Azithromax

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZITHROMAX

Composition:

Active substance: azithromycin (azithromycin monohydrate hemiethanolate);

250 mg tablets:

1 tablet contains 250 mg of azithromycin;

Excipients: microcrystalline cellulose, sodium croscarmellose, povidone, poloxamer 188, anhydrous lactose, talc, magnesium stearate;

Coating composition: titanium dioxide (E 171), hydroxypropylmethylcellulose, polyethylene glycol; colourants: sunset yellow FCF (E 110), D&C red № 27, FD&C red № 40 (E 129), indigo carmine (E 132);

600 mg tablets:

1 tablet contains 600 mg of azithromycin;

Excipients: microcrystalline cellulose, sodium croscarmellose, povidone, poloxamer 188, anhydrous lactose, talc, magnesium stearate;

Coating composition: titanium dioxide (E 171), hydroxypropylmethylcellulose, polyethylene glycol, polysorbate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets:

film-coated tablets of dark pink colour, elongated in shape, with the imprint of the logo “P” or “AZI” or no inscription on one side, and “250” on the other;

600 mg tablets:

film-coated tablets of white or almost white colour, elongated in shape, with the imprint of the logo “P” or “AZI” or no inscription on one side, and “600” 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

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

Azithromycin demonstrates cross-resistance to gram-positive isolates resistant to erythromycin. Decreased susceptibility to macrolides over time has been particularly noted for Streptococcus pneumoniae and Staphylococcus aureus. Similarly, reduced susceptibility has been observed among Streptococcus viridans and Streptococcus agalactiae (group B) to other macrolides and lincosamides.

Cut-off

Breakpoints for typical bacterial pathogens susceptible to azithromycin according to EUCAST data:

Susceptibility

The prevalence of acquired resistance may vary geographically and over time for specific species; therefore, local information on resistance is necessary, 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 exhibits very high prevalence of acquired resistance to macrolides and is listed here due to rare susceptibility to azithromycin.

Pediatric population

Following assessment of studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, either as monotherapy or in combination with chloroquine-based or artemisinin-based agents, as there is no established efficacy of antimalarial medicinal products recommended for the treatment of uncomplicated malaria.

Pharmacokinetics.

Absorption

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

Distribution

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

Protein binding in serum 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 (Vss) is 31.1 L/kg.

Elimination

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 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 results from liquid chromatography and microbiological assays showed that azithromycin metabolites are not microbiologically active.

Studies in animals have revealed high concentrations of azithromycin in phagocytes. It has also been established that higher concentrations of azithromycin are released from inactive phagocytes during active phagocytosis. In animal models, this leads to high concentrations of azithromycin reaching the site of infection.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• infections of the ear, nose and throat (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; treatment of mild forms of acne vulgaris;
• sexually transmitted infections: uncomplicated and complicated urethritis/cervicitis caused by Chlamydia trachomatis;
• prevention of dissemination of Mycobacterium avium complex in HIV-infected patients as monotherapy or in combination with rifabutin.

Contraindications.

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

Due to the theoretical possibility of ergotism, azithromycin should not be co-administered with ergot alkaloids.

Interaction with other medicinal products and other forms of interaction.

Azithromycin should be administered with caution to patients receiving other medicinal products that may prolong the QT interval.

Antacids. In studies evaluating the effect of concomitant antacid administration on the pharmacokinetics of azithromycin, no overall changes in bioavailability were observed, although plasma peak concentrations of azithromycin were reduced by approximately 24%. Azithromycin should be taken at least 1 hour before or 2 hours after antacid administration.

Cetirizine. In healthy volunteers, co-administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not show evidence of pharmacokinetic interaction or significant changes in QT interval.

Didanosine (ddI). Concomitant administration of azithromycin 1200 mg daily and didanosine 400 mg daily in 6 HIV-positive patients likely did not affect the steady-state pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine (P-glycoprotein substrates). There have been reports of increased serum levels of P-glycoprotein substrates, such as digoxin, when co-administered with macrolide antibiotics, including azithromycin. Clinical monitoring and possibly serum digoxin level determination are required during and after azithromycin therapy.

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

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

Ergot alkaloids. Due to the theoretical possibility of ergotism, concomitant administration of azithromycin with ergot derivatives is not recommended (see section "Contraindications").

Pharmacokinetic studies have been conducted on the co-administration of azithromycin and the following drugs, 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).

Carbamazepine. In a pharmacokinetic interaction study, azithromycin did not significantly affect plasma levels of carbamazepine or its active metabolites.

Cimetidine. In a pharmacokinetic interaction study, a single dose of cimetidine administered 2 hours before azithromycin did not alter azithromycin pharmacokinetics. Administration of cimetidine (800 mg) 2 hours before azithromycin did not affect azithromycin absorption.

Oral anticoagulants of the coumarin type. In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. During the post-marketing period, reports of potentiation of the anticoagulant effect following concomitant use of azithromycin and oral anticoagulants of the coumarin type have been received. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine. 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 of these medicinal products. If combination therapy is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are necessary.

Efavirenz. Concomitant administration of a single 600 mg dose of azithromycin with 400 mg of 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. Total exposure and elimination half-life of azithromycin were not altered when co-administered with fluconazole, although a clinically insignificant reduction in Cmax (18%) of azithromycin was observed.

Indinavir. Concomitant administration of a single 1200 mg dose of azithromycin did not have 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.

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 serum concentrations of either drug. Neutropenia was observed in patients 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 that azithromycin (500 mg daily for 3 days) affects AUC or Cmax values of sildenafil or its main circulating metabolite.

Terfenadine. Pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. In some cases, the possibility of such interaction cannot be completely excluded, but there are no specific data confirming such interaction.

Theophylline. There are no data on clinically significant pharmacokinetic interactions with concomitant administration of azithromycin and theophylline.

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.

Trimethoprim/sulfamethoxazole. Concomitant administration of double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 did not show a significant effect on peak concentrations, total exposure, or urinary excretion of trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

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

Currently, there is no information on the interaction of azithromycin with gentamicin or other amphiphilic drugs that may affect intracellular lipid metabolism.

Special precautions for use.

Allergic reactions. 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), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Some of these reactions caused by azithromycin have been associated with recurrent symptoms and required prolonged observation and treatment.

Hepatic function impairment. Since the liver is the primary route of elimination for 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 during azithromycin therapy (see section "Adverse reactions").

Some patients may have pre-existing liver disease or may be taking other hepatotoxic medicinal products.

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

If hepatic dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives. In patients taking ergot derivatives, concomitant administration of certain macrolide antibiotics has led to the rapid onset of ergotism. Data on the potential interaction between ergot derivatives and azithromycin are lacking. However, due to the theoretical possibility of ergotism, azithromycin should not be co-administered with ergot derivatives.

Prolongation of cardiac repolarization and QT interval, which may increase the risk of cardiac arrhythmia and ventricular tachyarrhythmia (torsade de pointes), has been observed with other macrolide antibiotics. A similar effect of azithromycin cannot be entirely ruled out in patients at increased risk of prolonged cardiac repolarization; therefore, the drug should be used with caution in patients:

• with congenital or documented acquired QT prolongation;
• currently receiving treatment with other active substances 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.

Superinfections. As with other antibiotics, monitoring for signs of superinfection caused by resistant organisms, including fungi, is recommended.

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

C. difficile 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 should be considered in all patients presenting with diarrhea following antibiotic use. Careful medical history is essential, as CDAD has been reported to occur up to two months after antibiotic administration. If necessary, discontinuation of azithromycin therapy and initiation of specific treatment for C. difficile should be considered.

Streptococcal infections. Azithromycin is generally effective in the treatment of streptococcal pharyngitis. However, there are no data demonstrating the efficacy of azithromycin in the prevention of rheumatic fever. An antimicrobial agent with anaerobic activity should be used in combination with azithromycin if anaerobic microorganisms are suspected to contribute to the infection.

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.

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

Other.

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

Excipients.

Since this medicinal product contains lactose, patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

The coating of 250 mg tablets contains a colouring agent (Yellow Sunset FCF (E 110)) which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy.

Reproductive toxicity studies in animals were conducted using doses corresponding to moderately toxic levels for the maternal organism. These studies provided no evidence of teratogenic effects of azithromycin. However, adequate and well-controlled studies in pregnant women are lacking. Since animal reproductive studies do not always predict effects in humans, azithromycin should be prescribed during pregnancy only if clearly needed.

Breastfeeding.

Azithromycin has been reported to pass into human milk, but appropriate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion in 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 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 the ability to drive or operate machinery, should be considered.

Method of Administration and Dosage

Azithromax tablets are intended for oral use only.

Azithromycin should be taken 1 hour before or 2 hours after a meal, as concomitant food intake impairs azithromycin absorption. Tablets should be swallowed whole. The drug should be taken once daily. 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 ≥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: 500 mg once daily. The duration of treatment is 3 days.

For vulgar acne, the recommended total dose of azithromycin is 6 g, administered as follows: 500 mg once daily for 3 days, followed by 500 mg once weekly for 9 weeks. The second week's dose should be taken 7 days after the first dose, and the next 8 doses should be taken at 7-day intervals.

For migrating erythema, the total dose of azithromycin is 3 g: on day 1, take 1 g (4 tablets in a single dose), then 500 mg (2 tablets in a single dose) from day 2 to day 5. The duration of treatment is 5 days.

For sexually transmitted infections: the total dose of azithromycin is 1 g (4 tablets in a single dose).

Prophylaxis of Mycobacterium avium complex dissemination.

The recommended dose of Azithromax is 1200 mg (2 tablets of 600 mg) once weekly. Treatment may be combined with the appropriate dose of rifabutin.

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 and 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 tablets should be administered to children with body weight ≥45 kg.

For treatment of children with body weight less than 45 kg, Azithromax should be administered as a 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 (diarrhea, nausea, vomiting, reversible hearing loss). In case of overdose, administration of activated charcoal and general symptomatic and supportive treatment are recommended if necessary.

Adverse reactions.

The table below lists adverse reactions identified from clinical trials and post-marketing surveillance for all dosage forms of azithromycin, organized by system organ class and frequency of occurrence.

Frequency groups were defined according to the following scale: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data). Within each frequency category, adverse events are listed in order of decreasing severity.

Undesirable reactions possibly or probably related to azithromycin based on data obtained during 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 trials and post-marketing surveillance. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release dosage forms.

Shelf life. 5 years.

Storage conditions.

Keep out of reach of children at a temperature not exceeding 30 °C.

Packaging.

Tablets 250 mg. 30 tablets in a bottle, 6 tablets in a blister pack, 1 blister pack in a cardboard box.

Tablets 600 mg. 30 tablets in a bottle.

Prescription status. Prescription only.

Manufacturer.

Pharmascience Inc./Pharmascience Inc.

Manufacturer's address and place of business.

6111 Royalmount Avenue, Suite 100, Montreal, Quebec H4P 2T4, Canada
6111 Royalmount Avenue, Suite 100, Montreal, Quebec H4P 2T4, Canada.