Zoxi

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOKSY (ZOXY)

Composition:

Active substance: azithromycin;

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

Excipients: calcium hydrogen phosphate anhydrous, sodium lauryl sulfate, sodium croscarmellose, pregelatinized starch, magnesium stearate, film coating Opadry White (hypromellose, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets 250 mg: film-coated tablets, white in color, oval-shaped, with embossing "2" on one side and "AZI" on the other side;

Film-coated tablets 500 mg: film-coated tablets, white in color, oval-shaped, with embossing "5" and a break line on one side and "AZI" on the other side.

Pharmacotherapeutic group.

Antibacterial agents 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 chain translocation from one ribosomal subunit to another.

Mechanism of resistance

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

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

Breakpoint values for azithromycin susceptibility of typical bacterial pathogens, published by EUCAST

Microorganisms	MIC Reference Values (mg/l)
	Susceptible (S≤)	Resistant (R>)
Staphylococcus spp.	1	2
Streptococcus groups A, B, C and G	0.25	0.5
Streptococcus pneumoniae	0.25	0.5
Haemophilus influenzae	0.125	4
Moraxella catarrhalis	0.25	0.5
Neisseria gonorrhoeae	0.25	0.5

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, it is desirable to have local information on resistance, especially when treating severe infections. If necessary, expert consultation should be sought if local resistance prevalence renders the usefulness of the drug at least questionable for certain types of infections.

Antimicrobial spectrum of azithromycin

Aerobic gram-positive microorganisms

Staphylococcus aureus Methicillin-susceptible

Streptococcus pneumoniae Penicillin-susceptible

Streptococcus pyogenes* (Group A)

Aerobic gram-negative microorganisms

Haemophilus influenzae Haemophilus parainfluenzae

Legionella pneumophila

Moraxella catarrhalis

Neisseria gonorrhoeae

Pasteurella multocida

Anaerobic microorganisms

Clostridium perfringens

Fusobacterium spp.

Prevotella spp.

Porphyromonas spp.

Other microorganisms

Chlamydia trachomatis

Organisms for which acquired resistance may be a problem

Aerobic gram-positive microorganisms

Streptococcus pneumoniae Penicillin-intermediate Penicillin-resistant

Naturally resistant organisms

Aerobic gram-positive microorganisms

Enterococcus faecalis

Staphylococci MRSA, MRSE*

Anaerobic microorganisms

Bacteroides fragilis group

*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.

Absorption.

The bioavailability after oral administration is approximately 37%. Maximum serum concentration is reached within 2–3 hours after administration. The Cmax after a single 500 mg dose is 0.4 µg/mL.

Distribution.

After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that tissue concentrations of azithromycin are significantly higher (up to 50-fold) than plasma concentrations, indicating extensive tissue binding (the apparent volume of distribution at steady state, Vss, is 31.1 L/kg). With recommended dosing regimens, no accumulation of the drug occurs in plasma/serum. According to study data, three days after a single 500 mg dose of azithromycin, the following tissue concentrations were observed: in lung tissue – 1.3–4.8 µg/g, in prostate – 0.6–2.3 µg/g, in tonsils – 2.0–2.8 µg/g, and in blood plasma – 0–0.3 µg/mL. The concentrations observed in lung, prostate, and tonsil tissues exceed the MIC90 values for the most common pathogens following a single 500 mg dose of azithromycin.

In vitro and in vivo experimental studies have demonstrated accumulation of azithromycin in macrophages, followed by its release upon phagocytic activation. Animal studies have also shown that this process contributes to the accumulation of azithromycin in organ tissues.

Protein binding in serum varies depending on plasma concentrations, ranging from 18% at 0.5 µg/mL to 52% at 0.05 µg/mL in serum.

Metabolism and Excretion.

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 (the majority within the first 24 hours). Particularly high concentrations of unchanged azithromycin have been detected in human bile two days after a 5-day treatment course (up to 237 µg/mL). 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 liquid chromatography and microbiological assay results has shown that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• infections of the upper respiratory tract, paranasal sinuses, and middle ear (bacterial pharyngitis, tonsillitis, sinusitis, otitis media);
• infections of the lower respiratory tract (bacterial bronchitis, community-acquired pneumonia);
• skin and soft tissue infections (erythema migrans (Stage I Lyme disease), scabies, impetigo, and secondary pyoderma);
• sexually transmitted infections (uncomplicated genital infections caused by Chlamydia trachomatis).

According to preclinical data, azithromycin is effective against many sexually transmitted infections.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, macrolide/ketolide antibiotics, or to any of the excipients of the drug.

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

Interaction with other medicinal products and other types of interactions.

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

Antacids.

In a pharmacokinetic interaction study, no effect on overall bioavailability was observed when antacids were administered concomitantly with azithromycin, although peak serum concentrations were reduced by approximately 24%. Patients receiving both azithromycin and antacids should not take these drugs 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. Azithromycin should be used cautiously in patients receiving other drugs that may prolong the QT interval.

Didanosine.

When azithromycin 1200 mg/day was administered concomitantly with didanosine 400 mg/day, no effect on the pharmacokinetics of didanosine was observed compared to placebo.

Digoxin and colchicine (P-glycoprotein substrates).

Concomitant administration 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 co-administered with a P-glycoprotein substrate such as digoxin, the possibility of increased substrate concentration in serum should be considered. Clinical monitoring and, possibly, measurement of serum digoxin levels during and after azithromycin treatment are required.

Zidovudine.

Single doses of 1000 mg and 1200 mg or multiple doses of 600 mg of azithromycin had minimal effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide 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 fully understood, but may be beneficial for patients.

Ergot derivatives.

Concomitant administration of azithromycin with ergot derivatives is not recommended due to the potential risk of ergotism.

Interactions related to the cytochrome system.

Azithromycin has no significant interaction with the hepatic cytochrome P450 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 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). However, cases of rhabdomyolysis have been reported in the post-marketing period in patients receiving 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, a single dose of cimetidine administered 2 hours prior to azithromycin did not result in any changes in azithromycin pharmacokinetics.

Oral anticoagulants of the coumarin type.

In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. However, post-marketing reports have described potentiation of the anticoagulant effect when azithromycin was co-administered with oral anticoagulants of the coumarin type. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine.

In a pharmacokinetic study involving healthy volunteers who received azithromycin 500 mg/day orally for 3 days followed by a single oral dose of 10 mg/kg cyclosporine, Cmax and AUC0-5 of cyclosporine were significantly increased (by 24% and 21%, respectively), although no significant changes in AUC0-∞ were observed. Therefore, caution should be exercised when considering concomitant administration of these drugs. If co-administration is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

Efavirenz.

Concomitant administration of a single 600 mg dose of azithromycin and efavirenz 400 mg 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. The overall exposure and elimination half-life of azithromycin were not altered by concomitant fluconazole administration, although a clinically insignificant reduction in Cmax (18%) of azithromycin was observed.

Indinavir.

Concomitant administration of a single 1200 mg dose of azithromycin did not have a statistically significant effect on the pharmacokinetics of indinavir administered at 800 mg three times daily for 5 days.

Methylprednisolone.

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

Midazolam.

In healthy volunteers, concomitant administration of azithromycin 500 mg/day for 3 days did not result in clinically significant changes in the pharmacokinetics or 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) resulted 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 an effect of azithromycin (500 mg/day for 3 days) on the AUC or Cmax of sildenafil or its primary circulating metabolite.

Terfenadine.

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

Theophylline.

There are no data on clinically significant pharmacokinetic interactions between azithromycin and theophylline when administered concomitantly.

Triazolam.

Concomitant administration of azithromycin 500 mg on the first day and 250 mg on the second day with 0.125 mg triazolam did not significantly affect any pharmacokinetic parameters of triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole.

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

Hydroxychloroquine or chloroquine.

Observational data have shown that concomitant use of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. The benefit-risk balance should be carefully considered before prescribing azithromycin to any patient receiving hydroxychloroquine. Similarly, the benefit-risk balance should be carefully evaluated before prescribing azithromycin to any patient receiving chloroquine due to a similar potential risk.

Other antibiotics.

Potential cross-resistance between azithromycin and other macrolide antibiotics (e.g., erythromycin), as well as with lincomycin and clindamycin, should be considered when these drugs are used concomitantly. Concomitant use of multiple agents from this class is not recommended.

Special precautions for use.

Allergic reactions.

As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioedema and anaphylaxis (in isolated cases – with fatal outcome), 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 syndrome). Some of these reactions caused by azithromycin have been associated with recurrent symptoms and required prolonged observation and treatment.

In case of an allergic reaction, the drug should be discontinued and appropriate therapy initiated. Physicians should be aware that recurrent symptoms of allergy may occur after discontinuation of symptomatic treatment.

Hepatic function impairment.

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, potentially leading to life-threatening liver failure, have been reported with azithromycin use. Some patients may have had pre-existing liver disease or concomitant use of other hepatotoxic drugs.

Liver function tests should be performed promptly in case of signs or symptoms of liver dysfunction, such as rapidly developing fatigue accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy. If liver function abnormalities are detected, azithromycin should be discontinued.

Ergot derivatives.

In patients taking ergot derivatives, concomitant administration of certain macrolide antibiotics may lead 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 administered concomitantly with ergot derivatives.

Superinfections.

As with other antibiotics, monitoring for signs of superinfection caused by non-susceptible organisms, including fungi, is recommended.

Cross-resistance.

Due to existing cross-resistance between erythromycin-resistant Gram-positive strains and most strains of methicillin-resistant staphylococci, the use of azithromycin is not recommended.

Local epidemiology and susceptibility patterns should be taken into account.

Severe infection.

Azithromycin is not intended for the treatment of severe infections where rapid attainment of high antibiotic concentrations in the blood is required.

Clostridium difficile.

C. 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. 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 may occur up to two months after antibiotic administration. Discontinuation of azithromycin therapy and initiation of specific C. difficile treatment should be considered.

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. Azithromycin should be used with caution in patients with severe renal impairment.

Prolongation of cardiac repolarization and QT interval, which increases the risk of cardiac arrhythmias and ventricular tachycardia (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 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 disturbances, particularly hypokalemia and hypomagnesemia;
• with clinically relevant bradycardia, cardiac arrhythmias, or severe heart failure.

Myasthenia gravis.

Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.

Long-term use.

There is no experience regarding the safety and efficacy of long-term use of azithromycin for the indications listed above. In cases of rapidly recurring infections, treatment with alternative antibiotics should be considered.

Neurological and psychiatric disorders.

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

Hearing impairment.

Hearing damage has been reported with macrolide antibiotics. Cases of hearing loss, deafness, and tinnitus have been reported in some patients receiving azithromycin. Many of these cases occurred in experimental studies where azithromycin was administered at high doses over prolonged periods. However, according to available post-marketing reports, most of these events were reversible.

Streptococcal infections.

For the 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. Azithromycin is generally effective in treating streptococcal infection of the oropharynx; however, there are no data demonstrating the efficacy of azithromycin in preventing rheumatic fever.

Hydroxychloroquine or chloroquine.

The benefit-risk balance should be carefully considered before prescribing azithromycin to any patient taking hydroxychloroquine or chloroquine due to the potential increased risk of cardiovascular events and cardiovascular mortality (see section "Special precautions for use").

An antimicrobial agent with anaerobic activity should be used in combination with azithromycin if anaerobic microorganisms are suspected to be involved in the infection.

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

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

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

Breastfeeding period.

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. Because it is unknown whether azithromycin may have harmful effects on the nursing infant, breastfeeding should be discontinued during azithromycin therapy. Potential complications in the infant include diarrhea, fungal mucosal infections, and hypersensitivity due to exposure to azithromycin in breast milk. It is recommended to discontinue breastfeeding during treatment with the drug and for 2 days after discontinuation of therapy. Breastfeeding may be resumed thereafter.

Fertility.

Fertility studies have been conducted in animals; a decreased pregnancy rate was observed 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, and seizures should be taken into account.

Method of Administration and Dosage

The ZOKSI medication should be taken once daily at the prescribed dose, regardless of food intake. Tablets should be swallowed whole, without chewing, with half a glass of water. If a dose is missed, it should be taken as soon as possible, and subsequent doses administered at 24-hour intervals.

Adults and children with body weight ≥45 kg.

The total treatment dose is usually 1500 mg, administered as 500 mg once daily for 3 days. An alternative regimen is a 5-day course: 500 mg on day 1 and 250 mg daily from day 2 to day 5.

For the treatment of uncomplicated urethritis or cervicitis caused by Chlamydia trachomatis, a single dose of 1000 mg is recommended.

For gonorrhea treatment, the recommended total dose is 1000 mg or 2000 mg, administered in combination with 250 mg or 500 mg of ceftriaxone, respectively, according to current clinical guidelines.

Alternative treatment regimens should be prescribed for patients with allergies to cephalosporins or penicillins.

Elderly patients.

Dosage adjustment is not required in elderly patients.

Patients with renal impairment.

For patients with mild to moderate 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). In patients with severe renal dysfunction (glomerular filtration rate <10 mL/min), a 33% increase in systemic exposure to azithromycin has been observed.

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. Studies on azithromycin use in such patients have not been conducted.

Children.

The medication is not recommended for children with body weight below 45 kg.

Overdose.

Clinical experience with azithromycin indicates that adverse effects observed following overdose are similar to those seen with standard therapeutic doses and may include diarrhea, nausea, vomiting, and reversible hearing loss. In case of overdose, administration of activated charcoal and general symptomatic and supportive measures are recommended, if necessary.

Adverse Reactions

The adverse reactions listed below were identified from clinical trials and post-marketing surveillance for all dosage forms of azithromycin, classified by system organ class and frequency. Frequency groups were defined using the following scale: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated based on available data). Within each frequency group, adverse events are listed in order of decreasing severity.

The listed adverse reactions are considered possibly or probably related to azithromycin based on data from clinical trials and post-marketing experience.

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

Blood and lymphatic system disorders: uncommon – leukopenia, neutropenia, eosinophilia; frequency not known – thrombocytopenia, hemolytic anemia.

Immune system disorders: uncommon – angioedema, hypersensitivity reactions; very rare – anaphylactic shock.

Metabolism and nutrition disorders: common – anorexia (loss of appetite).

Psychiatric disorders: uncommon – nervousness, insomnia; rare – agitation; very rare – aggression, restlessness, delirium, hallucinations.

Nervous system disorders: common – headache; uncommon – dizziness, somnolence, paraesthesia, dysgeusia; frequency not known – loss of consciousness, convulsions, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis, hypoaesthesia.

Eye disorders: common – visual disturbances.

Ear and labyrinth disorders: uncommon – hearing disturbance, vertigo; very rare – hearing impairment, including deafness and/or tinnitus.

Cardiac disorders: uncommon – palpitations; very rare – ventricular fibrillation (torsade de pointes), arrhythmia including ventricular tachycardia, QT interval prolongation on ECG.

Vascular disorders: uncommon – flushing; very rare – hypotension.

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

Gastrointestinal disorders: very common – diarrhoea, abdominal cramps, flatulence, nausea; common – vomiting, dyspepsia; uncommon – gastritis, constipation, dysphagia, abdominal distension, dry mouth, belching, mouth ulcers, hypersalivation; very rare – pancreatitis, tongue discoloration.

Hepatobiliary disorders: rare – hepatic function abnormalities, cholestatic jaundice; very rare – liver failure (rarely leading to fatal outcome), fulminant hepatitis, necrotic hepatitis.

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

Musculoskeletal and connective tissue disorders: uncommon – osteoarthritis, myalgia, back pain, neck pain; not known – arthralgia.

Renal and urinary disorders: uncommon – dysuria, renal pain; not known – acute renal failure, interstitial nephritis.

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

General disorders and administration site conditions: uncommon – fatigue; chest pain, swelling, malaise, asthenia, facial swelling, hyperthermia, pain, peripheral oedema.

Investigations: common – decreased white blood cell count, increased eosinophil count, decreased blood bicarbonate level, increased basophil, monocyte, and neutrophil counts; uncommon – increased levels of AST, ALT, alkaline phosphatase, bilirubin, urea, creatinine in blood, electrolyte abnormalities, increased glucose level, increased platelet count, decreased haematocrit, increased bicarbonate level, abnormal sodium levels.

Injury, poisoning and procedural complications: uncommon – procedural complications.

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

Metabolism and nutrition disorders: common: anorexia.

Nervous system disorders: common: dizziness, headache, paraesthesia, dysgeusia; rare: hypoaesthesia.

Eye disorders: common: visual impairment.

Ear and labyrinth disorders: common: deafness; rare: hearing impairment, tinnitus.

Cardiac disorders: rare: tachycardia.

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

Hepatobiliary disorders: rare: hepatitis.

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

Musculoskeletal and connective tissue disorders: common: arthralgia.

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

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 250 mg dosage – 3 years; 500 mg dosage – 3.5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

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

3 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Evertogen Life Sciences Limited.

Manufacturer's address and location of its operations.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.