Clarithromycin Tablets USP 250mg Taj Pharma

Name of the medicinal product

Clarithromycin tablets USP 250mg Taj Pharma
Clarithromycin tablets USP 500mg Taj Pharma

Qualitative and quantitative composition

a) Clarithromycin tablets USP 250mg Taj Pharma
Each film-coated tablet contains:
Clarithromycin USP 250mg
Excipients: Q.S.

b) Clarithromycin tablets USP 500mg Taj Pharma
Each film-coated tablet contains:
Clarithromycin USP 500mg
Excipients: Q.S.

For the full list of excipients, see section 6.1.

Pharmaceutical form

Film-coated tablet

Light yellow coloured, oval shaped, biconvex film-coated tablets

Clinical particulars

4.1 Therapeutic indications

Clarithromycin Taj Pharma film-coated tablets are indicated for the treatment of the following bacterial infections, when caused by Clarithromycin Taj Pharma-susceptible bacteria (see section 4.4 and 5.1).

Bacterial pharyngitis
Mild to moderate community acquired pneumonia
Acute bacterial sinusitis (adequately diagnosed)
Acute exacerbation of chronic bronchitis
Skin infections and soft tissue infections of mild to moderate severity,
In appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer healing agent for the eradication of Helicobacter pylori in patients with Helicobacter pylori associated ulcers (see section 4.2).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology and method of administration

Posology

The dosage of Clarithromycin Taj Pharma film-coated tablets depends on the type and severity of the infection and has to be defined in any case by the physician.

Adults and adolescents (12 years and older)

Standard dosage: The usual dose is 250mg twice daily (in the morning and in the evening)
High dosage treatment (severe infections): The usual dose may be increased to 500mg twice daily in severe infections.

Children younger than 12 years:

Use of Clarithromycin Taj Pharma film-coated tablets is not recommended for children younger than 12 years with a body weight less than 30 kg. Clinical trials have been conducted using Clarithromycin Taj Pharma pediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use Clarithromycin Taj Pharma paediatric suspension.

For children with a body weight of more than 30kg, the dose for adults apply.

Dosage in renal functional impairment:

In patients with renal impairment with creatinine clearance less than 30 mL/min, the dosage of Clarithromycin Taj Pharma should be reduced by one-half, i.e. 250mg once daily, or 250mg twice daily in more severe infections. Treatment should not be continued beyond 14 days in these patients.

Patients with hepatic impairment:

Caution should be exercised when administrating Clarithromycin Taj Pharma in patients with hepatic impairment (see section 4.3 and 4.4).

pylori eradication in peptic ulcer disease

For the eradication of H. pylori the selection of antibiotics should consider the individual patient’s drug tolerance, and should be undertaken in accordance with national, regional and local resistance patterns and treatment guidelines.

Usually Clarithromycin Taj Pharma is administered in combination with another antibiotic and a proton-pump inhibitor for one week.

The therapy may be repeated if the patient is still H. pylori-positive

Duration of therapy:

The duration of therapy with Clarithromycin Taj Pharma film-coated tablets depends on the type and severity of the infection and has to be defined in any case by the physician.

The usual duration of treatment is 7 to 14 days.
Therapy should be continued at least for 2 days after symptoms have subsided.
In Streptococcus pyogenes (group A beta-haemolytic streptococcus) infections the duration of therapy should be at least 10 days.
Combination therapy for the eradication of H. pylori infection should be continued for 7 days.

Method of administration:

The tablet should be swallowed whole with a sufficient amount of fluid (eg. one glass of water).

Clarithromycin Taj Pharma film-coated tablets may be given irrespective of food intake.

Contraindications

Clarithromycin Taj Pharma is contraindicated in patients with known hypersensitivity to the active substance Clarithromycin Taj Pharma, to other macrolides or to any of the excipients listed in section 6.1.

Concomitant administration of Clarithromycin Taj Pharma and any of the following active substances is contraindicated: astemizole, cisapride, pimozide and terfenadine as this may result in QT prolongation (congenital or documented acquired QT prolongation) and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes (see section 4.5).

Concomitant administration with ticagrelor or renolazine is contraindicated.

Concomitant administration of Clarithromycin Taj Pharma and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity.

Clarithromycin Taj Pharma should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointe (see sections 4.4 and 4.5).

Clarithromycin Taj Pharma should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolosed by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5).

Clarithromycin Taj Pharma should not be given to patients with hypokalaemia (risk of prolongation of QT-time).

Clarithromycin Taj Pharma should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.

As with other strong CYP3A4 inhibitors, Clarithromycin Taj Pharma should not be used in patients taking colchicine.

Special warnings and precautions for use

The physician should not prescribe Clarithromycin Taj Pharma to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy (see section 4.6).

Caution is advised in patients with severe renal insufficiency (see section 4.2).

Clarithromycin Taj Pharma is principally excreted by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering Clarithromycin Taj Pharma to patients with moderate to severe renal impairment.

Cases of fatal hepatic failure (see section 4.8) have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents including Clarithromycin Taj Pharma, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C.difficile. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Therefore, discontinuation of Clarithromycin Taj Pharma therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Drugs inhibiting peristalsis should be avoided.

There have been post-marketing reports of colchicine toxicity with concomitant use of Clarithromycin Taj Pharma and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5). Concomitant administration of Clarithromycin Taj Pharma and colchicines is contraindicated (see section 4.3).

Caution is advised regarding concomitant administration of Clarithromycin Taj Pharma and triazolobenzodiazepines, such as triazolam, and midazolam (see section 4.5).

Caution is advised regarding concomitant administration of Clarithromycin Taj Pharma with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment.

Cardiovascular Events

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatment with macrolides including Clarithromycin Taj Pharma (see section 4.8). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes), Clarithromycin Taj Pharma should be used with caution in the following patients;

Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia.
Patients with electrolyte disturbances such as hypomagnesaemia. Clarithromycin Taj Pharma must not be given to patients with hypokalaemia (see section 4.3).
Patients concomitantly taking other medicinal products associated with QT prolongation (see section 4.5).
Concomitant administration of Clarithromycin Taj Pharma with astemizole, cisapride, pimozide and terfendine is contraindicated (see section 4.3).
Clarithromycin Taj Pharma must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see section 4.3).

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Some observational studies have identified a rare short-term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including Clarithromycin Taj Pharma. Consideration of these findings should be balanced with treatment benefits when prescribing Clarithromycin Taj Pharma.

Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing Clarithromycin Taj Pharma for community-acquired pneumonia. In hospital-acquired pneumonia, Clarithromycin Taj Pharma should be used in combination with additional appropriate antibiotics.

Skin and soft tissue infections of mild to moderate severity: These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta–lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome, and toxic epidermal necrolysis, Clarithromycin Taj Pharma therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Clarithromycin Taj Pharma should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see section 4.5).

HMG-CoARreductase Inhibitors (statins): Concomitant use of Clarithromycin Taj Pharma with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when prescribing Clarithromycin Taj Pharmawith other statins. Rhabdomyolysis has been reported in patients taking Clarithromycin Taj Pharma and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of Clarithromycin Taj Pharma with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered.

Oral hypoglycemic agents/Insulin: The concomitant use of Clarithromycin Taj Pharma and oral hypoglycemic agents (such as sulfonylurias) and/or insulin can result in significant hypoglycemia. Careful monitoring of glucose is recommended.

Oral anticoagulants: There is a risk of serious hemorrhage and significant elevations in International Normalized Ratio (INR) and prothrombin time when Clarithromycin Taj Pharma is co-administered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving Clarithromycin Taj Pharma and oral anticoagulants concurrently.

Use of any antimicrobial therapy, such as Clarithromycin Taj Pharma, to treat H. pylori infection may select for drug-resistant organisms.

Long-term use may, as with other antibiotics, result in colonization with increased numbers of non-susceptible bacteria and fungi. If super-infection occur,appropriate therapy should be instituted.

Attention should also be paid to the possibility of cross resistance between Clarithromycin Taj Pharma and other macrolide drugs, as well as lincomycin and clindamycin.

Interaction with other medicinal products and other forms of interaction

The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects:

Cisapride, pimozide, astemizole and terfenadine

Elevated cisapride levels have been reported in patients receiving Clarithromycin Taj Pharma and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking Clarithromycin Taj Pharma and pimozide concomitantly (see section 4.3).

Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see section 4.3). In one study in 14 healthy volunteers, the concomitant administration of Clarithromycin Taj Pharma and terfenadine resulted in a two to three fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.

Ergotamine/dihydroergotamine

Postmarketing reports indicate that co-administration of Clarithromycin Taj Pharma with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of Clarithromycin Taj Pharma and these medicinal products is contraindicated (see section 4.3).

HMG-CoA Reductase Inhibitors (statins)

Concomitant use of Clarithromycin Taj Pharma with lovastatin or simvastatin is contraindicated (see 4.3) as these statins are extensively metabolized by CYP3A4 and concomitant treatment with Clarithromycin Taj Pharma increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking Clarithromycin Taj Pharma concomitantly with these statins. If treatment with Clarithromycin Taj Pharma cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Caution should be exercised when prescribing Clarithromycin Taj Pharma with statins. In situations where the concomitant use of Clarithromycin Taj Pharma with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin.Use of a statin that is not dependent on CYP3A metabolism (e.g.fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.

Effects of other medicinal products on Clarithromycin Taj Pharma

Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carabamazepin, phenobarbital, St. Johns wort) may induce the metabolism of Clarithromycin Taj Pharma. This may result in sub-therapeutic levels of Clarithromycin Taj Pharma leading to a reduced efficacy. Furthermore it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by Clarithromycin Taj Pharma (see also the relevant product information for the CYP3A4 inhibitor administered). Concomitant administration of rifabutin and Clarithromycin Taj Pharma resulted in an increase in rifabutin, and decrease in Clarithromycin Taj Pharma serum levels together with an increased risk of uveitis.

The following drugs are known or suspected to affect circulating concentrations of Clarithromycin Taj Pharma; Clarithromycin Taj Pharma dosage adjustment or consideration of alternative treatments may be required.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine

Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of Clarithromycin Taj Pharma and thus lower the plasma levels of Clarithromycin Taj Pharma, while increasing those of 14-OH-Clarithromycin Taj Pharma, a metabolite that is also microbiologically active. Since the microbiological activities of Clarithromycin Taj Pharma and 14-OH-Clarithromycin Taj Pharma are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of Clarithromycin Taj Pharma and enzyme inducers.

Etravirine

Clarithromycin Taj Pharma exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-Clarithromycin Taj Pharma, were increased. Because 14-OH-Clarithromycin Taj Pharma has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to Clarithromycin Taj Pharma should be considered for the treatment of MAC.

Fluconazole

Concomitant administration of fluconazole 200mg daily and Clarithromycin Taj Pharma 500mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum Clarithromycin Taj Pharma concentration (Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14-OH-Clarithromycin Taj Pharma were not significantly affected by concomitant administration of fluconazole. No Clarithromycin Taj Pharma dose adjustment is necessary.

Ritonavir

A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200mg every eight hours and Clarithromycin Taj Pharma 500mg every 12 hours resulted in a marked inhibition of the metabolism of Clarithromycin Taj Pharma. The Clarithromycin Taj Pharma Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-Clarithromycin Taj Pharma was noted. Because of the large therapeutic window for Clarithromycin Taj Pharma, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of Clarithromycin Taj Pharma should be reduced by 50%. For patients with CLCR <30 mL/min the dose of Clarithromycin Taj Pharma should be decreased by 75%. Doses of Clarithromycin Taj Pharma greater than 1 g/day should not be coadministered with ritonavir.

Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see section below, Bi-directional drug interactions).

Effect of Clarithromycin Taj Pharma on other medicinal products

CYP3A-based interactions

Co-administration of Clarithromycin Taj Pharma, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin Taj Pharma should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolized by this enzyme.

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 Taj Pharma.

The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine but this list is not comprehensive. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

Antiarrhythmics

There have been postmarketing reports of torsades de pointes occurring with concurrent use of Clarithromycin Taj Pharma and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of Clarithromycin Taj Pharma with these drugs. Serum levels of quinidine and disopyramide should be monitored during Clarithromycin Taj Pharma therapy.

There have been post marketing reports of hypoglycemia with the concomitant administration of Clarithromycin Taj Pharma and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of Clarithromycin Taj Pharma and disopyramide.

Oral hypoglycemic agents/Insulin

With certain hypoglycemic drugs such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by Clarithromycin Taj Pharma may be involved and could cause hypolgycemia when used concomitantly. Careful monitoring of glucose is recommended.

Omeprazole

Clarithromycin Taj Pharma (500mg every 8 hours) was given in combination with omeprazole (40mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of Clarithromycin Taj Pharma. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with Clarithromycin Taj Pharma.

Sildenafil, tadalafil, and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered Clarithromycin Taj Pharma. Co-administration of Clarithromycin Taj Pharma with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with Clarithromycin Taj Pharma.

Theophylline, carbamazepine

Results of clinical studies indicate there was a modest but statistically significant (p≤0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with Clarithromycin Taj Pharma. Dose reduction may need to be considered.

Tolterodine

The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as Clarithromycin Taj Pharma in the CYP2D6 poor metabolizer population.

Triazolobenzodiazepines (e.g. alprazolam, midazolam, triazolam)

When midazolam was co-administered with Clarithromycin Taj Pharma tablets (500mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and Clarithromycin Taj Pharma should be avoided. If intravenous midazolam is co-administered with Clarithromycin Taj Pharma, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam.

For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with Clarithromycin Taj Pharma is unlikely.

There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of Clarithromycin Taj Pharma and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

Other drug interactions

Aminoglycosides

Caution is advised regarding concomitant administration of Clarithromycin Taj Pharma with other ototoxic drugs, especially with aminoglycosides. See 4.4

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin Taj Pharma and other macrolides are known to inhibit CYP3A and Pgp. When Clarithromycin Taj Pharma and colchicine are administered together, inhibition of Pgp and/or CYP3A by Clarithromycin Taj Pharma may lead to increased exposure to colchicine (see section 4.3 and 4.4).

Digoxin

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin Taj Pharma is known to inhibit Pgp. When Clarithromycin Taj Pharma and digoxin are administered together, inhibition of Pgp by Clarithromycin Taj Pharma may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving Clarithromycin Taj Pharma 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 Taj Pharma simultaneously.

Zidovudine

Simultaneous oral administration of Clarithromycin Taj Pharma tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because Clarithromycin Taj Pharma appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of Clarithromycin Taj Pharma and zidovudine to allow for a 4-hour interval between each medication. This interaction does not appear to occur in paediatric HIV-infected patients taking Clarithromycin Taj Pharma suspension with zidovudine or dideoxyinosine. This interaction is unlikely when Clarithromycin Taj Pharma is administered via intravenous infusion.

Phenytoin and Valproate

There have been spontaneous or published reports of interactions of CYP3A inhibitors, including Clarithromycin Taj Pharma with drugs not thought to be metabolized by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with Clarithromycin Taj Pharma. Increased serum levels have been reported

Bi-directional drug interactions

Atazanavir

Both Clarithromycin Taj Pharma and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of Clarithromycin Taj Pharma (500mg twice daily) with atazanavir (400mg once daily) resulted in a 2- fold increase in exposure to Clarithromycin Taj Pharma and a 70% decrease in exposure to 14-OH-Clarithromycin Taj Pharma, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for Clarithromycin Taj Pharma, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of Clarithromycin Taj Pharma should be decreased by 50%. For patients with creatinine clearance <30 mL/min, the dose of Clarithromycin Taj Pharma should be decreased by 75% using an appropriate Clarithromycin Taj Pharma formulation.

Doses of Clarithromycin Taj Pharma greater than 1000mg per day should not be co-administered with protease inhibitors.

Calcium Channel Blockers

Caution is advised regarding the concomitant administration of Clarithromycin Taj Pharma and calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of Clarithromycin Taj Pharma as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking Clarithromycin Taj Pharma and verapamil concomitantly.

Itraconazole

Both Clarithromycin Taj Pharma and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction. Clarithromycin Taj Pharma may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of Clarithromycin Taj Pharma. Patients taking itraconazole and Clarithromycin Taj Pharma concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.

Saquinavir

Both Clarithromycin Taj Pharma and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Concomitant administration of Clarithromycin Taj Pharma (500mg twice daily) and saquinavir (soft gelatin capsules, 1200mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin Taj Pharma AUC and Cmax values were approximately 40% higher than those seen with Clarithromycin Taj Pharma alone. No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on Clarithromycin Taj Pharma

Fertility, pregnancy and lactation

Pregnancy

The safety of Clarithromycin Taj Pharma for use during pregnancy has not been established. Based on variable results obtained from studies in mice, rats, rabbits and monkeys, the possibility of adverse effects on embryofoetal development cannot be excluded. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk.

Breast-feeding

The safety of Clarithromycin Taj Pharma for use during breast feeding of infants has not been established. Clarithromycin Taj Pharma is excreted into human breast milk.

Fertility

There is no data available on the effect of Clarithromycin Taj Pharma on fertility in humans. In rats, the limited data available do not indicate any effects on fertility.

Effects on ability to drive and use machines

There are no data on the effect of Clarithromycin Taj Pharma on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

Undesirable effects

Summary of the safety profile

The most frequent and common adverse reactions related to Clarithromycin Taj Pharma therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics (see section b of section 4.8).

There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.

Tabulated summary of adverse reactions

The following table displays adverse reactions reported in clinical trials and from post-marketing experience with Clarithromycin Taj Pharma immediate-release tablets, granules for oral suspension, powder for solution for injection, extended release tablets and modified-release tablets.

The reactions considered at least possibly related to Clarithromycin Taj Pharma are displayed by system organ class and frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed.

System Organ Class	Very common (≥1/10	Common ≥ 1/100 to < 1/10	Uncommon ≥1/1,000 to < 1/100	Not Known (cannot be estimated from the available data)
Infections and infestations			Cellulitis¹, candidiasis, gastroenteritis², infection³, vaginal infection	Pseudomembranous colitis, erysipelas
Blood and lymphatic system			Leukopenia, neutropenia⁴, thrombocythemia³, eosinophilia⁴	Agranulocytosis, thrombocytopenia
Immune system disorders⁵			Anaphylactoid reaction¹, Hypersensitivity	Anaphylactic reaction, angioedema
Metabolism and nutrition disorders			Anorexia, decreased appetite
Psychiatric disorders		Insomnia	Anxiety, nervousness³	Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania
Nervous system disorders		Dysgeusia, headache, taste perversion	Loss of consciousness¹, dyskinesia¹, dizziness, somnolence⁶, tremor	Convulsion, ageusia, parosmia, anosmia, paraesthesia
Ear and labyrinth disorders			Vertigo, hearing, impaired, tinnitus	Deafness
Cardiac disorders			Cardiac arrest¹, atrial fibrillation¹, electrocardiogram QT prolonged⁷, extrasystoles¹, palpitations	Torsade de pointes⁷, ventricular tachycardia⁷ ventricular fibrillation
Vascular disorders		Vasodilation¹		Hemorrhage⁸
Respiratory, thoracic and mediastinal disorder			Asthma¹, epistaxis², pulmonary embolism¹
Gastrointestinal disorders		Diarrhea⁹, vomiting, dyspepsia, nausea, abdominal pain	Esophagitis¹, gastrooesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, abdominal distension⁴, constipation, dry mouth, eructation, flatulence	Pancreatitis acute, tongue discolouration, tooth discoloration
Hepatobiliary disorders		Liver function test abnormal	Cholestasis⁴, hepatitis⁴, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4	Hepatic failure¹⁰, jaundice hepatocellular
Skin and subcutaneous tissue disorders		Rash, hyperhidrosis	Dermatitis bullous¹, pruritus, urticaria, rash maculo-papular³	Stevens-Johnson syndrome⁵, toxic epidermal necrolysis⁵, drug rash with eosinophilia and systemic symptoms (DRESS), acne, acute generalised exanthematous pustulosis (AGEP)
Musculoskeletal and connective tissue disorders			Muscle spasms³, musculoskeletal stiffness¹, myalgia²	Rhabdomyolysis^{2, 11}, myopathy
Renal and urinary disorders			Blood creatinine increased¹, blood urea increased¹	Renal failure, nephritis interstitial
General disorders and administration site conditions	Injection site phlebitis¹	Injection site pain¹, injection site inflammation¹	Malaise⁴, pyrexia³, asthenia, chest pain⁴, chills⁴, fatigue⁴
Investigations			Albumin globulin ratio abnormal¹ , blood alkaline phosphatase increased⁴, blood lactate dehydrogenase increased⁴	International normalised ratio increased⁸, prothrombin time prolonged⁸, urine color abnormal

¹ ADRs reported only for the Powder for Solution for Injection formulation

²ADRs reported only for the Extended-Release Tablets formulation

³ ADRs reported only for the Granules for Oral Suspension formulation

⁴ ADRs reported only for the Immediate-Release Tablets formulation

⁵, ^{7, 9, 10,}See section a)

^{6, 8, 11} See section c)

Description of selected adverse reactions

Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the Clarithromycin Taj Pharma intravenous formulation.

In some of the reports of rhabdomyolysis, Clarithromycin Taj Pharma was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).

There have been post-marketing reports of colchicine toxicity with concomitant use of Clarithromycin Taj Pharma and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal outcome (see sections 4.4 and 4.5).

There have been rare reports of Clarithromycin Taj Pharma ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different Clarithromycin Taj Pharma formulation (e.g. suspension) or another antibiotic.

Special population: Adverse Reactions in Immunocompromised Patients (see section e)

Paediatric populations

Clinical trials have been conducted using Clarithromycin Taj Pharma paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use Clarithromycin Taj Pharma paediatric suspension. There are insufficient data to recommend a dosage regimen for use of the Clarithromycin Taj Pharma IV formulation in patients less than 18 years of age.

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Other special populations

Immunocompromised patients

In AIDS and other immunocompromised patients treated with the higher doses of Clarithromycin Taj Pharma over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with Clarithromycin Taj Pharma administration from underlying signs of Human Immunodeficiency Virus (HIV) disease or intercurrent illness.

In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1,000mg and 2,000mg of Clarithromycin Taj Pharma were: nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1,000mg and 2,000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4,000mg of Clarithromycin Taj Pharma.

In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1,000mg or 2,000mg of Clarithromycin Taj Pharma daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4,000mg daily for all parameters except White Blood Cell.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Overdose

Symptoms of intoxication:

Reports indicate that the ingestion of large amounts of Clarithromycin Taj Pharma can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested eight grams of Clarithromycin Taj Pharma and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxemia.

Therapy of intoxication:

Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, Clarithromycin Taj Pharma serum levels are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

In the case of overdosage, Clarithromycin Taj Pharma IV (powder for solution for injection) should be discontinued and all other appropriate supportive measures should be instituted.

Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Macrolides

Mode of action:

Clarithromycin Taj Pharma is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial 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. The minimum inhibitory concentrations (MICs) of Clarithromycin Taj Pharma are generally two-fold lower than the MICs of erythromycin.

The 14-hydroxy metabolite of Clarithromycin Taj Pharma also has antimicrobial activity. The MICs of this metabolite are equal or twofold higher than the MICs of the parent compound, except for H. influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.

PK/PD relationship

Clarithromycin Taj Pharma is extensively distributed into body tissues and fluids. Due to the high tissue penetration, intracellular concentrations higher than serum concentrations. The main pharmacodynamic parameters to predict macrolidenactiviteit are unconvincing established. The time above the MIC (T / MIC) is the best determinant for the efficacy of Clarithromycin Taj Pharma. Because the concentrations of Clarithromycin Taj Pharma in the lung tissues and epithelial tissue fluid reaches the plasma concentrations exceed, the use of plasma concentrations-based parameters are insufficient to accurately predict response for respiratory infections.

Mechanisms of resistance:

Resistance mechanisms against macrolide antibiotics include alteration of the target site of the antibiotic or are based on modification and/or the active efflux of the antibiotic. Resistance development can be mediated via chromosomes or plasmids, be induced or exist constitutively.

Macrolideresistant bacteria generate enzymes which lead to methylation of residual adenine at ribosomal RNA and consequently to inhibition of the antibiotic binding to the ribosome. Macrolide-resistant organisms are generally cross-resistant to lincosamides and streptogramine B based on methylation of the ribosomal binding site. Clarithromycin Taj Pharma ranks among the strong inducers of this enzyme as well. Furthermore, macrolides have a bacteriostatic action by inhibiting the peptidyl transferase of ribosomes. A complete cross-resistance exists among Clarithromycin Taj Pharma, erythromycin and azithromycin. Methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae are resistant to macrolides such as Clarithromycin Taj Pharma.

Breakpoints:

The following breakpoints for Clarithromycin Taj Pharma, separating susceptible organisms from resistant organisms, have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST) 2010-04-27 (v 1.1)

Species related

break points (S<R>)

Non species related break points S<R>

Enterobacterialaceae

Pseudomonas

Acinebacteria

Staphylococcus

Enterococcus

Streptococcus

A, B, G

S.pneumoniae

Other Streptococci

H. influenzae

N.gonorrhoeae

N.meningitidis

Gram-ve Anaerobs

Gram+ve

Anaerobes

Clarithromycin Taj Pharma

^ANon-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the table or footnotes However, pharmacodynamic data for calculation of macrolide, lincosamines and streptogramins non-species related breakpoints are not robust, hence IE.

^BErythromycin can be used to determine the susceptibility of the listed bacteria to the other macrolides (azithromycin, Clarithromycin Taj Pharma and roxithromycin

^C Clarithromycin Taj Pharma is used for the eradication of H. pylori (MIC ≤0.25mg/L for wild type isolates).

^D The correlation between H. influenzae macrolide MICs and clinical outcome is weak. Therefore, breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate.

Clarithromycin Taj Pharma is used for the eradication of H. pylori; minimum inhibitory concentration (MIC) ≤ 0.25 μg/ml which has been established as the susceptible breakpoint by the Clinical and Laboratory Standards Institute (CLSI).

Susceptibility:

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalance of resistance is such that the utility of the agent in atleast some types of infections is questionable.

Commonly susceptible species

Aerobic, Gram-positive microorganisms

Streptococcus group F

Corynebacterium diptheriae

Aerobic, Gram-negative microorganisms

Bordetella pertusis

Moraxella catarrhalis

Pasteurella multocida

Legionella spp.

Anaerobic microorganisms

Clostridium spp., other than C. difficile

Other microorganisms

Mycoplasma pneumoniae

Chlamydia trachomatis

Clamydophila pneumoniae

Clamydophilapsitacci

Mycobacterium spp.

Species for which acquired resistance may be a problem#

Aerobic, Gram-positive microorganisms

Streptococcus group A*, C, G

Streptococcus group B

Streptococcus viridans

Enterococcus spp⁺

Staphylococcus aureus, methicillin-susceptible and methicillin-resistant+

Streptococcus pneumoniae*+

Staphylococcus epidermidis+

Aerobic, Gram-negative microorganisms

Haemophilus influenzae$

Helicobacter pylori

Anaerobic microorganisms

Bacteroides spp.

Peptococcus/Peptostreptococcus spp.

Inherently resistant microorganisms

Aerobic, Gram-negative microorganisms

Pseudomonas aeruginosa

Acinetobacter

Enterobacteriacea

Anaerobic microorganisms

Fusobacterium spp.

Other microorganisms

Mycobacterium tuberculosis

# ≥ 10% resistance in at least one country of the European Union

* Species against efficacy has been demonstrated in clinical investigations (if susceptible)

+ Indicates species for which a high rate of resistance (i.e. greater than 50%) have been observed in one or more area/country/region(s) of the EU

Breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzaeas intermediate

Other information:

Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to Clarithromycin Taj Pharma can be predicted by testing erythromycin.

Most available clinical experience from controlled randomised clinical trials indicate that Clarithromycin Taj Pharma 500mg twice daily in combination with another antibiotic e.g. amoxicillin or metronidazole and e.g. omeprazole (given at approved levels) for 7 days achieve > 80% H. pylori eradication rate in patients with gastro-duodenal ulcers. As expected, significantly lower eradication rates were observed in patients with baseline metronidazole-resistant H. pylori isolates. Hence, local information on the prevalence of resistance and local therapeutic guidelines should be taken into account in the choice of an appropriate combination regimen for H. pylori eradication therapy. Furthermore, in patients with persistent infection, potential development of secondary resistance (in patients with primary susceptible strains) to an antimicrobial agent should be taken into the considerations for a new retreatment regimen.

Pharmacokinetic properties

Absorption:

Clarithromycin Taj Pharma is rapidly and well absorbed from the gastrointestinal tract – primarily in the jejunum – but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of a 250-mg Clarithromycin Taj Pharma tablet is approximately 50%. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, Clarithromycin Taj Pharma tablets may be given without regard to food. Due to its chemical structure (6-O-Methylerythromycin) Clarithromycin Taj Pharma is quite resistant to degradation by stomach acid. Peak plasma levels of 1 – 2 μg/ml Clarithromycin Taj Pharma were observed in adults after oral administration of 250mg twice daily. After administration of 500mg Clarithromycin Taj Pharma twice daily the peak plasma level was 2.8 μg/ml. After administration of 250mg Clarithromycin Taj Pharma twice daily the microbiologically active 14-hydroxy metabolite attains peak plasma concentrations of 0.6 μg/ml. Steady state is attained within 2 days of dosing.

Distribution:

Clarithromycin Taj Pharma penetrates well into different compartments with an estimated volume of distribution of 200-400 l. Clarithromycin Taj Pharma provides concentrations in some tissues that are several times higher than the circulating drug levels. Increased levels have been found in both tonsils and lung tissue. Clarithromycin Taj Pharma also penetrates the gastric mucus.

Clarithromycin Taj Pharma is approximately 70% bound to plasma proteins at therapeutic levels.

Biotransformation and elimination:

Clarithromycin Taj Pharma is rapidly and extensively metabolised in the liver. Metabolism is in the liver involving the P450 cytochrome system. Three metabolites are described: N-demethyl Clarithromycin Taj Pharma, decladinosyl Clarithromycin Taj Pharma and 14-hydroxy Clarithromycin Taj Pharma. The pharmacokinetics of Clarithromycin Taj Pharma is non-linear due to saturation of hepatic metabolism at high doses. Elimination half-life increased from 2-4 hours following administration of 250mg Clarithromycin Taj Pharma twice daily to 5 hours following administration of 500mg Clarithromycin Taj Pharma twice daily. The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration of 250mg Clarithromycin Taj Pharma twice daily.

Approximately 20 -40% of Clarithromycin Taj Pharma is excreted as the unchanged active substance in the urine. This proportion is increased when the dose is increased. An additional 10% to 15% is excreted in the urine as 14-hydroxy metabolite. The rest is excreted in the faeces. Renal insufficiency increases Clarithromycin Taj Pharma levels in plasma, if the dose is not decreased. Total plasma clearance has been estimated to approximately 700 mL/min (11,7 mL/s), with a renal clearance of approximately 170 mL/min (2,8 mL/s).

Special populations:

Renal impairment: Reduced renal insufficiency function results in increased plasma levels of Clarithromycin Taj Pharma and the active metabolite levels in plasma.

Preclinical safety data

In 4-week-studies in animals, toxicity of Clarithromycin Taj Pharma was found to be related to the dose and to the duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which lesions were seen within 14 days in dogs and monkeys. The systemic levels of exposure, related to this toxicity, are not known in detail, but toxic doses were clearly higher than the therapeutic doses recommended for humans. Other tissues affected included the stomach, thymus and other lymphoid tissues as well as the kidneys. At near therapeutic doses conjunctival injection and lacrimation occurred only in dogs. At a dose of 400mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema.

No mutagenic effects were found in in vitro– and in vivo -studies with Clarithromycin Taj Pharma

Studies on reproduction toxicity showed that administration of Clarithromycin Taj Pharma at doses 2x the clinical dose in rabbit (i.v.) and x10 the clinical dose in monkey (p.o.) resulted in an increased incidence of spontaneous abortions. These doses were related to maternal toxicity. No embryotoxicity or teratogenicity was noted in rat studies. Cardiovascular malformations were observed in rats treated with doses of 150mg/kg/d. In mouse at doses x70 the clinical dose cleft palate occurred at varying incidence (3-30%).

Clarithromycin Taj Pharma has been found in the milk of lactating animals.

In 3-day old mice and rats, the LD50 values were approximately half those in adult animals. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported in some studies. Slight reductions in erythrocytes, platelets and leukocytes have also been found in juvenile animals.

Clarithromycin Taj Pharma has not been tested for carcinogenicity.

Pharmaceutical particulars

6.1 List of excipients

Core:

Microcrystalline cellulose

Croscarmellose sodium

Silica, colloidal anhydrous

Magnesium stearate

Povidone (K-30)

Coating:

Hypromellose

Propylene glycol

Titanium dioxide

Hydroxypropyl cellulose

Vanillin,

Sorbic acid

Iron oxide yellow

Incompatibilities

Not applicable.

Shelf life

3 years.

Special precautions for storage

This medicinal product does not require any special storage conditions.

Nature and contents of container

Clarithromycin Taj Pharma 250mg tablets are available in clear PVC /PVdC/Aluminium blister packs of: Clarithromycin Taj Pharma film-coated tablets.

Pack size:

Each box contains 5, 10, 15, 20, 25, 30, 50, 60, 120, 240, 360, and 500 film coated tablets.

Not all pack sizes may be marketed.

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Package leaflet: Information for the user

Clarithromycin Taj Pharma 250mg film-coated tablets Clarithromycin Taj Pharma 500mg film-coated tablets

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

What Clarithromycin Taj Pharma is and what it is used for
What you need to know before you take Clarithromycin Taj Pharma
How to take Clarithromycin Taj Pharma
Possible side effects
How to store Clarithromycin Taj Pharma
Contents of the pack and other information.
What Clarithromycin Taj Pharma is and what it is used for

Clarithromycin Taj Pharma belongs to a group of medicine called macrolide antibiotics. Antibiotics stop the growth of bacteria which cause infections.

Clarithromycin Taj Pharma is used to treat following infections:

Chest infections such as bronchitis and pneumonia,
Throat and sinus infections,
Skin and soft tissue infections,
Helicobacter pylori infections associated with duodenal ulcers.

What you need to know before you take Clarithromycin Taj Pharma

Do not take Clarithromycin Taj Pharma if:

you are allergic to clarithromycin,
other macrolide antibiotics or any of the other ingredients of this medicine (listed in section 6).
you have a history of certain abnormal heart rhythms (ventricular arrhythmia, including torsades de pointes) or changes in the heart activity as measured in the electro-cardiogram called “QT prolongation”,
you suffer from severe liver failure and kidney problems at the same time,
You are taking medicines called terfenadine or astemizole (for hay fever or allergies) or cisapride or pimozide tablets as combining these drugs can sometimes cause serious disturbances in heart rhythm. Consult
your doctor for advice on alternative medicines.
You are taking other medicines which are known to cause serious disturbances in heart rhythm.
you have abnormally low levels of potassium in your blood (hypokalaemia)
You or someone in your family has a history of heart rhythm disorders (ventricular cardiac arrhythmia, including torsade de pointes) or abnormality of electrocardiogram (ECG, electrical recording of the heart) called “long QT syndrome”.
you are taking any of the following medicines
ergotamine, dihydroergotamine (medicines to treat migraine)
lovastatin, simvastatin (medicines to lower cholesterol),
colchicines (medicine to treat gout),
ticagrelor or ranolazine (medicines to prevent stroke or heart attack). Consult your doctor and take this medicine if any of the above cases apply to you, or that in the past.

Warnings and precautions

Talk to your doctor or pharmacist before taking Clarithromycin Taj Pharma,

if you are allergic to lincomycin or clindamycin
if you have reduced liver or kidney function,
if you have, or have had, heart problems
if you are pregnant (see section
“Pregnancy, breast-feeding and
fertility”)
if your blood magnesium level have previously been low.
if you develop severe or prolonged diarrhoea (pseudomembranous colitis) during or after taking Clarithromycin Taj Pharma, consult your doctor immediately. Inflammation of the colon (Pseudomembranous colitis) has been reported with nearly all antibacterial medicines including clarithromycin.
if you have used clarithromycin before on several occasions or for a long time.
Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.
if you take combination a combination of clarithromycin and benzodiazepines, such as alprazolam, triazolam and midazolam (see section “Othermedicines and Clarithromycin Taj Pharma”)
if you take other drugs which affect your auditory function. Loss of hearing will be checked during and after treatment.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section “Do not take Clarithromycin Taj Pharma if”). Caution should be exercised when using clarithromycin with other statins. If you also use oral anticoagulants besides clarithromycin. There is a risk of serious bleeding.

If any of these apply to you, consult your doctor before taking Clarithromycin Taj Pharma tablets.

Other medicines and Clarithromycin Taj Pharma

Certain other medicines may affect the

effectiveness of Clarithromycin Taj Pharma or viceversa. Clarithromycin Taj Pharma may increase the effect of the following medicines:

astemizole, terfenadine (antiallergic), pimozide (antipsychotic), cisapride (gastric medicine), ergotamine, dihydroergotamine (migraine medicines), lovastatin, simvastatin (medicines to lower cholesterol) (see “Do not take Clarithromycin Taj Pharma”)
alprazolam, triazolam, midazolam (hypnotics)
atorvastatin, rosuvastatin (cholesterol lowering agents)
warfarin, phenprocoumon (blood thinners): concomitant use may increase the risk of bleeding. Checking of the blood clotting should be more frequent if Clarithromycin Taj Pharma used concomitantly.
Nateglinide, repaglinide or insulin (antidiabetics)
carbamazepin, phenytoin, valproate (medicines to treat epilepsy)
cilostazol (used to improve circulation in the legs)
colchicine (to treat gout)
cyclosporine, sirolimus, tacrolimus (immunosuppressants)
digoxin, verapamil, quinidine, disopyramide (heart medicines), concomitant use of clarithromycin and these agents may cause cardiac arrhythmias..
methylprednisolone (a cortisone to treat inflammation)
omeprazole (gastric medicine)
rifabutin (antibiotic)
sildenafil, tadalafil, vardenafil (medicines to treat erectile dysfunction)
theophylline (antiasthmatic)
tolterodine (to treat overactive bladder syndrome)
vinblastine (medicine for cancer therapy)
medicines with the risk to affect hearing, especially aminoglycosides (group of antibiotics that are given to vein)
atypical antipsychotics (e.g. quetiapine)
Both, the effect of Clarithromycin Taj Pharma and the effect of the following medicines may be increased when taken together:
atazanavir, saquinavir (medicines to
treat HIV)
itraconazole (medicine to treat fungal
infections) If your doctor has specifically recommended to take Clarithromycin Taj Pharma and
any of the above mentioned medicines at the same time, your doctor may need to monitor you more closely.

Clarithromycin Taj Pharma may weaken the effect of following medicines:

zidovudine ((used to treat HIV infection). In order to avoid this you should leave a 4 hour interval between taking these medicines.

The following medicines may weaken the effect of Clarithromycin Taj Pharma:

rifampicin, rifabutin, rifapentine (antibiotics)
efavirenz, nevirapine, etravirine (medicines to treat HIV)
phenytoin, carbamazepine, phenobarbitone (antiepileptic)
St John’s Wort (a herbal product used to treat depression)
The following medicines may strengthen the effect of Clarithromycin Taj Pharma:
ritonavir (antiviral)
fluconazole (medicine to treat fungal infections)

The use of clarithromycin at the same time as digoxin, quinidine, disopyramide or verapamil (heart medicines), or other macrolide antibiotics may cause cardiac arrhythmia.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

If you are pregnant or breast-feeding do not take Clarithromycin Taj Pharma before consulting your doctor.

Driving and using machines

Clarithromycin Taj Pharma has generally no effect on the ability to drive or use machines. However, if side effects, such as dizziness, confusion and disorientation, your reaction may be adversely affected.

Use caution when driving or operating machinery until you know how you react to this medicine.

How to take Clarithromycin Taj Pharma

Always take this medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Clarithromycin Taj Pharma may be taken with or without food Clarithromycin Taj Pharma 500mg film-coated tablet is not suitable for doses below 500mg.

There are other options for this strength available on the market.

The recommendations for the usual doses are given below:

Adults including the elderly and adolescents (children over 12 years)

The usual dose is 250mg twice a day.

The usual dose is 250mg twice daily. In severe infections, your doctor may increase the dose to 500mg twice daily. The treatment takes 7-14 days and should last at least two days after the disappearance of the symptoms.

Use in infections with H. pylori:

In adult patients with ulcers of stomach and duodenum by infection with H. Pylori, as a part of triple combination therapy administered usual dose is 500mg twice a day.

Patients with kidney problems

If you have severe kidney problems your doctor may need to reduce your dose by half, i.e. once daily and restrict treatment to 14 days at the most.

Children under 12 years

Use of Clarithromycin Taj Pharma tablets for children

under the age of 12 years (under 30 kg

bodyweight) is not recommended. Your doctor will prescribe another medication that is appropriate for your chlid.

For children with a body weight of more than 30 kg, the same dose as for adults is

used.

If you feel that the effect of this medicine is too strong or too weak? Please contact your doctor or pharmacist.

If you take more Clarithromycin Taj Pharma than you should

If you have taken too much of Clarithromycin Taj Pharma, contact your doctor or nearest hospital emergency department as soon as possible. Overdose can cause gastrointestinal discomfort and possibly other complaints.

If you forget to take Clarithromycin Taj Pharma

If you forget to take a dose of Clarithromycin Taj Pharma, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose and just carry on as before. Do not take a double dose to make up for a forgotten dose.

If you stop taking Clarithromycin Taj Pharma

It is important that you take your medicine in accordance with the doctor’s instructions. Do not suddenly stop using Clarithromycin Taj Pharma without discussing it first with your doctor. Otherwise symptoms may return.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects:

If any of the following happens, stop taking this medicine and tell your doctor immediately or go to the casualty department at your nearest hospital:

allergic reactions such as sudden difficulty in breathing, speaking and swallowing
extreme dizziness or fainting
severe or itchy skin rash, especially if this shows blistering and there is soreness of the eyes, mouth or genital organs

Take as soon as possible, contact your doctor if the following symptoms develop:

diarrhoea that is serious, lasts a long time or has blood in it, with stomach pain or fever. This can be a sign of a serious bowel inflammation. Your doctor may discontinue treatment. Do not take medicines that reduce bowel movements.
Liver function with following possible symptoms
loss of appetite
yellowing of the skin or whites of the eyes (jaundice),
pale stools, dark urine
Itchy rash
Abdominal pain
Palpitations or irregular heartbeat
severe pain in the abdomen and back, caused by pancreas inflammation

Other possible side effects:

Common (may affect up to 1 in 10 people):

difficulty sleeping
headache
changes in sense of taste
abdominal pain, nausea, vomiting, diarrhoea, indigestion
abnormal liver function test results
skin rash
excessive sweating.

Uncommon (may affect up to 1 in 100 people):

yeast infections (candidiasis) (Eg: in the mouth)
infections of the vagina
reduction in the level of certain white blood cells, which can make infections more likely ( leucopenia and neutropenia)
increased number of certain white blood cells (eosinophilia)
loss of appetite
anxiety, dizziness, difficulty sleeping,
chills
spinning sensation
impaired hearing, ringing in the ears
(tinnitus)
palpitations
inflammation of the stomach, mouth
and tongue
Flatulence, constipation and
indigestion
dry mouth
chlolestasis
increase of liver enzymes in the blood
itching, hives
muscle pain
generally feeling unwell
weakness
chest pain
chills
fatigue

Frequency not known [frequency cannot be estimated from the available data]:

Inflammation of the gut with severe diarrhea called Pseudomembranous collitus,
Saint Anthony’s fire (erysipelas), acne
severe reduction of white blood cells associated with sudden high fever, severe sore throat and mouth ulcers (agranulocytosis)
unusual bruising or bleeding caused by low blood platelets
Serious allergic reaction which causes swelling of the face or throat (angioedema)
psychosis, a feeling of loss of identity
confusion, change in sense of reality or panicking,
depression, nightmares, disorientation, hallucinations, mania
convulsions
disturbed sense of smell, loss of sense of smell or taste
deafness
tingling or numbness in the hands or feet
difficulty with your blood clotting
discoloration of the teeth and tongue
acne
pain or weakness in muscles
Inflammation of the kidneys, renal failure
abnormal urine colour.

Contact a doctor immediately if you experience a serious skin reaction: a red, scaly rash with bumps under the skin and blisters (exanthematous pustulosis). The frequency of this side effect is not known (cannot be estimated from the available

data).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

How to store Clarithromycin Taj Pharma

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Contents of the pack and other information

What Clarithromycin Taj Pharma contains

The active substance is clarithromycin.

Each film-coated tablet contains 250mg of clarithromycin

Each film-coated tablet contains 500mg of clarithromycin

The other ingredients are:

Microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous, magnesium stearate, povidone, hypromellose, propylene glycol, titanium dioxide, hydroxypropyl cellulose, vanillin, sorbic acid and iron oxide yellow.

What Clarithromycin Taj Pharma looks like and contents of the pack

Film-coated tablet Clarithromycin Taj Pharma 250mg film-coated tablets:

Light yellow coloured, oval shaped, biconvex film-coated tablets

Clarithromycin Taj Pharma 500mg film-coated tablets:

Light yellow coloured, oval shaped, biconvex film-coated tablets

Clarithromycin Taj Pharma 250mg & 500mg tablets are available in clear PVC/PVDC/ Aluminium blister packs of Clarithromycin Taj Pharma film-coated tablets.

Pack size:

Each box contains 5, 10, 15, 20, 25, 30, 50, 60, 120, 240, 360, and 500 film coated tablets.

Not all pack sizes may be marketed.