Azo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZO (AZO)

Composition:

Active substance: azithromycin;

1 tablet contains azithromycin dihydrate equivalent to azithromycin 500 mg;

Excipients: calcium hydrogen phosphate, microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, povidone K-30, colloidal anhydrous silicon dioxide, crospovidone, magnesium stearate, hypromellose E-15, purified talc, titanium dioxide (E 171), polyethylene glycol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, elongated, 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 representative of the macrolide antibiotics group – azalides – with a broad spectrum of antimicrobial activity. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis through binding to the 50 S ribosomal subunit and prevention of peptide translocation, without affecting polynucleotide synthesis.

Mechanism of resistance

Resistance to azithromycin may be intrinsic or acquired. 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.

Antimicrobial spectrum of azithromycin

Pharmacokinetics.

The 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.

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 (VVss) is 31.1 L/kg.

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

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in urine over the following three 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 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, ecthyma, secondary pyoderma, moderate acne vulgaris;
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to the active substance, to any other component of the medicinal product, or to other macrolide antibiotics, erythromycin, or any ketolide antibiotic. Due to the theoretical possibility of ergotism, azithromycin should not be administered concurrently with ergot derivatives. The medicinal product is contraindicated:

• in children with body weight less than 45 kg;
• for the treatment of infected burn wounds;
• concomitantly with other medicinal products that prolong the QT interval, such as class IA and III antiarrhythmic agents, cisapride, and terfenadine;
• in patients with severe liver disease (hepatitis);
• in patients with congenital or documented QT prolongation;
• in patients with fluid and electrolyte imbalances, particularly in cases of hypokalaemia and hypomagnesaemia;
• in patients with clinically significant bradycardia, arrhythmia, or severe heart failure.

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: azithromycin should be taken at least one hour before or two hours after antacid administration.

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

Cimetidine: a single dose of cimetidine administered 2 hours prior to azithromycin does not affect the pharmacokinetics of azithromycin.

Cyclosporine: the therapeutic situation should be carefully evaluated before considering concomitant administration of azithromycin with cyclosporine. If combination therapy is considered justified, careful monitoring of cyclosporine levels is required, with appropriate dose adjustments.

Digoxin: certain macrolide antibiotics have been reported to affect digoxin metabolism in the gut. Therefore, when azithromycin and digoxin are used concomitantly, the possibility of increased digoxin concentrations should be considered, and digoxin levels should be monitored. Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin may lead to increased serum levels of the P-glycoprotein substrate.

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

Ergot derivatives: due to the theoretical risk of ergotism, concomitant administration of azithromycin with ergot derivatives is not recommended.

Azithromycin does not significantly interact with the hepatic cytochrome P450 system. It is considered not to 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.

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

Atorvastatin: concomitant administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter atorvastatin plasma concentrations (based on HMG-CoA reductase inhibition analysis).

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

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

Nelfinavir: a study conducted in 12 healthy volunteers receiving combination therapy with azithromycin (1200 mg) and nelfinavir (750 mg three times daily) in an inpatient setting resulted in a 100% increase in absorption and bioavailability of azithromycin. This did not significantly affect the rate of absorption or elimination. The clinical implications of this interaction are unknown; therefore, azithromycin should be administered with caution to patients receiving nelfinavir.

Terfenadine: pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. However, as with other macrolide antibiotics, azithromycin should be used with caution in combination with terfenadine.

Theophylline: combined use of theophylline and azithromycin has occasionally led to elevated serum theophylline levels.

Coumarin anticoagulants: increased tendency to bleeding has been reported with concomitant use of azithromycin and warfarin or coumarin-like oral anticoagulants. Close monitoring of prothrombin time is required.

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

Didanosine: in six subjects, co-administration of daily doses of 1200 mg azithromycin with didanosine did not affect the pharmacokinetics of didanosine compared to placebo.

Rifabutin: concomitant administration of azithromycin and rifabutin did not affect plasma concentrations of either agent. 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 was not established.

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

Ergot derivatives: due to the theoretical possibility of ergotism, azithromycin should not be administered concurrently with ergot derivatives.

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 significantly affect the maximum concentrations, total exposure, or urinary excretion of trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

Fluconazole: no clinically significant interaction between fluconazole and azithromycin has been observed. Total exposure and elimination half-life of azithromycin were unchanged when fluconazole was co-administered; however, a clinically insignificant reduction in Cmax (18%) of azithromycin was observed.

Cisapride: metabolized in the liver via the CYP3A4 enzyme. Macrolides inhibit this enzyme, and therefore concomitant use of cisapride and azithromycin may lead to QT prolongation, ventricular arrhythmias, and ventricular tachycardia such as "torsades de pointes".

Astemizole, triazolam, midazolam, alfentanil: pharmacokinetic studies have not reported interactions between azithromycin and these medicinal products. However, they should be used with caution together with azithromycin due to enhanced effects when used concomitantly with erythromycin, a macrolide antibiotic.

Protease inhibitors: a single 1200 mg dose of azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered at 800 mg three times daily for 5 days.

Special precautions for use.

Allergic reactions: In rare cases, serious allergic (and rarely fatal) reactions to azithromycin, such as angioedema and anaphylaxis, have been reported. Some of these reactions were associated with recurrent symptoms and required prolonged observation and treatment.

Prolonged cardiac repolarization and QT interval: Prolongation of the QT interval and cardiac repolarization, which may increase the risk of developing cardiac arrhythmias and ventricular fibrillation-torsade de pointes, has been observed during treatment 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 the drug to patients:

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

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

Streptococcal infections: Azithromycin is generally effective in treating Streptococcus in the oropharynx; however, there are no data demonstrating azithromycin's efficacy in preventing acute rheumatic fever.

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

Pseudomembranous colitis: The use of macrolide antibiotics is associated with the risk of pseudomembranous colitis. This diagnosis should be considered in patients who develop severe diarrhea during or after azithromycin therapy. If pseudomembranous colitis is suspected to be caused by azithromycin, antidiarrheal agents are contraindicated.

Diarrhea associated with Clostridium difficile (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 administration of antibacterial agents.

Sexually transmitted infections: Concurrent infection with T. pallidum should be ruled out when treating these conditions.

Renal impairment: Dose adjustment is not required in patients with mild renal dysfunction (glomerular filtration rate 10–80 mL/min). Azithromycin should be used with caution in patients with glomerular filtration rate <10 mL/min.

Hepatic impairment: Since azithromycin is metabolized in the liver and excreted via bile, it should not be administered to patients with severe hepatic disease. Studies on azithromycin treatment in such patients have not been conducted. Treatment with azithromycin should be discontinued if severe hepatic impairment develops.

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 or symptoms of hepatic dysfunction develop, such as rapidly progressing asthenia accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy.

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

Azithromycin is not a first-line agent for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes. For these conditions, as well as for prevention of acute rheumatic fever, penicillins are the drugs of choice.

Azithromycin should be used with caution in patients with neurological or psychiatric disorders.

Azithromycin should not be used for the treatment of infected burn wounds.

The drug AZO (film-coated tablets) should not be used to treat severe infections requiring rapid achievement of high antibiotic concentrations in the blood.

Other.

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

Use during pregnancy or breastfeeding.

The potential risk of azithromycin to the fetus is unknown. Azithromycin should not be used during pregnancy except in cases of extreme necessity.

Studies on the passage of azithromycin into breast milk are lacking; therefore, azithromycin may be used during breastfeeding only if absolutely necessary.

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.

Patients taking azithromycin should exercise caution when driving or operating machinery due to the possibility of dizziness, somnolence, seizures, and visual disturbances.

Method of Administration and Dosage

AZO 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, it 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 treatment duration is 3 days.

For vulgaris acne, the recommended total dose of azithromycin is 6 g, administered 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 week’s dose should be taken 7 days after the first tablet, and the following 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 (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 for 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 developing 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 used in patients with severe hepatic impairment. Studies on the treatment of such patients using azithromycin have not been conducted.

Children.

AZO 500 mg tablets are not recommended for children with body weight below 45 kg.

Overdose.

Typical symptoms of overdose: reversible hearing impairment, pronounced nausea, vomiting, diarrhea. In case of overdose, activated charcoal should be administered and symptomatic therapy aimed at supporting vital functions should be initiated.

Adverse Reactions

AZO is well tolerated with a low incidence of adverse effects.

Haematopoietic and lymphatic system disorders:
Rare (>1/10,000, <1/1,000) – thrombocytopenia, haemolytic anaemia;
Uncommon (>1/1,000, <1/100) – leukopenia.

In clinical studies, isolated reports of transient, mild neutropenia, neutrophilia, and eosinophilia have been observed. However, a causal relationship with azithromycin therapy has not been established.

Psychiatric disorders:
Rare (>1/10,000, <1/1,000) – aggression, restlessness, nervousness, anxiety, depersonalization, delirium (mainly in elderly patients);
Not known – hallucinations.

Nervous system disorders:
Uncommon (>1/1,000, <1/100) – dizziness/vertigo, somnolence, syncope, headache, convulsions (also reported with other macrolide antibiotics), hyperkinesia, taste disturbances, and altered sense of smell;
Rare (>1/10,000, <1/1,000) – paraesthesia, asthenia, insomnia, hyperactivity;
Not known – myasthenia gravis, hypoaesthesia.

Eye disorders:
Common (>1/100, <1/10) – visual disturbances.

Ear and labyrinth disorders:
Rare (>1/10,000, <1/1,000) – hearing impairment has been reported with macrolide antibiotics. Cases of hearing loss, deafness, and tinnitus have been reported in patients receiving azithromycin. Most of these cases occurred during clinical trials involving high-dose, prolonged azithromycin therapy. According to available post-marketing surveillance data, most of these events were reversible.

Cardiac disorders:
Rare (>1/10,000, <1/1,000) – palpitations, arrhythmia associated with ventricular tachycardia (also reported with other macrolide antibiotics). Rare reports of QT prolongation and ventricular fibrillation;
Uncommon (>1/1,000, <1/100) – palpitations.

Vascular disorders:
Rare (>1/10,000, <1/1,000) – hypotension reported;
Uncommon (>1/1,000, <1/100) – flushing.

Respiratory system disorders:
Uncommon (>1/1,000, <1/100) – dyspnoea, epistaxis.

Gastrointestinal disorders:
Common (>1/100, <1/10) – nausea, vomiting, diarrhoea, abdominal discomfort (pain/spasms);
Uncommon (>1/1,000, <1/100) – loose stools, flatulence, dyspepsia, anorexia, gastritis, constipation, dysphagia, dry mouth, belching, oral ulcers, hypersalivation;
Rare (>1/10,000, <1/1,000) – constipation, tongue discoloration. Cases of pseudomembranous colitis and pancreatitis have been reported.

Hepatobiliary disorders:
Rare (>1/10,000, <1/1,000) – hepatitis and cholestatic jaundice reported, including abnormal liver function test results, as well as rare cases of necrotizing hepatitis and hepatic dysfunction, rarely leading to fatal outcome;
Not known – hepatic failure (rarely resulting in death), fulminant hepatitis.

Skin and subcutaneous tissue disorders:
Uncommon (>1/1,000, <1/100) – allergic reactions including pruritus and rash, dermatitis, dry skin, hyperhidrosis;
Rare (>1/10,000, <1/1,000) – allergic reactions including angioneurotic oedema, urticaria, photosensitivity; serious skin reactions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders:
Uncommon (>1/1,000, <1/100) – arthralgia, osteoarthritis, myalgia, back pain, neck pain.

Renal and urinary disorders:
Rare (>1/10,000, <1/1,000) – interstitial nephritis, acute renal failure;
Uncommon (>1/1,000, <1/100) – dysuria, renal pain.

Reproductive system and breast disorders:
Uncommon (>1/1,000, <1/100) – vaginitis, uterine bleeding, testicular disorders.

General disorders and administration site conditions:
Rare (>1/10,000, <1/1,000) – anaphylaxis, including oedema (rarely leading to fatal outcome), candidiasis, fatigue, malaise;
Uncommon (>1/1,000, <1/100) – vaginal infections, pneumonia, bacterial infection, pharyngitis, respiratory dysfunction, rhinitis, facial oedema, hyperthermia, pain, peripheral oedema.

Other: conjunctivitis.

Laboratory findings:
Common (>1/100, <1/10) – decreased white blood cell count, increased eosinophil count, decreased blood bicarbonate level, increased basophil count, increased monocyte count, increased neutrophil count;
Uncommon (>1/1,000, <1/100), Not known – increased aspartate aminotransferase, increased alanine aminotransferase, increased blood bilirubin, increased blood urea nitrogen, increased blood creatinine, potassium level changes, increased alkaline phosphatase, increased chloride level, increased glucose level, increased platelet count, decreased haematocrit, increased bicarbonate level, sodium level deviations.

Shelf life: 2 years.

Storage conditions.
Store in a place protected from light and inaccessible to children, at a temperature not exceeding 25°C.

Packaging.
3 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status.
Prescription only.

Manufacturer.
Tulip Lab Pvt. Ltd.
Tulip Lab Pvt. Ltd.

Manufacturer's address and site of operations.

Registered address:
4024, A-Wing, Oberoi Garden Estate, Chandivali, Andheri (East), Mumbai-400072, India
4024, A-Wing, Oberoi Garden Estate, Chandivali, Andheri (East), Mumbai-400072, India.

Manufacturing address:
F - 20/21, Ranjangaon MIDC, Tal. Shirur, Dist - Pune, India
F - 20/21, Ranjangaon MIDC, Tal. Shirur, Dist - Pune, India