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

Composition:

Active substance: azithromycin;

1 capsule contains azithromycin (as dihydrate) 250 mg;

Excipients: anhydrous lactose, maize starch, sodium lauryl sulfate, magnesium stearate;

Capsule shell contains:

Body: gelatin, titanium dioxide (E 171);

Cap: gelatin, titanium dioxide (E 171), indigo carmine (E 132);

Cap marking: blue ink.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules No. 1 with white-colored body, blue-colored cap, and dark blue marking.

The capsule contents – white or almost white powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATC code J01FA10.

Pharmacological Properties

Pharmacodynamics

Azithromycin is a representative of a new generation of macrolide antibiotics and belongs to the azalide subgroup. The antibacterial action of the drug is due to inhibition of protein biosynthesis in susceptible microorganisms by binding to the 50S ribosomal subunits and suppression of peptide translocation. The drug is active against the following microorganisms: Streptococcus pneumoniae (penicillin-sensitive), Streptococcus pyogenes, Staphylococcus aureus (methicillin-sensitive), H. influenzae, H. parainfluenzae, M. catarrhalis, Pasteurella multocida, Clostridium perfringens, Legionella pneumophila, Fusobacterium spp., Prevotella spp., Porphyromonas spp., Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma pneumoniae.

Microorganism species for which acquired resistance may be problematic: Streptococcus pneumoniae with intermediate sensitivity to penicillin and penicillin-resistant strains. Resistant organisms: complete cross-resistance exists in Streptococcus pneumoniae, group A beta-hemolytic streptococci, Enterococcus faecalis, the Bacteroides fragilis group, MRSA and MRSE (methicillin-resistant staphylococci exhibit very high prevalence of acquired resistance to macrolides; sensitivity to azithromycin in such strains is rare).

The prevalence of acquired resistance among specific microorganisms may vary depending on geographical location and time; therefore, local resistance data are essential, especially when treating severe infections. Expert advice should be sought if local resistance patterns suggest that the efficacy of the drug may be questionable for at least some types of infections.

Pharmacokinetics

After oral administration, azithromycin is well absorbed and rapidly distributed throughout the body. Maximum plasma concentration is reached approximately within 2–3 hours. The bioavailability of azithromycin is approximately 37%. Following oral intake, azithromycin is widely distributed throughout the body. Tissue concentrations of azithromycin are significantly higher (up to 50 times) than plasma concentrations, indicating strong tissue binding of the drug. Protein binding to plasma proteins is variable depending on plasma concentrations, ranging from 12% at 0.5 µg/mL to 52% at 0.05 µg/mL. The terminal plasma half-life fully reflects the elimination half-life from tissues, lasting 2–4 days. Approximately 12% of an intravenously administered dose of azithromycin is excreted unchanged in urine over the next 3 days. Particularly high concentrations of unchanged azithromycin are found in human bile. Ten metabolites are also detected in bile, formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

Ear, nose, and throat (ENT) 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;
Sexually transmitted infections: uncomplicated and complicated urethritis/cervicitis caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, or to any macrolide or ketolide antibiotic, or to any other component of the drug. Due to the theoretical possibility of ergotism, azithromycin should not be co-administered 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. In studies evaluating the effect of concomitant antacid administration on azithromycin pharmacokinetics, no overall changes in bioavailability were observed, although plasma peak concentrations of azithromycin decreased by 25%. Azithromycin should be taken at least 1 hour before or 2 hours after antacid administration.

Cetirizine. Concomitant administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not result in any pharmacokinetic interaction or significant changes in QT interval.

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

Digoxin. It has been reported that 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. Therefore, when azithromycin is co-administered with digoxin, the possibility of increased digoxin serum concentrations should be considered.

Zidovudine. Single doses of 1000 mg and 1200 mg or multiple doses of 600 mg of azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, azithromycin 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.

Ergot derivatives. Due to the theoretical risk of ergotism, concomitant use of azithromycin with ergot derivatives is not recommended.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is considered not to have the pharmacokinetic interactions commonly observed with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via the cytochrome-metabolite complex.

Data are available from pharmacokinetic studies of original azithromycin co-administered 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 receiving azithromycin with statins.

Carbamazepine. Azithromycin did not significantly affect plasma levels of carbamazepine or its active metabolites.

Cimetidine. No changes in azithromycin pharmacokinetics were observed when cimetidine was administered 2 hours prior to azithromycin.

Oral anticoagulants of the coumarin group. Increased tendency to bleeding has been reported with concomitant use of azithromycin and warfarin or coumarin-like oral anticoagulants. Close monitoring of prothrombin time and international normalized ratio (INR) is required.

Cyclosporine. In a pharmacokinetic study involving healthy volunteers who received oral azithromycin 500 mg/day for 3 days followed by a single oral dose of cyclosporine 10 mg/kg, a significant increase in Cmax and AUC0-5 of cyclosporine was demonstrated. Some related macrolide antibiotics affect cyclosporine metabolism. The therapeutic situation should be carefully evaluated before prescribing concomitant use of these drugs. If combination therapy is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are necessary.

Efavirenz. Concomitant administration of a single 600 mg dose of azithromycin with daily 400 mg efavirenz for 7 days did not result in any significant 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. Overall exposure and elimination half-life of azithromycin were not changed with concomitant fluconazole, although an 18% clinically insignificant decrease in azithromycin Cmax 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. Azithromycin did not significantly affect the pharmacokinetics of methylprednisolone.

Midazolam. Concomitant administration of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics or pharmacodynamics 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 necessary.

Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect plasma concentrations of either drug. Neutropenia has been observed in patients receiving both azithromycin and rifabutin. Although neutropenia is associated with rifabutin use, a causal relationship with concomitant azithromycin administration has not been established.

Sildenafil. There is no evidence that administration of azithromycin 500 mg daily for 3 days affects AUC or Cmax values of sildenafil or its main metabolite in males.

Terfenadine. No interaction between azithromycin and terfenadine has been reported. However, as with other macrolide antibiotics, azithromycin should be administered with caution when combined with terfenadine.

Theophylline. Azithromycin did not affect the pharmacokinetics of theophylline when administered concomitantly.

Triazolam. Concomitant administration 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.

Trimethoprim/sulfamethoxazole. Concomitant administration of trimethoprim/sulfamethoxazole 160/800 mg for 7 days and azithromycin 1200 mg on day 7 showed no significant effect on peak concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin concentrations were also unchanged.

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 resulting in death), as well as dermatological reactions, including acute generalized exanthematous pustulosis. Some of these reactions were recurrent in nature and required prolonged observation and treatment.

Hepatic function impairment. Since the liver is the primary route of elimination for azithromycin, caution should be exercised when prescribing azithromycin to patients with severe hepatic disease. Cases of fulminant hepatitis associated with azithromycin, leading to life-threatening liver dysfunction, have been reported. 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. If hepatic dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives. In patients receiving ergot derivatives, concomitant administration of certain macrolide antibiotics has led to rapid development of ergotism. There are no data available on the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be co-administered with ergot derivatives.

Superinfections. As with other antibacterial agents, monitoring for signs of superinfection caused by resistant organisms, including fungi, is recommended. Clostridium difficile-associated diarrhea (CDAD), with severity ranging from mild diarrhea to fatal colitis, has been reported with nearly all antibacterial agents, including azithromycin. Antibacterial therapy alters the normal gut flora, leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to CDAD development. Hyperproducing toxin strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and require colectomy. CDAD should be considered in all patients presenting with diarrhea following antibiotic use. Careful medical history is essential, as CDAD has been reported to occur up to two months after antibiotic administration.

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 arrhythmias, including ventricular fibrillation (torsades de pointes), has been observed with other macrolide antibiotics. A similar effect of azithromycin cannot be entirely ruled out in patients at increased risk of prolonged cardiac repolarization; therefore, caution is advised when prescribing azithromycin to patients:

with congenital or documented QT interval prolongation;
currently taking other medicinal products that prolong the QT interval, such as class IA (quinidine, procainamide) and class III (amiodarone, sotalol, dofetilide) 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. Worsening of symptoms of myasthenia gravis or new-onset myasthenic syndrome has been reported in patients receiving azithromycin.

Streptococcal infections. Azithromycin is generally effective in the treatment of oropharyngeal streptococcal infections; however, there are no data demonstrating efficacy in preventing rheumatic fever. An antimicrobial agent with anti-anaerobic activity should be used in combination with azithromycin if anaerobic microorganisms are suspected to contribute to the infection.

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

The product contains lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy. Azithromycin crosses the placenta. However, no evidence of toxic effects on the fetus was observed in animal studies with the original azithromycin formulation. Nevertheless, adequate and well-controlled studies in pregnant women have not been conducted. Since animal reproductive studies do not always predict effects in humans, azithromycin should be used during pregnancy only if clearly needed.

Breastfeeding. Azithromycin is excreted in breast milk, but appropriate and controlled pharmacokinetic studies on excretion are lacking. Azithromycin may be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility. Animal studies in rats have shown a reduced pregnancy rate following azithromycin administration. The relevance of these findings to humans is unknown.

Ability to affect reaction speed when driving or operating machinery.

There are no data indicating that azithromycin impairs the ability to drive or operate machinery. However, the possibility of adverse reactions such as dizziness, somnolence, and visual disturbances should be considered.

Method of Administration and Dosage

The capsules should be taken orally once daily, 1 hour before or 2 hours after eating, with a small amount of liquid. If a dose is missed, it should be taken as soon as possible, and the next dose should be taken 24 hours after the previous one.

Adults and children with body weight over 45 kg.

For respiratory tract, ENT, skin and soft tissue infections (except chronic migrating erythema), azithromycin should be administered at 500 mg (2 capsules) once daily for 3 days. The total therapeutic dose is 1500 mg.

For sexually transmitted infections, patients should receive a single dose of 1 g (4 capsules).

For migratory erythema: once daily for 5 days; on day 1 – 1 g (4 capsules of 250 mg), then 500 mg (2 capsules) from day 2 to day 5.

For elderly patients, there is no need to adjust the dosage. However, since elderly patients may be at increased risk for disturbances in cardiac conduction, caution is recommended when using azithromycin due to the risk of developing cardiac arrhythmias, including torsades de pointes.

Patients with renal impairment. In patients with mild renal dysfunction (glomerular filtration rate 10–80 mL/min), dosage adjustment is not required. Azithromycin should be used 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. There are no data available on treatment of such patients.

Children. Azithromycin in capsule form can be prescribed to children with body weight over 45 kg.

Overdose.

Symptoms.

In cases of azithromycin overdose, pronounced nausea, vomiting, diarrhea, abdominal pain, and reversible hearing loss may occur.

Treatment.

Administration of activated charcoal and implementation of general symptomatic and supportive measures.

Side effects.

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

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

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

Metabolism and nutrition disorders: anorexia.

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

Nervous system disorders: headache, dizziness, somnolence, paresthesia, dysgeusia, loss of consciousness, seizures, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis, hypesthesia.

Eye disorders: visual disturbances, blurred vision.

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

Cardiac disorders: palpitations, ventricular fibrillation (torsades de pointes), arrhythmia including ventricular tachycardia, QT interval prolongation on ECG.

Vascular disorders: flushing, hypotension.

Respiratory system disorders: dyspnea, epistaxis.

Gastrointestinal disorders: diarrhea, abdominal distension, frequent loose stools, vomiting, abdominal pain, nausea, gastritis, constipation, flatulence, gastrointestinal discomfort, dyspepsia, dysphagia, dry mouth, belching, oral ulcers, hypersalivation, pancreatitis, change in tongue color.

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

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

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

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

Reproductive system 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 white blood cell count, increased eosinophil count, decreased blood bicarbonate level, increased basophil count, increased monocyte count, increased neutrophil count, increased aspartate aminotransferase (AST) level, increased alanine aminotransferase (ALT) level, increased blood bilirubin level, increased blood urea level, increased blood creatinine level, changes in blood potassium levels, increased alkaline phosphatase level, increased chloride level, increased glucose level, increased platelet count, decreased hematocrit level, increased bicarbonate level, deviations in sodium levels.

Injury and poisoning: procedural complications.

Shelf life.

3 years. Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

6 capsules in a white plastic container sealed with a plastic cap with a tamper-evident seal, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Ukrainian-Spanish joint venture "Sperco Ukraine".

Manufacturer's address and place of business.

25, 600-Richchia Street, Vinnytsia, Ukraine, 21027.

Tel. + 38 (0432) 52-30-36.

E-mail: [email protected].

Ormax