CLARITHROCID 125 mg/5mL and 250 mg/5 mL

Description

The Cathay Drug Co., Inc.

FORMULATION

Clarithrocid 125 mg/mL Granules for Pediatric Suspension:

Each 5 mL (1 teaspoonful) of reconstituted suspension contains:

Clarithromycin, USP ……………………..125 mg.

 

Clarithrocid 250 mg/mL Granules for Pediatric Suspension:

Each 5 mL (1 teaspoonful) of reconstituted suspension contains:

Clarithromycin, USP …………………….. 250 mg.

 

PRODUCT DESCRIPTION

Clarithromycin (Clarithrocid) 125 mg/mL Granules for Pediatric Suspension

Clarithromycin (Clarithrocid) 250 mg/5 mL Granules for Pediatric Suspension are free-flowing powder, light pink in color with cherry odor; pink, cherry odor and flavor suspension upon reconstitution.

 

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.

 

PHARMACOLOGICAL PROPERTIES

PHARMACODYNAMICS

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 cryptosporidium.

 

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

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 is a macrolide dervived from erythromycin with similar actions and uses. It is indicated for the treatment of infections caused by susceptible organisms. Indications include:

• Respiratory tract infections (e.g. pharyngitis/ tonsillitis caused by Streptococcus pyogenes, acute maxillary sinusitis, chronic bronchitis, pneumonia) including otitis media.
• Skin and skin structure infections caused by Staphylococcus aureus, Streptococcus pyogenes
• For prophylaxis and treatment of opportunistic Mycobacterial infections commonly caused by 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

The usual duration of treatment is 5 to 10 days depending on the pathogen involved or the severity of the condition. The reconstituted suspension may be taken with or without meals, and may be taken with milk.

Dosage based on body weight (kg)

Weight (kg)	Approx. age (yrs)	Dosage 125 mg/5mL BID
8 – 11	1 – 2	2.5 mL (1/2 tsp)
12 – 19	3 – 6	5 mL (1 tsp)
20 – 29	7 – 9	7.5 mL (1 ½ tsp)
30 – 40	10 – 12	10 mL (2 tsp)

 

Children less than 8 kg should be dosed on a per kg basis (approximately 7.5 mg/kg daily). Or as prescribed by the physician.

 

Directions for reconstitution

Clarithromycin 125 mg/5mL Granules for Pediatric Suspension:

• To make a 10 mL suspension, add 7.6 mL of water to the granules in the bottle.
• To make a 25 mL suspension, add 19 mL of water to the granules in the bottle.
• To make a 35 mL suspension, add 28 mL of water to the granules in the bottle.
• To make a 50 mL suspension, add 37 mL of water to the granules in the bottle.
• To make a 70 mL suspension, add 53 mL of water to the granules in the bottle.

 

Clarithromycin 250 mg/5mL Granules for Pediatric Suspension:

• To make a 10 mL suspension, add 7.5 mL of water to the granules in the bottle.
• To make a 25 mL suspension, add 18 mL of water to the granules in the bottle.
• To make a 35 mL suspension, add 25 mL of water to the granules in the bottle.
• To make a 50 mL suspension, add 36 mL of water to the granules in the bottle.
• To make a 70 mL suspension, add 51 mL of water to the granules in the bottle.

Shake well until the contents are evenly suspended. The reconstituted suspension can be used up to 14 days when stored at temperatures not exceeding 30°C.

 

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.

 

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.

 

PREGNANCY AND LACTATION

Clarithromycin should not be used in pregnant women except during clinical circumstances when no alternative therapy is appropriate. If pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.

It should not be used during pregnancy if possible: 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.

 

RESISTANCE

Prescribing Clarithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication in unlikely to provide benefit to the patient and increases the risk of the development of drug-resistance.

 

Erythromycin- resistant isolates of Streptococcus pneumonia are commonly cross-resistant to Clarithromycin. The incidence of resistance to Clarithromycin and other macrolides is higher among penicillin-resistant strains than among penicillin-sensitive strains.

 

AVAILABILITY

Clarithromycin Oral Suspension 125 mg/5mL Granules for Pediatric Suspension:

25 mL (Bottle size of 30 mL) in 25 mL Opaque White HDPE Plastic Bottle

35 mL (Bottle size of 50 mL) in 35 mL Opaque White HDPE Plastic Bottle

50 mL (Bottle size of 50 mL) in 50 mL Opaque White HDPE Plastic Bottle

70 mL (Bottle size of 70 mL) in 70 mL Opaque White HDPE Plastic Bottle

 

Clarithromycin Oral Suspension 250mg/5mL Granules for Pediatric Suspension:

25 mL (Bottle size of 30 mL) in 25 mL Opaque White HDPE Plastic Bottle

35 mL (Bottle size of 50 mL) in 35 mL Opaque White HDPE Plastic Bottle

50 mL (Bottle size of 75 mL) in 50 mL Opaque White HDPE Plastic Bottle

70 mL (Bottle size of 70 mL) in 70 mL Opaque White HDPE Plastic Bottle

 

 

STORAGE

• Store at temperatures not exceeding 30°C.
• For reconstituted suspension:

After mixing, store at temperatures not exceeding 30°C.

Shake well before each use.

Keep tightly closed. Do not refrigerate.

 

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