Zytrox

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZITROX (ZITHROX)

Composition:

Active ingredient: azithromycin;

1 tablet contains azithromycin dihydrate equivalent to azithromycin 250 mg or 500 mg;

Excipients: calcium hydrogen phosphate, pregelatinized starch, crospovidone, polysorbate 80, colloidal anhydrous silicon dioxide, microcrystalline cellulose, sodium lauryl sulfate, talc, magnesium stearate, hypromellose, titanium dioxide (E 171), polyethylene glycol 400.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: white, capsule-shaped, biconvex tablets, film-coated, smooth on both sides;

500 mg tablets: white, capsule-shaped, biconvex film-coated tablets, with a break 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 through binding to the 50 S 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 geographically and over time for isolated 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.

The bioavailability after oral administration is approximately 37%. Maximum serum concentration is achieved within 2–3 hours after drug intake.

After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have demonstrated that tissue concentrations of azithromycin are significantly higher (up to 50-fold) than plasma concentrations, indicating extensive 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 blood serum. The apparent volume of distribution at steady state (V_ss) 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 detected 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.

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, bacillary dysentery; moderate severity acne vulgaris (common acne);
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

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

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. When studying the effect of concomitant antacid administration on the pharmacokinetics of azithromycin, 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 and cetirizine 20 mg at steady state did not reveal any pharmacokinetic interaction or significant changes in QT interval.

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

Digoxin and colchicine. There have been reports that concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin and colchicine, may lead to increased serum levels of P-glycoprotein substrates. Therefore, when azithromycin is used concomitantly with a P-glycoprotein substrate such as digoxin, the possibility of increased substrate concentration in serum 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 fully understood, 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 exhibit 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 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) did not alter atorvastatin plasma concentrations (based on HMG-CoA reductase inhibition analysis). However, post-marketing reports have documented cases of rhabdomyolysis in patients taking azithromycin with statins.

Carbamazepine. In a pharmacokinetic interaction study in healthy volunteers, azithromycin showed no significant effect on plasma levels of carbamazepine or its active metabolites.

Cimetidine. In a pharmacokinetic interaction study, a single dose of cimetidine administered 2 hours prior to azithromycin did not result in any changes in the pharmacokinetics of 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 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.

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 cyclosporine Cmax and AUC0-5 was demonstrated. Therefore, caution should be exercised when administering 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 not changed when fluconazole was co-administered; however, a clinically insignificant reduction in the maximum concentration of azithromycin (18%) 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 a dose of 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 or 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 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 intake 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 between azithromycin and theophylline in healthy volunteers.

Triazolam. Concomitant administration in healthy volunteers of azithromycin (500 mg on day 1 and 250 mg on day 2) with triazolam 0.125 mg 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 1200 mg azithromycin on day 7 showed no significant effect on peak concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

Special precautions for use.

Allergic reactions. As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (in isolated cases fatal), dermatological reactions, including acute generalized exanthematous pustulosis (AGEP), Stevens–Johnson syndrome, and toxic epidermal necrolysis (in isolated cases fatal). Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also been reported in patients. Some of these azithromycin-induced reactions have recurred and required prolonged monitoring and treatment.

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

Liver function tests should be performed if signs or symptoms of liver dysfunction develop, such as rapidly developing asthenia associated with 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 use of certain macrolide antibiotics has led to rapid development of ergotism. There are no data on the potential interaction between ergot derivatives and azithromycin. 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 non-susceptible organisms, including fungi, is recommended.

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 gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Strains of C. difficile that hyperproduce toxins 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 with diarrhea following antibiotic use. Careful medical history is essential, as CDAD has been reported to occur up to two months after the 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.

Prolongation of cardiac repolarization and QT interval, increasing the risk of cardiac arrhythmia and ventricular tachyarrhythmia (torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin.

Since conditions associated with an 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 arrhythmia, or severe heart failure.

Myasthenia gravis. Worsening 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 the drug of choice and is also used for prevention of acute rheumatic fever. While azithromycin is generally effective in treating oropharyngeal streptococcal infection, there are no data demonstrating the efficacy of azithromycin in preventing rheumatic fever. The safety and efficacy of intravenous azithromycin for treatment of infections in children have not been established.

Other.

The safety and efficacy of azithromycin for prophylaxis or treatment of Mycobacterium Avium Complex (MAC) in children have not been established.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on azithromycin use in pregnant women. In reproductive toxicity studies in animals, azithromycin did not show teratogenic harmful effects 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, but 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; pregnancy rates decreased 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, visual disturbances, loss of consciousness, and seizures, which may affect the ability to drive or operate machinery, should be considered.

Method of Administration and Dosage

The medication must be taken 1 hour before or 2 hours after eating, as concomitant food intake impairs azithromycin absorption. Tablets should be swallowed whole, without chewing. The drug is taken once daily.

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 treatment duration 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 dose should be taken 7 days after the first tablet, and the subsequent 8 doses should be taken at 7-day intervals.

For migrating erythema, the total dose of azithromycin is 3 g, administered as follows: 1 g 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 or 4 tablets of 250 mg) as a single dose.

Elderly patients.

Dosage adjustment is not required in elderly patients.

However, since elderly patients may be at increased risk for disturbances in cardiac conduction, caution is recommended when administering azithromycin due to the potential risk of developing cardiac arrhythmias, 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 administered to patients with severe hepatic impairment. Clinical studies on azithromycin use in such patients have not been conducted.

Children.

Zytrox should be administered to children with body weight ≥ 45 kg. For this pediatric group, the adult dosage is recommended.

Overdose.

Clinical experience with azithromycin indicates that adverse effects associated with overdose are similar to those observed with standard 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 treatment measures are recommended, if necessary.

Adverse Reactions

Infections and infestations: candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory tract disorders, rhinitis, pseudomembranous colitis.

Blood and lymphatic system disorders: leukopenia, neutropenia, eosinophilia, thrombocytopenia, hemolytic anemia.

Immune system disorders: angioedema, hypersensitivity reactions, anaphylactic reaction.

Metabolic and nutritional disorders: anorexia.

Psychiatric disorders: nervousness, insomnia, agitation, aggression, restlessness, delirium, hallucinations.

Nervous system disorders: headache, dizziness, somnolence, paresthesia, dysgeusia, syncope, convulsions, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis, hypesthesia.

Eye disorders: visual disturbances.

Ear and labyrinth disorders: hearing impairment; vertigo; worsening of hearing, including deafness and/or tinnitus.

Cardiac disorders: palpitations, ventricular flutter-fibrillation (torsade de pointes), arrhythmia including ventricular tachycardia, QT interval prolongation on ECG, flushing, arterial hypotension.

Respiratory, thoracic and mediastinal disorders: dyspnea, epistaxis.

Gastrointestinal disorders: diarrhea, vomiting, abdominal pain, nausea, gastritis, constipation, flatulence, dyspepsia, dysphagia, abdominal distension, dry mouth, belching, oral mucosal ulceration, hypersalivation, pancreatitis, change in tongue color.

Hepatobiliary disorders: hepatic function abnormalities, cholestatic jaundice, hepatic failure (rarely leading to fatal outcome), fulminant hepatitis, hepatic necrosis.

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP).

Musculoskeletal and connective tissue disorders: osteoarthritis, myalgia, back pain, neck pain, arthralgia.

Renal and urinary disorders: dysuria, renal pain, acute renal failure, interstitial nephritis.

Reproductive system and breast disorders: uterine bleeding, testicular disorders.

General disorders and administration site conditions: chest pain, edema, malaise, asthenia, fatigue, facial swelling, hyperthermia, pain, peripheral edema.

Investigations: decreased lymphocyte count, increased eosinophil count, decreased blood bicarbonate level, increased basophil level, increased monocyte level, increased neutrophil level, increased aspartate aminotransferase (AST) level, increased alanine aminotransferase (ALT) level, increased blood bilirubin level, increased blood urea level, increased blood creatinine level, blood potassium level abnormalities, increased alkaline phosphatase level, increased chloride level, increased glucose level, increased platelet count, decreased hematocrit level, increased bicarbonate level, sodium level abnormalities.

Injury and poisoning: procedural complications.

Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on clinical trial data and post-marketing surveillance. These adverse reactions differ in type or frequency from those reported with immediate-release and extended-release formulations.

Metabolic and nutritional disorders: anorexіa.

Psychiatric disorders: dizziness, headache, paresthesia, dysgeusia, hypesthesia.

Eye disorders: visual disturbances.

Ear and labyrinth disorders: deafness, hearing impairment, tinnitus.

Cardiac disorders: palpitations.

Gastrointestinal disorders: diarrhea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools.

Hepatobiliary disorders: hepatitis.

Skin and subcutaneous tissue disorders: rash, pruritus, Stevens-Johnson syndrome, photosensitivity.

Musculoskeletal and connective tissue disorders: arthralgia.

General disorders and administration site conditions: increased fatigue, asthenia, malaise.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

250 mg tablets: 6 tablets per strip; each strip in a cardboard package;

500 mg tablets: 3 tablets per strip; each strip in a cardboard package.

Prescription category. Prescription only.

Manufacturer.

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and location of business operations.

Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh - 174101, India (Block No. 1).