Claricule 500 mg Powder for solution for Infusion

CLARICULE is indicated in the treatment of infections due to susceptible organisms whenever parenteral therapy is required;

• Lower respiratory tract infections for example, acute and chronic bronchitis, and pneumonia
• Upper respiratory tract infections for example, pharyngitis and tonsillitis due to S. pyrogenes, sinusitis
• Skin and soft tissue infections due to S.aureus
• There is some evidence that disseminated and localised infections in HIV-positive adults, due to Mycobacterium avium or Mycobacterium intracellulare respond to CLARICULE. Based on bacteriological results; CLARICULE should be used in conjunction with other antimycobacterials. To a lesser extent, localised infections due to Mycobacterium kansasil have responded to CLARICULE.

Posology

Adults: The recommended dosage of CLARICULE is 1.0 gram daily, divided into two equal doses, each infused after dilution with an appropriate I.V diluent, over a 60 minute period.

Dosage in patients with Mycobacterial infections: In disseminated or localised mycobacterial infections (M.avium; M. intracellulare; M.cheloane; M.kansasi) the recommended treatment in adults is 1000 mg/day in two divided doses. Treatment of disseminated MAC infections in AIDS patients should continue as long as clinical and microbiological benefit is demonstrated. A decrease in efficacy has been noted in patients on treatment exceeding 12 weeks. CLARICULE should be used in conjunction with other antimycobacterial medicines.

CLARICULE should not be given as a bolus or an lntra-muscular Injection. Intravenous therapy may be limited for up to 2 to 5 days in the very ill patient and should be changed to oral therapy whenever possible as determined by the medical practitioner.

Special populations

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

Paediatric population: The safety of CLARICULE for use in children has not been established.

Method of administration: For intravenous administration only. For preparation or reconstitution instructions, refer to section 6.6.

Hypersensitivity to macrolide antibiotic medicines or to any of the excipients listed in section 6.1. Concomitant administration of CLARICULE and ergot alkaloids (e.g. ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see section 4.5). Concomitant administration of CLARICULE and oral midazolam is contraindicated (see section 4.5). Concomitant administration of CLARICULE and any of the following medicines is contraindicated: astemizole, cisapride, domperidone, pimozide and terfenadine as this may result in QT prolongation and cardiac dysrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section 4.4 and 4.5). CLARICULE should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac dysrhythmia, including torsades de pointes (see sections 4.4 and 4.5). Concomitant administration with ticagrelor or ranolazine is contraindicated. CLARICULE should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4, (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis. CLARICULE should not be used in patients taking colchicine (see sections 4.4 and 4.5). CLARICULE should not be given to patients with hypokalaemia (risk of prolongation of QT- time). CLARICULE should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.

The medical practitioner should not prescribe CLARICULE to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy (see section 4.6). CLARICULE is principally metabolised by the liver. Therefore, caution should be exercised in administering this antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering CLARICULE to patients with moderate to severe renal impairment (see section 4.2). Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with CLARICULE. This hepatic dysfunction may be severe and is usually reversible. Cases of fatal hepatic failure (see section 4.8) 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. 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 CLARICULE and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. 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 CLARICULE therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Medicines 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. Deaths have been reported in some such patients (see section 4.5). Concomitant administration of CLARICULE and colchicine is contraindicated (see section 4.3). Caution is advised regarding concomitant administration of CLARICULE and triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal midazolam (see section 4.5). Cardiovascular Events: Prolongation of the QT interval, reflecting effects on cardiac repolarisation imparting a risk of developing cardiac dysrhythmia and torsades de pointes, have been seen in patients treated with macrolides including clarithromycin (see section 4.8). Due to increased risk of QT prolongation and ventricular dysrhythmias (including torsades de pointes), the use of clarithromycin is contraindicated: in patients taking any of astemizole, cisapride, domperidone, pimozide and terfenadine; in patients who have hypokalaemia; and in patients with a history of QT prolongation or ventricular cardiac dysrhythmia (see section 4.3). Furthermore, CLARICULE should be used with caution in the following:

• Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia;
• Patients with hypomagnesaemia;
• Patients concomitantly taking other medicinal products associated with QT prolongation other than those which are contraindicated.

The use of the following medicines is strictly contraindicated due to the potential for severe medicine interaction effects: Astemizole, cisapride, domperidone, pimozide, and terfenadine: Elevated cisapride levels have been reported in patients receiving CLARICULE and cisapride concomitantly. This may result in QT prolongation and cardiac dysrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking CLARICULE and pimozide concomitantly (see section 4.3). Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac dysrhythmias, such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see section 4.3). In one study in 14 healthy volunteers, the concomitant administration of CLARICULE and terfenadine resulted in 2- to 3-fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides. Ergot alkaloids: Post-marketing reports indicate that co-administration of CLARICULE with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischaemia of the extremities and other tissues including the central nervous system. Concomitant administration of CLARICULE and ergot alkaloids is contraindicated (see section 4.3). Oral Midazolam: When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 7-fold after oral administration of midazolam. Concomitant administration of oral midazolam and clarithromycin is contraindicated (see section 4.3). HMG-CoA Reductase Inhibitors (statins): Concomitant use of CLARICULE with lovastatin or simvastatin is contraindicated (see 4.3) as these statins are extensively metabolized by CYP3A4 and concomitant treatment with CLARICULE increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking CLARICULE concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment. Caution should be exercised when prescribing CLARICULE with statins. In situations where the concomitant use of CLARICULE with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.

Pregnancy: The safety of CLARICULE for use during pregnancy has not been established. The medical practitioner should not prescribe CLARICULE to pregnant women, particularly in the first trimester of pregnancy.

Breastfeeding: The safety of clarithromycin during lactation has not been established. CLARICULE is excreted into human breast milk.

Fertility: In the rat, fertility studies have not shown any evidence of harmful effects (see section 5.3).

There are no data on the effect of CLARICULE on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with CLARICULE, should be taken into account before patients drive or use machines.

The most frequent and common adverse reactions related to CLARICULE therapy for both adult and paediatric populations are abdominal pain, diarrhoea, nausea, vomiting and taste perversion. The reactions considered at least possibly related to CLARICULE are displayed by system organ class and frequency.

System Organ Class

Frequent

Less Frequent

Frequency unknown

Infections and infestations

Cellulitis, candidiasis, gastroenteritis

Pseudomembranous colitis, erysipelas

Blood and lymphatic system

Leukopenia, Agranulocytosis, thrombocytopenia

Immune system disorders

Anaphylactoid reaction, hypersensitivity

Anaphylactic reaction. angioedema

Metabolism and nutrition disorders

Anorexia, decreased appetite

Psychiatric disorders

Insomnia

Anxiety

Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania

Nervous system disorders

Dysgeusia, headache

Loss of consciousness, dyskinesia, dizziness, tremor

Convulsion, ageusia, parosmia, anosmia, paraesthesia

Ear and labyrinth disorders

Vertigo, hearing impaired, tinnitus

Deafness

Cardiac disorders

Cardiac arrest, atrial fibrillation, electrocardiogram QT prolonged, extrasystoles, palpitations

Torsades de pointes

Vascular disorders

Vasodilation

Haemorrhage

Respiratory, thoracic and mediastinal disorder

Asthma, pulmonary embolism

Gastrointestinal disorders

Diarrhoea, vomiting, dyspepsia, nausea, abdominal pain

Oesophagitis, gastrooesophageal reflux disease, constipation, dry mouth, eructation, flatulence.

Pancreatitis acute, tongue discolouration, tooth discolouration

Hepatobiliary disorders

Liver function test abnormal

alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased

Hepatic failure, jaundice hepatocellular

Skin and subcutaneous tissue disorders

Rash, hyperhidrosis

Dermatitis bullous, pruritus, urticaria

Severe cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, toxic epidermal necrolysis, medicine rash with eosinophilia and systemic symptoms (DRESS))

acne

Musculoskeletal and connective tissue disorders

musculoskeletal stiffness

Renal and urinary disorders

Blood creatinine increased, blood urea increased

Renal failure, nephritis interstitial

General disorders and administration site conditions

Injection site phlebitis

Injection site pain

Investigations

Albumin globulin ratio abnormal, International normalised ratio increased, prothrombin time prolonged, urine colour abnormal

Reporting of suspected adverse reactions

Reporting 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 to SAHPRA via the u201c6.04 Adverse Medicine Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Reports indicate that the ingestion of large amounts of clarithromycin orally can be expected to produce gastro-intestinal symptoms. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxaemia. Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed medicine and supportive measures. As with other macrolides, CLARICULE serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis. In the case of overdosage, CLARICULE should be discontinued and all other appropriate supportive measures should be instituted.