic acid 57 mg.
Amoxycillin is present as amoxycillin trihydrate (oral formulations) or amoxycillin sodium (IV formulation) and clavulanic acid as potassium clavulanate.

Mechanism of Action

Pharmacology: Pharmacodynamics: Resistance to many antibiotics is caused by bacterial enzymes which destroy the antibiotic before it can act on the pathogen. The clavulanate in Clavokor suspension anticipates this defense mechanism by blocking the β-lactamase enzymes, thus rendering the organisms sensitive to amoxycillin's rapid bactericidal effect at concentrations readily attainable in the body.
Clavulanate by itself has little antibacterial activity; however, in association with amoxycillin as Clavokor, it produces an antibiotic agent of broad spectrum with wide application in hospital and general practice.
Infections caused by amoxycillin-susceptible organisms are amenable to Clavokor treatment due to its amoxycillin content. Mixed infections caused by amoxycillin-susceptible organism in conjunction with Clavokor-susceptible β-lactamase-producing organisms may therefore be treated with Clavokor.
Pharmacokinetics: The pharmacokinetics of the 2 components of Clavokor are closely matched.
457 mg/5 mL Suspension: Amoxycillin and clavulanate acid are each fully dissociated in aqueous solution at physiological pH.
The oral route of administration rapidly and well absorbs both components.
Absorption of Clavokor is optimised when taken at the start of a meal.
The mean area under the concentration-time curve (AUC) values for amoxycillin are essentially the same following twice-daily dosing with 875/125-mg tablet or thrice-daily dosing with 500/125 mg tablet, in adults. No differences between the 875 mg twice daily and 500 mg 3 times daily dosing regimes are seen when comparing the amoxycillin half-life or peak plasma concentrations (Cmax) after normalisation for the different doses of amoxycillin administered. Similarly, no differences are seen for the clavulanate half-life, C max or AUC values after appropriate dose normalisation.
The time of dosing of Clavokor relative to the start of a meal has no marked effects on the pharmacokinetics of amoxycillin in adults. In a study of 875/125-mg tablet, the time of dosing relative to ingestion of a meal had a marked effect on the pharmacokinetics of clavulanate. For clavulanate AUC and Cmax, the highest mean values and smallest intersubject variabilities were achieved by administering Clavokor at the start of a meal, compared to the fasting state or 30 min or 150 min after the start of a meal.
The mean Cmax, tmax, half-life and AUC values for amoxycillin and clavulanate are given in Table 1 for an 875/125-mg dose of amoxycillin/clavulanic acid administered at the start of a meal . Amoxycillin serum concentrations achieved with Clavokor are similar to those produced by the oral administration of equivalent doses of amoxycillin alone.
Microbiology: Clavokor is bactericidal to a wide range of organisms including: Gram-Positive:Aerobes: Enterococcus faecalis,*Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Streptococcus agalactiae, Streptococcus species, *Staphylococcus aureus, *coagulase negative staphylococci (including Staphylococcus epidermidis),Corynebacterium sp, Bacillus anthracis, Listeria monocytogenes.
Anaerobes: Clostridium sp, Peptococcus sp, Peptostreptococcus.
Gram-Negative: Aerobes: *Haemophilus influenzae, Helicobacter pylori, *Escherichia coli,Gardnerella vaginalis, *Proteus mirabilis, *Proteus vulgaris, *Klebsiella species, Legionella species,*Moraxella catarrhalis, *Salmonella sp, *Shigella sp, Bordetella pertussis, Brucella sp, *Neisseria gonorrhoeae, Neisseria meningitidis, Vibrio cholerae, Pasteurella multocida, Yersinia enterocolita.
Anaerobes: *Bacteroides spp including B. fragilis, Fusobacterium species.
*Including β-lactamase producing strains resistant to ampicillin and amoxycillin.
Some members of these species of bacteria produce β-lactamase, rendering them insensitive to amoxycillin alone.
Distribution: Both clavulanate and amoxycillin have low levels of serum-binding; about 70% remains free in the serum.
Doubling the dosage of Clavokor approximately doubles the serum levels achieved.

MIMS Class

Penicillins

ATC Classification

J01CR02 - amoxicillin and enzyme inhibitor ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.

Poison Classification

A

Presentation/Packing

Susp 457 mg/5 mL dry powder