Adverse reactions : תופעות לוואי

4.8. Undesirable effects
a. Summary of the safety profile

The most frequent and common adverse reactions related to clarithromycin therapy for both adult and peadiatric 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 pre-existing 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         Very common          Common                Uncommon               Not Known* Class                ≥1/10                ≥ 1/100 to < 1/10     1/1,000 to < 1/100     (cannot be estimated from the available
data)
Infections and                                                  Cellulitis1,           Pseudomembranous infestations                                                    candidiasis,           colitis, erysipelas, gastroenteritis2,
infection3, vaginal
infection
Blood and                                                       Leukopenia,        Agranulocytosis, lymphatic system                                                neutropenia4,      thrombocytopenia thrombocythaemia3,
eosinophilia4
Immune system                               Anaphylactoid           Anaphylactic reaction.
disorders5                                  reaction1,              angioedema hypersensitivity
Metabolism and                              Anorexia,
nutrition disorders                         decreased appetite
Psychiatric           Insomnia              Anxiety,                Psychotic disorder, disorders                                   nervousness3,           confusional state, screaming3              depersonalisation,
depression,
disorientation,
hallucination,
abnormal dreams,
mania
Nervous system        Dysgeusia,            Loss of                 Convulsion, ageusia, disorders             headache, taste       consciousness1,         parosmia, anosmia, perversion            dyskinesia1,            paraesthesia
dizziness,
somnolence6,
tremor
Ear and labyrinth                           Vertigo, hearing        Deafness disorders                                   impaired, tinnitus
Cardiac disorders                           Cardiac arrest1,        Torsades de pointes7, atrial fibrillation1,   ventricular
electrocardiogram       tachycardia7
QT prolonged7,          ventricular
extrasystoles1,         fibrillation
palpitations
Vascular disorders    Vasodilation1                                 Haemorrhage8 Respiratory,                                Asthma1, epistaxis2,
thoracic and                                pulmonary
mediastinal                                 embolism1
disorder
Gastrointestinal      Diarrhoea9,           Esophagitis1,          Pancreatitis acute, disorders             vomiting,             gastrooesophageal tongue discolouration, dyspepsia, nausea,    reflux disease2,       tooth discolouration
abdominal pain        gastritis,
proctalgia2,
stomatitis, glossitis,
abdominal
distension4,
constipation, dry
mouth, eructation,
flatulence,
Hepatobiliary         Liver function test   Cholestasis4,           Hepatic failure10, disorders                                 abnormal              hepatitis4, alanine jaundice aminotransferase     hepatocellular
increased, aspartate
aminotransferase
increased, gamma-
glutamyltransferase
increased4
Skin and                                  Rash, hyperhidrosis Dermatitis bullous1,    Stevens-Johnson subcutaneous                                                  pruritus, urticaria,    syndrome5, toxic tissue disorders                                              rash maculo-            epidermal necrolysis5, papular3                drug rash with
eosinophilia and
systemic symptoms
(DRESS), acne,
Musculoskeletal                                                 Muscle spasms3,      Rhabdomyolysis2,11**, and connective                                                  musculoskeletal      myopathy tissue disorders                                                stiffness1, myalgia2 Renal and urinary                                               Blood creatinine      Renal failure, disorders                                                       increased1, blood     nephritis interstitial urea increased1
General disorders Injection site          Injection site pain1, Malaise4, pyrexia3, and administration phlebitis1             injection site        asthenia, chest 1
site conditions                           inflammation          pain4, chills4, fatigue4
Investigations                                                  Albumin globulin      International ratio abnormal1,      normalised ratio
blood alkaline        increased8,
phosphatase           prothrombin time
increased4,           prolonged8, urine
blood lactate         color abnormal
dehydrogenase
increased4

* 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 of the 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
5,7,9,10
See section a)
6,8, 11
See section c)
c. Description of selected adverse reactions

Injection 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 ER 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) 
d. Paediatric populations

Clinical 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 patients
In 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 1000 mg 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 levels. Slightly higher incidences of abnormal values were noted for patients who received 4000mg daily for all parameters except White Blood Cell.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic @moh.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL)