Azithromycin Tablets IP 500mg (Zithromin)

Azithromycin Tablets IP 500mg (Zithromin) Taj Pharma

1. Name of the medicinal product

Azithromycin Tablets IP 100mg (Zithromin) Taj Pharma

Azithromycin Tablets IP 250mg (Zithromin) Taj Pharma

Azithromycin Tablets IP 500mg (Zithromin) Taj Pharma

2. Qualitative and quantitative composition

a) Each film-coated tablet contains:
Azithromycin Dihydrate IP equivalent to
Anhydrous Azithromycin                         100mg
Excipients                                                   q.s.
Colour: Titanium Dioxide IP

b) Each film-coated tablet contains:
Azithromycin Dihydrate IP equivalent to
Anhydrous Azithromycin                         250mg
Excipients                                                   q.s.
Colour: Titanium Dioxide IP

c) Each film-coated tablet contains:
Azithromycin Dihydrate IP equivalent to
Anhydrous Azithromycin                      500mg
Excipients                                                    q.s.
Colour: Titanium Dioxide IP 

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-Coated Tablet

4. Clinical particulars

4.1 Therapeutic indications

Azithromycin is indicated for the following bacterial infections induced by microorganisms susceptible to azithromycin (see sections 4.4 and 5.1):

• Acute bacterial sinusitis (adequately diagnosed)
• Acute bacterial otitis media (adequately diagnosed)
• Pharyngitis, tonsillitis
• Acute exacerbation of chronic bronchitis (adequately diagnosed)
• Mild to moderately severe community acquired pneumonia
• Infections of the skin and soft tissues of mild to moderate severity e.g. folliculitis, cellulitis, erysipelas
• Uncomplicated Chlamydia trachomatis urethritis and cervicitis

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

4.2 Posology and method of administration

Posology

Azithromycin should be given as a single daily dose. Duration of the treatment for the different infection diseases is given below.

Children and adolescents with a body weight above 45 kg, adults and the elderly

The total dose is 1500 mg, administered as 500 mg once daily for 3 days. Alternatively, the same total dose (1500 mg) can be administered in a period of 5 days, 500 mg on the first day and 250 mg on day 2 to 5.

In the case of uncomplicated Chlamydia trachomatis urethritis and cervicitis, the dose is 1000 mg as a single oral dose.

Children and adolescents with a body weight below 45 kg

Azithromycin tablets are not suitable for patients under 45 kg body weight. Other dosage forms are available for this group of patients.

Elderly patients

For elderly patients the same dose as for adults can be applied. Since elderly patients can be patients with ongoing proarrhythmic conditions a particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes. (see section 4.4).

Patients with renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 ml/min) Caution should be exercised when azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/min) (see section 4.4 and section 5.2)

Patients with hepatic impairment

Dose adjustment is not required for patients with mild to moderate hepatic dysfunction (see section 4.4).

Method of administration

Azithromycin should be given as a single daily dose . The tablets can be taken with or without food.

The tablets should be taken with ½ glass of water.

4.3 Contraindications

Hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any of the excipient listed in section 6.1.

4.4 Special warnings and precautions for use

Hypersensitivity:

As with erythromycin and other macrolides, rare serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), dermatologic reactions including acute generalised exanthematous pustulosis (AGEP), Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (rarely fatal) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

Hepatic impairment:

Since the liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see section 4.8). Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products.

In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests/ investigations should be performed immediately. Azithromycin administration should be stopped if liver dysfunction has emerged.

Ergot alkaloids and azithromycin

In patients receiving ergot derivatives, ergotism has been precipitated by coadministration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergotamine derivatives and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered (see section 4.5).

Superinfections:

As with any antibiotic preparation, it is recommended to pay attention to signs of superinfection with nonsusceptible microorganisms like fungi. A superinfection may require an interruption of the azithromycin treatment and initiation of adequate measures.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

1. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C.difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. In case of CDAD anti-peristaltics are contraindicated

Renal impairment

In patients with severe renal impairment (GFR < 10 ml/min) a 33% increase in systemic exposure to azithromycin was observed (see section 5.2).

Cardiovascular events

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides, including azithromycin (see section 4.8). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes) which can lead to cardiac arrest, azithromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients) such as patients:

– With congenital or documented acquired QT prolongation.

– Currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of class IA (quinidine and procainamide) and class III (dofetilide, amiodarone and sotalol), cisapride and terfenadine; antipsychotic agents such as pimozide; antidepressants such as citalopram; and fluoroquinolones such as moxifloxacin and levofloxacin.

– With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia

– With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

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 azithromycin. Consideration of these findings should be balanced with treatment benefits when prescribing azithromycin.

Myasthenia gravis

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (see section 4.8).

Paediatric population

Safety and efficacy for the prevention or treatment of Mycobacterium avium Complex in children have not been established.

The following should be considered before prescribing azithromycin:

Azithromycin is not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.

The selection of azithromycin to treat an individual patient should take into account the appropriateness of using a macrolide antibacterial agent based on adequate diagnosis to ascertain the bacterial etiology of the infection in the approved indications and the prevalence of resistance to azithromycin or other macrolides.

In areas with a high incidence of erythromycin A resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to azithromycin and other antibiotics.

Pharyngitis/ tonsillitis

Azithromycin is not the substance of first choice for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes. For this and for the prophylaxis of acute rheumatic fever penicillin is the treatment of first choice.

Sinusitis

Often, azithromycin is not the substance of first choice for the treatment of sinusitis

Acute otitis media

Often, azithromycin is not the substance of first choice for the treatment of acute otitis media.

Skin and soft tissue infections

The main causative agent of soft tissue infections, Staphylococcus aureus, is frequently resistant to azithromycin. Therefore, susceptibility testing is considered a precondition for treatment of soft tissue infections with azithromycin.

Infected burn wounds:

Azithromycin is not indicated for the treatment of infected burn wounds.

Sexually transmitted disease:

In case of sexually transmitted diseases a concomitant infection by T. pallidium should be excluded.

Neurological or psychiatric diseases:

Azithromycin should be used with caution in patients with neurological or psychiatric disorders.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

Azithromycin contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially ‘sodium-free.’

4.5 Interaction with other medicinal products and other forms of interaction

Antacids:

In a pharmacokinetic study investigating the effects of simultaneous administration of antacids with azithromycin, no effect on overall bioavailability was seen, although peak serum levels were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the medicinal products should not be taken simultaneously. Azithromycin must be taken at least 1 hour before or 2 hours after antacids.

Co-administration of azithromycin prolonged-release granules for oral suspension with a single 20 ml dose of co-magaldrox (aluminium hydroxide and magnesium hydroxide) did not affect the rate and extent of azithromycin absorption.

Co-administration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.

Cetirizine:

In healthy volunteers, coadministration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Didanosins (Dideoxyinosine): Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV- positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.

Digoxin (P-gp substrates) and colchicine:

Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate should be considered.

Zidovudine:

Single 1000 mg doses and multiple doses of 600 mg or 1200 mg azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome metabolite complex does not occur with azithromycin.

Ergotamine derivatives:

Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see section 4.4).

Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.

Astemizole, alfentanil

There are no known data on interactions with astemizole or alfentanil. Caution is advised in the co-administration of these medicines with Azithromycin because of the known enhancing effect of these medicines when used concurrently with the macrolide antibiotic erythromycin.

Atorvastatin:

Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.

Carbamazepine:

In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.

Cisapride

Cisapride is metabolized in the liver by the enzyme CYP 3A4. Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and torsades de pointes.

Cimetidine: In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.

Coumarin Type Oral Anticoagulants:

In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15-mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin type oral anticoagulants.

Cyclosporin:

In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of cyclosporin, the resulting cyclosporin C_max and AUC_0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

Efavirenz:

Coadministration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.

Fluconazole:

Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the coadministration of fluconazole, however, a clinically insignificant decrease in C_max (18%) of azithromycin was observed.

Indinavir:

Coadministration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.

Methylprednisolone:

In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.

Midazolam:

In healthy volunteers, coadministration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.

Nelfinavir:

Coadministration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.

Rifabutin:

Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either medicinal product . Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established (see section 4.8).

Sildenafil:

In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3days) on the AUC and C_max of sildenafil or its major circulating metabolite.

Terfenadine:

Pharmacokinetic studies have reported no evidence of an interaction between azithromycin and terfenadine. There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred.

Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered to healthy volunteers. As interactions of other macrolides with theophylline have been reported, alertness to signs that indicate a rise in theophylline levels is advised.

Triazolam:

In 14 healthy volunteers, coadministration of azithromycin 500 mg on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole:

Coadministration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1200 mg on Day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of azithromycin in pregnant women. In reproduction toxicity studies in animals azithromycin was shown to pass the placenta, but no teratogenic effects were observed (see section 5.3). The safety of azithromycin has not been confirmed with regard to the use of the active substance during pregnancy. Therefore azithromycin should only be used during pregnancy if the benefit outweighs the risk.

Breastfeeding

Azithromycin has been reported to be secreted into human breast milk, but there are no adequate and well controlled clinical studies in nursing women that have characterized the pharmacokinetics of azithromycin excretion into human breast milk.

Because it is not known whether azithromycin may have adverse effects on the breast-fed infant, nursing should be discontinued during treatment with azithromycin. Among other things diarrhoea, fungus infection of the mucous membrane as well as sensitisation is possible in the nursed infant. It is recommended to discard the milk during treatment and up until 2 days after discontinuation of treatment. Nursing may be resumed thereafter.

Fertility

In fertility studies conducted in rat, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.

4.7 Effects on ability to drive and use machines

No data are available regarding the influence of azithromycin on a patient’s ability to drive or operate machinery. However, the possibility of undesirable effects like dizziness and convulsions should be taken into account when performing these activities. Visual impairment and vision blurred may have an effect on a patient’s ability to drive or operate machinery (section 4.8).

4.8 Undesirable effects

The table below lists the adverse reactions identified through clinical trial experience and post-marketing surveillance by system organ class and frequency. Adverse reactions identified from post-marketing experience are included in italics.

The frequency grouping is defined using the following convention: Very common (≥1/10); Common (≥ 1/100 to <1/10);Uncommon (≥1/1,000 to <1/100); Rare (≥ 1/10,000 to <1/1,000); Very Rare (< 1/10,000);and Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions possibly or probably related to azithromycin based on clinical trial experience and post-marketing surveillance:

Adverse reactions possibly or probably related to Mycobacterium Avium Complex prophylaxis and treatment based on clinical trial experience and post-marketing surveillance. These adverse reactions differ from those reported with immediate release or the prolonged release formulations, either in kind or in frequency:

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.

4.9 Overdose

Adverse events experienced in higher than recommended doses were similar to those seen at normal doses.

Symptoms

The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea.

Treatment

In the event of overdose, general symptomatic and supportive measures are indicated as required.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, macrolides.

Azithromycin is a macrolide antibiotic belonging to the azalide group.

The molecule is constructed by adding a nitrogen atom to the lactone ring of erythromycin A. The chemical name of azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. The molecular weight is 749.0.

Mechanism of action

Azithromycin is an azalide, a sub-class of the macrolide antibiotics. By binding to the 50S ribosomal sub-unit, azithromycin avoids the translocation of peptide chains from one side of the ribosome to the other. As a consequence of this, RNA-dependent protein synthesis in sensitive organisms is prevented.

PK/PD relationship:

For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.

Mechanism of resistance:

Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of the antibiotic.

Complete cross resistance exists among Streptococcus pneumoniae, betahaemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.

5.2 Pharmacokinetic properties

Absorption:

Bioavailability of azithromycin after oral administration is approximately 37%. Peak plasma concentrations are attained after 2-3 hours.The mean maximum concentration observed (C_max) after a single dose of 500 mg is approximately 0.4 μg/ml.

Distribution:

Orally administered azithromycin is widely distributed throughout the body.

Pharmacokinetic studies have demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (up to 50 times the maximum observed concentration in plasma) than those measured in plasma. This indicates that the agent strongly binds to tissues (steady-state distribution volume approx. 31 l/kg).

At the recommended dose no accumulation appears in the serum. Accumulation appears in tissues where levels are much higher than in serum. Three days after administration of 500 mg as a single dose or in partial doses concentrations of 1,3-4,8 μg/g, 0,6-2,3 μg/g, 2,0-2,8 μg/g and 0-0,3 μg/ml have been measured in resp. lung, prostate, tonsil and serum.

In experimental in vitro and in vivo studies azithromycin accumulates in phagocytes. Release is stimulated by active phagocytosis. In animal models this process contributes to the accumulation of azithromycin in tissue.

Binding of azithromycin to serum proteins is variable and varies from 50% at 0,05 mg/l to 18% at 0,5 mg/l, depending on the serum concentration.

Elimination:

The terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2-4 days.

Approximately 12% of an intravenously administered dose is excreted in unchanged form with the urine over a period of 3 days; the major proportion in the first 24 hours. Concentrations of up to 237 μg/ml azithromycin, 2 days after a 5-day course of treatment, have been found in human bile. Ten metabolites have been identified (formed by N and O demethylation, by hydroxylation of the desosamine and aglycone rings, and by splitting of the cladinose conjugate). Investigations suggest that the metabolites do not play a role in the microbiological activity of azithromycin.

Pharmacokinetics in Special populations:

Renal Insufficiency:

Following a single oral dose of azithromycin 1 g, mean C_max and AUC_0-120 increased by 5.1% and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR > 80ml/min). In subjects with severe renal impairment, the mean C_max and AUC_0-120 increased 61% and 33% respectively compared to normal.

Hepatic insufficiency:

In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.

Elderly:

The pharmacokinetics of azithromycin in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred.

In elderly volunteers (> 65 years) higher (29%) AUC values have been measured after a 5 day treatment than in younger volunteers (< 45 years). These differences are not regarded as clinically relevant; dose adjustment is therefore not recommended.

Infants, toddlers, children and adolescents:

Pharmacokinetics has been studied in children aged 4 months – 15 years taking capsules, granules or suspension. At 10 mg/kg on day 1 followed by 5 mg/kg on days 25, the C_max achieved is slightly lower than in adults, with 224 μg/l in children aged 0.6-5 years and after 3 days dosing, and 383 μg/l in those aged 6-15 years. The half-life of 36 h in the older children was within the expected range for adults.

5.3 Preclinical safety data

In animal studies using exposures 40 times those achieved at the clinical therapeutic dosages, azithromycin was found to have caused reversible phospholipidosis, but as a rule there were no associated toxicological consequences. The relevance of this finding to humans receiving azithromycin in accordance with the recommendations is unknown.

Electrophysiological investigations have shown that azithromycin prolongs the QT interval.

Carcinogenic potential:

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

Mutagenic potential:

There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.

Reproductive toxicity:

Teratogenic effects were not observed in rat reproductive toxicity studies. In rats, azithromycin doses of 100 and 200 mg/kg body weight/ day led to mild retardation in foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats mild retardations in physical and reflex development were noted following treatment with 50 mg/kg/day azithromycin and above.

6. Pharmaceutical particulars

6.1 List of excipients
Tablet core:
Calcium hydrogen phosphate, anhydrous Starch, pregelatinized (maize starch), Croscarmellose sodium, Sodium lauryl sulfate, Magnesium stearate
Tablet coating:
Lactose monohydrate, Hypromellose, Titanium dioxide, Triacetin

6.2 Incompatibilities
Not applicable.

6.3 Shelf life
3 years.

6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container
Azithromycin film-coated tablets are available in clear PVC- Aluminium blister packs.
Blister packs: 2, 3, 4, 6 and 12 film-coated tablets
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
At Plot No.: 220, Mahagujarat Industrial Estate,
At & Post: Moraiya, Tal – Sanand, Dist. Ahmedabad, Gujarat, INDIA.

Azithromycin Tablets IP 500mg (Zithromin) Taj Pharma

Azithromycin Tablets IP 100mg (Zithromin) Taj Pharma

Azithromycin Tablets IP 250mg (Zithromin) Taj Pharma

Azithromycin Tablets IP 500mg (Zithromin) Taj Pharma

Package leaflet: Information for the patient

Azithromycin

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 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:

1. What Zithromin is and what it is used for
2. What you need to know before you take Zithromin
3. How to take Zithromin
4. Possible side effects
5. How to store Zithromin
6. Contents of the pack and other information

1 What Zithromin is and what it is used for

Azithromycin belongs to a group of medicines called macrolide antibiotics. Antibiotics are used to treat infections caused by micro-organisms like bacteria.

Azithromycin is used for the treatment of certain infections caused by bacteria that are sensitive to it, such as:

• chest, throat or nasal infections (such as bronchitis, pneumonia, tonsillitis, sore throat (pharyngitis) and sinusitis)
• ear infections
• skin and soft tissue infections, with exception of infected burn
• infection of the tube that carries urine from the bladder (urethra) or the neck of the womb (cervix) caused by Chlamidia trachomatis (bacteria).

2 What you need to know before you take Zithromin

Do not take Zithromin:

• if you are allergic to azithromycin dihydrate, erythromycin or any macrolide or ketolide antibiotic,

if you are allergic to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk with your doctor or pharmacist before taking Azithromycin if:

• you have ever had a serious allergic reaction causing swelling of the face and throat, possibly with breathing problems, rash, fever, swollen gland you develop severe and persistent diarrhoea during or after treatment
• you have severe liver or kidney problems
  • you have severe heart problems or problems with your heart beat such as long QT syndrome (shown on an electro-cardiogram or ECG machine)
  • your blood levels of potassium or magnesium are too low
  • you develop signs of another infection
  • you are taking any ergot derivatives such as ergotamine (to treat migraine) as these medicines should not be taken together with Azithromycin (see section “Other medicines and Azithromycin”)
• you have a certain type of muscle weakness called myasthenia gravis you have nervous (neurological) or mental (psychiatric)

Other medicines and Azithromycin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any of the following medicines:

• Antacids – used for heartburn and indigestion. Azithromycin should be taken at least 1 hour before or 2 hours after the antacid
• Ergotamine -dihydroergotamine (used for migraine) should not be taken at the same time as serious side effects may develop (ergotism – i.e. itching in the limbs, muscle cramps and gangrene of hands and feet due to poor blood circulation)
• Cholesterol lowering medicines(statins)
• Warfarin or any similar medicines – to prevent blood clots: concomitant use can increase the risk of bleeding
• Cisapride – (used to treat stomach problems) or terfenadine (used to treat hay fever): should not be taken at the same time as this may cause severe heart problems (shown on an electro-cardiogram or ECG machine)
• Zidovudine or nelfinavir – used to treat HIV infections. Taking nelfinavir with Azithromycin may mean that you get more of the side effects listed in this leaflet
• Rifabutin – used to treat tuberculosis (TB)
• Quinidine – used to treat heart rhythm problems called anti-arrythmics)
• Cyclosporin – used to suppress the immune system to prevent and treat rejection of an organ or bone marrow transplant. Your doctor will regularly check your blood levels of cyclosporin and may change your

Tell your doctor or pharmacist if you are taking any of the following medicines. Azithromycin can make the effects of these other medicines stronger. Your doctor may change your dose:

• Alfentanil – a painkiller used e.g. during operations
• Theophylline – used for breathing problems such as asthma and chronic obstructive pulmonary disease (COPD)
• Digoxin – used to treat heart failure
• Colchicine (used for gout and familial Mediterranean fever)
• Astemizol – used to treat hay fever
• Pimozide – used to treat mental health

Azithromycin with food and drink

This medicine can be taken with or without food.

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.

There is insufficient information available about the use of Azithromycin during pregnancy. Therefore you should not use Azithromycin during pregnancy, unless explicitly advised by your doctor.

Azithromycin is partially passed through the mother’s milk,

It is not known whether azithromycin may have adverse effects on the breast-fed infant. Breastfeeding should therefore be discontinued during treatment with Azithromycin. It is recommended to discard the milk during treatment and up until 2 days after discontinuation of treatment. Breast-feeding may be resumed thereafter.

Driving and using machines

There are no data available about the influence of Azithromycin on the ability to drive or operate machines. However Azithromycin may cause dizziness and seizures so make sure you are not affected before driving or operating machinery.

Azithromycin contains lactose monohydrate.

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking medicinal product.

Sodium

Azithromycin contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially ‘sodium-free.’

3 How to take Zithromin

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

The recommended dose:

For adults and children with a body weight of 45 kg or more

Azithromycin is taken as a 3 or 5 day course:

• 3 days course: Take 500 mg (two 250 mg or one 500 mg tablet) once each day
• 5 days course:
• Take 500 mg on Day 1 (two 250 mg tablets)
• Take 250 mg (one 250 mg tablet) on Days 2, 3, 4 and 5

For infections of the neck of the womb and urethra caused by Chlamydia trachomatis

One dose of 1000 mg, (four 250 mg tablets or two 500 mg tablets) to be taken one time.

Children and adolescents under 45kg

The tablets are not recommended. Children with a body weight of less than 45kg should use other forms of this medicine.

Patients with kidney or liver problems You should tell your doctor if you have kidney or liver problems as your doctor may need to alter the normal dose.

Dosage for elderly

For elderly the same dosage as for adults applies.

The tablet can be divided into equal doses.

Method of administration

The tablets should be taken with ½ glass of water.

The tablets can be taken with or without food.

If you take more Azithromycin than you should

If you have taken too much Azithromycin, contact your doctor, pharmacist or go to your nearest hospital at once.

Symptoms of overdose are loss of hearing, feeling sick or being sick and diarrhoea. In case of overdosage admission into hospital may be necessary.

If you forget to take Azithromycin

If you forget to take Azithromycin, take your dose as soon as possible. If it is almost time for the next dose, just skip that dose and take the next one when it is due. If in doubt, please contact your doctor or pharmacist. If you have to skip a dose, still take all of your tablets. This means that you will finish your course a day later.

Do not take a double dose to make up for a forgotten dose.

If you stop taking Azithromycin

Never stop the treatment with Azithromycin on your own, but first discuss this with your doctor. If the prescribed treatment is not completely finished, the infection may come back again.

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

4 Possible side effects

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

If you have any of the following symptoms of a severe allergic reaction stop taking this medicine and tell your doctor immediately or go to the casualty department at your nearest hospital

The frequency of the these reactions is not known (frequency cannot be estimated from the available data)

• Sudden difficulty in breathing, speaking and swallowing
• Swelling of lips, tongue, face and neck
• Extreme dizziness or collapse
• Severe or itchy skin rash, especially if this shows blistering and there is soreness of the eyes, mouth or genital
• Serious skin reactions:
• blistering of the skin, mouth, eyes and genitals (Stevens-Johnson Syndrome (SJS))
• blistering of the skin, severe skin reaction (Toxic Epidermal Necrosis (TEN))
• skin rash accompanied by other symptoms such as fever, swollen glands and an increase of eosinophils (a type of white blood cell). A rash appears as small, itchy red bumps (Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS))

If you experience any of the following side effects contact your doctor as soon as possible

Rare (may affect up to 1 in 1,000 people):

• Increased or reduced urine output, or traces of blood in your urine
• Skin eruption that is characterised by the rapid appearance of areas of red skin studded with small pustules (small blisters filled with white/yellow fluid)

Not known (frequency cannot be estimated from the available data)

• 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. This is something that can rarely happen after taking antibiotics
• Yellowing of the skin or whites of the eyes (jaundice) caused by liver problems
• Inflammation of the pancreas (pancreatitis), which causes severe pain in the abdomen and back
• Increased or reduced urine output, or traces of blood in your urine
• Skin rash caused by sensitivity to sunlight
• Unusual bruising or bleeding
• Irregular heart-

These are all serious side effects. You may need urgent medical attention.

Other side effects include:

Very common (may affect more than 1 in 10 people)

• diarrhoea
• abdominal pain
• feeling sick (nausea)
• loose wind (flatulence)

Common (may affect up to 1 in 10 people)

• lack of appetite (anorexia)
• headache
• feeling dizzy
• sensation of pins and needles or numbness (paraesthesia)
• changes in your sense of taste
• visual impairment
• deafness
• being sick (vomiting), stomach pain or cramps, loss of appetite, problems digesting your food
• skin rashes and itching
• joint pain (arthralgia)
• fatigue
• change in the quantity of the white blood cells and the concentration of bicarbonate in the

Uncommon (may affect up to 1 in 100 people)

• thrush (candidiasis) – a fungal infection
• bacterial infection
• inflammation of the throat (pharyngitis)
• breathlessness, chest pain, wheeze and cough (respiratory disorder)
• inflammation of the mucous membrane inside the nose (rhinitis)
• stomach flu (gastroenteritis)
• inflammation inside your vagina (vaginitis)
• pneumonia
• reduction in the number of white blood cells
• angioedema
• hypersensitivity
• nervousness
• reduced sense of touch (hypoaesthesia)
• feeling drowsy (somnolence)
• having difficulty sleeping (insomnia)
• ear disorder
• dizziness
• spinning sensation (vertigo)
  • palpitations
  • hot flushes
  • shortness of breath
  • nosebleed
  • inflammation of the lining of the stomach (gastritis)
  • constipation
  • difficulty swallowing
  • swollen abdomen
  • dry mouth
  • belching
  • mouth ulcer
  • increased salivary flow
• liver problems such as hepatitis
• allergic skin reactions such as being sensitive to sunlight, red, flaking and swollen skin
• skin rash
• itching
• inflammation of the skin (dermatitis)
• dry skin
• increased sweating
• pain, swelling and reduced motion in your joints (osteoarthritis)
• muscle pain
• back pain
• neck pain
• increase in blood urea levels
• painful or difficult urination
• pain in the upper back (renal pain)
• spotting
• testicular disorder
• urticaria
• chest pain
• face swelling
• fever
• pain
• swelling of extremities (peripheral edema)
• swelling (oedema)
• general feeling of being unwell (malaise)
• weakness (asthenia)
• change in liver enzyme levels and blood levels
• post procedural complications
• skin more sensitive to sunlight than normal
• abnormal laboratory test values (e.g. blood or liver tests).

Rare (may affect up to 1 in 1,000 people)

• feeling agitated, feeling of unreality to the self and own feeling
• abnormal hepatic function
• allergic skin reactions
• skin eruption that is characterised by the rapid appearance of areas of red skin studded with small pustules (small blisters filled with white/yellow fluid).
• swelling of the hands, feet, lips, genitals or throat (angioneurotic oedema)
• kidney problems

Not known (frequency cannot be estimated from the available data)

• gut (colon) infection (pseudomembranous colitis)
• reduced number of red blood cells due to destruction (haemolytic anaemia); reduction in number of platelets (thrombocytopenia)
• anaphylactic reaction
• feeling angry, aggressive
• anxiety
• confusion
• hallucination
• fainting (syncope)
• fits (convulsions)
• reduced sense of touch (hypoaesthesia)
• feeling hyperactive
• change in your sense of smell (anosmia, parosmia)
• change in your sense of taste (ageusia)
• exacerbation or aggravation of muscle weakness (myasthenia gravis)
• blurred vision
• impaired hearing including loss of hearing, ringing in your ears
• rapid (ventricular tachycardia) or irregular heart-beat, sometimes being life-threatening, changes  of the heart rhythm found by an electro- cardiogram (QT prolongation and torsade de pointes)
• low blood pressure
• inflammation of the pancreas (pancreatitis)
• your tongue changes colour
• liver failure
• severe allergic skin reactions
• inflammation within the

The following side effects have been reported in prophylactic treatment against Mycobacterium Avium complex (MAC):

Very common (may affect more than 1 in 10 people)

• diarrhoea
• abdominal pain
• feeling sick (nausea)
• loose wind (flatulence)
• abdominal discomfort
• loose stools

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

• lack of appetite (anorexia)
• feeling dizzy
• headache
• sensation of pins and needles or numbness (paraesthesia)
• changes in your sense of taste
• visual impairment
• deafness
• being sick (vomiting), stomach pain or cramps, loss of appetite, problems digesting your food
• skin rashes and itching
• joint pain (arthralgia)
• fatigue

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

• reduced sense of touch (hypoaesthesia)
• hearing loss or ringing in your ears
• palpitations
• liver problems such as hepatitis
• severe form of skin flushing
• allergic skin reactions such as being sensitive to sunlight, red, flaking and swollen skin
• general feeling of being unwell (malaise)
• weakness (asthenia)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5 How to store Zithromin

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 carton after EXP. The expiry date refers to the last day of that month.

The 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.

6 Contents of the pack and other information
What Azithromycin contains

• The active substance is azithromycin dihydrate.

Each film-coated tablet contains 100mg of azithromycin (as dihydrate). Each film-coated tablet contains 250mg of azithromycin (as dihydrate). Each film-coated tablet contains 500mg of azithromycin (as dihydrate).

The other ingredients are Tablet core: Calcium hydrogen phosphate, anhydrous, starch, pregelatinized (maize starch), croscarmellose sodium, sodium lauryl sulfate, magnesium stearate. Tablet coating: Lactose monohydrate, hypromellose, titanium dioxide, triacetin.

Contents of the pack
Azithromycin film-coated tablets are available in clear PVC- Aluminium blister packs.
Blister packs: 2, 3, 4, 6 and 12 film- coated tablets
Not all pack sizes may be marketed. 

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
At Plot No.: 220, Mahagujarat Industrial Estate,
At & Post: Moraiya, Tal – Sanand, Dist. Ahmedabad, Gujarat, INDIA.