Azithromycin euro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZITHROMYCIN EURO (AZITHROMYCINEURO)

Composition:

Active ingredient: azithromycin;

One tablet contains azithromycin dihydrate equivalent to anhydrous azithromycin – 250 mg or 500 mg;

Excipients: calcium hydrogen phosphate; lactose monohydrate; pregelatinized starch; sodium croscarmellose; magnesium stearate; sodium lauryl sulfate; Opadry Blue 03B50883: hypromellose, titanium dioxide (E 171), polyethylene glycol, indigo carmine (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: 250 mg tablets – blue, round, biconvex film-coated tablets; 500 mg tablets – blue, capsule-shaped, biconvex film-coated tablets with a score line on one side.

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

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a representative of a new subclass of macrolide antibiotics – the azalides. It binds to the 50S subunit of the 70S ribosomes of susceptible microorganisms, inhibiting RNA-dependent protein synthesis, thereby slowing bacterial growth and reproduction. At high concentrations, a bactericidal effect is possible.

Mechanism of resistance.

Complete cross-resistance exists among Streptococcus pneumoniae, beta-hemolytic streptococcus group A, 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 for specific bacterial species; therefore, local resistance data are essential, especially when treating severe infections. Expert advice should be sought if local resistance patterns are such that the efficacy of the drug in treating at least some types of infections is questionable.

Antimicrobial spectrum of azithromycin

Methicillin-resistant Staphylococcus aureus has a very high prevalence of acquired resistance to macrolides and is listed 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 drug intake.

After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that tissue concentrations of azithromycin are significantly higher (up to 50 times) than plasma concentrations, indicating strong tissue binding of the drug.

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 serum. The apparent volume of distribution at steady state (VVss) is 31.1 L/kg.

The terminal plasma elimination half-life fully reflects the elimination half-life from tissues over 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 were also detected 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 and microbiological assays showed 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), impetigo, secondary pyoderma, moderate acne vulgaris;
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

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

Due to the theoretical possibility of ergotism, azithromycin should not be administered concomitantly with ergot derivatives.

Interaction with other medicinal products and other forms of interaction.

Azithromycin should be used with caution when co-administered with other medicinal products that may prolong the QT interval.

Antacids: Concurrent use of antacids generally does not result in changes in bioavailability, although peak plasma concentrations of azithromycin are reduced by approximately 25%. Azithromycin should be taken at least 1 hour before or 2 hours after antacids. Concomitant administration of azithromycin and antacids is not recommended.

Cimetidine: In a pharmacokinetic interaction study, a single dose of cimetidine administered 2 hours prior to azithromycin did not affect the pharmacokinetics of azithromycin.

Carbamazepine: Pharmacokinetic interaction of azithromycin does not show a significant effect on plasma levels of carbamazepine or its active metabolites.

Cyclosporine: In a pharmacokinetic study involving 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 administering these drugs concomitantly. Some related macrolide antibiotics affect cyclosporine metabolism. Since pharmacokinetic and clinical studies on the potential interaction between azithromycin and cyclosporine have not been conducted, the therapeutic situation should be carefully evaluated before prescribing concomitant use. If combination therapy is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are necessary.

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 regarding potentiation of the anticoagulant effect following concomitant use of azithromycin and oral coumarin-type 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-type anticoagulants.

Digoxin and colchicine: Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, may lead to increased serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is used concomitantly with digoxin, the possibility of increased digoxin serum concentrations should be considered.

Methylprednisolone: Azithromycin does not significantly affect the pharmacokinetics of methylprednisolone.

Terfenadine: No interaction between azithromycin and terfenadine has been reported. However, as with other macrolide antibiotics, azithromycin should be administered with caution in combination with terfenadine.

Theophylline: No data on clinically significant pharmacokinetic interactions were observed when azithromycin and theophylline were administered concomitantly to healthy volunteers.

Zidovudine: Concomitant administration of azithromycin (single 1000 mg and multiple 1200 mg or 600 mg doses) had minimal effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentration of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is not established, but it may be beneficial for patients.

Didanosine: In six HIV-positive volunteers, concomitant administration of daily doses of 1200 mg azithromycin and 400 mg didanosine per day showed no effect on the pharmacokinetics of didanosine compared to placebo.

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

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

Cetirizine: Five-day co-administration of azithromycin with 20 mg cetirizine at steady state did not result in pharmacokinetic interaction or significant changes in QT interval.

Ergot derivatives: Due to the theoretical possibility of ergotism, azithromycin should not be used concomitantly with ergot derivatives.

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

Pharmacokinetic studies have been conducted on the co-administration of azithromycin with the following drugs, whose metabolism is largely mediated by cytochrome P450.

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

Cimetidine: No changes in azithromycin pharmacokinetics were observed when cimetidine was administered 2 hours prior to azithromycin.

Fluconazole: Concomitant administration of a single 1200 mg dose of azithromycin does not alter the pharmacokinetics of a single 800 mg dose of fluconazole. Overall exposure and elimination half-life of azithromycin are not altered when co-administered with fluconazole; however, a clinically insignificant reduction in Cmax of azithromycin (by 18%) was observed.

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

Midazolam: Concomitant administration of 500 mg azithromycin daily for 3 days did not result in clinically significant changes in the pharmacokinetics or pharmacodynamics of a single 15 mg dose of midazolam.

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

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.

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

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

Doxorubicin: Clinical drug interaction studies between azithromycin and doxorubicin have not been conducted. The clinical relevance of these preclinical findings is unknown.

Special precautions for use.

Allergic reactions. Rare cases of serious allergic (and rarely, fatal) reactions to azithromycin, including angioneurotic edema and anaphylaxis, as well as dermatological reactions such as acute generalized exanthematous pustulosis, have been reported. Some of these reactions led to recurrence of symptoms and required prolonged monitoring and treatment.

Prolonged cardiac repolarization and QT interval.

Prolongation of cardiac repolarization and QT interval, associated with an increased risk of cardiac arrhythmias and ventricular tachycardia (torsade de pointes), has been observed with other macrolide antibiotics. A similar effect of azithromycin cannot be completely ruled out in patients at increased risk of prolonged cardiac repolarization; therefore, caution is advised when prescribing azithromycin to patients:

• with congenital or documented QT interval 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. Cases of development of myasthenic syndrome and exacerbation of symptoms in patients with myasthenia gravis receiving azithromycin have been reported.

Streptococcal infections. For treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, penicillin is generally the drug of choice and is also used for prevention of acute rheumatic fever. Azithromycin is generally effective in treating oropharyngeal streptococcal infections; however, there are no data demonstrating efficacy of azithromycin in preventing rheumatic fever.

The safety and efficacy of intravenous azithromycin for treatment of infections in children have not been established.

The safety and efficacy of azithromycin for prevention or treatment of Mycobacterium avium complex in children have not been established.

Superinfections. As with other antibacterial agents, superinfections (e.g., fungal infections) may occur during treatment.

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

The C. difficile strain produces toxins A and B, which contribute to the development of CDAD. Hyperproducing toxin strains of C. difficile are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients presenting with diarrhea following antibiotic use. A careful medical history is essential, as CDAD has been reported to occur up to 2 months after antibiotic administration.

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.

Hepatic function impairment. Since the liver is the primary route of elimination of azithromycin, caution is advised when prescribing azithromycin to patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported with azithromycin use. 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 fatigue accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy.

If hepatic dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives. Ergotism has been reported in patients receiving ergot derivatives concurrently with certain macrolide antibiotics. There are no data on a potential drug interaction between ergot derivatives and azithromycin; however, due to the theoretical possibility of ergotism, concomitant use of azithromycin with ergot derivatives is not recommended.

Other.

The safety and efficacy of azithromycin for prevention 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. Reproductive toxicity studies in animals did not show teratogenic effects of azithromycin on the fetus; however, the drug crosses the placenta. The safety of azithromycin use during pregnancy has not been established. Therefore, azithromycin should be used during pregnancy only if the potential benefit outweighs the potential risk.

Breastfeeding.

Azithromycin has been reported to pass into human milk; however, adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion in human breast milk have not been conducted.

Fertility.

Fertility studies were conducted in rats; a decreased pregnancy rate was observed after administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to affect driving and 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, loss of consciousness, and seizures, which may affect such abilities, should be taken into account.

Method of Administration and Dosage.

Azithromycin Euro tablets should be taken as a single daily dose, independently of food intake. The tablets should be swallowed whole, without chewing. 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.

Adults and children with body weight over 45 kg.

For infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema): the total dose of azithromycin is 1500 mg, administered as 500 mg once daily for 3 days.

For acne vulgaris: the recommended total dose of azithromycin is 6 g, to be taken according to the following regimen: 1 tablet of 500 mg once daily for 3 days, followed by 1 tablet of 500 mg once weekly for 9 weeks. The second dose should be taken 7 days after the first dose, and the next 8 doses should be taken at 7-day intervals.

For migratory erythema: the total dose of azithromycin is 3 g, administered as follows: 1 g (2 tablets of 500 mg as a single dose) on day 1, followed by 500 mg once daily from day 2 to day 5.

For sexually transmitted infections: the recommended dose of azithromycin is 1000 mg (2 tablets of 500 mg as a single dose).

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.

Elderly patients.

Dosage adjustment is not required for elderly patients.

Since elderly patients may belong to risk groups for cardiac conduction disorders, caution is recommended when using azithromycin due to the risk of developing cardiac arrhythmia, including torsade de pointes.

Patients with renal impairment.

For patients with mild renal impairment (glomerular filtration rate 10–80 mL/min), the same dosage as for patients with normal renal function may be used. 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 impairment. Clinical studies on the use of azithromycin in such patients have not been conducted.

Children.

Azithromycin Euro tablets are recommended for children with body weight over 45 kg.

Overdose.

Clinical experience with azithromycin indicates that adverse effects observed after ingestion of higher than recommended doses are similar to those seen 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 measures are recommended if necessary.

Adverse reactions.

The table below lists adverse reactions identified from clinical trials and during the post-marketing surveillance period with all dosage forms of azithromycin. Adverse reactions are listed by system organ class and frequency. Reactions reported during the post-marketing period are indicated in italics. Frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency category, adverse events are listed in decreasing order of severity.

Adverse reactions probably related to azithromycin based on data obtained from clinical trials and post-marketing surveillance

Information on adverse reactions that may be associated with the prevention and treatment of Mycobacterium Avium Complex is based on data from clinical studies and post-marketing observations. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release dosage forms.

Adverse reactions that may be associated with the prevention and treatment of Mycobacterium Avium Complex

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging. 250 mg tablets – 6 tablets in a blister; 1 blister in a cardboard box.

500 mg tablets – 3 tablets in a blister; 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Unique Pharmaceuticals Laboratories (a division of "J. B. Chemicals and Pharmaceuticals Ltd.").

Manufacturer's address and place of business.

Plot Nos. 215-219, G.I.D.C. Industrial Area, Panoli - 394 116, District Bharuch, India.