Klarithran Mr 500 500 mg Tablet.

KLARITHRAN MR 500 is indicated for the treatment of the following mild to moderately severe infections caused by susceptible organisms:

• Lower respiratory tract infections such as bronchitis and pneumonia.
• Upper respiratory tract infections such as pharyngitis and sinusitis.
• Mild to moderately severe acute otitis media due to S. pneumoniae, M. catarrhalis and H. influenza.
• Skin and soft tissue infections such as folliculitis, cellulitis or erysipelas.
• Eradication of Helicobacter pylori when used in combination with a proton pump inhibitor and another antibiotic to decrease recurrence of duodenal ulcer.

Adults: 500 mg once daily with food. In more severe infections, the dosage may be increased to 2 x 500 mg once daily.

Renal impairment: Creatinine clearance (<30 ml/min): Klarithran MR 500 should not be used in patients with significant renal impairment (creatinine clearance less than 30 ml/min). Klarithran 250 and 500 mg immediate release tablets may be utilized in this patient population.

Eradication of H. pylori: Adults: 2 x 500 mg once daily with food, in combination with an appropriate antibiotic and an acid lowering agent, for 7 to 10 days. The safety and efficacy of Klarithran MR 500 in combination with proton-pump inhibitors other than omeprazole has not been established.

Atypical mycobacterial infections (MAC) in HIV patients: Adults: 2 x 500 mg once daily with food. 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 taking KLARITHRAN MR 500 for more than 12 weeks. KLARITHRAN MR 500 should be used in conjunction with other antimycobacterial agents. KLARITHRAN MR 500 must be taken with meals.

Method of administration: Administration is by the oral route.

• Hypersensitivity to macrolide antibiotics or excipients in listed in section 6.1.
• Concomitant administration of KLARITHRAN MR 500 with astemizole, cisapride, pimozide and terfenadine (See Interactions).
• Porphyria.

KLARITHRAN MR 500 should be used with caution in:

• Liver function impairment u2013 The pharmacokinetics are altered. No dosage adjustment is required in patients with hepatic function impairment, unless there is also concurrent severe renal function impairment.
• Renal function impairment (severe) u2013 The elimination of KLARITHRAN MR 500 is reduced in patients with renal function impairment, especially those with a creatinine clearance of < 30 ml/min. The dose of KLARITHRAN MR 500 should be halved or the dosing interval doubled in patients with a creatinine clearance of < 30 ml/min.
• Rhabdomyolysis has been reported with concomitant use of KLARITHRAN MR 500 and the HMGCoA reductase inhibitors e.g. simvastatin (See Section 4.5).
• Rifabutin and rifampicin u2013 May decrease serum concentration of KLARITHRAN MR 500 by > 50 %. Co-administration has been reported to cause a higher incidence of uveitis compared to rifabutin alone. (See Section 4.5).
• Theophylline u2013 The area under the plasma concentration-time curve is increased. Monitoring of theophylline serum concentrations is recommended (See Section 4.5).
• Cross-resistance between KLARITHRAN MR 500 and other macrolides, lincomycin and clindamycin have been reported.
• Treatment with KLARITHRAN MR 500 should be discontinued if any signs of hepatic dysfunction develop. Hepatic dysfunction is usually reversible, but may be severe. In rare instances, hepatic failure with fatal outcome has been reported, usually associated with other serious underlying diseases and/or concomitant medicines. Isolated cases of increased serum creatinine have been reported, but an association with KLARITHRAN MR 500 has not been established.
• There have been less frequent reports of hypoglycaemia, some of which occurred in patients on concomitant oral hypoglycaemics or insulin.
• Adverse effects in immunocompromised patients treated with higher doses of KLARITHRAN MR 500 over long periods include nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, hearing disturbance, AST (Aspartate aminotransferase) and ALT (Alanine aminotransferase) elevations, elevated BUN (Blood Urea Nitrogen) levels and abnormally low white blood cell and platelet counts. Additional low-frequency events included dyspnoea, insomnia and dry mouth.
• Contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Concomitant use of KLARITHRAN MR 500 with:

• Astemizole, cisapride, pimozide and terfenadine u2013 Has resulted in cardiac arrhythmias, including QTc-interval prolongation, ventricular arrhythmia, ventricular tachycardia, ventricular fibrillation and torsade de pointes. Fatalities have occurred. The most likely cause is the inhibition of metabolism of these medicines by KLARITHRAN MR 500. Concurrent use is contra-indicated. (See Section 4.3)
• Anticoagulants such as warfarin u2013 KLARITHRAN MR 500 may result in the potentiation of the effects of warfarin. Prothrombin time should be monitored closely.
• Digoxin u2013 KLARITHRAN MR 500 has been shown to increase serum digoxin concentrations. Monitoring of digoxin serum concentrations is recommended.
• Carbamazepine or other medicines metabolised by the cytochrome P450 enzyme system for example, alprazolam, cyclosporine, disopyramide, ergot alkaloids, methylprednisolone, midazolam, omeprazole, quinidine, sildenafil, simvastatin, tacrolimus, triazolam, vinblastine, phenytoin, and valproate u2013 KLARITHRAN MR 500 may be associated with increased levels of these medicines. Serum concentrations of these medicines may require monitoring.
• Rhabdomyolysis has been reported with concomitant use of KLARITHRAN MR 500 and the HMGCoA reductase inhibitors e.g. simvastatin (See Section 4.4).
• Rifabutin and rifampicin u2013 May decrease serum concentration of KLARITHRAN MR 500 by > 50 %. Co-administration has been reported to cause a higher incidence of uveitis compared to rifabutin alone (See Section 4.4).
• Theophylline u2013 The area under the plasma concentration-time curve is increased. Monitoring of theophylline serum concentrations is recommended (See Section 4.4).
• Zidovudine u2013 A decrease in the steady-state concentration of zidovudine may occur. Doses of zidovudine and Klarithran MR 500 should be taken at least 4 hours apart.
• Ritonavir u2013 The metabolism of Klarithran MR 500 is inhibited. No dosage reduction of Klarithran MR 500 is needed in patients with normal renal function. Patients with renal function impairment require a reduction in the dosage of Klarithran MR 500 as follows: Creatinine clearance 30 to 60 ml/min u2013 Reduce dose by 50 %. Creatinine clearance of <30 ml/min u2013 Reduce dose by 75 %. Do not exceed a dose of 1 g/day during concurrent administration of Klarithran MR 500 with ritonavir. It has been suggested that other HIV-protease inhibitors and non-nucleoside reverse transcriptase inhibitors may have a similar effect on Klarithran MR 500.

Safety and efficacy in pregnancy and lactation have not been established. KLARITHRAN MR 500 is excreted in the breast milk.

The effects on ability to drive and use machines has not been established.

System Organ Class Frequency Adverse Reaction

• Blood and lymphatic system disorders: Less frequent Leucopenia, thrombocytopenia.
• Endocrine disorders: Less frequent Hypoglycaemia.
• Nervous system disorders: Less frequent Headache, anxiety, dizziness, insomnia, hallucinations, bad dreams, vertigo, tinnitus, disorientation, depersonalisation, confusion, hearing loss, convulsions.
• Cardiac disorders: QT prolongation, ventricular tachycardia, torsades de pointes.
• Gastro-intestinal disorders: Frequent Nausea, vomiting, abdominal pain, abnormal taste, diarrhoea. Less frequent Glossitis, stomatitis, oral candidiasis, tongue discolouration, tooth discolouration, pseudomembranous colitis (abdominal cramps or pain, tenderness, severe, watery diarrhoea which may also be bloody, fever).
• Hepato-biliary disorders: Less frequent Increase in liver enzymes, hepatocellular and/or cholestatic hepatitis (with or without jaundice), pancreatitis.
• Skin and subcutaneous tissue disorders: Frequency Unknown Mild skin eruptions, urticaria, Stevenu2019s - Johnson syndrome, toxic epidermal necrolysis.
• Other: Frequency Unknown Allergic reactions, anaphylaxis.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Ingestion of large amounts of Klarithran MR 500 can be expected to produce gastro-intestinal symptoms. Allergic reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed medicine and supportive measures. Treatment is symptomatic and supportive. KLARITHRAN MR 500 is not expected to be appreciably affected by haemodialysis or dialysis.