INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo KLARITHRAN MR 500 (Tablets)
SCHEDULING STATUS:
Schedule 4

PROPRIETARY NAME
(and dosage form):

KLARITHRAN MR 500 (Tablets)

COMPOSITION:
Each film-coated tablet contains clarithromycin500 mg.
Sugar free.

PHARMACOLOGICAL CLASSIFICATION
A 20.1.1 Broad and medium spectrum antibiotics

PHARMACOLOGICAL ACTION
Clarithromycin is a macrolide antibiotic. It exerts its antibacterial action by binding reversibly to the 50S ribosomal subunit of the 70S ribosome of sensitive micro organisms, thereby inhibiting bacterial RNA-dependant protein synthesis. The in vitro antibacterial spectrum of pathogens sensitive to clarithromycin includes:
(in vitro sensitivity does not necessarily imply in vivo efficacy)
Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumoniae, Legionelle pneumophilia
Mycoplasma pneumoniae
Chlamydia trachomatis
Moraxella (Branhamella) catarrhalis
Haemophilus influenzae
Staphylococcus aureus (methicillin sensitive)
Helicobacter pylori
Mycobacterium avium, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium intracellulare

Pharmacokinetics
Clarithromycin is absorbed rapidly from the gastro-intestinal tract after oral administration, but its bioavailability is reduced to 50% to 55% because of rapid first-pass metabolism. Peak plasma concentration occurs approximately 5 to 7 hours after administration. Clarithromycin may be given with or without food. Clarithromycin is metabolised by the liver to the active metabolite, 14-hydroxyclarithromycin, as well as to several other metabolites. Both clarithromycin and 14-hydroxyclarithromycin distribute widely throughout the body and achieve high intracellular concentrations. Tissue concentrations generally exceed serum concentrations. Clarithromycin does not achieve significant levels in the cerebrospinal fluid. Protein binding of clarithromycin ranges from 40 to 70% and is concentration-dependent. The elimination half-lives of clarithromycin and 14-hydroxyclarithromycin are approximately 3 to 7 and 5 to 9 hours respectively. Longer half-lives are observed after larger doses. Clarithromycin is eliminated by renal and non-renal routes. The amount of clarithromycin excreted unchanged in the urine ranges from 20 to 40%, depending on the dose administered and the formulation. Between 10 and 15% of the dose is excreted in the urine as the 14-hydroxy metabolite. Although the pharmacokinetics of clarithromycin are altered in patients with hepatic or renal dysfunction, dosage adjustment is not necessary unless a patient has severe renal dysfunction (creatinine clearance of <30 mL/minute). At higher doses in HIV-infected patients clarithromycin and 14-hydroxyclarithromycin concentrations are much higher when compared with usual doses in non-infected patients. The elimination half-lives also appear to be lengthened.

INDICATIONS
• Klarithran MR 500 is indicated for the treatment of the following mild to moderate 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 andH. 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.

CONTRA-INDICATIONS
• Hypersensitivity to macrolide antibiotics or to any component of the formulation.
• Concomitant administration of Klarithran MR 500 with astemizole, cisapride, pimozide and terfenadine (See Interactions).
• Porphyria.

WARNINGS
Klarithran MR 500 should be used with caution in:
• Liver function impairment - 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) - 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 Interactions).
• Rifabutin and rifampicin - 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 Interactions).
• Theophylline - The area under the plasma concentration-time curve is increased. Monitoring of theophylline serum concentrations is recommended (See Interactions).
• Cross-resistance between Klarithran MR 500 and other macrolides, lincomycin and clindamycin have been reported.

INTERACTIONS
Concomitant use of Klarithran MR 500 with:
• Astemizole, cisapride, pimozide and terfenadine - 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 Contra-indications.
• Anticoagulants such as warfarin - Klarithran MR 500 may result in the potentiation of the effects of warfarin. Prothrombin time should be monitored closely.
• Digoxin - 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 - 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 Warnings).
• Rifabutin and rifampicin - 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 (SeeWarnings).
• Theophylline - The area under the plasma concentration-time curve is increased. Monitoring of theophylline serum concentrations is recommended (See Warnings)
• Zidovudine - 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 - 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 - Reduce dose by 50%.
           Creatinine clearance of <30 mL/min - 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.

PREGNANCY AND LACTATION
Safety and efficacy in pregnancy and lactation have not been established. Klarithran MR 500 is excreted in the breast milk.

DOSAGE AND DIRECTIONS FOR USE
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 x500 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.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The adverse events considered at least possibly related to the treatment are listed below by body system, organ class and frequency (wherever applicable). Frequencies are defined as very common (>1/10), common (frequent) (>1/100, <1/10), uncommon (infrequent) (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000) or isolated case reports.
Haematological:
• Less frequent: Leucopenia, thrombocytopenia.
Endocrine/Metabolic:
•Less frequent: Hypoglycaemia.
Nervous System:
• Headache, anxiety, dizziness, insomnia, hallucinations, bad dreams, vertigo, tinnitus, disorientation, depersonalisation, confusion, hearing loss, convulsions.
Cardiovascular:
•QT prolongation, ventricular tachycardia, torsades de pointes.
Gastro-intestinal:
• 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).
Liver:
• Less frequent: Increase in liver enzymes, hepatocellular and/or cholestatic hepatitis (with or without jaundice), pancreatitis
Skin:
•Mild skin eruptions, urticaria, Steven’s-Johnson syndrome, toxic epidermal necrolysis.
Other:
•Allergic reactions, anaphylaxis.
Special Precautions
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 and ALT elevations, elevated BUN levels and abnormally low white blood cell and platelet counts. Additional low-frequency events included dyspnoea, insomnia and dry mouth.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See Side-effects and Special Precautions.
Symptoms of overdose
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 of overdose
Treatment is symptomatic and supportive. Klarithran MR 500 is not expected to be appreciably affected by haemodialysis or dialysis.

IDENTIFICATION
Pale yellow coloured, oval, biconvex, film coated tablets printed with ‘CLNXL’in black ink on one side and plain on the other.

PRESENTATION
5 or 10 tablets packed in blister strips. Blister strips comprise of clear, transparent, PVC film-coated with PVdC, having a backing of plain aluminium foil.
Cartons contain 5 or 10 tablets.

STORAGE INSTRUCTIONS
Store below 25°C in the original container protected from moisture.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
A39/20.1.1/0619

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
RANBAXY (SA) (PTY) LTD
Third Floor
Outspan House
1006 Lenchen Avenue North
Centurion

DATE OF PUBLICATION OF THE PACKAGE INSERT
December 2006

Updated on this site: February 2007
Source: Pharmaceutical Industry

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