For Ziomycin Tablets 250 mg
Each film-coated tablet contains;
Azithromycin dehydrate USP equivalent to Azithromycin ………… 250 mg
For Ziomycin Tablets 500 mg
Each film-coated tablet contains;
Azithromycin dehydrate USP equivalent to Azithromycin ………… 500 mg
For excipients, see section 6.1

Therapeutic indications
Azithromycin is indicated for the following bacterial infections induced by micro-organisms 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.
Posology and method of administration
The preparation should be surely taken one hour before or two hours after meal, because synchronous use increases the absorption of azithromycin. The preparation is used 1 time per day.
Adults, including elderly patients, and children with body weight over 45 kg:
The preparation should be surely taken one hour before or two hours after meal, because synchronous use increases the absorption of azithromycin. The preparation is used 1 time per day. Tablets are swallowed without chewing.
Infections of ENT-organs, respiratory tract, skin and soft tissues (except of erythema migrans):
500 mg per day during 3 days.
Erythema migrans:
adults – 1 time per day during 5 days, 1 g is in the first day following 500 mg in the 2d to 5th day.
Sexually transmitted infections:
Uncomplicated and complicated urethritis/cervicitis – 1 g of the preparation as a single use. Course dose – 1 g. In case of missed dose it should be taken as soon as possible and the following ones – at interval of 24 hours.
Renal insufficiency:
There is no need to change dosage to patients with minor renal dysfunction (creatinine clearance > 40 ml/min). There has not been any study in patients with creatinine clearance < 40 ml/min. Therefore, it is necessary to use azithromycin to those patients.
Liver impairment:
As azithromycin is metabolized in liver and excreted with bile, the preparation should not be used to patients with severe hepatic disease.

Undesirable effects
In this section undesirable effects are defined as follows:
Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

Approximately 13% of the patients in clinical trials reported undesirable effects. Undesirable gastrointestinal effects were most common, approximately 10%.

Infections and infestations:
Uncommon:
Vaginitis
Rare:
Candidiasis

Blood and the lymphatic system disorders:
Rare: Thrombocytopenia, haemolytic anaemia. Transient mild reductions in neutrophil counts have occasionally been observed in clinical trials for which a causal relationship with azithromycin treatment has not been confirmed.

Immune system disorders:
Rare:
Anaphylaxis, including oedema (rarely fatal) (see section 4.4).

Metabolism and nutrition disorders:
Uncommon:
Anorexia

Psychiatric disorders:
Rare:
Aggressive reaction, agitation, anxiety, nervousness, depersonalisation, in elderly patients delirium may occur.

Nervous system disorders:
Uncommon:
Dizziness/vertigo, convulsions, headache, somnolence, disturbances of smell and/or taste.
Rare:
Paraesthesia, syncope, insomnia, hyperactivity.

Ear and labyrinth disorders:
Rare:
Impaired hearing.
Impaired hearing including deafness and/or tinnitus has been reported after prolonged treatment at high doses in clinical trials. A majority of these cases has been reversible, of those that were possible to follow up.

Cardiac disorders:
Rare:
Palpitations, arrhythmia (including ventricular tachycardia). There is a potential risk of QT prolongation and torsades de pointes, particularly in patients who are susceptible to these conditions.

Gastrointestinal disorders:
Common:
Nausea, diarrhoea, abdominal discomfort (pain/cramps), vomiting.
Uncommon:
Loose stools (as a result of infrequent dehydration), flatulence, dyspepsia.
Rare:
Constipation, pseudomembranous colitis, pancreatitis, discolouration of the teeth, tongue discolouration.

Hepato-biliary disorders:
Rare:
Abnormal liver function test values, hepatitis, cholestatic jaundice, rare cases of hepatic necrosis and hepatic failure which have rarely resulted in death.

Skin and subcutaneous tissue disorders:
Uncommon:
Rash, pruritus.

Rare:
Angioneurotic oedema, urticaria, photosensitivity, erythema multiforme, Stevens-Johnson’s syndrome, toxic epidermal necrolysis.

Musculoskeletal, connective tissue and bone disorders:
Uncommon:
Arthralgia

Renal and urinary disorders:
Rare:
Interstitial nephritis, acute renal failure.

General disorders:
Rare:
Asthenia, fatigue, malaise.

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%. Azithromycin must be taken at least 1 hour before or 2 hours after antacids.

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):
Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin, 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 macrolid 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 coumarintype 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 Cmax and AUC0-5 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 Cmax (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 drug. 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 3 days) on the AUC and Cmax 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.

Special warnings and precautions for use
Rare serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.

Observations for signs of superinfection with non-susceptible organisms, including fungi is recommended.

Pseudomembranous colitis has been reported with the use of macrolide antibiotics. This diagnosis should therefore be considered in patients who get diarrhoea after starting the treatment with azithromycin. Should pseudomembranous colitis be induced by azithromycin, then anti-peristaltics should be contraindicated. There is no experience regarding the safety and efficacy of the long-term application of azithromycin for the above mentioned indications. In case of quickly recurring infections, treatment with an other antibacterial agent should be considered.

Due to the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered (see section 4.5).

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. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation.

Therefore azithromycin should not be used:
– in patients with congenital or documented acquired QT prolongation.
– with other active substances that prolong QT interval such as antiarrhythmics of classes IA and III, cisapride and terfenadine.
– in patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia
– in patients with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

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.

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

Use in renal impairment:
No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10–80 ml/min). Caution is advised in patients with severe renal impairment (GFR < 10 ml/min) as systemic exposure may be increased (see section 5.2).

Use in hepatic impairment:
Since azithromycin is metabolised in the liver and excreted in the bile, the medicinal product should not be given to patients suffering from severe liver disease. No studies have been conducted regarding the treatment of such patients with azithromycin. When severe liver impairment occurs, the treatment with azithromycin should be ceased.

Azithromycin should be administered with caution to patients with neurological or psychiatric disorders.

Azithromycin is not indicated for the treatment of infected burn wounds. Azithromycin film-coated tablets are not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.

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. Lactation
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.

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.

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.

Contraindications
The use of this product is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic.

PHARMACEUTICAL FORM
Film-coated tablet
For Ziomycin Tablets 250 mg
Yellow colored, film-coated capsule shaped tablets with engraving “A 250” on one side and plain on other side.
For Ziomycin Tablets 500 mg
Yellow colored, film-coated capsule shaped tablets with engraving “A 500” on one side and plain on other side

PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group:
Antibacterials for systemic use, macrolides

ATC Code:
J01FA10

Azithromycin is an azalide, derived from the macrolide class of antibiotics. The mode of action of azithromycin is inhibition of protein synthesis in bacteria by binding to the 50s ribosomal subunit and preventing translocation of peptides. Azithromycin is usually bacteriostatic. However, in high concentrations, azithromycin may be bactericidal against selected microorganisms. Azithromycin is active against many Gram-positive and Gram-negative aerobic and anaerobic bacteria and bacterial pathogens such as Mycobacterium avium complex, Mycoplasma spp., Borrelia burgdorferi, Chlamydia spp. and Campylobacter spp. In addition, azithromycin has activity against protozoan microorganisms such as Toxoplasma gondii.

Breakpoints:
According to the NCCLS (National Committee on Clinical Laboratory Standards) in 2001 the following breakpoints have been defined for azithromycin:
− 2 μg/ml susceptible; 4 μg/ml intermediate; 8 μg/ml resistant
− Haemophilus spp.: 4 μg/ml susceptible
− Streptococcus pneumoniae and Streptococcus pyogenes: 0.5 μg/ml susceptible;
1 μg/ml intermediate; 2 μg/ml resistant
There are currently no recommended NCCLS breakpoints for Enterobacteriaceae, Neisseria gonorrhoeae, Moraxella catarrhalis and Mycobacterium avium complex.

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 prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Other information:
The diagnostic procedures available in vitro at this moment to determine the susceptibility of Mycobacterium avium complex (MAC) organisms are not generally accepted and validated.

Streptococci and staphylococci that are resistant to erythromycin are also resistant to azithromycin. Cross-resistance to Mycobacterium avium complex organisms occurs between clarithromycin and azithromycin.

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 (Cmax) 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 52% at 0,05 mg/l to 18% at 0,5 mg/l, depending on the serum concentration.

Excretion:
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 Cmax and AUC0-120 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 Cmax and AUC0-120 increased 61% and 35% 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 2-5, the Cmax 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.

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 dosages of 100 and 200 mg/kg bodyweight/ 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.

PHARMACEUTICAL PARTICULARS
List of excipients
Microcrystalline cellulose, Croscarmellose sodium, Sodium lauryl sulfate, Povidone, Purified talc, Purified water, Magnesium stearate and Opadry yellow 04B520005.
Incompatibilities
Not applicable.

Shelf life
36 years

Special precautions for storage
Store below 30 ºC in dry place.
Keep out of reach of children.

Nature and contents of container
Ziomycin Tablets 250 mg
10 or 6 Tablets are packed in PVC/PVDC blister & such 10 blisters are packed in a carton along with pack insert.
Ziomycin Tablets 500 mg
10 or 3 Tablets are packed in PVC/PVDC blister & such 10 blisters are packed in a carton along with pack insert.

MARKETING AUTHORISATION HOLDER
Kusum Healthcare Private Limited
D-158 A, Okhla Industrial Area,
Phase I, New Delhi-110020,
India.

MARKETING AUTHORISATION NUMBER(S)
——-

MANUFACTURER NAME
Kusum Healthcare Private Limited
SP 289 (A), RIICO Industrial Area
Chopanki, Bhiwadi
Distt. Alwar – 301707
India.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
——-
DATE OF REVISION OF THE TEXT