Azithromycin 500

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT

AZITHROMYCIN 250 (AZITHROMYCIN 250)
AZITHROMYCIN 500 (AZITHROMYCIN 500)
AZITHROMYCIN 1000 (AZITHROMYCIN 1000)

Composition:

Active substance: azithromycin;

One film-coated tablet contains azithromycin equivalent to 250 mg, 500 mg, or 1000 mg of anhydrous azithromycin;

Excipients:

Azithromycin 250: microcrystalline cellulose, calcium hydrogen phosphate, maize starch, povidone, magnesium stearate, talc, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, sodium starch glycolate (type A);

Tablet coating: hydroxypropylmethylcellulose, titanium dioxide (E 171), yellow iron oxide (E 172);

Azithromycin 500: microcrystalline cellulose, maize starch, povidone, magnesium stearate, talc, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, sodium starch glycolate (type A);

Tablet coating: hydroxypropylmethylcellulose, titanium dioxide (E 171), yellow iron oxide (E 172);

Azithromycin 1000: calcium hydrogen phosphate, maize starch, povidone, microcrystalline cellulose, magnesium stearate, talc, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A);

Tablet coating: hydroxypropylmethylcellulose, polyethylene glycol 6000, titanium dioxide (E 171), talc, yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: yellow, round, biconvex tablets, film-coated;

500 mg tablets: yellow, elongated, biconvex tablets, film-coated, with a score line on one side and smooth on the other;

1000 mg tablets: yellow, elongated, biconvex tablets, film-coated, with a score line on one side and smooth on the other.

Pharmacotherapeutic group. Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATC code J01FA10.

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by insertion of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis by binding to the
50S ribosomal subunit and suppression of peptide translocation.

Mechanism of resistance

Complete cross-resistance exists among Streptococcus pneumoniae, beta-haemolytic group A streptococci, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

The prevalence of acquired resistance may vary depending on geographical location and time; therefore, local information on resistance patterns is necessary, especially when treating severe infections. Expert advice should be sought if local resistance prevalence renders the efficacy of the drug questionable for at least some types of infections.

Antimicrobial spectrum of azithromycin.

* Methicillin-resistant Staphylococcus aureus exhibits very high prevalence of acquired resistance to macrolides and is included here due to rare susceptibility to azithromycin.

Pharmacokinetics.

Bioavailability after oral administration is approximately 37%. Maximum serum concentration is reached within 2–3 hours after dosing.

After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have demonstrated that azithromycin concentrations in tissues are significantly higher (up to 50-fold) than in blood plasma, indicating extensive tissue binding.

Binding to serum proteins varies depending on plasma concentrations, ranging from 12% at 0.5 µg/mL to 52% at 0.05 µg/mL in blood serum. The apparent volume of distribution at steady state (VVss) is 31.1 L/kg.

The terminal plasma half-life fully reflects the tissue elimination half-life of 2–4 days.

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in urine over the following 3 days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Ten metabolites have also been identified in bile, formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of liquid chromatography results with microbiological assays has shown that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• Otorhinolaryngological infections (bacterial pharyngitis/tonsillitis, sinusitis, otitis media).
• Respiratory tract infections (bacterial bronchitis, community-acquired pneumonia).
• Skin and soft tissue infections: erythema migrans (early stage of Lyme disease), pertussis, impetigo, secondary pyoderma, acne vulgaris (moderate severity acne).
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, other macrolide or ketolide antibiotics, or to any component of the drug.

Interaction with other medicinal products and other forms of interaction.

Antacids. When studying the effect of concomitant antacid administration on azithromycin pharmacokinetics, no overall changes in bioavailability were observed, although the peak plasma concentration of azithromycin decreased by approximately 25%. Azithromycin and antacids should not be taken simultaneously.

Cetirizine. In healthy volunteers, no pharmacokinetic interaction or significant changes in QT interval were observed when azithromycin was administered for 5 days together with cetirizine 20 mg at steady state.

Didanosine. When daily doses of azithromycin 1200 mg were administered concomitantly with didanosine 400 mg in six HIV-positive volunteers, no effect on steady-state pharmacokinetics of didanosine was observed compared to placebo.

Digoxin and colchicine. It has been reported that concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxine and colchicine, may lead to increased serum levels of P-glycoprotein substrates. Therefore, when azithromycin is used concomitantly with P-glycoprotein substrates such as digoxin, the possibility of increased substrate concentrations in serum should be considered.

Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg azithromycin had minimal effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, administration of azithromycin increased the concentration of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these data is not fully understood, but may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. The drug is considered not to have the pharmacokinetic drug interactions typical of erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via the cytochrome-metabolite complex.

Ergot derivatives. Due to the theoretical possibility of ergotism, concomitant administration of azithromycin with ergot derivatives is not recommended.

Pharmacokinetic studies have been conducted on the use of azithromycin with the following medicinal products, whose metabolism is largely mediated by cytochrome P450.

Atorvastatin. Concomitant administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter atorvastatin plasma concentrations (based on HMG-CoA reductase inhibition analysis). However, during the post-marketing period, cases of rhabdomyolysis have been reported in patients receiving azithromycin together with statins.

Carbamazepine. In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not show a significant effect on plasma levels of carbamazepine or its active metabolites.

Cimetidine. In a pharmacokinetic interaction study, no changes in azithromycin pharmacokinetics were observed when a single dose of cimetidine (administered 2 hours before azithromycin) was given.

Coumarin 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. However, during the post-marketing period, reports have been received of potentiation of the anticoagulant effect after concomitant use of azithromycin and oral coumarin anticoagulants. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral coumarin anticoagulants.

Cyclosporine. In a pharmacokinetic study in healthy volunteers who received oral azithromycin 500 mg/day for 3 days followed by a single oral dose of cyclosporine 10 mg/kg, a significant increase in Cmax and AUC0-5 of cyclosporine was demonstrated. Therefore, caution should be exercised when these drugs are used concomitantly. If concomitant use is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

Efavirenz. Concomitant administration of a single 600 mg dose of azithromycin with 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interaction.

Fluconazole. Concomitant administration of a single 1200 mg dose of azithromycin did not alter the pharmacokinetics of a single 800 mg dose of fluconazole. The overall exposure and elimination half-life of azithromycin were not altered when fluconazole was co-administered; however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

Indinavir. Concomitant administration of a single 1200 mg dose of azithromycin did not cause a statistically significant effect on the pharmacokinetics of indinavir administered at 800 mg three times daily for 5 days.

Methylprednisolone. In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not significantly affect the pharmacokinetics of methylprednisolone.

Midazolam. In healthy volunteers, concomitant administration of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam administered as a single 15 mg dose.

Nelfinavir. Concomitant administration of azithromycin (1200 mg) and nelfinavir at steady-state concentrations (750 mg three times daily) results in increased azithromycin concentrations. No clinically significant adverse events were observed; therefore, dose adjustment is not required.

Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect plasma concentrations of either drug in serum. Neutropenia was observed in subjects receiving both azithromycin and rifabutin. Although neutropenia was associated with rifabutin use, a causal relationship with concomitant azithromycin administration has not been established.

Sildenafil. In healthy male volunteers, no evidence was found of the effect of azithromycin (500 mg daily for 3 days) on AUC and Cmax values of sildenafil or its main circulating metabolite.

Terfenadine. Pharmacokinetic studies did not report any interaction between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be completely ruled out, although there are no specific data confirming such an interaction.

Theophylline. There are no data on clinically significant pharmacokinetic interaction when azithromycin and theophylline are administered concomitantly to healthy volunteers.

Triazolam. Concomitant administration to healthy volunteers of azithromycin 500 mg on the first day and 250 mg on the second day together with 0.125 mg triazolam did not significantly affect any pharmacokinetic parameters of triazolam compared to triazolam with placebo.

Trimethoprim/sulfamethoxazole. Concomitant administration of double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 showed no significant effect on the maximum concentration, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentration values were consistent with those observed in other studies.

Medicinal products that may prolong the QT interval. Azithromycin should be prescribed cautiously with other drugs that may prolong the QT interval.

Special precautions for use.

Hypersensitivity.

As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioedema and anaphylaxis (in isolated cases with fatal outcome), dermatological reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN, rarely with fatal outcome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Adverse reactions"). Some of these azithromycin-induced reactions have been associated with recurrent symptoms and required prolonged observation and treatment.

If an allergic reaction occurs, administration of the drug should be discontinued and appropriate therapy initiated. Physicians should be aware that allergic symptoms may recur after discontinuation of symptomatic treatment.

Hepatic function impairment.

Since the liver is the primary route of elimination of azithromycin, caution should be exercised when prescribing azithromycin to patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported with azithromycin. Some patients may have had pre-existing liver disease or concomitant use of other hepatotoxic medicinal products.

Liver function tests should be performed if signs or symptoms of hepatic dysfunction develop, such as rapidly progressing asthenia accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy.

If hepatic dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives.

In patients receiving ergot derivatives, concomitant administration of certain macrolide antibiotics has been associated with rapid development of ergotism. There are no data available on the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be co-administered with ergot derivatives.

Superinfections.

As with other antibiotics, monitoring for signs of superinfection caused by non-susceptible organisms, including fungi, is recommended.

When using nearly all antibacterial agents, including azithromycin, Clostridium difficile-associated diarrhea (CDAD) has been reported, with severity ranging from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hyper-toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients with diarrhea following antibiotic use. Careful medical history is necessary, as CDAD has been reported to occur up to two months after administration of antibacterial agents.

Renal function impairment.

In patients with severe renal dysfunction (glomerular filtration rate <10 mL/min), a 33% increase in systemic exposure to azithromycin has been observed.

QT interval prolongation.

Prolonged cardiac repolarization and QT interval, increasing the risk of developing cardiac arrhythmias and ventricular tachycardia (torsade de pointes), have been observed with other macrolide antibiotics, including azithromycin. Since conditions associated with increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be used with caution in patients with existing proarrhythmic conditions (particularly women and elderly patients), especially in patients:

• with congenital or documented acquired QT prolongation;
• currently receiving treatment with other medicinal products known to prolong the QT interval, such as class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol) antiarrhythmics, cisapride, terfenadine, neuroleptics such as pimozide, antidepressants such as citalopram, and fluoroquinolones such as moxifloxacin and levofloxacin;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmias, or severe heart failure.

Myasthenia gravis.

Exacerbation of symptoms of myasthenia gravis or new onset of myasthenic syndrome has been reported in patients receiving azithromycin therapy.

Streptococcal infections.

Azithromycin is generally effective in the treatment of streptococcal pharyngitis; however, there are no data demonstrating the efficacy of azithromycin in preventing acute rheumatic fever.

Safety and efficacy for prophylaxis or treatment of Mycobacterium avium complex in children have not been established.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of azithromycin in pregnant women. In reproductive toxicity studies in animals, azithromycin showed no teratogenic or harmful effects on the fetus; however, the drug crosses the placenta. The safety of azithromycin during pregnancy has not been established. Therefore, azithromycin should be prescribed during pregnancy only if the potential benefit justifies the potential risk to the fetus.

breastfeeding.

Azithromycin has been reported to be excreted into human breast milk; however, appropriate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion into human breast milk have not been conducted. Azithromycin may be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant.

fertility.

Fertility studies have been conducted in rats; pregnancy rates were reduced after administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to affect reaction speed when driving or operating machinery.

There is no evidence that azithromycin impairs the ability to drive or operate machinery. However, the possibility of adverse reactions such as delirium, hallucinations, dizziness, somnolence, syncope, and seizures, which may affect the ability to drive or operate machinery, should be considered.

Method of Administration and Dosage

The drug should be administered as a single daily dose, regardless of food intake. If a dose is missed, the missed dose should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals. Tablets should be swallowed whole, without chewing.

Adults and children with body weight ≥ 45 kg.

For infections of the ear, nose, throat, respiratory tract, skin and soft tissues (except erythema migrans): the total dose is 1500 mg (500 mg once daily). The duration of treatment is 3 days.

For acne vulgaris: the recommended total dose of azithromycin is 6 g, to be taken according to the following regimen: 500 mg once daily for 3 days, followed by 500 mg once weekly for 9 weeks. The dose for the second week should be taken 7 days after the first tablet, and the next 8 doses should be taken at 7-day intervals.

For erythema migrans: the total dose of azithromycin is 3 g, to be taken as follows: 1 g on the first day, followed by 500 mg once daily from day 2 to day 5.

For sexually transmitted infections: the recommended dose of azithromycin is 1 g as a single dose; total course dose is 1 g.

Elderly patients.

Dosage adjustment is not required in elderly patients.

Since elderly patients may be at increased risk of cardiac conduction disorders, caution is recommended when using azithromycin due to the potential risk of cardiac arrhythmia, including torsade de pointes.

Patients with renal impairment.

The same dosage as in patients with normal renal function may be used in patients with mild renal impairment (glomerular filtration rate 10–80 mL/min). Azithromycin should be administered with caution in patients with severe renal impairment (glomerular filtration rate <10 mL/min).

Patients with hepatic impairment.

Since azithromycin is metabolized in the liver and excreted via bile, the drug should not be used in patients with severe hepatic disorders. Clinical studies on the use of azithromycin in such patients have not been conducted.

Children.

The drug may be administered to children with body weight ≥ 45 kg. Children with body weight ≤ 45 kg should receive azithromycin in another pharmaceutical form, such as oral suspension.

Overdose.

Clinical experience with azithromycin indicates that adverse effects associated with doses higher than recommended are similar to those observed with standard therapeutic doses. These may include diarrhea, nausea, vomiting, and reversible hearing loss.

In case of overdose, administration of activated charcoal and implementation of general symptomatic and supportive treatment are recommended, if necessary.

Adverse Reactions

Events are categorized by frequency according to the following scale: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); unknown (cannot be estimated from available data). Within each frequency category, adverse events are listed in order of decreasing severity.

Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on data from clinical trials and post-marketing observations. These adverse reactions differ in type or frequency from those reported during the use of immediate-release and extended-release medicinal products.

Adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Physicians are encouraged to report any suspected adverse reactions.

Shelf life.

2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Packaging.

Azithromycin 250: 6 tablets in a blister pack, 1 blister pack in a cardboard box.

Azithromycin 500: 3 tablets in a blister pack, 1 blister pack in a cardboard box.

Azithromycin 1000: 4 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Artura Pharmaceuticals Pvt. Ltd. – for Azithromycin 250, Azithromycin 500, Azithromycin 1000 film-coated tablets 250 mg, 500 mg or 1000 mg.

or

Ananta Medicare Limited – for Azithromycin 500, film-coated tablets 500 mg.

Address of the manufacturer and location of manufacturing site.

Artura Pharmaceuticals Pvt. Ltd.
1505 Portia Road, Sri City SEZ, Sedyavedu Mandal, Chittoor District – 517 588, Andhra Pradesh State, India.

or

Ananta Medicare Limited
Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udiog Vihar, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorisation Holder.

Ananta Medicare Ltd.

Address of the Marketing Authorisation Holder.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.