ORMAX

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

Composition:

Active ingredient: azithromycin;

200 mg of azithromycin (as dihydrate) in 5 ml of suspension;

Excipients: sodium benzoate (E 211), sucrose or sucrose with anhydrous colloidal silicon dioxide, sodium phosphate, hydroxypropyl cellulose, xanthan gum, anhydrous colloidal silicon dioxide, apricot fruit flavor. Does not contain dyes.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white or almost white powder with a characteristic fruity odor.

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

The prevalence of acquired resistance among specific microorganisms may vary depending on geographical location and time; therefore, local information on resistance patterns is required, especially when treating severe infections. Expert advice should be sought if local resistance prevalence renders the drug's efficacy 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 serum proteins varies 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 tissue elimination half-life, which lasts 2–4 days. Approximately 12% of an intravenously administered dose of azithromycin is excreted unchanged in urine within the subsequent 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:

• Otorhinolaryngological infections (bacterial pharyngitis/tonsillitis, sinusitis, otitis media);
• Respiratory tract infections (bacterial bronchitis, community-acquired pneumonia);
• Skin and soft tissue infections: erythema migrans (early stage of Lyme disease), impetigo, secondary pyoderma.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, or to any macrolide or ketolide antibiotic, or to any component of the drug. 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 cautiously in patients receiving other drugs that may prolong the QT interval.

Antacids. In studies evaluating the effect of concomitant antacid administration on the pharmacokinetics of azithromycin, no overall changes in bioavailability were observed, although plasma peak concentrations of azithromycin decreased by 25%. Azithromycin should be taken at least 1 hour before or 2 hours after antacids.

Cetirizine. No pharmacokinetic interaction or significant changes in QT interval were observed when azithromycin was administered for 5 days concomitantly with cetirizine 20 mg at steady state.

Didanosine. No effect on the pharmacokinetics of didanosine was observed when daily doses of azithromycin 1200 mg were coadministered with didanosine, compared to placebo.

Digoxin and colchicine. Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, has been reported to increase serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is administered concomitantly with a P-glycoprotein substrate such as digoxin or colchicine, potential increases in serum substrate 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 not fully understood, but may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is considered that the drug does not exhibit the pharmacokinetic drug interactions typical of erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via the cytochrome-metabolite complex.

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

Pharmacokinetic studies have been conducted with original azithromycin and 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 showed no significant effect on 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. 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 administered concomitantly with oral coumarin-type anticoagulants. Although a causal relationship has not been established, careful monitoring of prothrombin time and international normalized ratio (INR) is recommended when azithromycin is prescribed to patients receiving coumarin-type oral anticoagulants.

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 administration of these drugs. If combination therapy is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are required.

Efavirenz. Concomitant administration of a single 600 mg dose of azithromycin with daily 400 mg doses of 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. Total exposure and elimination half-life of azithromycin were unchanged when coadministered with fluconazole, although a clinically insignificant 18% decrease in Cmax of azithromycin was observed.

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

Methylprednisolone. Azithromycin showed no significant effect on 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 administered as a single 15 mg dose.

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

Rifabutin: concomitant administration of azithromycin and rifabutin did not affect plasma 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. There is no evidence of an effect of azithromycin 500 mg daily for 3 days on AUC or Cmax values of sildenafil or its main metabolite in male subjects.

Terfenadine: no interaction between azithromycin and terfenadine has been reported. However, as with other macrolide antibiotics, azithromycin should be used with caution in combination 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 0.125 mg triazolam 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.

Allergic reactions. As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioedema 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 have been reported, leading to life-threatening liver dysfunction. Some of these patients may have had pre-existing liver disease or concomitant use of other hepatotoxic drugs. Liver function tests should be performed if signs or symptoms of liver dysfunction develop, such as rapidly progressing fatigue accompanied by jaundice, darkening of urine, tendency to bleed, or hepatic encephalopathy. If liver dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives. In patients receiving ergot derivatives, concomitant use of certain macrolide antibiotics has been associated with rapid onset of ergotism. There are no data on the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical risk of ergotism, azithromycin should not be co-administered with ergot derivatives.

Superinfections. As with other antibacterial agents, monitoring for signs of superinfection caused by resistant organisms, including fungi, is recommended. With nearly all antibacterial agents, including azithromycin, Clostridium difficile-associated diarrhea (CDAD) has been reported, with severity ranging from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal gut flora, leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. Strains of C. difficile that hyperproduce toxins are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients 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, which increases the risk of cardiac arrhythmias, including torsades de pointes, has been observed 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 azithromycin to patients:

• with congenital or documented acquired QT prolongation;
• currently taking other drugs 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, or 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. For 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. 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 prophylaxis or treatment of Mycobacterium avium complex in children have not been established.

Sucrose. 5 mL of suspension contains 2.6 g of sucrose, which may be harmful to teeth and should be considered in patients with diabetes mellitus. This medicinal product should not be used in patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Azithromycin as a powder for oral suspension contains 7.65 mg of sodium per dose (one dose contains 5 mL of suspension). Caution should be exercised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Azithromycin crosses the placenta, but no evidence of fetal toxicity was observed in animal studies with the original azithromycin formulation. However, adequate and well-controlled studies in pregnant women are lacking. Since animal reproductive studies do not always predict human response, azithromycin should be used during pregnancy only if clearly needed.

Breastfeeding. Azithromycin is excreted in human milk, but there are no adequate and well-controlled studies on the pharmacokinetics of excretion. 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 influence 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 delirium, hallucinations, dizziness, somnolence, loss of consciousness, seizures, and visual disturbances, which may affect the ability to drive or operate machinery, should be considered.

Method of administration and dosage.

To prepare the suspension, invert the container so that the powder separates from the bottom, then add boiled water at room temperature using the dosing syringe according to the following ratio:

After adding water, close the vial and shake thoroughly until a homogeneous suspension is formed. After this, the date of suspension preparation must be indicated in the designated space on the label. Store the prepared suspension in the refrigerator. Before each administration, the suspension should be shaken well. The suspension should be taken orally once daily, 1 hour before or 2 hours after a meal. Immediately after administration, the child should be given several sips of liquid to rinse and swallow any residual suspension remaining in the oral cavity.

If a dose is missed, it should be taken as soon as possible, and the next dose should be taken 24 hours later.

Use in adults.

For infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema), Ormax should be administered at a dose of 500 mg (12.5 ml) once daily for 3 days.

For migrating erythema (Lyme disease), Ormax should be administered once daily for 5 days: 1000 mg (25 ml) on the first day, followed by 500 mg (12.5 ml) from the second to the fifth day (total treatment duration is 5 days).

Use in children.

For infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema), Ormax should be administered at a dose of 10 mg/kg body weight once daily for 3 days.

Depending on the child's body weight, the following dosing schedule is recommended:

In migratory erythema (Lyme disease), Ormax should be administered once daily for 5 days: on the first day at a dose of 20 mg/kg body weight, followed by 10 mg/kg body weight from day 2 to day 5 (total treatment duration is 5 days).

Clinical studies of original azithromycin have shown it to be effective in the treatment of streptococcal pharyngitis in children at doses of 10 mg/kg and 20 mg/kg once daily for 3 days. Similar clinical efficacy has been observed with both dosing regimens, although bacteriological efficacy (eradication) was significantly higher with the 20 mg/kg daily dose. However, penicillin is generally the drug of choice for the prophylaxis of pharyngitis caused by Streptococcus pyogenes and for preventing rheumatic fever as a secondary complication.

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

Patients with 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 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. Ormax oral suspension 200 mg/5 mL should be administered to children with body weight of 15 kg and above. Ormax oral suspension 100 mg/5 mL should be used in children with body weight below 15 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.

Adverse reactions.

The adverse reactions listed in the table below are classified by system organ class and frequency of occurrence, as identified in clinical studies and during the post-marketing surveillance period, and observed during the use of all azithromycin dosage forms. Adverse reactions reported during the post-marketing period are indicated in italics. Frequency groups were defined according to the following scale: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Adverse reactions possibly or probably related to azithromycin, based on data obtained from clinical studies and post-marketing surveillance

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

Adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex

Shelf life.

2 years. The shelf life of the prepared suspension is no more than 5 days.

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 reach of children. The prepared suspension should be stored for no more than 5 days at a temperature between 2 °C and 8 °C.

Packaging.

11.74 g of powder (for 20 ml (800 mg) of suspension) or 17.6 g of powder (for 30 ml (1200 mg) of suspension) in a container closed with a tamper-evident child-resistant cap, with a dosing spoon and a dosing syringe, in a cardboard box.

Prescription status.

By prescription only.

Manufacturer.

Ukrainian-Spanish joint venture "Sperco Ukraine".

Manufacturer's address and place of business.

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

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

E-mail: [email protected]

www.sperco.ua