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

Logo KLARITHRAN 250 Tablets
KLARITHRAN 500 Tablets
KLARITHRAN SUSPENSION 125 mg/5 mL (Granules for Oral Suspension)
KLARITHRAN SUSPENSION 250 mg/5 mL (Granules for Oral Suspension)

SCHEDULING STATUS:
Schedule 4

PROPRIETARY NAME
(and dosage form):

KLARITHRAN 250 Tablets
KLARITHRAN 500 Tablets
KLARITHRAN SUSPENSION 125 mg/5 mL (Granules for Oral Suspension)
KLARITHRAN SUSPENSION 250 mg/5 mL (Granules for Oral Suspension)

COMPOSITION
Klarithran 250 Tablets
Each film coated tablet contains
Clarithromycin        250 mg
Sugar free
Klarithran 500 Tablets
Each film coated tablet contains
Clarithromycin        500 mg
Sugar free
Klarithran Suspension 125 mg/5 mL
Each 5 mL of constituted suspension contains
Clarithromycin        125 mg
Sodium benzoate (as preservative) 0,2%m/v
Sugar +3 g
Klarithran Suspension 250 mg/5 mL
Each 5 mL of constituted suspension contains
Clarithromycin        250 mg
Sodium benzoate (as preservative) 0,2%m/v
Sugar +2,5 g

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 vitroantibacterial spectrum of pathogens sensitive to clarithromycin includes:
(in vitrosensitivity does not necessarily imply in vivoefficacy)
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 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 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
Klarithranis indicated for the treatment of the following mild to moderate severe infections caused by susceptible organisms:
        o Lower respiratory tract infections such as bronchitis and pneumonia.
        o Upper respiratory tract infections such as pharyngitis and sinusitis.
        o Mild to moderately severe acute otitis media due to S. pneumoniae, M. catarrhalis andH. influenza.
        o Skin and soft tissue infections such as folliculitis, cellulitis or erysipelas.
Eradication of Helicobacter pyloriwhen 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 with astemizole, cisapride, pimozide and terfenadine (See Interactions).
Porphyria.

WARNINGS
Klarithran
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 Klarithranis reduced in patients with renal function impairment, especially those with a creatinine clearance of <30 mL/min. The dose of Klarithranshould 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 Klarithranand the HMGCoA reductase inhibitors e.g. simvastatin (See Interactions).
Rifabutin and rifampicin –May decrease serum concentration of Klarithranby >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 Klarithranand other macrolides, lincomycin and clindamycin have been reported.

INTERACTIONS
Concomitant use of Klarithranwith:
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. Concurrent use is contra-indicated. See Contra-indications.
Anticoagulants such as warfarin –Klarithranmay result in the potentiation of the effects of warfarin. Prothrombin time should be monitored closely.
Digoxin –Klarithran 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 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 and the HMGCoA reductase inhibitors e.g. simvastatin (See Warnings).
Rifabutin and rifampicin –May decrease serum concentration of Klarithranby >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 Klarithranshould be taken at least 4 hours apart.
Ritonavir –The metabolism of Klarithranis inhibited. No dosage reduction of Klarithranis needed in patients with normal renal function. Patients with renal function impairment require a reduction in the dosage of Klarithranas 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 Klarithranwith ritonavir.
  It has been suggested that other HIV-protease inhibitors and non-nucleoside reverse transcriptase inhibitors may have a similar effect on Klarithran.

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

DOSAGE AND DIRECTIONS FOR USE
Children
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. See dosage table below.
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 Klarithranshould be reduced by half. Do not continue treatment in these patients for more than 14 days.
Klarithranmay be taken with or without meals and can be taken with milk.
Weight Approximate age Dose in mL of
125 mg/5 mL suspension
Dose in mL of
250 mg/5 mL suspension
8 to 11 kg 1 to 2 years 2,5 mL twice daily -
12 to 19 kg 2 to 4 years 5 mL twice daily 2,5 mL twice daily
20 to 29 kg 4 to 8 years 7,5 mL twice daily 3,75 mL twice daily
30 to 40 kg 8 to 12 years 10 mL twice daily 5 mL twice daily
Reconstitution instructions:
The quantity of distilled water specified for the pack size in the table below should be added to the granules and the contents shaken well.
Pack size Volume of water to be added
60 mL         34 mL
70 mL         40 mL
100 mL         55 mL
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 Klarithranin 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 Klarithranfor more than 12 weeks. Klarithranshould be used in conjunction with other antimycobacterial agents.
Klarithranmay be taken with or without 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 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 Klarithranhas 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 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 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. Klarithranis not expected to be appreciably affected by haemodialysis or dialysis.

IDENTIFICATION
Klarithran 250 Tablets:
Light yellow coloured, oval shaped, biconvex, film coated tablets, debossed with “C1”on one side.
Klarithran 500 Tablets: Light yellow coloured, oval shaped, biconvex, film coated tablets with “C”and “2” debossed on either side of breakline on one side and notched on either sides along with the breakline.
Klarithran Suspension 125 mg/5 mL: White to off-white granular powder forming a white to off-white suspension on constitution with water. The resulting suspension has a sweet taste and fruity flavour.
Klarithran Suspension 250 mg/5 mL: White to off-white granular powder forming a white to off-white suspension on constitution with water. The resulting suspension has a sweet taste and fruity flavour.

PRESENTATION
Klarithran 250 Tablets:
Blister strips comprising of clear PVC film (coated uniformly with PVdC on outer side) with a backing of aluminium foil (coated with heat seal lacquer) containing 4, 10 or 14 tablets.
Klarithran 500 Tablets: Blister strips comprising of clear PVC film (coated uniformly with PVdC on outer side) with a backing of aluminium foil (coated with heat seal lacquer) containing 10 or 14 tablets.
Klarithran Suspension 125 mg/5 mL: Natural translucent HDPE bottle pack of 60 mL, 70 mL and 100 mL.
Klarithran Suspension 250 mg/5 mL: Natural translucent HDPE bottle pack of 60 mL, 70 mL and 100 mL.

STORAGE INSTRUCTIONS
Klarithran 250 and 500 Tablets:
Store below 25°C in original package, protected from moisture.
Klarithran Suspension 125 and 250 mg/5 mL:
Store below 25°C. Keep the bottle tightly closed. Do not refrigerate or freeze. Discard the unused portion of constituted suspension after 14 days.
SHAKE THE BOTTLE WELL BEFORE USE.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBERS
Klarithran 250 Tablets
: 37/20.1.1/0436
Klarithran 500 Tablets: 37/20.1.1/0437
Klarithran Suspension 125 mg/5 mL: 38/20.1.1/0174
Klarithran Suspension 250 mg/5 mL: 38/20.1.1/0175

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
June 2005

Updated on this site: Aug 2007
Source: Pharmaceutical Industry

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