Instructions for Azimax film-coated tablets 500 mg No. 3
Composition
active ingredient: azithromycin;
1 tablet contains azithromycin dihydrate equivalent to azithromycin 250 mg or 500 mg;
excipients: calcium hydrogen phosphate anhydrous, pregelatinized starch (corn starch), croscarmellose sodium, sodium lauryl sulfate, magnesium stearate; tablet coating: Opadry II 31K58902 white (lactose, monohydrate; hypromellose; titanium dioxide (E171); triacetin).
Dosage form
Film-coated tablets.
Main physicochemical properties:
250 mg tablets: film-coated tablets, white to off-white, oblong, biconvex, engraved with “66” on one side and “D” on the other side;
500 mg tablets: film-coated tablets, white to off-white, oval, biconvex, engraved with “6” and “7” on either side of the score on one side and “D” on the other side.
Pharmacotherapeutic group
Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATC code J01F A10.
Pharmacological properties
Pharmacodynamics
Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by the introduction of a nitrogen atom into the 15-membered lactone ring of erythromycin A.
Mechanism of action
By binding to the 50S ribosomal subunit, azithromycin prevents the translocation of peptide chains from one side of the ribosome to the other. As a result, RNA-dependent protein synthesis in sensitive microorganisms is inhibited, which leads to a bacteriostatic effect.
Relationship between pharmacokinetics (PK) and pharmacodynamics (PD)
For azithromycin, the area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) is the main PK/PD parameter that best correlates with the efficacy of azithromycin.
Mechanism of resistance
Resistance to azithromycin can arise through the following mechanisms:
- change in antibiotic transport: resistance due to an increase in the number of efflux pumps in the cytoplasmic membrane, which excrete only 14- and 15-membered macrolides (M-phenotype);
- modification of the antibiotic target: due to methylation of 23S-rRNS, the affinity for ribosomal binding sites is reduced, which leads to resistance to macrolides (M), lincosamides (L) and group B streptogramins (SB) (the so-called MLSB phenotype);
- enzymatic inactivation of macrolides has little clinical significance.
The M phenotype shows complete cross-resistance between azithromycin and clarithromycin, erythromycin and roxithromycin. The MLSB phenotype has additional cross-resistance to clindamycin and streptogramin B. There is also partial cross-resistance to the 16-membered macrolide spiramycin.
Control values.
Azithromycin testing is performed at standard dilutions. Microorganisms are determined to be susceptible or resistant based on the following MICs:
MIC values established by the European Committee on Antibiotic Susceptibility Testing (EUCAST)
| Pathogen | Sensitive | Resistant |
| Staphylococcus spp.1) | ≤ 1 mg/l | > 2 mg/l |
| Streptococcus spp. (groups A, B, C, G)1) | ≤ 0.25 mg/l | > 0.5 mg/l |
| Streptococcus pneumoniae1) | ≤ 0.25 mg/l | > 0.5 mg/l |
| Moraxella catarrhalis1) | ≤ 0.25 mg/l | > 0.5 mg/l |
| Neisseria gonorrhoeae2) | ≤ 0.25 mg/l | > 0.5 mg/l |
1) Erythromycin can be used as a test substance to demonstrate susceptibility to azithromycin.
2) Values for a single dose of 2 g in monotherapy.
The prevalence of acquired resistance may vary depending on the location and time for individual species, so local information on resistance should be taken into account, especially when treating severe infections or treatment failure. If necessary, microbiological diagnostics with isolation of the pathogen and determination of its individual sensitivity to azithromycin can be used.
Pharmacokinetics
Absorption
The maximum serum concentration (Cmax) is reached 2-3 hours after oral administration. The terminal plasma half-life fully reflects the tissue half-life of 2-4 days. Elderly patients (>65 years) after five days of treatment had a slightly higher AUC than those under 40 years of age. The clinical significance is so small that no dose adjustment is necessary.
In animal studies, high concentrations of azithromycin were observed in phagocytes, with higher concentrations being released during active phagocytosis in experimental studies than in unstimulated phagocytes. In animal models, this resulted in increased concentrations of azithromycin at the site of infection.
Nonlinearity
These studies indicate nonlinear pharmacokinetics of azithromycin in the therapeutic range.
Distribution
Serum protein binding varies with plasma concentrations and ranges from 12% at 0.5 μg/mL to 52% at 0.05 μg/mL in serum. The mean volume of distribution at steady state (Vss) is 31.1 l/kg.
Breeding
After oral administration, azithromycin is excreted mainly in the bile in unchanged form. In human bile, particularly high concentrations of unchanged azithromycin have been found, as well as 10 metabolites formed by N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of cladinose conjugates. Relevant studies show that the metabolites of azithromycin do not have antimicrobial activity.
Kidney dysfunction
In patients with glomerular filtration rate (GFR) from 10 to 80 ml/min, the pharmacokinetic parameters after taking a single oral dose of 1 g of azithromycin were not changed. In patients with GFR 0-120 (8.8 μg x h/ml vs. 11.7 μg x h/ml), Cmax (1.0 μg/ml vs. 1.6 μg/ml) and CLr (renal clearance) (2.3 ml/min/kg vs. 0.2 ml/min/kg) compared to patients with normal renal function.
Liver dysfunction
In patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, there is no evidence of altered serum pharmacokinetics of azithromycin compared to patients with normal hepatic function. In these patients, urinary excretion of azithromycin is increased, possibly to compensate for reduced hepatic clearance.
Indication
Infections caused by microorganisms sensitive to azithromycin:
· upper respiratory tract infections (including sinusitis, pharyngitis, tonsillitis);
Lower respiratory tract infections (including bronchitis, pneumonia);
· ENT infections (acute otitis media);
· skin and soft tissue infections;
· sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis or Neisseria gonorrhoeae (except multidrug-resistant strains).
Contraindication
Hypersensitivity to azithromycin, erythromycin or other macrolide or ketolide antibiotics, or to any other component of the drug.
Interaction with other medicinal products and other types of interactions
Antacids or gastric secretion inhibitors: Concomitant use of mineral antacids generally does not alter bioavailability, although peak plasma concentrations of azithromycin are reduced by approximately 24%. Azithromycin should be taken 2 to 3 hours before antacids.
Cimetidine did not affect the rate and extent of absorption of azithromycin, so it can be taken simultaneously with Azimax tablets.
Cetirizine. Coadministration of a five-day course of azithromycin with 20 mg of cetirizine at steady state did not result in a pharmacokinetic interaction or significant changes in the QT interval.
Ergot alkaloids: Due to the theoretical possibility of ergotism (vasoconstrictive effects such as circulatory disorders, especially in the fingers and toes), azithromycin should not be used concomitantly with dihydroergotamine or non-hydrogenated ergot alkaloids.
Antiretroviral drugs: There are insufficient data on interactions with antiretroviral drugs to recommend dose adjustments.
The following drugs were studied:
Zidovudine. Coadministration of azithromycin (single doses of 1000 mg and multiple doses of 1200 mg or 600 mg) had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, azithromycin administration increased the concentration of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unknown but may be useful for patients.
Didanosine: Coadministration of daily doses of 1200 mg azithromycin with didanosine (400 mg/day) had no effect on the pharmacokinetics of didanosine compared to placebo.
Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect the plasma concentrations of these drugs. Neutropenia has been observed in patients receiving azithromycin and rifabutin concomitantly. Although neutropenia has been associated with rifabutin, a causal relationship to concomitant azithromycin has not been established.
Digoxin and colchicine. Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine results in increased serum levels of the P-glycoprotein substrate. Therefore, the possibility of increased serum digoxin concentrations should be considered when azithromycin and digoxin are coadministered. Clinical monitoring is necessary during and after discontinuation of azithromycin treatment.
The drugs atorvastatin, carbamazepine, efavirenz, fluconazole, indinavir, methylprednisolone, midazolam, sildenafil, triazolam, trimethoprim/sulfamethoxazole, which are metabolized by cytochrome P450, have not shown significant interactions with azithromycin in clinical trials. However, caution should be exercised when co-administering these drugs with azithromycin.
Atorvastatin: Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter plasma concentrations of atorvastatin (based on HMG-CoA reductase inhibition assay). However, rhabdomyolysis has been reported in patients receiving azithromycin in combination with statins.
Theophylline: Azithromycin does not affect the pharmacokinetics of theophylline when administered concomitantly with azithromycin and theophylline. The combined use of theophylline and other macrolide antibiotics sometimes leads to an increase in theophylline serum levels.
Coumarin anticoagulants. In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. Postmarketing reports of potentiation of the anticoagulant effect have been received following concomitant administration of azithromycin and oral coumarin anticoagulants. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral coumarin anticoagulants.
Cyclosporine: A pharmacokinetic study in healthy volunteers receiving oral azithromycin 500 mg daily for 3 days followed by a single oral dose of cyclosporine 10 mg/kg demonstrated a significant increase in Cmax and AUC0-5 of cyclosporine. 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 the dose adjusted accordingly.
Terfenadine. No pharmacokinetic interaction has been reported between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be completely excluded, but there is no specific data on the existence of such an interaction. As with other macrolide antibiotics, azithromycin should be prescribed with caution in combination with terfenadine.
Other antibiotics: Cross-resistance between azithromycin and macrolide antibiotics (e.g. erythromycin), as well as lincomycin and clindamycin, is possible. Therefore, concomitant administration of these drugs is not recommended.
Azithromycin should be administered with caution with other drugs that may prolong the QT interval.
Nelfinavir. Coadministration of azithromycin (1200 mg) and nelfinavir (750 mg 3 times daily) at steady state increases azithromycin concentrations. No clinically significant adverse events were observed, and therefore no dose adjustment is required.
Application features
Hepatotoxicity. Since the primary route of elimination of azithromycin is hepatobiliary, caution should be exercised when prescribing azithromycin to patients with severe liver disease. Cases of fulminant hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure (rarely fatal) have been reported with azithromycin. Some patients had a history of liver disease or were taking other hepatotoxic drugs.
Liver function tests should be performed if signs and symptoms of liver dysfunction develop, such as rapidly progressive asthenia accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy. Azithromycin should be discontinued if liver function is impaired.
Neonatal Hypertrophic Pyloric Stenosis (IHPS): Cases of infantile hypertrophic pyloric stenosis (IHPS) have been reported following the use of azithromycin in neonates (during treatment within the first 42 days of life). Parents and caregivers should seek medical advice if vomiting or gastrointestinal irritation occurs during feeding of infants receiving azithromycin.
Clostridium difficile-associated diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including azithromycin, and has ranged in severity from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of C. difficile.
Pseudomembranous colitis. There have been reports of cases of pseudomembranous colitis following the use of macrolide antibiotics. In patients diagnosed with diarrhea during or within approximately 3 weeks of treatment with azithromycin, the possibility of its occurrence should be considered. In the event of the development of pseudomembranous colitis or antiperistaltic phenomena, the drug is contraindicated.
Superinfections: As with other antibacterial agents, the possibility of superinfection (e.g., mycosis) exists. The occurrence of superinfection may require discontinuation of azithromycin therapy and appropriate measures.
Cross-resistance. Due to the presence of cross-resistance with erythromycin-resistant strains and most strains of methicillin-resistant staphylococci, azithromycin should not be prescribed in these cases. The regional status of acquired resistance to azithromycin and other antibiotics should be taken into account.
Renal impairment: In patients with severe renal dysfunction (GFR
Severe infections. Azimax tablets are not suitable for the treatment of severe infections in which a high concentration of the antibiotic in the blood must be achieved, since the concentration of azithromycin in the tissues is much higher than in the blood plasma.
Long-term treatment: There is no experience regarding the safety and efficacy of long-term use of azithromycin in the above indications. For rapidly recurring infections, treatment with another antibiotic should be considered.
Pharyngitis/tonsillitis. Penicillin is the drug of first choice for the treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes and for the prevention of acute rheumatic arthritis. Azithromycin is generally effective in the treatment of streptococcal infection of the oropharynx, but there are no data demonstrating the efficacy of azithromycin in the prevention of rheumatic fever.
Sinusitis: Azithromycin is often not the first choice for treating sinusitis.
Acute otitis media: Azithromycin is often not the drug of first choice for the treatment of acute otitis media.
Infected burns: Azithromycin is not indicated for the treatment of infected burns.
Sexually transmitted diseases. For the treatment of sexually transmitted diseases, concomitant infection with T. pallidum should be excluded.
Neurological and psychiatric disorders: Azithromycin should be used with caution in patients with neurological and psychiatric disorders.
Allergic reactions: As with erythromycin and other macrolides, rare allergic reactions to azithromycin have been reported, such as angioedema and anaphylaxis (rarely fatal), dermatological reactions including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN, rarely fatal), and drug reaction with eosinophilia and systemic symptoms (DRESS). Some of these reactions have resulted in recurrent symptoms and have required long-term monitoring and treatment. Physicians should be aware that discontinuation of symptomatic treatment may result in recurrence of allergic symptoms.
Ergot alkaloids and azithromycin. According to available observations, the simultaneous administration of ergot alkaloids and macrolide antibiotics accelerates the development of ergotism. The interaction between ergot alkaloids and azithromycin has not been studied, however, due to the theoretical possibility of ergotism, azithromycin should not be administered simultaneously with ergot derivatives.
Prolonged cardiac repolarization and QT interval. Prolonged cardiac repolarization and QT interval, which have been associated with a risk of cardiac arrhythmia and ventricular fibrillation (torsade de pointes), have been observed with other macrolide antibiotics. A similar effect of azithromycin cannot be completely excluded in patients at increased risk of prolonged cardiac repolarization, therefore, caution should be exercised when prescribing treatment to patients:
with congenital or documented prolongation of the QT interval; who are concomitantly treated with other active substances known to prolong the QT interval, such as antiarrhythmics of class IA (quinidine and procainamide) and III (dofetilide, amiodarone and sotalol), cisapride and terfenadine, neuroleptics such as pimozide; antidepressants such as citalopram, and fluoroquinolones such as moxifloxacin and levofloxacin; with electrolyte disturbances, especially in the case of hypokalemia and hypomagnesemia; with clinically relevant bradycardia, cardiac arrhythmias or severe heart failure; women and elderly patients with pre-existing proarrhythmias.
Myasthenia gravis: Cases of myasthenic syndrome and exacerbation of myasthenia gravis symptoms have been reported in patients receiving azithromycin.
Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
Pregnancy.
Breastfeeding period.
It has been documented that azithromycin passes into human milk, but adequate and well-controlled clinical studies that would allow characterizing the pharmacokinetics of azithromycin excretion into human breast milk have not been conducted. Azithromycin should be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the child.
Fertility.
Fertility studies have been performed in rats; pregnancy rates were reduced following administration of azithromycin. The relevance of these findings to humans is unknown.
Ability to influence reaction speed when driving vehicles or other mechanisms
It is known that azithromycin does not affect concentration and ability to react. However, the occurrence of side effects may affect the ability to drive or use other mechanisms.
Method of administration and doses
Dosage
Azimax tablets are used once a day, regardless of food intake. Swallow the tablets whole, without chewing and with water. If you miss a dose of the drug, the missed dose should be taken as soon as possible, and the following doses should be taken at intervals of 24 hours.
Adults, including the elderly, children and adolescents weighing more than 45 kg
The total dose is 1500 mg - 500 mg once daily for 3 days. Alternatively, the same total dose (1500 mg) can be administered for 5 days: 500 mg on the first day and 250 mg on the next 4 days.
In the treatment of pneumonia, the effectiveness of azithromycin is well proven when used in a 5-day regimen. In other cases, a 3-day treatment regimen is sufficient.
Dosage for the treatment of uncomplicated genital infections caused by Chlamydia trachomatis: 1000 mg of azithromycin once;
caused by Neisseria gonorrhoeae: 1000 or 2000 mg azithromycin in combination with 250 or 500 mg ceftriaxone according to established clinical protocols. In patients with penicillin and/or cephalosporin allergy, local treatment guidelines should be followed.
Elderly patients
There is no need to change the dosage in the elderly. Since elderly patients may be at risk for disturbances in the electrical conduction of the heart, caution is recommended when using azithromycin due to the risk of developing cardiac arrhythmias and ventricular tachycardia torsade de pointes.
Patients with renal impairment
No dose adjustment is required for patients with mild to moderate renal impairment (GFR 10-80 mL/min).
Patients with liver dysfunction
No dose adjustment is required for patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment should not use the drug, as azithromycin is metabolized in the liver and excreted in the bile.
Children.
The drug is not used in children weighing less than 45 kg.
Overdose
Adverse events that occurred with doses higher than recommended were similar to those observed with usual doses.
Symptoms
Typical symptoms of overdose with macrolide antibiotics include reversible hearing loss, severe nausea, vomiting, and diarrhea.
Treatment
In case of overdose, general symptomatic and supportive measures should be administered as necessary.
Adverse reactions
Adverse reactions are listed in the table below by system organ class and frequency. The frequency groups are defined as follows: very common (≥ 1/10); common (≥ 1/100 and < 1/100);
| Very often | Often | Infrequently | Rarely | Very rare | Frequency unknown |
| Infections and infestations | | | | | |
Candidiasis Vaginal infections Pneumonia Fungal infection Bacterial infection Pharyngitis Gastroenteritis Rhinitis Oral candidiasis | Pseudomembranous colitis | | | | |
| Blood and lymphatic system disorders | | | | | |
Leukopenia Neutropenia Eosinophilia | Thrombocytopenia Hemolytic anemia | | | | |
| On the part of the immune system | | | | | |
Angioedema Increased sensitivity | Anaphylactic reaction | | | | |
| Metabolism and nutrition | | | | | |
| Anorexia | | | | | |
| Mental disorders | | | | | |
Nervousness Insomnia | Excitation | Aggression Anxiety Delirium Hallucinations | | | |
| From the nervous system | | | | | |
| Headache | Dizziness Drowsiness Dysgeusia Paresthesia | Syncope Convulsions Psychomotor hyperactivity Anosmia Ageusia Parosmia Myasthenia gravis | | | |
| From the organs of vision | | | | | |
| Vision impairment | | | | | |
From the side of the organs of hearing and vestibular apparatus | | | | | | | Deafness | Hearing impairment Vertigo | Hearing impairment, including deafness and/or tinnitus | | | |
| Cardiological disorders | | | | | |
| Increased heartbeat | Ventricular fibrillation (torsade de pointes) Arrhythmia, including torsades de pointes QT prolongation on ECG | | | | |
| From the vascular side | | | | | |
| Tides | Arterial hypotension | | | | |
| Respiratory, thoracic and mediastinal disorders | | | | | |
Dyspnea Nosebleed | | | | | |
| From the gastrointestinal tract | | | | | |
| Diarrhea | Vomiting Abdominal pain Nausea | Constipation Flatulence Dysphagia Gastritis Abdominal bloating Dry mouth Eructation Mouth ulcers Hypersecretion of saliva | Pancreatitis Tongue discoloration | | |
| Hepatobiliary system | | | | | |
| Liver dysfunction Cholestatic jaundice | Liver failure (which has rarely been fatal) Fulminant hepatitis Liver necrosis | | | | |
| Skin and subcutaneous tissue disorders | | | | | |
Rash Itch Urticaria Dermatitis Dry skin Hyperhidrosis | Photosensitivity reaction Acute generalized exanthematous pustulosis (AGEP) Drug-induced eosinophilia with systemic symptoms (DRESS syndrome) | Stevens-Johnson syndrome Toxic epidermal necrolysis Erythema multiforme | | | |
| Musculoskeletal and connective tissue disorders | | | | | |
Osteoarthritis Myalgia Back pain Neck pain | Arthralgia | | | | |
| Kidney and urinary system disorders | | | | | |
Dysuria Kidney pain | Acute renal failure Interstitial nephritis | | | | |
| Reproductive system and breast disorders | | | | | |
| Uterine bleeding Testicular disorders | | | | | |
| General disorders and administration site conditions | | | | | |
Edema Asthenia Malaise Fatigue Facial swelling Chest pain Elevated body temperature Pain Peripheral edema | | | | | |
| Abnormalities detected as a result of laboratory tests | | | | | |
Decreased lymphocytes Increased eosinophils Decreased blood bicarbonate Increased basophils Increased monocytes Increased neutrophils | Increased aspartate aminotransferase levels Increased alanine aminotransferase levels Increased blood bilirubin levels Increased blood urea level Increased blood creatinine levels Abnormal blood potassium levels Increasing alkaline levels | | | | |
phosphatases in the blood Increased chloride levels Increased glucose levels Increased platelet levels Decreased hematocrit level Increased bicarbonate levels Abnormal sodium levels | | | | | |
| Injuries and poisoning | | | | | |
| Complications after the procedure | | | | | |
Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on clinical trial data. These adverse reactions differ in type or frequency from those reported with the immediate-release and long-release formulations:
| Organ system class | Adverse reaction | Frequency |
| Metabolic | Anorexia | often |
| From the psyche | Dizziness, headache, paresthesia, dysgeusia | often |
| Hypoesthesia | rarely | |
| From the organs of vision | Vision impairment | often |
| From the hearing organs | Deafness | rarely |
| Hearing loss, ringing in the ears | rarely | |
| From the heart | Palpitation | infrequently |
| From the digestive tract | Diarrhea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools | very often |
| Hepatobiliary system | Hepatitis | rarely |
| Skin and subcutaneous tissue disorders | Rash, itching | often |
Stevens-Johnson syndrome, photosensitivity | rarely | | | Musculoskeletal system | Arthralgia | often |
| General disorders and local reactions | Increased fatigue | often |
| Asthenia, malaise | rarely | |
Reporting of suspected adverse reactions. It is important to report suspected adverse reactions after the registration of a medicinal product. This will allow for continued monitoring of the benefit/risk balance. Healthcare professionals are requested to report suspected adverse reactions via the national reporting system.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 25 °C out of the reach of children.
Packaging
3 tablets in a blister; 1 blister (for a dosage of 500 mg) or 2 blisters (for a dosage of 250 mg) in a cardboard box.
Vacation category
According to the recipe.
Producer
Aurobindo Pharma Limited - Unit VII.
Location of the manufacturer and address of its place of business
Special Economic Zone, TSIIK, Plot No. S1, Sy. No. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India.
