CLARITHROCID 250 mg & 500 mg

Description

The Cathay Drug Co., Inc.

 

FORMULATION

CLARITHROCID 250 mg Film – Coated Tablet

Each film – coated tablet contains 250 mg of the active ingredient, Clarithromycin

 

CLARITHROCID 500 mg Film – Coated Tablet

Each film – coated tablet contains 500 mg of the active ingredient, Clarithromycin

 

Each film – coated tablet contains 500 mg of the active ingredient, Clarithromycin

 

PHARMACOLOGICAL PROPERTIES

Mechanism of Action

Clarithromycin, a semisynthetic macrolide antibiotic derived from erythromycin, inhibits bacterial protein synthesis by binding to the bacterial 50S ribosomal subunit. The binding inhibits peptidyl transferase activity and interferes with amino acid translocation during the translation and protein assembly process. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump. Clarithromycin may be bacteriostatic or bactericidal depending on the organism and drug concentration.

 

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 metabolite 14-hydroxyclarithromycin are reported to be about 0.6 and 0.7 μg per mL respectively following a single 250 mg dose by mouth; at steady-state the same dose given every 12 hours as tablets produce peak concentrations of clarithromycin of about 1μg per mL. The same dose given as a suspension produces a steady-state plasma concentration of about 2μg per mL.

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

Clarithromycin and its principal metabolite are widely distributed, and tissue concentrations exceed those found in serum, partly due to intracellular intake. Clarithromycin has been detected in breast milk.

Clarithromycin is extensively metabolized in the liver. It is excreted in feces via the bile. Substantial amounts are also excreted via urine; at steady state about 20 – 30% of a 250 mg or 500 mg dose, respectively, is excreted in this way in its unchanged form. 14- Hydroxylclarithromycin as well as other metabolites are also excreted in the urine accounting for 10 to 15% 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 500 mg twice daily. Half-life is prolonged in renal impairment.

 

INDICATIONS

Clarithromycin Film – Coated Tablet is indicated for the treatment of mild to moderate infections caused by susceptible organisms in the conditions as listed below:

• Respiratory tract infections (e.g. Pharyngitis/Tonsillitis due to Streptococcus pyogenes, Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae, Acute bacterial exacerbation of chronic bronchitis, pnemunonia) including otitis media
• Skin and soft tissue infections due to Staphylococcus aureus, or Streptococcus pyogenes
• For prophylaxis and treatment of opportunistic mycobacterial infections due to Mycobacterium kansasii, Mycobacterium avium, or Mycobacterium intracellulare and for the treatment of leprosy.
• For the prevention of disseminated infection due to Mycobacterium avium (MAC) in patients with advanced HIV infection
• Protozoal infection, including toxoplasmosis
• Clarithromycin may be given to eradicate Helicobacter pylori in the treatment regimens for peptic ulcer disease

 

DOSAGE AND ADMINISTRATION

Clarithromycin is given orally. The usual recommended dosage in adults is 250 mg twice daily. Dosage may be increased to 500 mg twice daily if necessary in cases of severe infection. Antibiotic course usually lasting for 7 to 14 days.

Dosage disseminated infection due to Mycobacterium avium complex

Prophylaxis and Treatment

Adult: Clarithromycin 500 mg twice daily by mouth

Children: The recommended dose is 7.5 mg/kg twice daily up to 500 mg twice daily.

Leprosy

Clarithromycin 500 mg daily by mouth, as part of an alternative multidrug therapy regimen.

Eradication of Helicobacter pylori associated peptic ulcer disease

Clarithromycin 500 mg twice daily, given concomitantly with other antibacterial and either a proton pump inhibitor or a histamine H2-receptor antagonist for 7-14 days.

 

 

In patients with severe renal impairment (Creatinine clearance of less than 30 mL per minute) dosage may need to be halved or the dosing intervals doubled, with or without coexisting hepatic impairment. However, in the presence of hepatic impairment and normal renal function, clarithromycin may be administered without dosage adjustment.

 

ANTIBACTERIAL ACTION

Clarithromycin is more active against susceptible streptococci and staphylococci in vitro. The minimum inhibitory concentrations of Clarithromycin are usually two-to fourfold lower than for erythromycin.

 

Clarithromycin is more active against some mycobacteria and have some in vitro activity against the protozoan Toxoplasma gondii, and may have some activity against cryptosporidia.

 

The major metabolite, 14-hydroxyclarithromycin, is also active, and may enhance the activity of clarithromycin in vivio, notably against Haemophilus influenza.

 

Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:

 

Gram-positive aerobes microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes

Gram-negative aerobic microorganisms: Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhea, Legionella pneumophila),

Mycobacteria: Mycobacteria kansasii, Mycobacterium leprae and Mycobacterium avium complex (MAC) which includes: Mycobacterium avium, Mycobacterium intracellulare

*Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin

Other organisms including Mycoplasma pneumoniae, Ureaplasma urealyticum, Chlamydia pneumoniae

Clarithromycin exhibits in-vitro activity against most strains of the following microorganisms, but their clinical significance is unknown

Gram-positive aerobes microorganisms: Streptococcus agalactiae, Streptococci (Group C,F G), Viridans group streptococci

Gram-negative aerobic microorganisms: Bordetella pertussis, Pasteurella multocida

Gram-positive anaerobes microorganisms: Bacteroides melaninogenicus

Sphirochetes: Borrelia burgdorferi, Treponema pallidum

Campylobacter: Campylobacter jejuni

 

CONTRAINDICATIONS

Clarithromycin is contraindicated in patients with known hypersensitivity to any macrolide antibiotics. Patients who are on Clarithrocid therapy should not take astemizole, cisapride or terfenadine concomitantly.

 

WARNINGS AND PRECAUTIONS

Clarithromycin is principally excreted via the liver and kidney. Therefore, it should be administered with caution to patients with impaired renal or hepatic function and doses should be reduced in those with severe renal impairment.

Attention should be considered to the possibility of cross resistance between cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.

Pseudomembranous colitis has been reported with nearly all antibacterial agents including clarithromycin, and may range severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who represent with diarrhea subsequent to the administration of clarithromycin and other antibacterial agents.

 

ADVERSE EFFECTS

Gastrointestinal disturbances (e.g. nausea, dyspepsia, abdominal pain, vomiting and diarrhea) are the most frequent adverse effects of clarithromycin but are usually mild and less frequent than with erythromycin.

Other adverse effects are taste disturbances, stomatitis, glossitis and tooth discoloration, hypoglycaemia and thrombocytopenia. Interstitial nephritis and renal failure have been reported rarely.

Transient elevations of liver enzyme values, cholestatic jaundice, and hepatitis have been reported. Headache and rashes from mild skin eruptions to, rarely, Steven Johnson syndrome have occurred.

There also have been reports of transient CNS effects such as anxiety, dizziness, insomnia, hallucinations and confusion. Hearing loss has been reported occasionally and is usually reversible.

Thrombocytopenia purpura, corneal opacities which is usually reversible upon discontinuation of the treatment, pseudomonas colitis associated with clostridium difficile developed in a child receiving clarithromycin, acute psychosis, pancreatitis, QT prolongation and torsade de pointes, fever associated with clarithromycin and leukocytoclastic vasculitis have also been reported.

 

DRUG INTERACTIONS

• Rifabutin. Increased rifabutin toxicity has been reported in patients receiving clarithromycin and rifabutin. There has also been a report of delirium following the concurrent use with fluoxetine.
• Antiretrovirals
• Concomitant administration of the HIV-protease inhibitor ritonavir inhibits the metabolism of clarithromycin producing elevated plasma concentrations and a prolonged half-life. It has been suggested that other HIV-protease inhibitors and non-nucleoside reverse trascriptase inhibitors may also affect the metabolism of clarithromycin.
• Concurrent use of efavirenz with clarithromycin has resulted in a decrease in clarithromycin plasma concentrations and an increase in its hydroxyl metabolite. This combination has been associated with a high incidence of skin rashes.
• Decreased concentrations of zidovudine have been reported in patients also taking clarithromycin. It is recommended that the administration of the two medications to be separated by 1 to 2 hours.
• Administration of cimetidine with clarithromycin may alter some of the pharmacokinetic parameters of clarithromycin. The clinical significance of such changes is unknown.
• Omeprazole. Concomitant administration of omeprazole with clarithromycin resulted in increased concentrations of clarithromycin and its active metabolite. There is also an increased and prolonged plasma concentration of omeprazole present. This interaction should account for the synergistic action with the combination when used in the eradication of Helicobacter pylori.
• Other antimycobacterials. Clarithromycin has been reported to enhance the activity of a number of antimycobacterials including ethambutol, isoniazid, pyrazinamide, and rifampicin against mycobacterium tuberculosis.
• Theophylline. The use of clarithromycin in patients 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.
• The concurrent use 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.
• Terfenadine, When clarithromycin and terfenadine were co-administered, plasma concentrations of the active acid metabolite of terfenadine were threefolds higher, on average, than the values observed when terfenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-hydroxyclarithromycin were not significantly affected by the co-administration of terfenadine once clarithromycin reached steady-state conditions.
• Co-administration of fluconazole and clarithromycin increased the mean steady state of clarithromycin C_min of 33% and AUC of 18%. Steady-state concentrations of 14-hydroxyclarithromycin were not significantly affected by the concomitant administration of fluconazole.
• Other anticoagulants. Concurrent use of clarithromycin and oral anticoagulants may potentiate the effect of the oral anticoagulant. Prothrombin time should be carefully monitored.
• There have been reports indicating increased in digoxin serum concentrations when clarithromycin is co-administered with digoxin. Serum levels of digoxin should be monitored.
• Colchicine toxicity have been reported with the concomitant use of clarithromycin and colchicine, particularly in the elderly, some of which occurred in patients with renal insufficiency.

 

Clarithromycin is a substrate and inhibitor of the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A). Co-administration of clarithromycin and a drug primarily metabolized by CYP3A may be associated with an elevation in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the drug taken concomitantly. The following are examples of clinically significant CYP3A based drug interactions observed with clarithromycin:

Anti-arrhythmics. There have been post marketing reports of torsade de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum concentrations of these medications should also be monitored.

Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin with ergotamine or dihydroergotamine is contraindicated.

Drug interactions and CNS effects (e.g. somnolence and confusion) have been reported with the concomitant use of clarithromycin and triazolobenzodiazepines (such as triazolam and alprazolam) and other related benzodiazepines (such as midazolam).

Clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin). There have been rare reports of rhabdomyolysis in patients taking these drugs concomitantly.

Clarithromycin has been reported to increase the systematic exposure (AUC) of sildenafil. Reduction of sildenafil dosage should be considered.

There have been published reports of CYP3A based interaction of clarithromycin with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methylprednisolone, cilostazol, and bromocriptine. In addition, there also have been reports of interactions of clarithromycin with drugs not thought to be metabolized via CYP3A, including hexobarbital, phenytoin and valproate.

 

PREGNANCY AND LACTATION

Clarithromycin should not be used in pregnant women except during clinical circumstances when no alternative therapy is appropriate because high doses of clarithromycin have been associated with embryotoxicity in animal studies with clarithromycin. It is not known whether clarithromycin is excreted in breast milk. Exercise caution when administering to nursing women.

 

AVAILABILITY

CLARITHROCID 250 mg Film – Coated Tablet: Strip foil x 6’s (Box of 30’s)

CLARITHROCID 500 mg Film – Coated Tablet: Strip foil x 6’s (Box of 30’s)

 

 

STORAGE

Store at temperatures not exceeding 30°C.

 

Manufactured by:

EL Laboratories, Inc.

109 North Main Avenue, Laguna Technopark

Biñan, Laguna

 

Marketing Authorization Holder

The Cathay Drug Co., Inc.

2/F Vernida I Condominium, 120 Amorsolo St.

Legaspi Village, Makati City

 

Date of revision: July 2019