a. Summary of the safety profileThe most frequent and common adverse reactions related to clarithromycin therapy for both adult and paediatric populations are abdominal pain, diarrhoea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics. (see section b. of section 4.8)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 reactionsThe 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; frequency 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.
* Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Patient exposure is estimated to be greater than 1 billion patient treatment days for clarithromycin.
** In some reports of rhabdomyolysis, clarithromycin was administered concomitantly with other drugs known to be associated with rhabdomyolysis (such as statins, fibrates, colchicine or allopurinol).
1 ADRs reported only for the Powder for Solution for Injection formulation
2 ADRs 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
c. Description of selected adverse reactionsInjection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested (see section 4.5).There have been rare reports of clarithromycin extended-release tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhoea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibiotic.Special population: Adverse Reactions in Immunocompromised Patients (see section e).
|System Organ Class
≥ 1/100 to < 1/10
≥1/1,000 to < 1/100
(*cannot be estimated from the available data)
|Infections and infestations
|| || ||Cellulitis1, candidiasis, gastroenteritis2, infection3, vaginal infection
||Pseudomembranous colitis, erysipelas
|Blood and lymphatic system
|| || ||Leukopenia, neutropenia4, thrombocythemia3, eosinophilia4||Agranulocytosis, thrombocytopenia
|Immune system disorders
|| || ||Anaphylactoid reaction1, hypersensitivity
||Anaphylactic reaction, angioedema
|Metabolism and nutrition disorders
|| || ||Anorexia, decreased appetite
||Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania
|Nervous system disorders
|| ||Dysgeusia, headache, taste perversion
||Loss of consciousness1, dyskinesia1, dizziness, somnolence, tremor
||Convulsion, ageusia, parosmia, anosmia, paraesthesia
|Ear and labyrinth disorders
|| || ||Vertigo, hearing impaired, tinnitus
|| || ||Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged, extrasystoles1, palpitations
||Torsades de pointes, ventricular tachycardia, ventricular fibrillation
|| ||Vasodilation1|| ||Haemorrhage
|Respiratory, thoracic and mediastinal disorder
|| || ||Asthma1, epistaxis2, pulmonary embolism1|| |
|| ||Diarrhoea, vomiting, dyspepsia, nausea, abdominal pain
||Oesophagitis1, gastrooesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence
||Pancreatitis acute, tongue discolouration, tooth discolouration
|| ||Liver function test abnormal
||Cholestasis4, hepatitis4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4||Hepatic failure, jaundice hepatocellular
|Skin and subcutaneous tissue disorders
|| ||Rash, hyperhidrosis
||Dermatitis bullous1, pruritus, urticaria, rash maculo-papular3||Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), acne
|Musculoskeletal and connective tissue disorders
|| || ||Muscle spasms3, musculoskeletal stiffness1, myalgia2||Rhabdomyolysis2, **, myopathy
|Renal and urinary disorders
|| || ||Blood creatinine increased1, blood urea increased1||Renal failure, nephritis interstitial
|General disorders and administration site conditions
||Injection site phlebitis1||Injection site pain1, injection site inflammation1||Malaise4, pyrexia3, asthenia, chest pain4, chills4, fatigue4|| |
|| || ||Albumin globulin ratio abnormal1, blood alkaline phosphatase increased4, blood lactate dehydrogenase increased4||International normalised ratio increased, prothrombin time prolonged, urine colour abnormal
d. Paediatric populationsClinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension.
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.e. Other special populations
Immunocompromised patientsIn AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of Human Immunodeficiency Virus (HIV) disease or intercurrent illness.In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1000mg and 2000mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1000mg and 2000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000mg of clarithromycin. In these immunocompromised patients evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1000mg or 2000mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen (BUN) levels. Slightly higher incidences of abnormal values were noted for patients who received 4000mg daily for all parameters except White Bood Cell.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: firstname.lastname@example.org