Dafraclav Amoxicillin Trihydrate and Potassium Clavulanate Tablets and Suspension

Dafraclav®

 

IDENTIFICATION OF PRODUCT

Film coated tablets

Each white FILMCOATED TABLET contains: amoxicillin trihydrate equivalent to 875 or 500 mg amoxicillin, potassium clavulanate equivalent to 125 mg clavulanic acid as active ingredients.

Excipients: Polyvinyl polypyrrolydone, Croscarmellose sodium, Colloidal anhydrous silica, Magnesium stearate, Microcrystalline cellulose. Coating suspension: Opadry white OY-S-7191, Methylene chloride, lsopropyl alcohol.

 

Powder for oral suspension

400/57 or 200/28 mg POWDER FOR ORAL SUSPENSION contains: 400 or 200 mg amoxicillin equivalent of amoxicillin trihydrate and potassium clavulanate equivalent to 57 or 28 mg Clavulanic acid activity per 5 ml of suspension as active ingredients.

Excipients: Citric acid, Sodium citrate, Sodium benzoate, Colloidal silicon dioxide, Microcrystalline cellulose, Xanthane Gum, Sucrose, Raspberry essence.

 

Presentation

Film coated tablets

Cardboard containing 2 or 3 blisters with 10 or 15 film coated tablets. Each tablet contains 875 or 500 mg amoxicillin as amoxicillin trihydrate and 125 mg Clavulanic acid as potassium clavulanate.

 

Suspension

Each cardboard box contains 1 bottle of 70 ml. Each bottle contains enough powder mixture to give 70 ml suspension after reconstitution with water. Supplied with a measuring spoon.

 

Available pharmaceutical forms

Dafraclav 625 mg Film coated tablet (15 tablets)

Dafraclav 1g Film coated tablet (10 tablets)

Dry powder Dafraclav 400/57 mg

Forte Oral Suspension, 70 ml.

Dry powder Dafraclav 200/28 mg

Pediatric Oral Suspension, 70 ml.

 

By Prescription Only

PROPERTIES

Pharmacological properties

Amoxicillin/Clavulanic acid is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid.

Clavulanic acid is produced by the fermentation of Streptomyces clavuIigerus. It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated B-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins.

Clavulanic acid binds and inhibits beta-lactamases that inactivate amoxicillin resulting in amoxicillin having an expanded spectrum of activity. Amoxicillin inhibits bacterial cell wall synthesis by binding to one or more of the penicillin binding proteins (PBPs); which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Following oral administration of Dafraclav, the bioavailability of Amoxicillin is between 72-94% and that of Clavulanic acid is 75%. Fasting or fed conditions affect minimally the bioavailability for Amoxicillin and Clavulanic acid. Both substances distribute into the most body tissues and fluids. However, under normal conditions, the passage into cerebrospinal fluid is insignificant. Binding to plasma proteins is 18% for Amoxicillin and 25% Clavulanic acid. Both substances are partially metabolized into the liver, and 50-70% of Amoxicillin and 25-40% of Clavulanic acid are excreted unchanged into the urine in 6 hours. The half-life is 1.3 hours for Amoxicillin and 1 hour for Clavulanic acid.

 

Bacteriology

Amoxicillin/Clavulanic acid is active in vitro and in clinical infections (see INDICATIONS section) against most strains of the following bacteria which may or may not be beta-lactamase producers:

 

GRAM-POSITIVE AEROBES

Staphylococcus aureus (methicillin/oxacillin resistant staphylococci are considered also to be resistant to amoxicillin/ clavulanic acid), Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus pyogenes, Viridans group streptococci, Enterococcus faecalis, Listeria monocytogenes, Bacillus anthracis, Corynebacterium species.

 

GRAM-NEGATIVE AEROBES

Enterobacter spp., Escherichia coli, Haemophilus influenzae, Kiebsiella spp., Moraxella catarrhalis, Eikenella corrodens, Neisseria gonorhoeae, Proteus mirabilis, Pasteurella multocida, Neisseria meningitides, Salmonella spp., Shigella spp., Bordetella pertussis, Brucella species, Vibrio cholerae.

 

ANAEROBIC BACTERIA

Bacteroides spp., Bacteroides fragilis, Fusobacterium spp., Peptostreptococcus spp., Clostridia species, Peptococcus species.

 

USE/INDICATIONS

DafracIav is indicated in the treatment of the following infections caused by the microorganisms indicated below:

Upper respiratory tract infections: (including otitis media and sinusitis) due to beta-lactamase producing strains of Haemophilus influenzae and Moraxella catarrhalis.

Lower respiratory tract infections: due to beta-lactamase producing strains of Haemophilus influenzae and Moraxella catarrhalis.

Skin and Skin Structure infections: due to beta-lactamase producing strains of Staphylococcus aureus, Escherichia coli and Klebsiella spp.

Urinary tract infections: caused by β-lactamase-producing strains of E. coli, KlebsieIla spp., and Enterobacter spp.

While Dafraclav is indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to treatment with Amoxicillin/ Clavulanic acid due to its amoxicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and β-lactamase producing organisms susceptible to Amoxicillin/Clavulanic acid should not require the addition of another antibiotic.

Because Amoxicillin has greater in vitro activity against S. 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 Amoxicillin/Clavulanic acid.

 

DOSAGE AND METHOD FOR USE

In general Dafraclav should be given during 5 to 10 days, but the duration of treatment depends on the severity of the infection and on the clinical and bacteriological evolution.

 

Tablets

625 mg tablets

Usual dose for adults and children ≥ 40kg is 1 Dafraclav 625 mg tablet every 12 hours. In severe infections and respiratory tract infections, 1 Dafraclav 625 mg tablet every 8 hours is recommended.

In patients with kidney disease, unless renal function impairment is very severe, dose adjustment is not necessary. If glomerular filtration is 10 to 30 ml/min, 1 Dafraclav 625 mg tablet is administered every 12 hours; if glomerular filtration is less than 10 ml/min, 1 Dafraclav 625 mg tablet is administered every 24 hours. Patients on haemodialysis are given 1 Dafraclav 625 mg tablet every 24 hours, plus 1 tablet during dialysis and 1 tablet at the end of the dialysis. Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

 

1000 mg tablets

Usual dose for adults and children over 12 years of age: for the treatment of severe infections and respiratory tract infections, the dose is 1 DafracIav 1000 mg tablet every 12 hours. Dafraclav 1000 mg should not be used in case of renal function impairment if the glomerular filtration is less than 30 ml/min. If there is hepatic function impairment, Dafraclav must be used with caution and liver function must be monitored. Dafraclav 1000 mg is not indicated for patients on haemodialysis.

 

Suspension

Directions for Mixing Oral suspension

Add water until the half of the bottle and shake well. Wait for 5 minutes for homogeneous dispersion. Add water until marked level on the bottle and shake well again. The reconstituted suspension is active for 7 days when stored in the refrigerator. Shake the bottle well before each use. Do not put in the icebox.

Pediatric patients: based on its Amoxicillin content Dafraclav 400/57 or 200/28 mg FORTE/PEDIATRIC ORAL SUSPENSION is used according to the following dosing
schedule.

Pediatric patients older than 12 weeks (3 months) of age:

INFECTION DOSING SCHEDULE
400 or 200 mg/5 ml suspension
Otitis media, sinusitis, lower respiratory tract infections and more severe infections 45 mg/kg/day – daily dose is divided into two equal
portions and administered 12 hours apart
Less severe infections 25 mg/kg/day – daily dose
is divided into two equal
portions and administered
12 h apart

In children > 40 kg of weight, adult dosing schedule is applied.

Amoxicillin/Clavulanic acid may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when Dafraclav is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin/clavulanate potassium should be taken at the start of a meal.

In patients with liver function impairment Dafraclav should be used carefully and liver functions should be monitored closely. Culture and susceptibility testing should be carried out prior to initiation of Dafraclav therapy. However, treatment may be started without waiting test results. Therapy may then be adjusted according to test results when these become available.

 

WHAT IN CASE OF OVERDOSE?

There is no known antidote for either Amoxicillin or Clavulanic acid.

In case of overdose patients should be treated symptomatically and supportive measures should be applied. If the drug has been ingested only recently emesis should be induced or gastric lavage should be performed.

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with Amoxicillin. 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 in patients with impaired renal function because of decreased renal clearance of both Amoxicillin and Clavulanic acid. Both Amoxicillin and Clavulanic acid are removed from the circulation by hemodialysis.

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.

 

WARNINGS AND CONTRA-INDICATIONS

During penicllin therapy serious hypersensitivity (anaphylactic) reactions may occur.

These reactions are more likely to appear in persons with a history of hypersensitivity to penicillin or multiple allergens. Prior to the initiation of Dafraclav therapy, careful inquiry should be made concerning previous hypersensitivity reactions to penicillin, cephalosporins and other allergens. If allergic reactions occur during therapy, treatment should be discontinued immediately. In case of serious anaphylactic reactions, administration of adrenaline, oxygen, intravenous steroids and intubation may be necessary.

Pseudomembranous colitis has been reported in association with all antibiotics including Amoxicillin/Clavulanic acid. This possibility should be taken into consideration in patients presenting with diarrhea.

DafracIav should be used carefully in patients with renal or hepatic dysfunction.

Hepatic, renal and hematopoetic functions should be assessed periodically during prolonged therapy. Hepatic toxicity associated with the use of Amoxicillin/ Clavulanic acid 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.

Administration of ampicillin to infectious mononucleosis patients has been reported to be associated with a morbilliform erythema. Dafraclav should not be used in these patients. If bacterial or mycotic superinfections occur during therapy (usually Pseudomonas or Candida) treatment should be discontinued and appropriate treatment should be instituted. Amoxicillin/clavulanic acid is contraindicated in patients with a history of allergic reactions to any penicillin. It is also contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin/clavulanate potassium.

 

SIDE EFFECTS AND ADVERSE REACTIONS

Amoxicillin/Clavulanic acid is generally well tolerated. The majority of side effects observed in clinical trials were of mild and transient nature and less than 3% of patients discontinued treatment because of drug-related side effects. The most frequently reported adverse effects were diarrhea (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 side effects have been reported with ampicillin class of antibiotics:

Gastrointestinal: diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black hairy tongue, mucocutanous candidiasis, enterocolitis and hemorrhage, pseudomembraneous colitis.

Hypersensitivity reactions: skin rashes, pruritus, urticaria, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme (rarely Stevens- Johnson syndrome), acute generalized exanthematous pustulosis, hypersensitivity vasculitis, 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 physician decides differently. Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with oral penicillin.

Liver: moderate increase in AST (SGOT) and/or ALT SGPT) has been noted in patients treated with the ampicillin-class of antibiotics, but the significance of these findings is unknown. Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin and/or alkaline phosphatase, has been infrequently reported with Amoxicillin/Clavulanic acid. 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, hematuria and crystalluria have been reported rarely.

Hematopoetic Lymphatic system: anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. A slight thrombocytosis was noted in less than 1% of the patients treated with Amoxicillin/ Clavulanic acid. There have been reports of increased prothrombin time in patients receiving Amoxicillin/Clavulanic Acid and anticoagulant therapy concomitantly.

Central nervous system: agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported rarely.

Miscellaneous: tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.

 

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS

Drug Interactions

Probenecid inhibits renal tubular secretion of amoxicillin and elevates its plasma concentrations. Dafraclav should not be used simultaneously with probenecid.

Concurrent use of ampicillin with allopurinol increases the incidence of skin rashes. It is not known whether this is due to allopurinol or hyperuricemia. Dafraclav should not be used in conjunction with disulfiram, as it may increase amoxicillin levels. In common with other broad-spectrum antibiotics, Amoxicillin/ Clavulanic acid may reduce the efficacy of oral contraceptives.

 

Diagnostic test interactions

Amoxicillin passes into urine in high concentrations and may cause the tests used for the demonstration of glucose in the urine to give false positive results. When testing for the presence of glucose in the urine it is recommended that tests based on enzymatic glucose oxidase method be used.

Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also occur with amoxicillin and therefore Amoxicillin/Clavulanic acid.

 

PREGNANCY I LACTATION

Pregnancy Category B: Although animal experiments did not demonstrate any teratogenic potential for Amoxicillin/ Clavulanic acid, controlled studies in humans have not been carried out. Dafraclav should be used in pregnancy only if it is clearly needed.

Use in Lactation: Antibiotics of ampicillin class are excreted in human milk. Dafraclav should be used carefully in nursing mothers.

 

EFFECT ON DRIVING AND OPERATING MACHINERY

Dafraclav has no pharmacodynamic action that can interfere with driving or machine operating skills.

 

PHARMACEUTICAL STORAGE

Do not use without prescription.

Store at room temperature below 30°C in a dry place.

 

Tablets

Caution: hygroscopic substance.

 

Suspension

After reconstitution suspension keeps its activity for 7 days in the refrigerator. Shake well before use. Keep out of reach and sight of children.

 

POWDER FOR ORAL SUSPENSION

200/28 mg

NAFDAC Reg. No.: A4-5118

400/57 mg

NAFDAC Reg. No.: A4-5074

 

FILM COATED TABLETS

1 g (10 tablets)

NAFDAC Reg. No.: A4-5747

625 mg (15 tablets)

NAFDAC Reg. No.: A4-5977

 

Name of manufacturer

Bilim Pharmaceuticals,

Cerkezkoy Plant,

59500 Cerkezkoy/Tekirdag,

Turkey.

 

On behalf of

Dafra Pharma GmbH.,

Weidboden 271,

4618 Boningen

Switzerland

 

Distributed by

Grace Drugs & Healthcare Ltd.,

1A, Ogunlana Drive,

Surulere, Lagos, Nigeria

 

Latest revision of the text

March 2015