KLARIM 250mg Tablet (Clarithromycin)

KLARIM 250mg Tablet (Clarithromycin)

KLARIM 250mg Tablet (Clarithromycin)

KLARIM (Clarithromycin) is a semi-synthetic macrolide antibiotic obtained by substitution of the hydroxyl group in position 6 by a CH3O group in the erythromycin lactonic ring. Chemically clarithromycin is 6-O-Methylerythromycin. The molecular formula is C38H69NO13 and the structural formula is:

COMPOSITION

KLARIM (Clarithromycin ) is available for oral administration as:

KLARIM Tablet 250mg

Each film-coated tablet contains:

Clarithromycin ……250m

 KLARIM Dry Suspension 125mg/5ml

 Each reconstituted 5ml contains:

 Clarithromycin ….…125mg

 CLINICAL PHARMACOLOGY

Mechanism of Action    

Clarithromycin exerts its anti-bacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and

suppresses protein synthesis. It is highly potent against a wide variety of aerobic and anaerobic gram positive and gram negative organisms.

Microbiology:

Clarithromycin has shown to be active against the following microorganisms:

Aerobic gram-positive microorganisms

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

Listeria monocytogenes

Aerobic gram-negative microorganisms

Haemophilus influenzae

Haemophilus parainfluenzae

Moraxella catarrhalis

Neisseria gonorrheae

Legionella spp. (e.g., Legionella pneumophila)

 Mycobacteria

Mycobacterium leprae

Mycobacterium kansasii

Mycobacterium chelonae

Mycobacterium fortuitum

Mycobacterium avium complex [MAC] (consisting of: Mycobacterium avium

Mycobacterium intracellulare)

Helicobacter

Helicobacter pylori

Other microorganisms

Mycoplasma pneumoniae

Chlamydia pneumoniae (TWAR)

Chlamydia trachomatis

Ureaplasma urealytieum

Protozoan Toxoplasma gondii

 Pharmacokinetics

Absorption:

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of a 250mg clarithromycin tablet is approximately 50%. The

bioavailability of the suspension is identical to or slightly higher than the bioavailability of the tablets. The pharmacokinetic profile of the suspension in children corresponds to the pharmacokinetic profile of the suspension in adults.Due to its chemical structure (6-O-Methylerythromycin) clarithromycin is quite resistant to degradation by stomach acid. After oral administration of 250mg & 500mg clarithromycin twice daily, peak plasma levels of 1-2 µg/mL & 2.8µg/mL were observed respectively in adults. The peak plasma concentration of pharmacological active 14-hydroxy metabolite was 0.6µg/mL after the administration of 250mg clarithromycin twice daily. Steady state is attained within 2 days of dosing.

Effect of Food

Food slightly delays the absorption of clarithromycin but does not affect the extent of bioavailability, therefore it may be given without regard to food.

Distribution:

Clarithromycin penetrates well into different compartments, with an estimated volume of distribution of 200-400L. Clarithromycin provides concentrations in some tissues that are several times higher than the circulating level of the active substance. Increased levels have been found in both tonsils and lung tissue. Clarithromycin also penetrates the gastric mucus. Clarithromycin is approximately 80% bound to plasma proteins at therapeutic levels.

Metabolism:

Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism involves mainly N-dealkylation, oxidation and sterespecific hydroxylation at position C14.

Excretion

Clarithromycin is excreted in the feces (5-10%) via the bile. At steady state approximately 20% and 30% of clarithromycin is excreted as unchanged drug in urine. 14-hydroxy clarithromycin as well as other metabolites are also excreted in the urine accounting for 10% to 15% of the dose. The elimination half-life of clarithromycin is reportedly about 3 to 4 hours in patients receiving 250mg doses twice daily, and about 5 to 7 hours in those receiving 500mg twice daily. The principal metabolite, 14-OH-clarithromycin has an elimination half-life of 5 to 6hours after a dose of 250mg twice daily and about 7 to 9 hours in those receiving 500 mg twice daily.

Special Populations

Renal impairment:

The plasma levels, half-life, Cmax and Cmin for both clarithromycin and its 14-OH metabolite were higher and the AUC was larger in subjects with renal impairment.

THERAPEUTIC INDICATIONS

KLARIM (Clarithromycin) is indicated for treatment of infections due to susceptible organisms. Such infections include:

– Lower respiratory tract infections (e.g., bronchitis, pneumonia)

– Upper respiratory tract infections (e.g. pharyngitis, sinusitis, tonsillitis)

– Acute otitis media in children

– Skin and soft tissue infections (e.g., folliculitis, cellulitis, erysipelas, impetigo, abscesses)

– Disseminated or localized mycobacterium infections due to MAC.

– To eradicate Helicobacter pylori in treatment regimens for peptic ulcer disease.

– To prevent disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.

– As an alternative treatment to penicillins for prophylaxis of endocarditic.

DOSAGE AND ADMINISTRATION

Adults:

The usual recommended dosage of CLARITEK (Clarithromycin) is 250mg tablet twice daily. In more severe infections the dosage can be increased to 500mg twice daily. The usual duration of therapy is 6 to 14 days.

The following table is a suggested guide for determining dosage:

ADULT DOSAGE GUIDELINES
Infection Dosage (q 12 h) Normal Duration (days)
Pharyngitis tonsillitis due to
S.pyogenes 250 mg 10
Acute maxillary sinusitis due to
H. influenzae 500 mg 14
S. pneumoniae 500 mg 14
Acute exacerbation of chronic bronchitis due to
H. influenzae 500 mg 7 -14
H. parainfluenzae 500 mg 7
M.clarrhals 250 mg 7 -14
S. pneumoniae 250 mg 7 -14
Community Acquired pneumonia due to
H. influenzae 250 mg 7
H. parainfluenzae
M.clarrhals
S. pneumoniae 250 mg 7 -14
C. pneumoniae 250 mg 7 -14
M. pneumoniae 250 mg 7 -14
Uncompleted skin and skin structure
S.aureus 250 mg 7 -14
S.pyogenes 250 mg 7 -14
         

Children:The usual recommended daily dosage of KLARIM  (Clarithromycin) suspension is 7.5mg/kg B.I.D up to a maximum of 500mg twice daily. The usual duration of treatment is 5 to 10 days depending on the pathogen involved and

the severity of the condition.

The following table is a suggested guide for determining dosage

PEDIATRIC DOSAGE GUIDELINES (Based on body Wt)
Weight Dosage in mg Dosage in ml

125ml/5ml

Dosage in ml

250ml/5ml

 

8- 11 Kg

 

52.5 mg b.i.d

 

2.5 ml b.i.d

 

1.25 ml b.i.d

 

11- 19 Kg

 

125mg b.i.d

 

5 ml b.i.d

 

2.5 ml b.i.d

 

20- 29 Kg

 

187.5mg b.i.d

 

7.5 ml b.i.d

 

3.75 ml b.i.d

 

30-40 Kg

 

250mg b.i.d

 

10 ml b.i.d

 

5 ml b.i.d

  • Children <8Kg should be dosed on per Kg basis (approx 7.5 mg/Kg B.I.D)

Dosage for the eradication of H. pylori associated with peptic ulcer disease KLARIM  (Clarithromycin), usually in a dose of 500mg twice daily, is given with another antibacterial and either a proton pump inhibitor or a histamine H2- receptor antagonist, for 7 to 14 days.

Dosage for Mycobacterial Infections

Adults:KLARIM  (Clarithromycin) is recommended as the primary agent for the prophylaxis and treatment of disseminated infection due to Mycobacterium avium complex. Clarithromycin should be used in combination with other antimycobacterial drug that have shown in vitro activity against MAC or clinical benefit in MAC treatment. The recommended dose for mycobacterial infections in adults is 500mg b.i.d.

Children:In children, the recommended dose is 7.5mg/kg b.i.d up to 500mg b.i.d. Dosing recommendations for children are in the table above.

Renal Impaired Patients:

The maximum recommended dosages should be reduced proportionately to renal impairment. At creatinine clearance rate of < 30 mL/min, the dosage should be halved to 250mg daily or in the most severe infections to 250mg twice daily for adults and 7.5 mg/kg once a day for children. The duration of treatment should not exceed 14 days in these patients.

Direction for reconstitution

Fill previously boiled and cooled water up to the mark on the bottle and shake well. After mixing, do not refrigerate. Keep tightly closed after use.

CONTRAINDICATIONS

– Clarithromycin is contraindicated in patients with known hypersensitivity to the active substance, other macrolide  

   antibiotics or to any of the excipients.

– Concomitant administration of clarithromycin with any of the following medicines is contraindicated: astemizole,

   cisapride, pimozide and terfenadine.

– Concomitant administration of Clarithromycin with ergot derivatives is contraindicated.

ADVERSE REACTIONS

The following side effects were reported with the use of Clarithromycin:

Common: Oral monilia, headache, smell alteration, nausea, diarrhea, vomiting, abdominal pain, dyspepsia, stomatitis, glossitis, reversible tooth and tongue discoloration, and taste perversion, i.e. metallic or bitter taste.

Uncommon: Decreased leucocyte levels, allergic reactions ranging from urticaria and mild skin eruptions to naphylaxis, hepatic dysfunction which is usually transient and reversible, hepatitis and cholestasis with or without jaundice,

arthralgia and myalgia.

Rare:Tinnitus

Very Rare: Thrombocytopenia, anxiety, insomnia, hallucinations, psychosis, disorientation, depersonalization, bad dreams and confusion, dizziness, vertigo, paraesthesia, convulsions, Reversible hearing loss, QT prolongation, ventricular tachycardia and Torsades de Pointes, pancreatitis, pseudomembranous colitis in range of severity from mild to life threatening, fatal hepatic failure in patientswith pre-existing liver disease or taking other hepatotoxic medicinal products, Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis and renal failure.

 PRECAUTIONS

-Caution should be taken in administering Clarithromycin to patients with impaired hepatic function.

– Caution should also be paid to the possibility of cross-resistances between Clarithromycin and other macrolide drugs,  as well as lincomycin and clindamycin.

– Pseudomembranous colitis has been reported with the use of broad-spectrum antibiotics. Therefore, it is important to

  consider its diagnosis in patients who develop severe diarrhea during or after therapy with Clarithromycin.

– Prolonged or repeated use of Clarithromycin may result in super infections with insusceptible organisms. In case of superinfection, Clarithromycin therapy should be stopped.

– Clarithromycin should be used with caution whenever indicated for use in patients receiving treatment with an inducer of CYP3A4.

– Clarithromycin in combination with ranitidine bismuth citrate therapy should not be used in patients with a history of acute porphyria.

– Clarithromycin, is an inhibitor of the metabolising enzyme CYP3A4 should not be used concomitantly with different

   CYP3A4 substrates unless plasma levels, therapeutic effect or adverse events of the CYP3A4 substrate are closely monitored.

Pregnancy:

There are no adequate or well-controlled studies in pregnant women. Clarithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:

Clarithromycin and its active metabolite are excreted in breast milk. Therefore, diarrhea and fungus infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility

of sensitisation should be born in mind. The benefit of treatment of the mother should be weighed against the potential risk for the infant.

Drug interactions

Digoxin:Elevated digoxin serum concentrations have been reported in patients receiving clarithromycin and digoxin concomitantly. Monitoring of serum digoxin levels should be considered.

Quinidine/Disopyramide: Concurrent use of clarithromycin and quinidine or disopyramide may cause Torsades de Pointes. Electrocardiogram and serum levels of these medications should be monitored during clarithromycin therapy.

HMG-CoA Reductase Inhibitors:As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g. statins). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.

Zidovudine:Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. This interaction does not appear to occur in pediatric

HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine.

Ritonavir:Concomitant administration of clarithromycin and ritonavir resulted in a 77% increase in clarithromycin AUC and a 100% decrease in the AUC of 14- OH clarithromycin. Clarithromycin may be administered without dosage adjustment to patients with normal renal function taking ritonavir. However, for patients with renal impairment, dosage adjustments should be considered.

 

OVERDOSAGE

Overdose of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea. Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug

and supportive measures. As with other macrolides, clarithromycin serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

STORAGE

Store below 300C.

Protect from sunlight & moisture.

The reconstituted suspension can be used for up to 14 days, when stored at room temperature.

PRESENTATION    

KLARIM (Clarithromycin) Tablets 250mg are available in blister pack of 10’s.

KLARIM (Clarithromycin) Tablets 500mg are available in blister pack of 10’s.

KLARIM (Clarithromycin) Dry Suspension 125mg/5ml are available in 60ml.