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

Logo Clarithromycin HEXAL™ 500 film coated tablets
SCHEDULING STATUS
S4

PROPRIETARY NAME
(and dosage form):

Clarithromycin HEXAL™ 500 film coated tablets

COMPOSITION
Clarithromycin HEXAL 500 film coated tablets: Each film coated tablet contains 500 mg clarithromycin

PHARMACOLOGICAL CLASSIFICATION
A 20.1.1 - Medium and broad 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 microorganisms, thereby inhibiting bacterial RNA-dependent 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 gastrointestinal tract after oral administration, but its bioavailability is reduced to 50 to 55% because of rapid first-pass metabolism. Peak plasma concentration occurs approximately 2 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 nonrenal 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
Clarithromycin HEXAL 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 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.

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

WARNINGS
Clarithromycin HEXAL 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 Clarithromycin HEXAL is reduced in patients with renal function impairment, especially those with a creatinine clearance of <30 mL/min. The dose of Clarithromycin HEXAL 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 Clarithromycin HEXAL and the HMGCoA reductase inhibitors e.g. simvastatin (See INTERACTIONS).
• Rifabutin and rifampicin - May decrease serum concentration of Clarithromycin HEXAL 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 Clarithromycin HEXAL and other macrolides, lincomycin and clindamycin has been reported.

INTERACTIONS
Concomitant use of Clarithromycin HEXAL 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 Clarithromycin HEXAL. Concurrent use is contraindicated. See CONTRAINDICATIONS.
• Anticoagulants such as warfarin - Clarithromycin HEXAL may result in the potentiation of the effects of warfarin. Prothrombin time should be monitored closely.
• Digoxin - Clarithromycin HEXAL 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) - Clarithromycin HEXAL 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 Clarithromycin HEXAL and the HMGCoA reductase inhibitors e.g. simvastatin (See WARNINGS).
• Rifabutin and rifampicin - May decrease serum concentration of Clarithromycin HEXAL by >50%. Co-administration has been reported to cause a higher incidence of uveitis compared to rifabutin alone (See WARNINGS).
• 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 Clarithromycin HEXAL should be taken at least 4 hours apart.
• Ritonavir - The metabolism of Clarithromycin HEXAL is inhibited. No dosage reduction of Clarithromycin HEXAL is needed in patients with normal renal function. Patients with renal function impairment require a reduction in the dose of Clarithromycin HEXAL 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 1g/day during concurrent administration of Clarithromycin HEXAL with ritonavir.
* It has been suggested that other HIV-protease inhibitors and non-nucleoside reverse transcriptase inhibitors may have a similar effect on Clarithromycin HEXAL.

PREGNANCY AND LACTATION
Safety and efficacy in pregnancy and lactation have not been established. Clarithromycin HEXAL is excreted in the breast milk.

DOSAGE AND DIRECTIONS FOR USE
Safety and efficacy in infants under 6 months of age has not been established. The recommended dose for children under 6 months is based upon a 7,5 mg/kg dose, administered twice daily.
The usual duration of treatment is 5 to 10 days, depending on the pathogen involved and the severity of infection.
In patients with severe renal function impairment (creatinine clearance <30 mL/min), the dosage of Clarithromycin HEXAL should be reduced by half. Do not continue treatment in these patients for more than 14 days.
Clarithromycin HEXAL may be taken with or without meals and can be taken with milk.
Adults: 250 mg twice daily.
In more severe infections, the dosage may be increased to 500 mg twice daily.
Renal impairment:
Creatinine clearance (<30 mL/min): Reduce dose by half i.e. 250 mg once daily or 250 mg twice daily for severe infections. Limit the duration of treatment to 14 days.

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

Atypical mycobacterial infections (MAC) in HIV patients
Adults: 500 mg twice daily
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 Clarithromycin HEXAL for more than 12 weeks. Clarithromycin HEXAL should be used in conjunction with other antimycobacterial agents.
Clarithromycin HEXAL may be taken with or without meals.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects:
Haematological:
• Less frequent: Leucopenia, thrombocytopenia
Cardiovascular
•QT prolongation, ventricular tachycardia, torsades de pointes Nervous system:
•Headache, anxiety, dizziness, insomnia, hallucinations, bad dreams, vertigo, tinnitus, disorientation, depersonalization, confusion, hearing loss, convulsionsEndocrine/Metabolic:
•Less frequent: HypoglycemiaGastrointestinal:
• 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: Increased in liver enzymes, hepatocellular and/or cholestatic hepatitis (with or without jaundice), pancreatitis
Skin:
•Mild skin eruptions, urticaria, Steven's-Johnson syndrome, toxic epidermal necrolysisOther:
•Allergic reactions, anaphylaxis
Special precautions:
Treatment with Clarithromycin HEXAL 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 Clarithromycin HEXAL 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 Clarithromycin HEXAL 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 Clarithromycin HEXAL can be expected to produce gastrointestinal 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. Clarithromycin HEXAL is not expected to be appreciably affected by haemodialysis or dialysis.

IDENTIFICATION
Clarithromycin HEXAL 500 tablets:
White, oblong, convex, coated tablets, scored on both faces.
Length: 18.5 + 0.2 mm
Width: 8.1 + 0.2 mm
Thickness: 6.4 + 0.3 mm

PRESENTATION
Clarithromycin HEXAL 500 tablets:
White opaque PVC/aluminium blister strips containing 10 tablets each.
1 blister strip of 10 tablets to be packed into a carton i.e. 10 tablets per carton.

STORAGE
Store below 25°C and protect from light.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBER
Clarithromycin HEXAL 500: 38/20.1.1/0006

NAME AND BUSINESS ADDRESS OF APPLICANT
HEXAL Pharma (SA) Pty LTD
46 Mahogany Road
Mahogany Ridge
Pinetown
3610

DATE OF PUBLICATION OF PACKAGE INSERT
06/2005

New addition to this site: July 2005
Source: Pharmaceutical Industry

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