Azitus 250 and 500 Tablets

Azithromycin Tablets IP 250 mg / 500 mg

Azitus 250

Each film coated tablet contains :

Azithromycin Dihydrate IP

equivalent to Azithromycin 250 mg

Excipients q.s.

Colour : Titanium Dioxide IP

Azitus 500

Each film coated tablet contains :

Azithromycin Dihydrate IP

equivalent to Azithromycin 500 mg

Excipients

Colour : Titanium Dioxide IP

Tablet 250 / 500 mg

4.1 Therapeutic indication

• Uncomplicated multidrug resistant enteric fever only
• Acute bacterial sinusitis.
• Acute bacterial otitis media
• Pharyngitis, tonsillitis
• Acute exacerbation of chronic bronchitis
• Mild to moderately severe community acquired pneumonia
• Skin and soft tissue infections
• Uncomplicated Chlamydia trachomatis urethritis and cervicitis

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

4.2 Posology and method of administration

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

Adults, children and adolescents with a body weight of 45 kg or over

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 dosage is 1000 mg as a single oral dose.

For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.

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

Patients with renal impairment

Dose adjustment is not required 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).

Patients with hepatic impairment

Since Azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with Azithromycin.

Method of administration

Azithromycin film-coated tablets are for oral administration only. 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 the formulation.

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.

Hepatotoxicity

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 lifethreatening liver failure have been reported with Azithromycin. 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 derivatives

In patients receiving Ergot derivatives, Ergotism has been precipitated by co-administration 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.

Prolongation of the QT interval

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, caution is required when treating patients :

• With congenital or documented QT prolongation.
• Currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of classes Ia and III, Cisapride and Terfenadine.
• With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia
• With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency

Superinfection

As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms including fungi is recommended.

Clostridium difficile associated diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including Azithromycin, and may range in severity from mild diarrhoea to fatal colitis. Strains of C. difficile producing hypertoxins A and B 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. Therefore, CDAD must be considered in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Discontinuation of therapy with Azithromycin and the administration of specific treatment for C. difficile should be considered.

Streptococcal infections

Penicillin is usually the first choice for treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes and also for prophylaxis of acute rheumatic fever. Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of Azithromycin in preventing acute rheumatic fever.

Renal impairment

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

Myasthenia gravis

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy. Co-administration with Hydroxychloroquine or Chloroquine

Carefully consider the balance of benefits and risks before prescribing Azithromycin for any patients taking Hydroxychloroquine or Chloroquine, because of the potential for an increased risk of cardiovascular events and cardiovascular mortality.

4.5 Drugs interactions

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 concentrations were reduced by approximately 24%. In patients receiving both Azithromycin and antacids, the drugs should not be taken simultaneously.

Cetirizine

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

Didanosine (Dideoxyinosine)

Co-administration 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 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-glycoprotein substrates such as Digoxin are administered concomitantly, the possibility of elevated serum Digoxin concentrations should be considered. Clinical monitoring, and possibly serum Digoxin levels, during treatment with Azithromycin and after its discontinuation are necessary.

Zidovudine

Single 1000 mg doses and multiple 1200 mg or 600 mg doses of 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.

Ergot derivatives

Due to the theoretical possibility of ergotism, the concurrent use of Azithromycin with Ergot derivatives is not recommended. Pharmacokinetic studies have been conducted between Azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.

Atorvastatin

Co-administration 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).

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.

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 dose of 15 mg Warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to co-administration 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.

Ciclosporin

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 Ciclosporin, the resulting Ciclosporin Cmax and AUC0-5were found to be significantly elevated (by 24% and 21% respectively), however no significant changes were seen in AUC0-∞. Consequently, caution should be exercised before considering concurrent administration of these drugs. If co-administration of these drugs is necessary, Ciclosporin levels should be monitored and the dose adjusted accordingly.

Efavirenz

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

Fluconazole

Co-administration 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 co-administration of Fluconazole, however, a clinically insignificant decrease in Cmax (18%) of Azithromycin was observed.

Indinavir

Co-administration 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, co-administration 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

Co-administration 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 was required.

Rifabutin

Co-administration 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.

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 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.

Triazolam

In 14 healthy volunteers, co-administration 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

Co-administration 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.

Hydroxychloroquine and Chloroquine

Observational data have shown that co-administration of Azithromycin with Hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Carefully consider the balance of benefits and risks before prescribing Azithromycin for any patients taking Hydroxychloroquine. Similar careful consideration of the balance of benefits and risk should also be undertaken before prescribing Azithromycin for any patients taking Chloroquine, because of the potential for a similar risk with Chloroquine.

4.6 Use in special populations

Pregnancy

Animal reproduction studies have been performed at doses up to moderately maternally toxic dose concentrations. In these studies, no evidence of harm to the foetus due to Azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Azithromycin should be used during pregnancy only if clearly needed.

Breast-feeding

Limited information available from published literature indicates that Azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. No serious adverse effects of Azithromycin on the breast-fed infants were observed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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.

4.8 Undesirable effects

Azithromycin is well tolerated with a low incidence of side effects

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. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

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, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.

5.1 Mechanism of action

The mechanism of action of Azithromycin is based upon the suppression of bacterial protein synthesis by means of binding to the ribosomal 50S sub-unit and inhibition of peptide translocation.

5.2 Pharmacodynamic properties

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

Table : Antibacterial spectrum of Azithromycin

Methycillin-resistant staphylococci have a very high prevalence of acquired resistance to macrolides and have been placed here because they are rarely susceptible to Azithromycin.

5.3 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. In pharmacokinetic studies it has been demonstrated that the concentrations of Azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma, which indicates that the agent strongly binds to tissues. Binding to serum proteins varies according to plasma concentration and ranges from 12% at 0.5 microgram/ml up to 52% at 0.05 microgram Azithromycin/ml serum. The mean volume of distribution at steady state (VVSS) has been calculated to be 31.1 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.

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.

6.1 Animal toxicology or pharmacology

Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given multiple doses of Azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of Azithromycin treatment. 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 as the drug is indicated for short-term treatment only and there were no signs indicative of carcinogenic activity.

Mutagenic potential

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

Reproductive toxicity

In animal studies for embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, Azithromycin doses of 100 and 200 mg/kg bodyweight/day led to mild retardation of foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation following treatment with 50 mg/kg/day Azithromycin and above was observed.

Azithromycin tablet contains the active ingredient Azithromycin, a macrolide antibacterial drug, for oral administration. Azithromycin has the,

Chemical name : (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy]-2-ethyl- 3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-

(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

Molecular formula : C₃₈H₇₂N₂O₁₂

Molecular weight : 749.00 g/mol

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Azitus 250 : A blister strip of 10 tablets.

Azitus 500 : A blister strip of 5 tablets.

8.5 Storage and handing instructions

Store below 30°C. Protect from light & moisture

Keep out of reach of children

Azithromycin tablets may be taken with or without food. However, increased tolerability has been observed when tablets are taken with food.

Patients should also be cautioned not to take Aluminium- and Magnesium-containing antacids and Azithromycin simultaneously

The patient should be directed to discontinue Azithromycin immediately and contact the Physician if any signs of an allergic reaction occur.

Patients should be counselled that antibacterial drugs, including Azithromycin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Azithromycin is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Azithromycin or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibacterial which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.