INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZIJUB (AZIJUB)

Composition:

Active substance: azithromycin;

1 tablet contains azithromycin 250 mg or 500 mg;

Excipients: calcium hydrogen phosphate anhydrous, sodium croscarmellose, pregelatinized starch, hypromellose (E 464), purified water, sodium lauryl sulfate, magnesium stearate (E 572), colorant Opadry white 31K58902.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Azijub 250 mg: white or almost white capsule-shaped film-coated tablets, embossed with "AZ" and "250" on one side and plain on the other;

Azijub 500 mg: white or almost white capsule-shaped film-coated tablets, embossed with "AZ", "500", and a break line on one side and plain on the other.

Pharmacotherapeutic group. Antibacterials for systemic use. Azithromycin. ATC code J01FA10.

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by the addition of a nitrogen atom to the lactone ring of erythromycin A.

Mode of action

The mechanism of action of azithromycin is based on the inhibition of bacterial protein synthesis by binding to the 50S ribosomal subunit and inhibition of peptide translocation.

Pharmacokinetic/pharmacodynamic relationship

For azithromycin, the primary pharmacological parameter is AUC/MIC, which best correlates with its efficacy.

Mechanism of resistance

Resistance of various bacterial strains to macrolides is known to occur via three mechanisms: target site modification, antibiotic modification, or altered antibiotic transport (efflux). Efflux in streptococci is confirmed by genes resulting in macrolide-limited resistance (M phenotype). Target site modification is controlled by methylases encoded by specific genes.

Complete cross-resistance exists between erythromycin, azithromycin, other macrolides, and lincosamides against Streptococcus pneumoniae, beta-hemolytic group A streptococci, Enterococcus spp., and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). Penicillin-susceptible Streptococcus pneumoniae are likely more susceptible to azithromycin than penicillin-resistant strains. Methicillin-resistant Staphylococcus aureus (MRSA) are less likely to be susceptible to azithromycin compared to methicillin-susceptible Staphylococcus aureus (MSSA).

Significant resistance induction, both in vitro and in vivo, occurs with increasing MIC dilution < 1 for Streptococcus pyogenes, Haemophilus influenzae, and Enterobacteriaceae after nine sublethal passages of the active substance and three dilutions; resistance increases for Staphylococcus aureus, while in vitro resistance development due to mutations is rare.

Clinical breakpoints

EUCAST-defined susceptibility breakpoints for typical bacterial pathogens susceptible to azithromycin:

Staphylococcus spp.: susceptible ≤ 1 mg/L; resistant > 2 mg/L;
Haemophilus spp.: susceptible ≤ 0.12 mg/L; resistant > 4 mg/L;
Streptococcus pneumoniae and Streptococcus A, B, C, G: susceptible ≤ 0.25 mg/L; resistant ≥ 0.5 mg/L;
Moraxella catarrhalis: susceptible ≤ 0.5 mg/L; resistant > 0.5 mg/L;
Neisseria gonorrhoeae: susceptible ≤ 0.25 mg/L; resistant > 0.5 mg/L.

Resistance in individual strains may vary depending on geographical location and time; therefore, obtaining local resistance data is advisable, especially when treating severe infections. The following are only approximate recommendations regarding possible susceptibility of organisms to azithromycin.

Organisms usually susceptible

Aerobic gram-negative:

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

Other microorganisms:

Chlamydophila pneumoniae

Chlamydia trachomatis

Legionella spp.

Mycobacterium avium

Mycoplasma pneumoniae*

Organisms with potential for secondary resistance development

Aerobic gram-positive:

Staphylococcus aureus (methicillin-susceptible)

Streptococcus pneumoniae

Streptococcus pyogenes (moderately susceptible to erythromycin)

Others:

Ureaplasma urealyticum

Naturally resistant organisms

Aerobic gram-positive:

Staphylococci MRSA, MRSE

Aerobic gram-negative:

Escherichia coli

Klebsiella spp.

Pseudomonas aeruginosa

Anaerobes:

Bacteroides fragilis group

*At the time of data publication, no standardized breakpoints were available. Literature, standard reference works, and treatment guidelines assume susceptibility.

Pharmacokinetics.

Absorption

After oral administration, the bioavailability of azithromycin is approximately 37%. Peak plasma concentrations are reached within 2–3 hours. The mean maximum concentration (Cmax) after a single 500 mg dose is approximately 0.4 μg/mL.

Distribution

After oral administration, azithromycin is widely distributed throughout the body.

Pharmacokinetic studies have shown significantly higher concentrations of azithromycin in tissues (up to 50 times) than in plasma. This indicates extensive tissue binding (volume of distribution at equilibrium is approximately 31 L/kg).

At recommended doses, no accumulation occurs in serum/plasma. However, accumulation occurs in tissues, where levels are significantly higher than serum/plasma levels. Concentrations in target tissues such as lungs, tonsils, and prostate after a single 500 mg dose exceed the MIC90 for likely pathogens.

In vitro and in vivo experimental studies have demonstrated that azithromycin accumulates in phagocytes, and release is facilitated by active phagocytes. Animal studies have confirmed that this process contributes to azithromycin accumulation in tissues. Plasma protein binding of azithromycin ranges from 52% at 0.05 μg/mL to 18% at 0.5 μg/mL, depending on serum concentration.

Metabolism and elimination

The terminal elimination half-life from plasma after tissue elimination ranges from 2 to 4 days. Approximately 12% of an intravenous dose is excreted unchanged in urine over 3 days, with a significant portion eliminated during the first 24 hours. Azithromycin concentrations up to 237 μg/mL have been detected in human bile 2 days after completion of a five-day treatment course. Ten metabolites have been identified (formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate). Study results suggest that metabolites do not play a significant role in the microbiological activity of azithromycin.

Pharmacokinetics in special patient populations

Renal impairment

After a single 1 g oral dose of azithromycin, mean Cmax and AUC0–120 values increased by 5.1% and 4.2%, respectively, in patients with mild to moderate renal impairment (glomerular filtration rate 10–80 mL/min) compared to those with normal renal function (GFR > 80 mL/min). In patients with severe renal impairment, mean Cmax and AUC0–120 values increased by 61% and 35%, respectively.

Hepatic impairment

In patients with mild to moderate hepatic impairment, no evidence of significant changes in serum pharmacokinetics of azithromycin was observed compared to normal liver function. In these patients, urinary excretion of azithromycin increases, possibly to compensate for reduced hepatic clearance.

Elderly patients

Azithromycin pharmacokinetics in elderly males were similar to those in younger individuals; however, in elderly females, peak concentrations were higher (by 30–50%), although no significant accumulation occurred.

In elderly volunteers (> 65 years), AUC values after a five-day regimen were consistently higher (by 29%) than in younger volunteers (< 45 years). However, this difference is not considered clinically significant, and dose adjustment is not recommended.

Paediatric population

Pharmacokinetics were studied in children aged 4 months to 15 years receiving capsules, granules, or suspension. With a dose of 10 mg/kg on day 1 and 5 mg/kg on days 2–5, Cmax was slightly lower than in adults: 224 µg/L in children aged 0.6–5 years and 383 µg/L in children aged 6–15 years. The elimination half-life in older children was within the range expected for adults (36 hours).

Clinical characteristics.

Indications.

Treatment of bacterial infections caused by microorganisms sensitive to azithromycin, such as:

Lower respiratory tract infections: acute exacerbation of chronic bronchitis (diagnosed), mild to moderate community-acquired pneumonia;
Upper respiratory tract infections: sinusitis, pharyngitis/tonsillitis;
Acute otitis media;
Skin and soft tissue infections (chronic migrating erythema (Stage I Lyme disease)), pertussis, impetigo, and secondary pyoderma;
Uncomplicated urethritis and cervicitis caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to azithromycin or to other macrolide or ketolide antibiotics, or to any excipients of the medicinal product. Due to the theoretical possibility of ergotism, azithromycin should not be administered concomitantly with ergot derivatives.

Interaction with other medicinal products and other forms of interaction.

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

Antacids: Patients taking azithromycin and antacids should not take these products simultaneously. Concurrent administration of azithromycin, prolonged-release granules for oral suspension, with a single 20 mL dose of Maalox (aluminium hydroxide and magnesium hydroxide) did not affect the rate and extent of azithromycin absorption.

Cetirizine: In healthy volunteers, no pharmacokinetic interaction or significant changes in QT interval were observed when azithromycin was administered for 5 days concurrently with 20 mg cetirizine at steady state.

Didanosine: When daily doses of azithromycin 1200 mg were administered concurrently with didanosine 400 mg in six subjects, no effect on the pharmacokinetics of didanosine was observed compared to placebo.

Digoxin and colchicine: It has been reported that concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, may lead to increased serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is administered concurrently with P-glycoprotein substrates such as digoxin, the possibility of increased digoxin serum concentrations should be considered.

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

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

Azithromycin does not have significant interactions with the cytochrome P450 hepatic system. It is considered that the drug does not exhibit the pharmacokinetic drug interactions observed with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via the cytochrome-metabolite complex.

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

Atorvastatin: Concurrent 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 cases of rhabdomyolysis have been reported in patients receiving azithromycin together with statins.

Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not show a significant effect on 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 prior to azithromycin.

Coumarin anticoagulants: In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. However, during the post-marketing period, increased bleeding tendency has been reported with concomitant use of azithromycin and warfarin or coumarin-like oral anticoagulants. Prothrombin time should be monitored frequently.

Cyclosporine: In a pharmacokinetic study involving healthy volunteers who received azithromycin 500 mg/day orally for three days followed by a single 10 mg/kg dose of cyclosporine, a significant increase in Cmax and AUC0-5 of cyclosporine was observed. Therefore, caution should be exercised when considering concomitant administration of these medicinal products. If combination therapy is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are necessary.

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

Fluconazole: Concurrent administration of a single 1200 mg dose of azithromycin did not alter the pharmacokinetics of a single 800 mg dose of fluconazole. The overall exposure and elimination half-life of azithromycin were not altered when fluconazole was co-administered; however, a clinically insignificant reduction in Cmax (18%) of azithromycin was observed.

Indinavir: Concurrent 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 show a significant effect on the pharmacokinetics of methylprednisolone.

Midazolam: In healthy volunteers, concurrent administration of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics or pharmacodynamics of midazolam.

Nelfinavir: Concurrent administration of azithromycin (1200 mg) and nelfinavir at steady-state concentrations (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse events were observed; therefore, dose adjustment is not required.

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

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

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

Theophylline: Azithromycin did not affect the pharmacokinetics of theophylline when administered concomitantly with theophylline in healthy volunteers. However, combined use of theophylline and other macrolide antibiotics has occasionally led to increased serum theophylline levels.

Triazolam: Concurrent 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: Concurrent 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 the maximum concentration, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Serum azithromycin concentrations were consistent with those observed in other studies.

Substrates of CYP3A4.

Although azithromycin is not considered to inhibit the CYP3A4 enzyme, this medicinal product should be used with caution when co-administered with drugs such as quinidine, cyclosporine, cisapride, astemizole, terfenadine, ergot alkaloids, pimozide, and other medicinal products with a narrow therapeutic index that are primarily metabolized by CYP3A4.

Cisapride.

Cisapride is metabolized in the liver by the CYP3A4 enzyme. Since macrolides inhibit this enzyme, concomitant use with cisapride may lead to changes in the QT interval, ventricular arrhythmias, or torsade de pointes.

Special precautions for use

When selecting azithromycin for treatment of an individual patient, consideration should be given to the appropriateness of using a macrolide antibiotic according to the diagnosis established, as well as to the bacterial etiology of the infection, its inclusion in the approved indications, and the prevalence of resistance to azithromycin or other macrolides.

In regions with a high prevalence of erythromycin A resistance, it is particularly important to consider the evolving susceptibility patterns to azithromycin and other antibiotics.

As with other macrolides, high resistance of Streptococcus pneumoniae to azithromycin has been reported in some European countries. This should be taken into account when treating infections caused by Streptococcus pneumoniae.

For bacterial pharyngitis, azithromycin is recommended only when first-line beta-lactam therapy is not feasible.

Allergic reactions

As with erythromycin and other macrolides, rare but serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (rarely with fatal outcome), DRESS syndrome, dermatological reactions including acute generalized exanthematous pustulosis, Stevens–Johnson syndrome, toxic epidermal necrolysis (rarely with fatal outcome), and drug reactions with eosinophilia and systemic symptoms (see section "Adverse reactions"). Some of these reactions with azithromycin led to recurrent symptoms and required a longer period of observation and treatment.

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

Renal impairment

Dose adjustment is not required in patients with mild to moderate renal impairment (glomerular filtration rate 10–80 mL/min). In patients with severe renal impairment (glomerular filtration rate <10 mL/min), a 33% increase in systemic azithromycin concentration has been observed.

Hepatic impairment

Since the liver is the primary route of elimination of azithromycin, it should be used with caution in patients with hepatic disease. Cases of fulminant hepatitis, potentially leading to liver failure and life-threatening complications, have been reported. In cases of detection of symptoms and signs of hepatic dysfunction, such as rapid onset of asthenia associated with jaundice, dark urine, bleeding tendency, or hepatic encephalopathy, liver function tests should be performed. Azithromycin should be discontinued if severe liver injury develops.

Ergot alkaloids and azithromycin

Some macrolide antibiotics have caused ergotism in patients taking ergot derivatives. There are no data on a possible interaction between ergot and azithromycin. Due to the theoretical risk of ergotism, concomitant use of azithromycin and ergot derivatives should be avoided.

QT interval prolongation

Prolonged cardiac repolarization and QT interval, increasing the risk of cardiac arrhythmia and ventricular tachycardia (torsade de pointes), have been observed with other macrolide antibiotics. Therefore, since the following conditions may increase the risk of ventricular arrhythmia (including paroxysmal ventricular tachycardia of the "pirouette" type), which may be fatal, azithromycin should be used with caution in patients with current conditions predisposing to arrhythmia (particularly in women and elderly patients), namely 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.

Pneumococcal infections

As with other macrolides, high resistance of Streptococcus pneumoniae (>30%) to azithromycin has been reported in some European countries. This should be taken into account when treating infections caused by Streptococcus pneumoniae.

Due to cross-resistance among macrolides, it is particularly important to consider the evolving susceptibility patterns to azithromycin and other antibiotics in regions with high erythromycin resistance.

Superinfections

Be aware of possible symptoms of superinfection caused by non-susceptible organisms, such as fungi. Superinfection may require discontinuation of treatment and appropriate interventions.

Neurological or psychiatric disorders

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

Pseudomembranous colitis

Pseudomembranous colitis has been reported following the use of macrolide antibiotics. This diagnosis should be considered in patients who develop diarrhea after initiation of azithromycin therapy. If pseudomembranous colitis is induced by azithromycin, antiperistaltic agents are contraindicated.

Clostridium difficile-associated diarrhea

Diarrhea associated with Clostridium difficile has been reported with nearly all antimicrobial agents, including azithromycin, with severity ranging from mild diarrhea to fatal colitis. Antimicrobial therapy alters the normal flora of the colon and leads to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of diarrhea. Hyper-toxin-producing strains of C. difficile are associated with increased complications and mortality, as these infections may not respond to antimicrobial therapy and may require colectomy. This should be considered in all patients developing diarrhea after antibiotic use. A careful medical history is necessary, as diarrhea has been reported up to 2 months after antibiotic administration.

Long-term use

There is no experience regarding the efficacy of long-term use of azithromycin for the approved indications. In case of rapid recurrence of infection, the appropriateness of treatment with other antibiotics should be considered.

Azithromycin is not intended for the treatment of infected burn wounds.

In sexually transmitted diseases, concomitant infection with T. pallidum should be ruled out.

Worsening of symptoms of myasthenia gravis and the onset of myasthenic syndrome have been reported in patients treated with azithromycin.

This drug is not intended for the treatment of severe infections requiring high antibiotic concentrations in the blood.

Efficacy for prevention or treatment of MAC in children has not been established.

This medicine should not be used by patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy.

Reproductive toxicity studies in animals were performed at doses corresponding to moderately toxic levels for the maternal organism. No evidence of toxic effects of azithromycin on the fetus was observed in these studies. However, adequate and well-controlled studies in pregnant women are lacking. Since animal reproductive studies do not always predict human response, azithromycin should be prescribed during pregnancy only if clearly needed.

Breastfeeding.

It has been reported that azithromycin is excreted into human breast milk, but appropriate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion into human breast milk have not been conducted. Use of azithromycin during breastfeeding should be considered only when the expected benefit to the mother outweighs the potential risk to the infant.

Fertility.

Fertility studies were conducted in rats; pregnancy rates decreased after administration of azithromycin. The relevance of these data to humans is unknown.

Ability to influence reaction speed when driving or operating machinery

Since azithromycin may cause certain nervous system disorders (see section "Adverse reactions"), it is not recommended to use the drug when driving or operating machinery.

Method of Administration and Dosage

The medication should be taken once daily. The tablet should be swallowed whole, one hour before or two hours after a meal. The treatment duration for various infectious diseases is provided below.

Adults and children with body weight over 45 kg

Azithromycin should be administered once daily, at least one hour before or two hours after food intake.

For respiratory tract infections and skin and soft tissue infections (except chronic migrating erythema): the dose is 500 mg once daily for 3 days.

Chronic migrating erythema: on day 1, 1 g (4 tablets of 250 mg or 2 tablets of 500 mg as a single dose); from day 2 to day 5, 500 mg daily (2 tablets of 250 mg or 1 tablet of 500 mg).

Uncomplicated and complicated urethritis/cervicitis: single dose of 1 g (4 tablets of 250 mg or 2 tablets of 500 mg). Total course dose – 1 g.

Missed dose instructions

If a dose is missed, it should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals.

Elderly patients

Dosage adjustment is not required in elderly patients.

Since elderly patients may belong to risk groups for cardiac conduction disorders, caution is recommended when administering 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 can 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 disease. Studies on azithromycin treatment in such patients have not been conducted.

Children

Tablets are not intended for use in children with body weight less than 45 kg. Azithromycin in other dosage forms, such as suspension, may be prescribed for these children.

Overdose

Typical symptoms of overdose: reversible hearing impairment, severe nausea, vomiting, and diarrhea. In case of overdose, activated charcoal should be administered and symptomatic therapy provided to support vital functions.

Adverse Reactions

Azithromycin is well tolerated and has a low incidence of adverse effects.

Assessment of adverse events is based on the following frequency classification: very common (≥10%); common (≥1%, <10%); uncommon (≥0.1%, <1%); rare (≥0.01%, <0.1%); very rare (<0.01%), including isolated cases.

Infections and infestations: uncommon – candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory dysfunction, rhinitis; not known – pseudomembranous colitis.

Blood and lymphatic system disorders: neutropenia; not known – haemolytic anaemia; rare – thrombocytopenia; uncommon – eosinophilia, leukopenia.

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

Immune system disorders: not known – anaphylactic reaction; uncommon – angioedema, hypersensitivity reactions.

Metabolism and nutrition disorders: uncommon – anorexia.

Psychiatric disorders: excitement, tinnitus; not known – restlessness, delirium, hallucinations; rare – aggression, hyperactivity, anxiety, nervousness; uncommon – insomnia.

Nervous system disorders: uncommon – dizziness/vertigo, somnolence, syncope, headache, convulsions (also reported with other macrolide antibiotics), taste and smell disturbances; rare – paraesthesia, asthenia, insomnia; not known – psychomotor hyperactivity, exacerbation of myasthenia gravis.

Eye disorders: common – visual disturbances.

Ear and labyrinth disorders: rare – hearing impairment has been reported with macrolide antibiotics. Cases of hearing impairment, deafness, and tinnitus have been observed in some patients receiving azithromycin. Most of these cases occurred during clinical trials where azithromycin was administered at high doses over prolonged periods. According to available follow-up data, most of these events were reversible.

Cardiac disorders: ventricular tachycardia of the torsades de pointes type; rare – palpitations, arrhythmia associated with ventricular tachycardia (also reported with other macrolide antibiotics). Rare cases of QT prolongation, ventricular fibrillation, and hypotension have been reported.

Vascular disorders: not known – hypotension; uncommon – flushing.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnoea, epistaxis.

Gastrointestinal disorders: abdominal distension; common – nausea, vomiting, diarrhoea, abdominal discomfort (pain/spasms); uncommon – loose stools, flatulence, dyspepsia, anorexia, gastritis, dysphagia, dry mouth, belching, oral ulcers, hypersalivation; rare – constipation, tongue discoloration. Pseudomembranous colitis and pancreatitis have been reported.

Hepatobiliary disorders: rare – hepatitis and cholestatic jaundice, including abnormal liver function test results; necrotic hepatitis and liver dysfunction, which in rare cases may lead to fatal outcome.

Skin and subcutaneous tissue disorders: uncommon – allergic reactions including pruritus and rash, dermatitis, dry skin, hyperhidrosis; rare – allergic reactions including angioedema, urticaria, photosensitivity; acute generalized exanthematous pustulosis; frequency not known – serious skin reactions including erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS).

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

Renal and urinary disorders: rare – interstitial nephritis, acute renal failure; uncommon – dysuria, renal pain.

Reproductive system and breast disorders: uncommon – vaginitis, uterine bleeding, testicular disorders.

Systemic disorders: rare – anaphylaxis, including oedema (in rare cases leading to fatal outcome), candidiasis.

General disorders: uncommon – fatigue, chest pain, malaise, asthenia, facial oedema, hyperthermia, pain, peripheral oedema.

Investigations: common – lymphopenia, decreased blood bicarbonate levels; uncommon – increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased blood bilirubin, increased blood urea, increased blood creatinine, changes in blood potassium levels, increased alkaline phosphatase, increased chloride levels, increased glucose levels, increased platelet count, decreased haematocrit, increased bicarbonate levels, sodium level abnormalities.

Injury and poisoning: uncommon – postoperative complications.

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

Metabolism and nutrition disorders: anorexia.

Psychiatric disorders: dizziness, headache, paraesthesia, dysgeusia, hypoaesthesia.

Eye disorders: blurred vision.

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

Cardiac disorders: palpitations.

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

Hepatobiliary disorders: hepatitis.

Skin disorders: rash, pruritus, Stevens–Johnson syndrome, photosensitivity.

Musculoskeletal disorders: arthralgia.

General disorders: increased fatigue, asthenia, malaise.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

Store in a place inaccessible to children at a temperature not exceeding 25°C.

Packaging.

6 tablets of 250 mg or 3 tablets of 500 mg in aluminium blisters. 1 blister in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Jubilant Generics Limited.

Manufacturer's address and place of business.

Village Sikandarpur, Bhainswal, Roorkee-Dehradun Highway, Bhagwanpur, Roorkee District Haridwar, Uttarakhand, IN-247661, India.

Azidjub