Azitro sandoz®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZITHRO SANDOZ®

Composition:

Active ingredient: azithromycin;

One tablet contains azithromycin 250 mg or 500 mg as azithromycin dihydrate;

Excipients: microcrystalline cellulose, maize starch, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate, sodium lauryl sulfate;

Coating: lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol 4000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: oval, film-coated tablets, white or almost white, with a notch on both sides and embossing "A250" on one side;

500 mg tablets: oval, film-coated tablets, white or almost white, with a notch on one side and embossing "A500" on one side.

Pharmacotherapeutic group. Antibacterials 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 translocation.

Mechanism of resistance.

Complete cross-resistance exists among Streptococcus pneumoniae, beta-hemolytic streptococcus group A, 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 geographically and over time for specific pathogens; 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.

Antimicrobial spectrum of azithromycin

*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.

Bioavailability after oral administration is approximately 37%. Maximum serum concentration is achieved within 2–3 hours after drug intake.

After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have demonstrated that tissue concentrations of azithromycin are significantly higher (up to 50-fold) than plasma concentrations, indicating extensive 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 in blood serum. The apparent volume of distribution at steady state (Vss) 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 following 3 days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Ten metabolites were also detected 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 results with microbiological assays showed that 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, moderate acne vulgaris;
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

The use of the drug is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, macrolide/ketolide antibiotics, or to any excipient.

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.

Antacids. In studies evaluating the effect of concomitant antacid administration on the pharmacokinetics of azithromycin, no overall changes in bioavailability were observed, although peak plasma concentrations of azithromycin decreased by approximately 24%. Azithromycin should be taken approximately 2 hours after antacid intake. Concomitant administration of azithromycin and antacids is not recommended.

Cetirizine. In healthy volunteers, co-administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not reveal any pharmacokinetic interaction or significant changes in QT interval. Caution is advised when prescribing azithromycin with other drugs that may prolong the QT interval.

Didanosine. Concomitant administration of 1200 mg/day azithromycin with 400 mg/day didanosine in six HIV-positive patients did not affect the steady-state pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine (P-glycoprotein substrates). There have been reports that concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digox游戏副本

Special precautions for use.

Hypersensitivity. 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 such as 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 led to recurrent symptoms and required prolonged observation and treatment.

In case of an allergic reaction, administration of azithromycin should be discontinued and appropriate therapy initiated. Physicians should be aware that symptoms of allergic reactions may recur after discontinuation of symptomatic treatment.

Hepatic function impairment. Since the liver is the primary route of elimination of azithromycin, azithromycin should be administered with caution in patients with significant hepatic disease. Cases of fulminant hepatitis, potentially leading to life-threatening hepatic failure, have been reported with azithromycin. Some patients may have had pre-existing liver disease or may have been taking other hepatotoxic medicinal products.

If signs or symptoms of hepatic dysfunction occur, such as rapidly developing asthenia associated with jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy, liver function tests/investigations should be performed immediately. Administration of azithromycin should be discontinued if hepatic dysfunction occurs.

In patients receiving ergot derivatives, ergotism has been provoked by concomitant administration of certain macrolide antibiotics. Data on the potential interaction between ergot derivatives and azithromycin are lacking. However, due to the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be taken concurrently.

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

Cross-resistance. Due to existing cross-resistance to 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.

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 flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD.

C. difficile strains producing hyper-toxin are associated with increased complications and mortality, as these infections may not respond to antimicrobial therapy and may require colectomy. This should be considered in all patients presenting with diarrhea following antibiotic use. A careful medical history is necessary, as diarrhea has been reported up to 2 months after antibiotic administration.

In patients with severe renal function impairment (GFR < 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 arrhythmia and paroxysmal ventricular tachycardia of the "torsade de pointes" type, has been observed with treatment using other macrolide antibiotics, including azithromycin. Since the above-mentioned conditions may lead to an increased risk of ventricular arrhythmia (including torsade de pointes), which may result in cardiac arrest, azithromycin should be used with caution in patients with current proarrhythmic conditions (especially women and elderly patients). This group includes patients:

• with congenital or documented acquired QT interval prolongation;
• currently receiving treatment with other active substances known to prolong the QT interval, such as class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol) antiarrhythmics, cisapride and terfenadine, neuroleptics such as pimozide; antidepressants such as citalopram, and fluoroquinolones such as moxifloxacin and levofloxacin;
• with electrolyte imbalances, particularly in cases of hypokalemia and hypomagnesemia;
• with clinically relevant bradycardia, cardiac arrhythmia, or severe heart failure.

Exacerbation of symptoms of myasthenia gravis or new onset of myasthenic syndrome has been reported in patients receiving azithromycin therapy (see section "Adverse reactions").

Paediatric population. Safety and efficacy of prophylaxis or treatment of Mycobacterium avium complex in children have not been established.

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 other antibiotics should be considered.

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

Hearing impairment. Ototoxicity has been described with macrolide antibiotics. In some patients receiving azithromycin, hearing disturbances, deafness, and tinnitus have been reported. Many of these cases relate to experimental studies where azithromycin was administered at high doses over a prolonged period. However, according to available follow-up reports, most of these problems were reversible.

Streptococcal infections. For the treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, penicillin is 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.

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

Azithromycin contains sodium compounds. Caution should be exercised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of azithromycin in pregnant women. Reproductive toxicity studies in animals have shown that azithromycin can cross the placental barrier, but no teratogenic effects were observed. The safety of azithromycin with respect to use during pregnancy has not been established. Therefore, azithromycin should be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Period of breastfeeding. It has been reported that azithromycin passes into human milk, but adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion into breast milk in lactating women have not been conducted.

No serious adverse effects of azithromycin on breastfed infants have been observed.

However, the use of azithromycin during breastfeeding is possible only when the expected benefit to the mother outweighs the potential risk to the child.

Fertility.

Fertility studies have been conducted in rats; a decreased pregnancy rate was observed after administration of azithromycin. The relevance of these data to humans is unknown.

Ability to influence the speed of reactions when driving or operating machinery.

There is no direct evidence that azithromycin may affect the ability to drive or operate machinery; however, the possibility of adverse reactions such as delirium, hallucinations, dizziness, somnolence, loss of consciousness, and seizures, which may impair the ability to drive or operate machinery, should be considered.

Method of Administration and Dosage.

Azithromycin should be administered as a single daily dose, regardless of food intake. Tablets should be swallowed whole, without chewing. 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 ≥ 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). The duration of treatment is 3 days.

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

For migrating erythema, the total dose of azithromycin is 3 g, to be taken as follows: 1 g (2 tablets of 500 mg as a single dose) on day 1, followed by 500 mg once daily from day 2 to day 5.

For sexually transmitted infections, the recommended dose of azithromycin is 1000 mg (single dose).

Elderly patients.

Dosage adjustment is not required in elderly patients.

Since elderly patients may be at increased risk of cardiac conduction disorders, caution is recommended when administering azithromycin due to the risk of developing cardiac arrhythmia and torsade de pointes arrhythmia.

Patients with renal impairment.

For patients with mild renal impairment (glomerular filtration rate 10–80 mL/min), the same dosage as for patients with normal renal function may be used. Azithromycin should be administered with caution in patients with severe renal impairment (glomerular filtration rate < 10 mL/min).

Patients with hepatic impairment.

Since azithromycin is metabolized in the liver and excreted via bile, the drug should not be used in patients with severe hepatic impairment. Studies on the treatment of such patients using azithromycin have not been conducted.

Children.

This medicinal product in the given pharmaceutical form is indicated for children with body weight ≥ 45 kg.

For children with body weight less than 45 kg, AZITHRO SANDOZ®, powder for oral suspension, is recommended.

Overdose.

Symptoms.

Adverse effects observed after ingestion of doses higher than recommended are similar to those seen with usual therapeutic doses and may include diarrhea, nausea, vomiting, and reversible hearing loss.

Treatment.

In case of overdose, activated charcoal may be administered if necessary, along with general symptomatic and supportive treatment measures.

Adverse Reactions

Adverse reactions are listed below by system organ class and frequency, based on clinical trial data and post-marketing surveillance.

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; 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 from clinical trials and post-marketing surveillance:

Infections and infestations. Uncommon: Candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infections, bacterial infections, pharyngitis, gastroenteritis, respiratory tract disorders, rhinitis, oral candidiasis. Not known: Pseudomembranous colitis.

Blood and lymphatic system disorders. Uncommon: Leukopenia, neutropenia, eosinophilia. Not known: Thrombocytopenia, haemolytic anaemia.

Immune system disorders. Uncommon: Angioneurotic oedema, hypersensitivity reactions. Not known: Anaphylactic reaction.

Metabolism and nutrition disorders. Uncommon: Anorexia.

Psychiatric disorders. Uncommon: Nervousness, insomnia. Rare: Irritability. Not known: Aggression, restlessness, delirium, hallucinations.

Nervous system disorders. Common: Headache. Uncommon: Dizziness, somnolence, paraesthesia, dysgeusia. Not known: Syncope, convulsions, hypoaesthesia, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis.

Eye disorders. Common: Visual disturbances.

Ear and labyrinth disorders. Uncommon: Hearing impairment, vertigo. Not known: Worsening of hearing, including deafness and/or tinnitus.

Cardiac disorders. Uncommon: Palpitations. Not known: Ventricular tachycardia (torsade de pointes), arrhythmia including ventricular tachycardia, QT interval prolongation on ECG.

Vascular disorders. Uncommon: Flushing. Not known: Hypotension.

Respiratory, thoracic and mediastinal disorders. Uncommon: Dyspnoea, epistaxis.

Gastrointestinal disorders. Very common: Diarrhoea. Common: Vomiting, abdominal pain, nausea.
Uncommon: Constipation, flatulence, dyspepsia, gastritis, dysphagia, abdominal distension, dry mouth, belching, oral ulceration, hypersalivation. Not known: Pancreatitis, tongue discoloration.

Hepatobiliary disorders. Uncommon: Hepatic function abnormalities, cholestatic jaundice. Not known: Hepatic failure (rarely fatal), fulminant hepatitis, necrotising hepatitis, hepatic necrosis.

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.

** Frequency estimated according to the "rule of three".

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: Oedema, asthenia, anxiety, fatigue, facial swelling, chest pain, malaise, pain, peripheral oedema, hyperthermia, procedural complications.

Investigations. Common: Decreased white blood cell count, increased eosinophil count, decreased blood bicarbonate, increased basophil count, increased monocyte count, increased neutrophil count. Uncommon: Increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood bilirubin, blood urea, blood creatinine; electrolyte imbalances including potassium; increased alkaline phosphatase, chloride, glucose, platelets; decreased haematocrit; increased bicarbonate, deviations in sodium levels.

Injury, poisoning and procedural complications. Uncommon: Procedural complications.

Information on adverse reactions possibly related to the prophylaxis 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 disturbances.

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: Fatigue. Rare: Asthenia, malaise.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of the reach of children.

Packaging.

250 mg tablets: 6 tablets in a blister; 1 blister per carton.

500 mg tablets: 3 or 6 tablets in a blister; 1 blister per carton.

Prescription status. Prescription only.

Manufacturer.

1. Sandoz GmbH (primary and secondary packaging, batch control, batch release).
2. Sandoz S.r.l. (complete-cycle manufacturing).

Manufacturer's address.

1. Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.
2. Strada Livezeni, No. 7A, 540472 Târgu Mureș, Mureș County, Romania.