Maclar 500 Clarithromycin Tablets USP

Maclar™ 500
Clarithromycin Tablets USP

For the use of Registered Medical Practitioners or a Hospital or a Laboratory

 

Composition

Each film coated tablet contains:

Clarithromycin USP 500mg

Excipients q.s.

Colours: Quinoline Yellow Lake and Titanium Dioxide BP

 

Description

Clarithromycin is a macrolide antiblotic. (2R,3S,4S,5R,6R,8R,10R,11R,12S,13R)-3-(2,6- Dideoxy-3-C, 30-dimethyI-alpha-L-ribo-hexopyranosyloxy)-11, 12-dihydroxy-6-methoxy-2,4,6,8, 10,12- hoxamethyI-9-oxo-5- (3,4,6-trideoxy-3-dimethylamino-beta-D-xylo- hexopyranosyloxy)pentadecan-13-olide; 6-O-Methylerythromycin. Its molecular formula is C38H69NO13 and the molecular weight is 748.0.

 

Clinical Pharmacology

Clarithromycin is a macrolide antibiotic which binds to the 50S subunit of the bacterial ribosome. By the binding to the ribosome, protein synthesis is inhibited. Clarithromycin is active against a host of aerobic and anaerobic gram-positive end gram-negative bacteria, as well as most Mycobacterium avium complex (MAC) bacteria. The main metabolite of clarithromycin (i.e. 14-hydroxyl clarithromycin) is twice as active as clarithromycin against Haemophilus influenzae, but is 4 to 7 times less active than clarithromycin against MAC isolates. The clinical role of the 14-hydroxyl clarithromycin metabolite against susceptible bacteria has not been evaluated.

Chemically, clarithromycin differs from erythromycin only in that it possesses a methoxy group rather than a hydroxyl group at position 6 of the macrolide ring. This not only makes the compound more stable in the presence of gastric acid, but also changes its metabolic fate such that a very active 14-hydroxy-clarithromycin metabolite is formed; this metabolite is more active than the parent compound against Haemophilus influenzae. Clarithromycin is more active than erythromycin against pathogens such as Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae.

Clarithrornycin accumulates in pulmonary tissue.

At serum concentrations of 2g/mL, clarithromycin accumulates in leukocytes at concentrations approximately 9 times those reached in the plasma, which makes the drug particularly effective against intracellular pathogens such as Legionella pneumophila and Staphylococcus aureus.

Antimicrobal activity: Clarithromycin is usually active against the following organism in vitro:

Aerobic Gram-positive microorganisms Staphylococcus aureus

Streptococcus pneumonia

Streptococcus pyogenes

Aerobic Gram-negative microorganisms

Haemophilus influenzae

Haemophilus parainfluenzae

Moraxella catarrhalis

Other microorganisms

Mycoplasma pneumoniae

Chlamydia pneumoniae (TWAR)

Legionella pneumophila

Mycobacteria

Mycobacterium avium complex (MAC) consisting of:

Mycobacterium avium

Mycobacterium intracellulare

Beta-lactamase production should have no effect on clarithromycin activity.

NOTE: Most strains of methicillin-resistant staphylococci are resistant to clarithromycin:

Helicobacter

Helicobacter pylori

Omeprazole/clarithromycin dual therapy; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin /amoxicillln triple therapy; and lansoprazole/clarithromycin /amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections.

 

Pharmacokinetics

Clarithromycin is rapidly absorbed from the gastrointestinal tract following oral administration, and undergoes first-pass metabolism; the bioavailability of the parent drug is about 55%. The extent of absorption is relatively unaffected by the presence of food. Peak concentrations of clarithromycin and its principal active metaboilte, 14-hydroxyclarithromycin, are reported to be about 0.9 and 0.6 g /mL respectively following a single 250-mg dose by mouth; at steady state the same dose given every 12 hours as tablets produces peak concentrations of clarithromycin of about 1 g/mL.

The pharmacokinetics of clarithromycin is non-linear and dose dependent; high doses may produce disproportionate increases in peak concentrations of the parent drug, due to saturation of the metabolic pathways.

Clarithromycin and its principal metabolite are widely distributed, and tissue concentrations exceed those in serum, in part because of intracellular uptake. Clarithromycin has been detected in breast milk. It is extensively metabolized in the liver, and excreted in faeces via the bile. At steady state about 20% and 30% of a 250-mg or 500-mg dose as tablets, respectively, is excreted in the urine as unchanged drug. 14-Hydroxyclarithromycin as well as other metabolites is also excreted in the urine accounting for 10 to 15% of the dose. The terminal half-life of clarithromycin is reportedly about 3 to 4 hours in patients receiving 250-mg doses twice daily, and about 5 to 7 hours in those receiving 500mg twice daily. The half-life is prolonged in renal impairment.

 

Indications

Clarithromycin tablets are indicated for the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions as listed below:

Adults

• Acute bacterial exacerbation of chronic bronchitis

• Community acquired pneumonia

• Disseminated infection due to Mycobacterium avium-intracellulare group

• Disseminated infection due to Mycobacterium avium-intracellulare group; Prophylaxis – HIV infection

• Helicobacter pylori gastrointestinal tract infection

• Acute Maxillary sinusitis

Children

• Acute otitis media

• Community acquired pneumonia caused by M. pneumoniae, S. pneumoniae, and C. pneumoniae

• Disseminated infection due to Mycobacterium avium-intracellulare group

• Disseminated infection due to Mycobacterium avium-intracellulare group; Prophylaxis – HIV infection

• Acute Maxillary sinusitis

 

Contraindications

• Hypersensitivity to clarithromycin, erythromycin or other macrolide antibiotics

• Concomitant therapy with cisapride, pimozide, astemizole, or terfenadine; increase risk of cardiac arrhythmias

 

Precautions

• Monitor prothrombin times when clarithromycin and oral anticoagulants are given simultaneously

• Presence of severe renal impairment (dosage adjustment is needed)

• Concomitant therapy with ranitidine bismuth citrate is not recommended in patients with a history of acute porphyria

• Clarithromycin-resistant strains of Helicobacter pylori are possible; under these conditions do not use regimens that use clarithromycin as the sole antibiotic.

• Treatment given to children should be supervised.

 

Drug Interactions

Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.

Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered.

When clarithromycin and terfenadine were coadministered, plasma concentrations of the active acid metabolite of terfenadine were threefold higher, on average, than the values observed when tartenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-hydroxy- clarithromycin were not significantly affected by coadministration of terfenadine clarithromycin reached steady-state conditions.

Concomitant administration of clarithromycin with terfenadine is contraindicated.

The steady-state plasma concentrations of omeprazole were increased (Cmax AUC0.24, and t1/2 increases of 30%, 89%, and 34%, respectively); by the concomitant administration of clarithromycin 500mg administered every 8 hours.

Co-administration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). However these observations were not clinically significant.

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients resulted in decreased steady-state zidovudine concentrations.
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to healthy volunteers led to increases in the mean steady-state clarithromycin Cmin and AUC of 33% and 18%, respectively.

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.

Concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants.

Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post-marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

Erythromycin and clarithromycin are substrates and inhibitors of the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A). Coadministration of erythromycin or clarithromycin and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the concomitant drug. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin or erythromycin.

Drug interactions have been observed with erythromycin products and/or with clarithromycin and the following drugs metabolized by the CYP3A pathway:

Antiarrhythmic drugs, ergotamine / dihydroergotamine, benzodiazepines like triazolam, alprazoIam and midazolam, HMG co-enzyme inhibitors like lovastatin and simvastatin, cyclosporine, tacrolimus, disopyramide, rifabutin, quinidine, methylprednisolone, cilostazol and bromocriptine.

Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated.

There have been reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A including hexobarbital, phenytoin, and valproate.

 

Carcinogenesis, Mutagenesis and Impairment of Fertility

In vitro mutagenicity tests like Salmonella/Mammallan Microsomes Test, Bacterial Induced Mutation Frequency Test, In Vitro Chromosome Aberration Test, Rat Hepatocyte DNA Synthesis Assay, Mouse Lymphoma Assay, Mouse Dominant Lethal Study, Mouse Micronucleus Test, have been conducted with clarithromycin. All tests had negative results except the In Vitro Chromosome Aberration Test which was weakly positive in one test and negative in another. The Bacterial Reverse-Mutation or Ames test on clarithromycin metabolites revealed negative results.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.

Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day (1.3 times the recommended maximum human dose based on mg/m2) to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were 2 times the human serum levels.

In the 150 mg/kg/day monkey Studies, plasma levels were 3 times the human serum levels. When given orally at 150 mg/kg/day (24 times the recommended maximum human dose based on mg/m2), clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed to marked maternal toxicity of the drug at this high dose.

In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m2, which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m2

 

Toxicology data

Toxicology studies (on a mg/m2 basis) in animals were associated with following adverse effects in animals: Hepatotoxicity (in rats and monkeys at doses 2 times greater than and, in dogs at doses comparable to the maximum human daily dose); Renal tubular degeneration (occurred in rats at doses 2 times, in monkeys at doses 8 times, and in dogs at doses 12 times greater than the maximum human daily dose); Testicular atrophy (in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8 times greater than the maximum human daily dose); Corneal opacity (in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose); Lymphoid depletion (in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose).

 

Pregnancy

Pregnancy Category C

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

It is known that clarithromycin is excreted in the milk of lactating animals and that other drugs of this class are excreted in human milk. However, it is not known whether clarithromycin is excreted in human milk. Clarithromycin should be used in nursing mothers only if the potential benefit justifies the potential risk.

 

Pediatric use

Safety and effectiveness of clarithromycin in pediatric patients under 6 months of age have not been established. The drug is therefore not recommended for use in infants less than 6 months of age. The safety of clarithromycin has not been studied in MAC patients under the age of 20 months.

The majority of side effects observed in clinical trials were of a mild and transient nature.

The most frequently reported events in adults taking clarithromycin tablets were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%).

 

Adverse Drug Reactions

In post-marketing studies, allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Other spontaneously reported adverse events include glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis, tongue discoloration, thrombocytopenia, leukopenia, neutopenia and dizziness. There have been reports of tooth discoloration in patients treated with clarithromycin. Tooth discoloration is usually reversible with professional dental cleaning. There have been isolated reports of hearing loss, which is usually reversible, occurring chiefly in elderly women. Reports of alterations of the sense of smell, usually in conjunction with taste perversion or taste loss have also been reported.

Transient CNS events including anxiety, behavioral changes, confusional states, convulsions, depersonalization, disorientation, hallucinations, insomnia, manic behavior, nightmares, psychosis, tinnitus, tremor, and vertigo have been reported during post-marketing surveillance. Events usually resolve with discontinuation of the drug.
Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible in very rare instances; hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.
There have been rare reports of hypoglycemia, some of which have occurred in patients taking oral hypoglycemic agents or insulin.

As with other macrolides, clarithromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.
Changes in Laboratory Values: Changes in laboratory values were observed in post-marketing studies with clarithromycin with possible clinical significance and were as follows:

Hepatic–elevated SGPT (ALT) < 1%; SGOT (AST) < 1%; GGT < 1%; alkaline phosphatase <1%; LDH <1%; total bilirubin < 1%.

Hematologic–decreased WBC <1%; elevated prothrombin time 1%.

Renal–elevated BUN 4%; elevated serum creatinine <1%.

Gamma- GT, alkaline phosphatase, and prothrombin time.

 

Overdosage

Overdosage 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.

 

DOSAGE AND ADMINISTRATION

Indication Dosage (every 12hours) Duration (days)
Acute exacerbations of
Chronic Bronchitis (AECB) due to
H. Influenzae
H. parainfluenzae
 
500 mg
500 mg
 
7 to 14
7
Endocarditis – prophylaxis 500 mg. 1 hour before procedure
Pneumonia caused by
C. pneumonae, M catarrhalis, and S. pneumoniae.
500 mg 10 days
Pneumonia due to Legionella pneumophila

Sinusitis

500 to 1000 mg
500 mg
Depending on
patient’s response to therapy.
14 days

Dosage in Renal Failure

In the presence of severe renal impairment (i.e., creatinine clearance less than 30 milliliters/minute), the dose should be halved or the dosing interval doubled.

Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with creatinine clearance less than 25 milliliters/minute.

Dosage in Hepatic Insufficiency

The dose of Clarithromycin does not need to be adjusted in the presence of hepatic impairment if renal function is normal. The metabolism of Carithromycin into its 14-hydroxyl metabolite was decreased but the renal clearance of Clarithromycin was increased with a net effect of no significant change in the pharmacokinetics of Clarithromycin.

Dosage in Geriatric Patients

Clarithromycin dosage adjustments are not required in healthy elderly patients. However, dosage adjustments should be considered in elderly patients with severe renal impairment.

Pediatric Dosage

Maclar tablets can be given to children who can swallow tablet. The safety and efficacy of clarithromycin have not been established in children less than 6 months of age. The safety of clarithromycin has not been studied in Mycobacterium avium complex patients under the age of 20 months. The total daily maximum dose is 2g/day. The dosage of clarithromycin tablets in children (over 6 months of age) is as follows:

Indication Dosage (every 12 hours) Duration (days)
Endocarditis prophylaxis 50 mg/kg (single dose) 1 hour before the procedure; do not exceed the adult dosage
Primary Prevention of
disseminated mycobacterium avium disease
7.5 mg/ kg (up to 500 mg)
Otitis media caused by H. influenzae, M. catarrhalis & S. pneumoniae 7.5 mg/kg 10 days
Pneumonia caused by
M. pneumoniae, S. pneumoniae and C. pneumoniae (TWAR)
7.5 mg /kg 10 days
Acute maxillary sinusitis caused by H. influenzae, M. catarrhalis, and S. pneumoniae 7.5 mg /kg 10 days

Dosage in Renal Failure

In the presence of severe renal Impairment (i.e. creatinine clearance less than 30 ml/min), the dose should be halved or the dosing interval doubled.

Dosage in Hepatic Insufficiency

The dose of clarithromycin does not need to be adjusted in the presence of hepatic impairment if renal function is normal .The pharmacokinetics of clarithromycin and its 14-hydroxy metabolite were studied in patients with moderate or severe hepatic dysfunction but normal renal function. The metabolism of clarithromycin into 14-hydroxy clarithromycin was decreased but the renal clearance of clarithromycin was increased with a net effect of no significant change in the
pharmacokinetics of clarithromycin.

 

STORAGE

Store below 25°C. Protect from moisture and light.

Keep all Medicines out of reach of children.

 

PRESENTATION

Pack containing 3 strips of 4 tablets.

 

NAFDAC Reg. No. A4-0695

 

MANUFACTURED BY

GLENMARK PHARMACEUTICALS LTD.

B/2, MAHALAXMI CHAMBERS, 22, BHULABHAI DESAI ROAD,

MUMBAI – 400 026, (INDIA).

AT: PLOT NO. E-37, 39, D-ROAD, M.I.D.C. INDUSTRIAL AREA,

SATPUR, NASIK – 422 007, INDIA.

™Trade Mark

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