Clamentin S, Clamentin Sf 31,25 mg/62,5 mg Suspension

CLAMENTIN formulations are indicated for the treatment of infections caused by amoxicillin resistant organisms producing u03b2-lactamases sensitive to clavulanic acid:

• Upper respiratory tract, such as sinusitis, otitis media or tonsillitis.
• Lower respiratory tract, such as bronchitis (caused by amoxicillin resistant u03b2-lactamase producing Escherichia coli, Haemophilus influenzae and Haemophilus para-influenzae) or pneumonia.
• Urinary tract infections, such as cystitis, urethritis or pyelonephritis.
• Skin and soft tissues.

CLAMENTIN formulations 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

Suspensions should be taken immediately before a meal.

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

Paediatric population:

• The dose of CLAMENTIN in children is 25-50 mg/kg/day of the 4 parts amoxicillin, 1-part clavulanic acid preparations (which corresponds to a daily dosage of the equivalent of 20-40 mg/kg of amoxicillin and 5-10 mg/kg of clavulanic acid) to be taken in divided doses every eight hours, at the start of a meal.

Dosage guide:

Amoxicillin-Sensitive Organisms

Product

• Upper Respiratory Tract Infections
• Lower Respiratory Tract Infections
• Urinary Tract Infections
• Skin & Soft Tissue Infections

CHILDREN:

CLAMENTIN S (9-18 kg) 5 - 10 ml 1 8 hourly

CLAMENTIN SF (18-37 kg) 5 ml 1 8 hourly

Amoxicillin-Resistant Organisms

Product

• Upper Respiratory Tract Infections (Otitis media)
• Lower Respiratory Tract Infections (Bronchitis)
• Urinary Tract Infections
• Skin & Soft Tissue Infections

CHILDREN:

CLAMENTIN S (9-18 kg) 5 - 10 ml 2 8 hourly

CLAMENTIN SF (18-37 kg) 5 - 10 ml 2 8 hourly

1) To correspond to a dosage of 25-50 mg/kg/day

2) To correspond to a dosage of 50 mg/kg/day

Method of administration

• For oral use.

• Hypersensitivity to the active substances, penicillins and cephalosporins or to any of the excipients listed in section 6.1.
• History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam medicines (e.g. a cephalosporin, carbapenem or monobactam).
• Safety in pregnancy has not been established.
• Safety in children under 6 months of age has not been established.
• CLAMENTIN is contraindicated in patients with a previous history of CLAMENTIN-associated jaundice/hepatic dysfunction.

Hypersensitivity reactions:

• Serious and occasionally fatal hypersensitivity (anaphylactoid) 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). 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. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. If an allergic reaction occurs, CLAMENTIN should be discontinued and the appropriate therapy instituted: adrenaline, corticosteroids and antihistamines.
• 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:

• CLAMENTIN is not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam medicines that are not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. CLAMENTIN should not be used to treat penicillin-resistant S. pneumoniae.
• Since CLAMENTIN 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 (morbilliform rash) if amoxicillin is used.
• The use of this antibiotic CLAMENTIN 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.

Overgrowth of non-susceptible microorganisms:

• Prolonged use may occasionally result in overgrowth of non-susceptible organisms.
• Antibiotic-associated colitis has been reported with nearly all antibacterial medicines including CLAMENTIN and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of CLAMENTIN. Should antibiotic-associated colitis occur, CLAMENTIN 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 function, 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), CLAMENTIN should be discontinued and/or appropriate therapy instituted.

Anticoagulants:

• Prolongation of prothrombin time has been reported. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections 4.5 and 4.8).

Impaired hepatic function:

• Changes in liver function tests have been observed in some patients receiving CLAMENTIN. It should be used with care in patients with evidence of severe hepatic dysfunction.
• Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. 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 medicines known to have the potential for hepatic effects (see section 4.8).
• Transient hepatitis and cholestatic jaundice have been reported.

Impaired renal function:

• In patients with moderate or severe renal impairment, the CLAMENTIN dosage should be adjusted.

Convulsions:

• Convulsions may occur in patients 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. During the administration of high doses of CLAMENTIN, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria.

Lymphatic leukaemia:

• CLAMENTIN 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 exercise when CLAMENTIN is administered to a woman that is breastfeeding her baby.
• 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 CLAMENTIN discontinuation and contraindicates any subsequent administration of amoxicillin.

Interference with laboratory tests:

• During treatment with CLAMENTIN, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods (see section 4.5).

Interference with serological testing:

• CLAMENTIN may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

Probenecid:

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

Allopurinol:

• The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both medicines as compared to patients receiving ampicillin alone.
• 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 CLAMENTIN and allopurinol administered concurrently.

Alcohol:

• No information is available about the concurrent use of CLAMENTIN and alcohol.
• However, the ingestion of alcohol whilst being treated with some other u03b2-lactam antibiotics has precipitated a disulfiram (Antabuse) like reaction in some patients. Therefore, the ingestion of alcohol should be avoided during and for several days after treatment with CLAMENTIN.

Oral contraceptives:

• Following administration of ampicillin to pregnant woman a transient decrease in plasma concentration of total conjugate oestriol, oestriol-glucuronide, conjugated oestrone and oestradiol has been noted. This effect may also occur with amoxicillin and therefore CLAMENTIN.
• In common with other broad-spectrum antibiotics, CLAMENTIN may reduce the efficacy of oral contraceptives and patients should be warned accordingly.

Oral anticoagulants:

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

Methotrexate:

• CLAMENTIN 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 (MPA) has been reported following commencement of oral CLAMENTIN. Close monitoring should be performed during the combination and shortly after antibiotic treatment.

Women of childbearing potential/ Contraception in males and females

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

Pregnancy

Safety in pregnancy has not been established.

Breastfeeding

Amoxicillin is excreted in breast milk; there are no data on the excretion of clavulanic acid in human milk. Therefore, caution should be exercise when CLAMENTIN is administered to a woman that is breastfeeding her baby.

CLAMENTIN may cause allergic reactions, dizziness or convulsions and may thus have an effect on 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).

Summary of the safety profile

The most frequently reported adverse effects were diarrhoea, nausea, vomiting, 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 minimised by administering CLAMENTIN 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.

Tabulated list of adverse reactions

Body System

Undesirable effect

• Frequent
• Less frequent
• Frequency not known

Infections and Infestations:

• Mucocutaneous candidosis
• Overgrowth of non-susceptible organisms

Blood and the lymphatic system disorders:

• Thrombocytopenic purpura, Eosinophilia
• Reversible leucopenia (including neutropenia), Thrombocytopenia
• Reversible agranulocytosis, Haemolytic anaemia, Prolongation of bleeding time and prothrombin time (see section 4.4)

Immune system disorders (see section 4.3 & 4.4):

• Angioneurotic oedema, Serum sickness-like syndrome, Hypersensitivity vasculitis

Nervous system disorders:

• Dizziness, Headache
• Reversible hyperactivity, Convulsions (see section 4.4), Aseptic meningitis

Cardiac disorders:

• Kounis syndrome (see section 4.4)

Gastrointestinal disorders:

• Diarrhoea, Nausea
• Vomiting, Gastritis, Stomatitis, Glossitis, Enterocolitis, Indigestion
• Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis) (see section 4.4), Black hairy tongue, Tooth discolouration
• Drug-induced enterocolitis syndrome, Pancreatitis acute

Hepato-biliary disorders:

• Rises in AST and/or ALT
• Hepatitis and cholestatic jaundice

Skin and subcutaneous tissue disorders:

• Skin rash, Pruritis, Urticaria, Stevens-Johnson syndrome, Erythema multiforme
• Toxic epidermal necrolysis, Bullous exfoliative dermatitis, Acute generalised exanthemous pustulosis (AGEP) (see section 4.4), Drug reaction with eosinophilia and systemic symptoms (DRESS), Linear IgA disease

Renal and urinary disorders:

• Interstitial nephritis, Crystalluria (including acute renal injury) (see section 4.9)

If gastro-intestinal reactions are evident, they may be reduced by taking CLAMENTIN at the start of a meal.

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

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 CLAMENTIN.

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.

A moderate rise in Aspartate transaminase and/or Alanine transaminase has been noted in patients treated with CLAMENTIN, the significance of these findings is unknown. Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking amoxicillin/clavulanic acid with a meal. These events have been noted with other penicillins and cephalosporins (see section 4.4).

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

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

Symptoms:

• Nausea, vomiting and diarrhoea may occur with overdosing.
• Convulsions may occur in patients with impaired renal function or in those receiving high doses.

Treatment:

• Treatment is symptomatic and supportive.
• Amoxicillin as contained in CLAMENTIN may be removed from 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.