Clavumed 375mg, 625 mg Film-coated tablets

CLAVUMED formulations are indicated for the treatment of infections caused by amoxicillin-resistant organisms producing beta-lactamases sensitive to clavulanic acid:

• Upper respiratory tract infections such as sinusitis, recurrent otitis media, tonsillitis.
• Lower respiratory tract infections such as bronchitis and bronchopneumonia.
• Genito-urinary tract infections such as cystitis, urethritis, pyelonephritis.
• Skin and soft tissue infections.

CLAVUMED tablet formulation will also be effective in the treatment of infections caused by amoxicillin-sensitive organisms at the appropriate amoxicillin dosage since in this situation the clavulanic acid component does not contribute to the therapeutic effect.

Posology

For Oral Formulations

Tablets should be taken immediately before a meal.

Dosages

General Information: For infections caused by amoxicillin sensitive organisms the dosage is that approved for amoxicillin as the clavulanic acid component does not contribute to the therapeutic effect.

Adults

The adult dose for CLAVUMED 375 and 625 Tablets is one CLAVUMED 375 Tablet every eight hours at the start of a meal. For more severe infections and infection of the respiratory tract, the dose should be one CLAVUMED 625 Tablet every eight hours at the start of a meal.

Since CLAVUMED 375, 625 and 1 g tablets contain the same amount of clavulanic acid (125 g as the potassium salt), two CLAVUMED 375 tablets are not equivalent to one CLAVUMED 625 tablet and two CLAVUMED 625 tablets are not equivalent to one CLAVUMED 1 g. Therefore, two CLAVUMED 375 tablets should not be substituted for one CLAVUMED 625 tablet or two CLAVUMED 625 tablets for one CLAVUMED 1 g tablet for the treatment of more severe infections.

Special populations

Impaired renal function

• Both amoxicillin and clavulanic acid are excreted by the kidneys and the serum half-life of each increases in patients with renal failure. Therefore, the dose may need to be reduced or the interval extended.
• Dosage adjustments are based on the maximum recommended level of amoxicillin. The following schedule is proposed.
• Mild impairment (creatinine clearance greater than 30 ml/min): No change in dosage.
• Moderate impairment (creatinine clearance 10 to 30 ml/min): 1 Tablet every 12 hours.

Haemodialysis decreases serum concentrations of both amoxicillin and clavulanic acid and an additional dose should be administered at the end of dialysis.

Dosage guide

Amoxicillin-Sensitive Organisms

Amoxicillin-Resistant Organisms

Method of administration

For oral use.

• Hypersensitivity to penicillins, and cephalosporins other beta-lactam medicines (e.g carbapenem or monobactam) or to any of the excipients (see section 6.1). Cross-sensitivity between penicillins and cephalosporins is well documented.
• Clavumed is contra-indicated in patients with a previous history of amoxicillin/clavulanic acid associated jaundice/hepatic dysfunction.

Hypersensitivity reactions:

• Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8). Before initiating therapy with CLAVUMED, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactam medicines or other allergens. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. 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.
• If an allergic reaction occurs, CLAVUMED should be discontinued and the appropriate therapy instituted. Serious anaphylactic reactions may require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubation may also be required.
• CLAVUMED 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 amoxicillin.
• Drug-induced enterocolitis syndrome (DIES) has been reported mainly in children receiving amoxicillin/clavulanate (see section 4.8). DIES is an allergic reaction with the leading symptom of protracted vomiting (1-4 hours after intake of amoxicillin/clavulanate) in the absence of allergic skin or respiratory symptoms. Further symptoms could comprise abdominal pain, diarrhoea, hypotension or leucocytosis with neutrophilia. There have been severe cases including progression to shock.

Non-susceptible microorganisms:

• Since CLAVUMED contains amoxicillin, an aminopenicillin, it is not the treatment of choice in patients presenting with sore throat or pharyngitis because of the possibility that the underlying cause is infectious mononucleosis, in the presence of which, there is a high incidence of rash if amoxicillin is used.
• The use of CLAVUMED may lead to the selection of resistant strains of organisms and sensitivity testing should, therefore, be carried out whenever possible to demonstrate the appropriateness of therapy.
• CLAVUMED is not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. CLAVUMED should not be used to treat penicillin-resistant S pneumoniae.

Overgrowth of non-susceptible microorganisms:

• Prolonged use may result in overgrowth of non-susceptible organisms.
• Pseudomembranous enterocolitis has been reported.
• Antibiotic-associated colitis has been reported. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of CLAVUMED. Should antibiotic-associated colitis occur, CLAVUMED should immediately be discontinued and a doctor should be consulted.
• Anti-peristaltic medicines are contraindicated in this situation.

Prolonged therapy:

• Periodic assessment of organ system functions, including renal, hepatic and haematopoietic functions, is advisable during prolonged therapy.
• The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Aerobacter, Pseudomonas or Candida), the agent should be discontinued and/or appropriate therapy instituted.

Anticoagulants:

• Prolongation of prothrombin time has been reported rarely in patients receiving CLAVUMED. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently (see section 4.5).

Impaired hepatic function:

• Changes in liver function tests have been observed in some patients receiving CLAVUMED. It should be used with care in patients with evidence of severe hepatic dysfunction.
• CLAVUMED should be used with caution in patients with evidence of hepatic dysfunction (see section 4.3).
• Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. The hepatic events are usually reversible. However, in extremely rare circumstances, death has been reported. These have almost always been cases associated with serious underlying disease or concomitant medication (see section 4.8).
• Transient hepatitis and cholestatic jaundice has been reported.

Impaired renal function:

• In patients with moderate or severe renal impairment the CLAVUMED dosage should be adjusted (see section 4.2).
• CLAVUMED should not be used in patients with a glomerular filtration rate of less than 30 ml/minute (See section 4.2).

Convulsions:

• Convulsions may occur with impaired renal function or in those receiving high doses. (see section 4.8).

Crystalluria:

• In patients with reduced urine output, crystalluria (including acute renal injury) has been observed very rarely, predominantly with parenteral therapy. When high doses are administered, adequate fluid intake and urinary output must be maintained in order to reduce the possibility of amoxicillin crystalluria (see section 4.8 and 4.9).

Jarisch-Herxheimer reaction:

• Caution is needed when administering amoxicillin to patients with syphilis as the Jarisch-Herxheimer reaction may occur in these patients.

Lymphatic leukaemia:

• CLAVUMED should be given with caution to patients with lymphatic leukaemia since they are especially susceptible to amoxicillin induced skin rashes.

Use in lactation:

• Amoxicillin is excreted in breast milk; there are no data on the excretion of clavulanic acid in human milk. Therefore, caution should be exercised when CLAVUMED is administered to a woman that is breastfeeding her baby. (see section 4.6).
• The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see section 4.8). This reaction requires CLAVUMED discontinuation and contraindicates any subsequent administration amoxicillin.

Probenecid:

• Probenecid decreases the renal tubular secretion of amoxicillin, but does not affect clavulanic acid excretion.
• Concurrent use with CLAVUMED may result in increased and prolonged blood levels of amoxicillin, but not of clavulanic acid.

Oral contraceptives:

• CLAVUMED may reduce the efficacy of oral contraceptives and patients should be warned accordingly.

Allopurinol:

• The concomitant administration of allopurinol and ampicillin substantially increases the incidence of skin rashes in patients receiving both agents as compared to patients receiving ampicillin alone (see section 4.4).
• It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricaemia present in these patients.
• There is no data on CLAVUMED and allopurinol administered concurrently.

Tetracyclines:

• Tetracyclines and other bacteriostatic medicines may interfere with the bactericidal effects of amoxicillin.

Interaction with laboratory tests:

• It is recommended that when testing for the presence of glucose in urine during CLAVUMED treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods (see section 4.4 u2018Interference with laboratory tests).

Oral anticoagulants:

• The prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of CLAVUMED. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8).

Methotrexate:

• CLAVUMED may reduce the excretion of methotrexate causing a potential increase in toxicity.

Mycophenolate mofetil:

• In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPC) has been reported following commencement of oral CLAVUMED. Close monitoring should be performed during the combination and shortly after antibiotic treatment.

Woman of childbearing potential

CLAVUMED may reduce the efficacy of oral contraceptives and patients should be warned accordingly (see section 4.5).

Pregnancy

The safety of Clavumed in pregnancy has not been established.

Breastfeeding

Amoxicillin is distributed in breast milk. Although significant problems in humans have not been documented, the use of amoxicillin by breastfeeding mothers may lead to sensitisation, diarrhoea, candidiasis and skin rash in the infant.

Fertility

No available fertility data.

Clavumed may cause allergic reactions, dizziness, and tiredness or convulsions which may influence mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision (see section 4.4 & 4.8).

Caution is advised for patients not to drive or use machines, until their individual susceptibility to the effects of CLAVUMED is known.

Summary of the safety profile

The most frequently reported adverse effects are diarrhoea, nausea, vomiting, indigestion, abdominal pain, skin rashes, urticaria and erythema multiforme, vaginitis, abnormal taste, headache, dizziness, tiredness and hot flushes. The incidence and severity of adverse effects, particularly nausea and diarrhoea, increased with the higher recommended dose and can be minimized by administering CLAVUMED at the start of a meal. In addition, as these symptoms are especially related to the potassium clavulanate component, where these gastro-intestinal symptoms occur and a higher concentration of amoxicillin is required, consideration should be given to administering the additional amoxicillin separately.

The side-effects considered at least possibly related to the treatment are listed below by body system, organ class and frequency (wherever applicable).

The following adverse reactions have been reported and may occur with CLAVUMED:

The following adverse reactions have been reported and may occur with CLAVUMED.

1 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking CLAVUMED with a meal.

2 The events may be severe, and occur predominantly in adult or elderly patients. 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.

The hepatic effects are usually reversible. However, in extremely rare circumstances, death has been reported. These have almost always been cases associated with serious underlying disease or concomitant medication.

3 A moderate rise in AST and/or ALT has been noted in patients treated with CLAVUMED.

4 Whenever such reactions occur, CLAVUMED should be discontinued. Serious and occasional fatal hypersensitivity (anaphylactic) reactions and angioneurotic oedema can occur with oral penicillin (see section 4.4).

5 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 CLAVUMED. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly.

6 Superficial tooth discolouration has been reported especially with the suspension and chewable tablet formulations. It can usually be removed by brushing.

7 These events have been noted with other penicillins and cephalosporins (see section 4.4).

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8).

Symptoms:

• Overdosage with amoxicillin is usually asymptomatic.
• Gastro-intestinal effects such as nausea, vomiting and diarrhoea may be evident and symptoms of water and electrolyte imbalance should be treated symptomatically.
• Adequate fluid intake and urinary output must be maintained to minimize the possibility of crystalluria.

Treatment:

• Amoxicillin may be removed from the circulation by haemodialysis. The molecular weight, degree of protein binding and pharmacokinetic profile of clavulanic acid together with information from a single patient with renal insufficiency all suggest that this compound may also be removed by haemodialysis.