Azax

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZAX® (AZAX®)

Composition:

Active substance: azithromycin;

One tablet contains 500 mg of azithromycin as azithromycin dihydrate;

Excipients: pregelatinized starch, low-substituted hydroxypropylcellulose, sodium lauryl sulfate, sodium croscarmellose, calcium hydrogen phosphate dihydrate, colloidal anhydrous silicon dioxide, anhydrous lactose, magnesium stearate;

Coating: Sepifilm 752 White: hypromellose, microcrystalline cellulose, polyethylene glycol stearate, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped, film-coated tablets of white color, 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 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-hemolytic group A streptococcus, 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 pathogens; 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

Staphylococcus aureus methicillin-resistant has a very high prevalence of acquired resistance to macrolides and is mentioned here due to rare susceptibility to azithromycin.

Pharmacokinetics.

Oral bioavailability is approximately 37%. Maximum serum concentration (Cmax) is achieved within 2–3 hours after administration.

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.

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 blood serum. The apparent volume of distribution at steady state is 31.1 L/kg.

The terminal plasma 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 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:

• upper respiratory tract (bacterial pharyngitis, tonsillitis, sinusitis, otitis media);
• lower respiratory tract (bacterial bronchitis, community-acquired pneumonia);
• skin and soft tissues (migratory erythema (Stage I Lyme disease), pertussis, impetigo, and secondary pyoderma);
• genital infections (uncomplicated urethritis/cervicitis caused by Chlamydia trachomatis).

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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

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

Didanosine. Concomitant administration of 1200 mg daily doses of azithromycin with didanosine showed no effect on the pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine. It has been reported that concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin 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.

Zidovudine. Single doses of 1000 mg or 1200 mg, or multiple doses of 600 mg azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, azithromycin increased the concentration of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these data is not established, but it 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 interaction typical of erythromycin and other macrolides. Azithromycin does not cause induction or inactivation of 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 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). However, post-marketing surveillance has reported cases of rhabdomyolysis in patients taking azithromycin with statins.

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

Cimetidine. In a pharmacokinetic interaction study, no changes in azithromycin pharmacokinetics were observed following a single dose of cimetidine administered 2 hours before azithromycin.

Oral coumarin-type 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, there have been reports of potentiation of the anticoagulant effect with 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.

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 using these drugs 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. Total exposure and elimination half-life of azithromycin were unchanged when fluconazole was coadministered; 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 a single 15 mg dose 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 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 have not reported interactions between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be completely ruled out; however, there are no specific data confirming such an interaction.

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

Triazolam. Concomitant administration of azithromycin (500 mg on the first day and 250 mg on the second day) with triazolam 0.125 mg 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 maximum concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Serum azithromycin concentrations were consistent with those observed in other studies.

Hydroxychloroquine. Azithromycin should be administered with caution to patients receiving medicinal products that prolong the QT interval and may cause cardiac arrhythmias, such as hydroxychloroquine.

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 including acute generalized exanthematous pustulosis, Stevens–Johnson syndrome, toxic epidermal necrolysis (in isolated cases – with fatal outcome), and drug reaction with eosinophilia and systemic symptoms (DRESS). Some of these reactions caused by azithromycin have been associated with recurrent symptoms.

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

Hepatotoxicity. 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 during azithromycin therapy. 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 of liver dysfunction develop, such as rapidly progressing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy. If liver dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives. In patients taking ergot derivatives, concomitant use of certain macrolide antibiotics may lead to rapid development of ergotism. Data on potential interaction between ergot derivatives and azithromycin are lacking. However, due to the theoretical risk of ergotism, azithromycin should not be co-administered with ergot derivatives.

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

Clostridium difficile-associated diarrhea (CDAD). Cases of diarrhea caused by Clostridium difficile (CDAD) have 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 refractory to antimicrobial therapy and 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 2 months after administration of antibacterial agents.

Renal 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. Prolongation of cardiac repolarization and QT interval, increasing the risk of cardiac arrhythmia and ventricular tachycardia (including torsade de pointes), has 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 administered with caution to patients with existing proarrhythmic conditions (particularly women and elderly patients), especially those:

• 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 arrhythmia, 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. 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. While azithromycin is generally effective in treating streptococcal pharyngeal infections, there are no data demonstrating the efficacy of azithromycin in preventing rheumatic fever.

Children.

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

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

Pregnancy and breastfeeding.

Pregnancy.

There are no adequate data on the use of azithromycin in pregnant women. In reproductive toxicity studies in animals, azithromycin did not show teratogenic effects, but it crossed the placenta. The safety of azithromycin 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 be excreted 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 have been conducted in animals; pregnancy rates were reduced following administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to affect driving performance and use of machinery.

There is no evidence that azithromycin impairs the ability to drive or operate machinery; however, the possibility of adverse reactions such as dizziness, somnolence, and visual disturbances should be taken into account.

Method of Administration and Dosage.

Azax® 500 mg tablets should be administered as a single daily dose, independent of food intake. 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 ≥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 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 the first day, followed by 500 mg once daily for 5 days.

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

Elderly patients.

Dosage adjustment is not required in elderly patients.

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

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 administered to patients with severe hepatic impairment. Clinical studies on the use of azithromycin in such patients have not been conducted.

Children.

Azax® 500 mg tablets are indicated for use in children with body weight ≥45 kg.

Overdose.

Clinical experience with azithromycin indicates that adverse effects observed after ingestion of doses higher than recommended are similar to those seen with normal therapeutic doses and may include diarrhea, nausea, vomiting, and reversible hearing loss. In case of overdose, administration of activated charcoal and implementation of general symptomatic and supportive measures are recommended as needed.

Adverse reactions.

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

Adverse reactions possibly or probably related to azithromycin based on data obtained from clinical trials and during the post-marketing period

Information on adverse reactions possibly 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:

Shelf life. 2 years.

Storage conditions.

Store in a dry, light-protected place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

3 tablets per blister, 1 blister in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Address of the manufacturer and place of business.

Sankaklar Quarter, Eskiakcakoca Avenue, No. 299, 81100, Duzce, Turkey.