CLARITHROMYCIN

0 gram daily of Clarithromycin powder for concentrate for solution for infusion (appropriately diluted as described below), administered as two separate 500mg doses at 12 hourly intervals.

Elderly:

Same as for adults.

Renal Impairment:

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

Paediatric population Children aged 12 or less:

Use of Clarithromycin powder for concentrate for solution for infusion is not recommended for children younger than 12 years. Use clarithromycin Paediatric Suspension.

Children older than 12 years:

As for adults.

Recommended administration:

Clarithromycin 500 mg, powder for concentrate for solution for infusion should be administered into one of the larger proximal veins as an IV infusion over 60 minutes, using a solution concentration of about 2mg/ml. Clarithromycin should not be given as a bolus or an intramuscular injection.

Method of administration For intravenous administration only. Clarithromycin may be given for 2 to 5 days by intravenous infusion, however, patients should be switched to the oral therapy should longer term treatment be required. 6

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. 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), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000) and not known: (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 com mon (≥1/1 0) Common (≥1/100 to <1/10) Uncommo n (≥1/1,000 to <1/100) Rare (≥1/10, 000 to <1/1,0 00) Very rare (<1/10,000) Not Known cannot be estimated from the available data Infection s and infestati ons --- Oral monilia (candidias is), prolonged use may result in the overgrowt h of non- susceptibl e Cellulitis1, candidiasis , gastroenter itis2, infection3, vaginal infection --- --- Pseudomembra nous colitis, erysipelas, erythrasma organisms Blood and Lympha tic system disorder s --- --- Leucopeni a, neutropeni a4, thrombocy thaemia3, eosinophili a4 --- Thrombocyt openia Agranulocytosis Immune System Disorder s --- --- Anaphylac toid reaction1, hypersensi tivity Allergic reactions ranging from urticaria to mild skin eruptions and angioedem a to anaphylaxi s.

8). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes), clarithromycin should be used with caution in the following patients; • Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia • Patients with electrolyte disturbances.

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. 6). 2). Clarithromycin is principally excreted by the liver. Therefore caution should be exercised in administering this antibiotic to patients with impaired hepatic function.

2). Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible.

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.

Antibiotic-associated diarrhoea Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life- threatening. Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis.

1. Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity. 5). 5). 5). 5). Concomitant administration with ticagrelor, ivabradine or ranolazine is contraindicated.

5). 4). Clarithromycin should not be given to patients with electrolyte disturbances (hypokalaemia or hypomagnesaemia, due to the risk of prolongation of the QT interval). Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.

5). 5).