Azipol

I N S T R U C T I O N for medical use of the medicinal product AZIPOL (AZIPOL)

Composition:

Active substance: azithromycin in the form of azithromycin dihydrate;

1 tablet contains azithromycin 250 mg or 500 mg in the form of azithromycin dihydrate;

Excipients: microcrystalline cellulose (101), microcrystalline cellulose (102), povidone (90), sodium croscarmellose, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate. Coating: polyethylene glycol (8000), hydroxypropylcellulose, hypromellose (E 5), hypromellose (E 15), Opaspray K-1R-4210A, indigotine (E 132).

Medicinal form. Film-coated tablets.

Main physicochemical properties: 250 mg tablets: blue, round, film-coated, biconvex tablets with a homogeneous surface;

500 mg tablets: blue, round, film-coated, biconvex tablets with a homogeneous surface.

Pharmacotherapeutic group. Antibiotics for systemic use. Macrolides.

ATC code J01FA10.

Pharmacological Properties.

Pharmacodynamics.

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by the insertion of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis through binding to the 50S ribosomal subunit and suppression of peptide translocation.

Mechanism of resistance

Complete cross-resistance exists among Streptococcus pneumoniae, beta-hemolytic group A streptococci, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

The prevalence of acquired resistance may vary depending on geographic location and time for specific bacterial species; therefore, local resistance data are essential, especially when treating severe infections. Expert advice should be sought when local resistance patterns are such that the efficacy of the drug in treating at least some types of infections is questionable.

Antimicrobial spectrum of azithromycin

* Methicillin-resistant Staphylococcus aureus exhibits very high prevalence of acquired resistance to macrolides and is listed here due to rare susceptibility to azithromycin.

Based on studies conducted in children, the use of azithromycin for the treatment of malaria is not recommended either as monotherapy or in combination with chloroquine-based or artemisinin-based drugs, since no superior efficacy has been demonstrated compared to antimalarial agents recommended for the treatment of uncomplicated malaria.

Pharmacokinetics.

Bioavailability after oral administration is approximately 37%. Maximum serum concentration (C_max) is reached within 2–3 hours after dosing.

Following oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that tissue concentrations of azithromycin are significantly higher (up to 50 times) than plasma concentrations, indicating extensive tissue binding of the drug.

Protein binding in serum varies depending on plasma concentrations, ranging from 12% at 0.5 mcg/mL to 52% at 0.05 mcg/mL in serum. The apparent volume of distribution at steady state (V_ss) is 31.1 L/kg.

The terminal plasma 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 next 3 days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Ten metabolites formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate have also been detected in bile. Comparison of liquid chromatography results with microbiological assays has shown that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• 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, vulgaris acne (common acne) of moderate severity;
• sexually transmitted infections: uncomplicated genital infections caused by

Chlamydia trachomatis.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, or to any macrolide or ketolide antibiotic, or to any other component of the drug.

Interaction with other medicinal products and other forms of interaction.

Antacids

When studying the effect of concomitant antacid administration on the pharmacokinetics of azithromycin, no changes in bioavailability were generally observed, although the peak plasma concentration of azithromycin decreased by approximately 25%. Azithromycin and antacids should not be taken simultaneously.

Cetirizine

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

Didanosine

In six HIV-positive volunteers, co-administration of daily doses of 1200 mg azithromycin with 400 mg didanosine per day showed no effect on the steady-state pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine

It has been reported that concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin and colchicine may lead to increased serum levels of P-glycoprotein substrates. Therefore, when azithromycin is used concomitantly with a P-glycoprotein substrate such as digoxin, the possibility of increased substrate concentration in serum should be considered.

Zidovudine

Single doses of 1000 mg and 1200 mg or 600 mg of azithromycin had minimal effect on 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 data is not fully understood, but it may be beneficial for patients.

Azithromycin does not have 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 a 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 on the use of azithromycin 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, during the post-marketing period, cases of rhabdomyolysis have been reported 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 study assessing the effect of a single dose of cimetidine administered 2 hours before azithromycin on azithromycin pharmacokinetics, no changes in azithromycin pharmacokinetics were observed.

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, during the post-marketing period, reports have been received regarding potentiation of the anticoagulant effect after concomitant use of azithromycin and 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 in 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. Therefore, caution should be exercised when these drugs are used concomitantly. If concomitant use of these drugs is necessary, cyclosporine levels should be monitored and dosage adjusted accordingly.

Efavirenz

Concomitant administration of a single 600 mg dose of azithromycin with 400 mg efavirenz 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. Total exposure and elimination half-life of azithromycin were unchanged when fluconazole was co-administered; however, a clinically insignificant reduction in Cmax (18%) of azithromycin was observed.

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 daily for 3 days did not cause clinically significant changes in the pharmacokinetics and 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) 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 the effect of azithromycin

(500 mg daily for 3 days) on AUC and Cmax values of sildenafil or its main circulating metabolite.

Terfenadine

Pharmacokinetic studies did not report any interaction between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be completely ruled out, but there are no specific data confirming such an interaction.

Theophylline

There are no data on clinically significant pharmacokinetic interaction when azithromycin and theophylline are administered concomitantly to healthy volunteers.

Triazolam

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

Trimethoprim/sulfamethoxazole

Concomitant administration of double-strength trimethoprim/sulfamethoxazole

(160 mg/800 mg) for 7 days with 1200 mg azithromycin on day 7 showed no significant effect on Cmax, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

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. Some of these reactions caused by azithromycin have led to recurrent symptoms and required prolonged observation and treatment.

Hepatic function impairment. Since the liver is the main route of elimination of azithromycin, azithromycin should be administered with caution in patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported with azithromycin use. 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, tendency to bleeding, or hepatic encephalopathy.

If hepatic dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives. In patients receiving ergot derivatives, concomitant use 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 co-administered with ergot derivatives.

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

With almost 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 may 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 arrhythmia and ventricular tachyarrhythmia (torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin. Since conditions associated with an increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be used with caution in patients with existing proarrhythmic conditions (particularly women and elderly patients), especially in those:

• with congenital or documented acquired QT prolongation;
• 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 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 oropharyngeal streptococcal infection; however, there are no data on the effectiveness of azithromycin in preventing rheumatic fever. The safety and efficacy of intravenous azithromycin for treatment of infections in children have not been established.

Other.

The safety and efficacy of the use of the medicinal product for prevention or treatment of Mycobacterium avium complex in children have not been established.

Sodium content

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

There are no adequate data on the use of azithromycin in pregnant women. In animal reproductive toxicity studies, azithromycin showed no teratogenic or harmful effects on the fetus; however, the drug crosses the placenta. The safety of azithromycin use during pregnancy has not been established. Therefore, azithromycin should be used during pregnancy only if the potential benefit outweighs the potential risk.

Breastfeeding period

Azithromycin has been shown to pass into human breast milk; however, appropriate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion in human breast milk have not been conducted. Azithromycin may be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility

Fertility studies have been conducted in animals: pregnancy rates decreased after administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to influence reaction speed when driving or operating machinery.

No studies on the effect of azithromycin on the ability to drive or operate machinery have been conducted. The possibility of adverse effects such as delirium, hallucinations, dizziness, somnolence, loss of consciousness, and seizures, which may affect the ability to drive or operate machinery, should be taken into account.

Method of Administration and Dosage

The drug is administered orally 1 hour before or 2 hours after eating, once daily. Tablets should not be divided. If a dose is missed, the missed dose should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals.

Adults and children with body weight above 45 kg

For infections of the ear, nose, throat, respiratory tract, skin and soft tissues (except chronic migrating erythema), the total dose of azithromycin is 1500 mg (500 mg once daily). Treatment duration is 3 days.

For acne vulgaris, the recommended total dose of azithromycin is 6 g, administered as follows: one 500 mg film-coated tablet once daily for 3 days, followed by one 500 mg film-coated tablet once weekly for 9 weeks. The second dose should be taken 7 days after the first tablet, and the following 8 doses should be taken at 7-day intervals.

For migratory erythema, the total dose of azithromycin is 3 g, administered as follows: 1 g (4 film-coated tablets of 250 mg taken simultaneously) on the first day, followed by 500 mg once daily for 5 days.

For sexually transmitted infections, the recommended dose of azithromycin is 1000 mg (4 film-coated tablets of 250 mg taken simultaneously; or 2 film-coated tablets of 500 mg taken simultaneously).

Elderly patients

Dosage adjustment is not required in elderly patients.

However, since elderly patients may belong to risk groups for disturbances in cardiac electrical conduction, caution is recommended when using azithromycin due to the risk of cardiac arrhythmia and torsade de pointes.

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 administered to patients with severe hepatic impairment.

Children. Azipol is prescribed to children with body weight of 45 kg and above. For this pediatric group, the adult dose is recommended.

Overdose

Adverse effects observed after ingestion of doses higher than recommended are similar to those seen with normal therapeutic doses: diarrhea, nausea, vomiting, reversible hearing loss. In case of overdose, administration of activated charcoal and symptomatic and supportive treatment are recommended if necessary.

Adverse reactions

Adverse reactions identified from clinical trials and post-marketing surveillance during administration of all medicinal forms of azithromycin, classified by system organ class and frequency. Reactions reported during post-marketing surveillance are indicated in italics. 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 from available data). Within each frequency group, adverse events are listed in order of decreasing severity.

Infections and infestations

Uncommon: candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory disorder, rhinitis.

Frequency not known: pseudomembranous colitis.

Blood and lymphatic system disorders

Uncommon: leukopenia, neutropenia, eosinophilia.

Frequency not known: thrombocytopenia, hemolytic anemia.

Immune system disorders

Uncommon: angioneurotic edema, hypersensitivity reactions.

Frequency not known: anaphylactic reaction.

Metabolism and nutrition disorders

Uncommon: anorexia.

Psychiatric disorders

Uncommon: nervousness, insomnia.

Rare: agitation.

Frequency not known: aggression, anxiety, 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.

Ear and labyrinth disorders

Uncommon: hearing impairment, vertigo.

Frequency not known: hearing disorders, including deafness and/or tinnitus.

Eye disorders

Uncommon: visual disturbance.

Cardiac disorders

Uncommon: palpitations.

Frequency not known: ventricular fibrillation/torsades de pointes, arrhythmia including ventricular tachycardia, QT interval prolongation on ECG.

Vascular disorders

Uncommon: flushing.

Frequency not known: arterial hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea, epistaxis.

Gastrointestinal disorders

Very common: diarrhea.

Common: vomiting, abdominal pain, nausea.

Uncommon: gastritis, constipation, flatulence, dyspepsia, dysphagia, abdominal distension, dry mouth, eructation, oral ulceration, hypersalivation.

Frequency not known: pancreatitis, change in tongue color.

Hepatobiliary disorders

Rare: hepatic function abnormalities, cholestatic jaundice.

Frequency not known: hepatic failure (rarely resulting in fatal outcome), fulminant hepatitis, hepatic necrosis.

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis.

Rare: photosensitivity, acute generalized exanthematous pustulosis.

Frequency not known: Stevens–Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders

Uncommon: osteoarthritis, myalgia, back pain, neck pain.

Frequency not known: arthralgia.

Renal and urinary disorders

Uncommon: dysuria, renal pain.

Frequency not known: acute renal failure, interstitial nephritis.

Reproductive system and breast disorders

Uncommon: uterine bleeding, testicular disorders.

General disorders and administration site conditions

Uncommon: chest pain, swelling, malaise, asthenia, fatigue, facial swelling, hyperthermia, pain, peripheral edema.

Investigations

Common: decreased lymphocyte count, increased eosinophil count, decreased blood bicarbonate level, increased basophil count, increased monocyte count, increased neutrophil count.

Uncommon: increased aspartate aminotransferase level, increased alanine aminotransferase level, increased blood bilirubin level, increased blood urea level, increased blood creatinine level, blood potassium level abnormalities, increased alkaline phosphatase level, increased chloride level, increased glucose level, increased platelet count, decreased hematocrit level, increased bicarbonate level, sodium level abnormalities.

Injury, poisoning and procedural complications

Uncommon: procedural complications.

Information on adverse reactions possibly associated with prophylaxis and treatment of Mycobacterium Avium Complex is based on data from clinical trials and post-marketing observations. These adverse reactions differ in type or frequency from those reported during administration of immediate-release and extended-release dosage forms:

Metabolism and nutrition disorders

Common: anorexia.

Nervous system disorders

Common: dizziness, headache, paraesthesia, dysgeusia.

Uncommon: hypoaesthesia.

Eye disorders

Common: visual disturbance.

Ear and labyrinth disorders

Very common: deafness.

Uncommon: worsening of hearing, tinnitus.

Cardiac disorders

Uncommon: palpitations.

Gastrointestinal disorders

Very common: diarrhea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools.

Hepatobiliary disorders

Uncommon: hepatitis.

Skin and subcutaneous tissue disorders

Common: rash, pruritus.

Uncommon: Stevens–Johnson syndrome, photosensitivity.

Musculoskeletal and connective tissue disorders

Common: arthralgia.

General disorders and administration site conditions

Common: increased fatigue.

Uncommon: asthenia, malaise.

Shelf life. 3 years.

Storage conditions. Store below 25 °C in the original packaging, in a place inaccessible to children.

Packaging. 250 mg tablets: 3 tablets in a blister; 2 blisters in a cardboard box. 500 mg tablets: 2 or 3 tablets in a blister; 1 blister in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Adamed Pharma S.A., Poland.

Address. ul. marsz. J. Piłsudskiego 5, 95–200 Pabianice, Poland.