CLARITHROMYCIN

Posology Intravenous therapy may be given for 2 to 5 days and should be changed to oral clarithromycin therapy when appropriate. 6).

Children older than 12 years:

As for adults.

Children under 12 years:

Use of “invented name” 500 mg powder for solution for infusion is not recommended for children younger than 12 years.

Elderly:

As for adults.

Renal impairment:

In patients with renal impairment who have creatinine clearance less than 30ml/min, the dosage of clarithromycin should be reduced to one half of the normal recommended dose.

Hepatic impairment:

Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment. Method of administration Clarithromycin should be administered into one of the larger proximal veins as an intravenous infusion over 60 minutes, using a solution concentration of about 2 mg/ml.

Clarithromycin should not be given as a bolus or an intramuscular injection. 6. The reconstituted product is a clear solution.

a. Summary of the safety profile The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics.

8) There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections. b. Tabulated summary of adverse reactions The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended-release tablets and modified-release tablets.

The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed. System Organ Class Very common Common Uncommon Not Known* (cannot be estimated from the available data) Infections and infestations Cellulitis1, candidiasis, gastroenteritis2,i nfection3, vaginal infection Pseudomembran ous colitis, erysipelas Blood and lymphatic system Leukopenia, neutropenia4, thrombocythemi a3, eosinophilia4 Agranulocytosis , thrombocytopen ia Immune system disorders Anaphylactoid reaction, hypersensitivity Anaphylactic reaction, angioedema Psychiatric disorders Insomnia Anxiety, nervousness3, screaming3 Psychotic disorder, confusional state, depersonalisatio n, depression, disorientation, hallucination, abnormal dreams Nervous system disorders Dysgeusia, Headache, taste perversion Loss of consciousness1, dyskinesia1, dizziness, somnolence7, tremor Convulsion, ageusia, parosmia, anosmia, paraesthesia Ear and labyrinth disorders Vertigo, hearing impaired, tinnitus Deafness Cardiac disorders Cardiac arrest, atrial fibrillation, electrocardiogra m QT prolonged, extrasystoles, palpitations Torsades de pointes, ventricular Tachycardia, ventricular fibrillation Respiratory, thoracic and mediastinal disorder Asthma1, epistaxis2, pulmonary embolism1 Vascular disorders Vasodilation1 Hemorrhage9 Gastrointestinal disorders Diarrhea10, vomiting, dyspepsia, nausea, abdominal pain Esophagitis1, gastrooesophage al reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence, Pancreatitis acute, tongue discolouration, tooth discoloration Hepatobiliary disorders Liver function test abnormal, Cholestasis4, hepatitis4, alanine aminotransferas e increased, aspartate aminotransferas e increased, gamma- glutamyltransfer ase increased4 Hepatic failure, jaundice hepatocellular Skin and subcutaneous tissue disorders Rash, hyperhidrosis Dermatitis bullous , pruritus, urticaria, rash maculo-papular3 Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), acne, acute generalised exanthematous pustulosis (AGEP) Musculoskeletal and connective tissue disorders Muscle spasms3, musculoskeletal stiffness1, myalgia2 Rhabdomyolysis 2,12, myopathy Renal and urinary disorders Blood creatinine increased , blood urea increased Renal failure, nephritis interstitial Investigations Albumin globulin ratio abnormal1, blood alkaline phosphatase increased4, blood lactate dehydrogenase increased4 International normalised ratio increased9, prothrombin time prolonged9, urine color abnormal General disorders and administration site conditions Injection site phlebitis1 Injection site pain1, injection site inflammation1 Malaise4, pyrexia3, asthenia, chest pain4, chills4, fatigue4 1 ADRs reported only for the Powder for Solution for Injection formulation 2ADRs reported only for the Extended-Release Tablets formulation 3 ADRs reported only for the Granules for Oral Suspension formulation 4 ADRs reported only for the Immediate-Release Tablets formulation 5,8,10,11,See section a) 6,7,9, 12See section c) c.

6). 2). Clarithromycin is mainly excreted by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering Clarithromycin to patients with moderate to severe renal impairment.

8) have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. Clostridium difficile-Associated Disease (CDAD) must be considered in all patients who present with diarrhoea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Therefore, discontinuation of clarithromycin therapy should be considered regardless of the indication.

Microbial testing should be performed and adequate treatment initiated. Medicinal products inhibiting peristalsis should be avoided. There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency.

5). 3). 5). Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. 8). 3). 5). 3). 3). Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results.

Some observational studies have identified a rare short-term, risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including clarithromycin. Consideration of these findings should be balanced with treatment benefits when prescribing clarithromycin.

1 • Concomitant administration with ticagrelor or ranolazine is contraindicated. 5). 5). • Clarithromycin must not be given to patients with electrolyte disturbance (hypokalaemia or hypomagnesaemia, due to the risk of prolongation of QT- interval) • Clarithromycin must not be used in patients who suffer from severe hepatic failure in combination with renal impairment.

5). 5). • Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity. • As with other strong CYP3A4 inhibitors, Clarithromycin must not be used in patients taking colchicine.

5).