Azithromycin Ecomed, 250 mg 6 pcs

Interaction

Nelfinavir. Co-administration of nelfinavir at equilibrium with a single oral dose of azithromycin resulted in a significant increase in serum concentrations (Cmax and AUC) of azithromycin. Although no azithromycin dose adjustment is recommended when taken in combination with nelfinavir, close monitoring is required for azithromycin side effects such as liver enzyme abnormalities and hearing impairment.

Warfarin. Although in a study involving 22 healthy men, a 5-day course of azithromycin had no effect on PV with a subsequent dose of warfarin, spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. Careful monitoring of PV should be undertaken if patients receive azithromycin and oral anticoagulants concomitantly.

Interaction studies have been conducted with azithromycin and other drugs that may be used simultaneously. When used in therapeutic doses azithromycin had moderate effect on pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (IV and oral), triazolam, trimethoprim/sulfamethoxazole and zidovudine. Combined use with efavirenz or fluconazole had a moderate effect on the pharmacokinetics of azithromycin. Dose adjustment of the above drugs is not recommended when combined with azithromycin.

In clinical trials of azithromycin no interactions with the drugs listed below have been reported. However, no specific studies have been conducted to evaluate potential interactions. Interactions have been observed with other drugs from the group of macrolides. It is recommended to carefully monitor patients until additional data on interaction of the following drugs with azithromycin are obtained: digoxin (increased concentration of digoxin); ergotamine or dihydroergotamine (acute ergotamine toxicity characterized by severe peripheral vasospasm and dysesthesia); terfenadine, cyclosporine, hexobarbital and phenytoin (concentration changes).

Interaction studies have been conducted with azithromycin and other drugs that can be used simultaneously. The effect of azithromycin co-administration on the pharmacokinetics of other drugs is shown in Table 1, and the effect of other drugs on the pharmacokinetics of azithromycin is shown in Table 2.

The concomitant use of azithromycin in therapeutic doses had a moderate effect on the pharmacokinetics of the drugs listed in Table 1. When concomitant use with azithromycin, no dose adjustments of the drugs listed in Table 1 are recommended.

The co-administration of azithromycin with efavirenz or fluconazole had a moderate effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased C and AUC of azithromycin. Dose adjustment of azithromycin is not recommended when taken with the drugs listed in Table 2.

Table 1

Interaction with other drugs: Pharmacokinetic parameters of co-administered drugs in the presence of azithromycin

Table 2

Interaction with other drugs: Pharmacokinetic parameters of azithromycin in the presence of co-administered drugs

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Special Instructions

Hypersensitivity

Serious allergic reactions, including angioedema, anaphylaxis and dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have rarely been observed in patients receiving azithromycin. Fatal cases, although rare, have been reported. Despite initially successful symptomatic treatment of allergic symptoms, after discontinuation of symptomatic therapy, some patients reappeared shortly thereafter with a recurrence of allergic symptoms without further exposure to azithromycin. Long-term follow-up and symptomatic treatment was required in these patients. The relationship of these episodes to the long half-life of azithromycin in the tissues and subsequent prolonged exposure to the antigen is currently unknown.

In the event of an allergic reaction, azithromycin should be discontinued and appropriate therapy should be prescribed. Physicians should be aware that allergic symptoms may reappear after discontinuing symptomatic therapy.

Hepatotoxicity

Hepatic dysfunction, hepatitis, cholestatic jaundice, hepatic necrosis and hepatic failure, some of which have resulted in death, have been reported. The use of azithromycin should be discontinued immediately if signs and symptoms of hepatitis appear.

The treatment of pneumonia

The safety and efficacy of azithromycin has been shown only in the treatment of community-acquired pneumonia caused by Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients who are indicated for oral therapy. Azithromycin should not be used in patients with pneumonia who are not indicated for oral therapy because of moderate to severe disease or when risk factors are present, such as patients with cystic fibrosis, patients with hospital-acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, elderly or frail patients, patients with serious underlying health problems that may impede responsiveness to the disease (including immunodeficiency or functional

Diarrhea associated with Clostridium difficile

The development of diarrhea associated with Clostridium difficile has been reported with virtually all antibacterials, including azithromycin for injection, and can range in severity from mild diarrhea to fatal colitis. Treatment with antibacterials leads to a modification of the normal flora of the large intestine and an overgrowth of C. difficile.

The C. difficile strains produce toxins A and B, which cause the development of diarrhea. C. difficile strains producing hypertoxin lead to an increased risk of morbidity and mortality because these infections may be resistant to antimicrobial therapy and require colectomy. The possibility of C. difficile-associated diarrhea should be considered in all patients who present with complaints of diarrhea after antimicrobial use. A thorough history should be taken, as C. difficile-associated diarrhea may develop within 2 months after antimicrobial use.

If C. difficile-associated diarrhea is suspected or confirmed, azithromycin should be stopped and appropriate treatment (including fluids and electrolytes, protein supplements, antibiotics to which C. difficile strains are sensitive) and surgical evaluation should be initiated if clinically indicated.

QT interval prolongation

In treatment with macrolides, including azithromycin, prolongation of cardiac repolarization and the QT interval have been observed, leading to a risk of cardiac arrhythmias and torsade de pointes. Cases of torsade de pointes have been reported during post-marketing follow-up in patients receiving azithromycin. The risk of QT interval prolongation, which can be fatal, should be considered when evaluating the risks and benefits of azithromycin for at-risk groups, including:

Patients with known QT interval prolongation, a history of torsade de pointes, congenital prolonged QT interval syndrome, bradyarrhythmia, or uncompensated heart failure;

Patients taking a medication that prolongs the QT interval;

Patients taking a medication that prolongs the QT interval – patients with current proarrhythmic conditions such as unadjusted hypokalemia or hypomagnesemia, clinically significant bradycardia, and patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.

The elderly patients may be more sensitive to the effects of drugs that cause prolongation of the QT interval.

The exacerbation of myasthenia gravis symptoms and myasthenic syndrome have been reported in patients receiving azithromycin therapy.

The development of resistant bacteria

The administration of azithromycin in the absence of a confirmed/suspected bacterial infection or for prophylactic reasons is unlikely to benefit the patient and increases the risk of development of resistant bacteria.

Hepatic impairment in adults

The pharmacokinetics of azithromycin in patients with hepatic impairment have not been established.

As azithromycin is mainly excreted through the liver, caution should be exercised when prescribing azithromycin in patients with hepatic impairment.

Dose adjustment is not recommended for patients with renal impairment with a GFR ≥80 mL/min. The AUC0-120 was similar in subjects with a GFR of 10-80 ml/min and those with normal renal function, whereas it was increased by 35% in patients with a GFR < 10 ml/min compared to those with normal renal function. Caution should be exercised when azithromycin is administered in patients with severe renal impairment (GFR < 10 ml/min) due to limited data.

Pediatric use

Acute otitis media. The safety and efficacy of oral azithromycin for the treatment of acute otitis media in children less than 6 months old has not been established.

Acute bacterial sinusitis. The safety and effectiveness of treatment of pediatric patients with acute bacterial sinusitis under 6 months of age have not been established. The oral use of azithromycin for the treatment of acute bacterial sinusitis in pediatric patients (6 months of age and older) is supported by adequate and well-controlled studies in adults, similar pathophysiology of acute sinusitis in adults and children, and studies of acute otitis media in pediatric patients.

Out-of-hospital pneumonia. The safety and effectiveness of treatment of pediatric patients with community-acquired pneumonia before 6 months of age have not been established.

Safety and effectiveness in pneumonia caused by Chlamydophila pneumoniae and Mycoplasma pneumoniae have been documented in pediatric clinical trials.

Safety and efficacy in pneumonia caused by Haemophilus influenzae and Streptococcus pneumoniae have not been confirmed bacteriologically in pediatric clinical trials because of difficulties in obtaining specimens. The use of azithromycin against these two microorganisms, however, is supported by data from adequate and well-controlled studies in adults.

Pharyngitis/tonsillitis. Safety and efficacy in the treatment of pediatric patients under 2 years of age with pharyngitis/tonsillitis have not been established.

There have been no studies evaluating the use of repeated courses of therapy.

Geriatric use

The pharmacokinetic parameters of azithromycin in elderly volunteers (65-85 years) were similar to those in younger volunteers (18-40 years) with a 5-day therapy regimen. Dose adjustment is not required in elderly patients with normal renal and hepatic function on this dosing regimen.

In clinical trials of multiple doses of oral azithromycin, 9% of patients were at least 65 years of age (458/494949) and 3% of patients (144/494949) were older than 75 years. No overall differences in safety or efficacy were observed between these and younger patients; other reported clinical experience showed no differences in response between older and younger patients, but the higher sensitivity of some older patients cannot be ruled out.

Elderly patients may be at greater risk of developing torsade de pointes arrhythmias than younger patients.

Synopsis

Capsule-shaped biconvex tablets with yellow film coating. Two layers are visible on the cross section; the inner layer is white or almost white.

Contraindications

Hypersensitivity to azithromycin, erythromycin, any antibiotics of macrolide or ketolide groups; history of cholestatic jaundice/liver dysfunction associated with previous use of azithromycin.

Side effects

In clinical trials, most side effects reported were mild to moderate in severity and reversible after azithromycin withdrawal. Potentially serious side effects, such as angioneurotic edema and cholestatic jaundice, were rarely reported. Approximately 0.7% of patients (adults and children) in 5-day multiple-dose clinical trials discontinued azithromycin therapy because of the development of treatment-related side effects.

In adults who received azithromycin at a dose of 500 mg/day, the rate of discontinuation due to treatment-related side effects after 3 days of treatment was 0.6%. In clinical trials involving pediatric patients, when 30 mg/kg was administered either as a single dose of azithromycin or for 3 days, discontinuation of azithromycin associated with the development of treatment-associated side effects was about 1%. Most side effects leading to discontinuation were GI-related, including nausea, vomiting, diarrhea, or abdominal pain.

The results of clinical trials

Because clinical trials are conducted with a different set of conditions, the incidence of adverse reactions observed in these clinical trials may not match that obtained in other clinical trials and observed in clinical practice.

Adults

Multidose regimens. Overall, the most common treatment-associated adverse reactions in adult patients receiving multiple doses of azithromycin were gastrointestinal effects. The most commonly reported adverse reactions were diarrhea/ fluid stools (4-5%), nausea (3%), and abdominal pain (2-3%).

There were no other treatment-related adverse effects with an incidence greater than 1% in patients receiving multiple doses of azithromycin.

The undesirable reactions that occurred with a frequency of ≤1% included the following.

Cardiovascular side: palpitations, chest pain.

Gastrointestinal disorders: dyspepsia, flatulence, vomiting, melena, cholestatic jaundice.

Urinary system: candidiasis, vaginitis, nephritis.

Nervous system disorders: dizziness, headache, vertigo, drowsiness.

General: fatigue.

Allergic reactions: rash, skin itching, photosensitivity, angioedema.

The single dose regimen is 1 g. In general, the most frequent adverse effects in patients who received azithromycin single dose 1 g were gastrointestinal related and were reported more frequently than in patients who received the multiple-dose regimen.

The side effects reported in patients on a single-dose azithromycin regimen with a frequency of 1% or more included diarrhea/iodine stool (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), vaginitis (1%).

The single dose regimen is 2 g. Overall, the most frequent side effects in patients who received azithromycin in a single dose of 2 g were gastrointestinal related.

The side effects reported in patients on a single dose of azithromycin in this study with a frequency of 1% or more included nausea (18%), diarrhea/ fluid stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%), and dizziness (1%). Most complaints were moderate in nature.

Pediatric patients

Single- and multiple-dose regimens. The types of side effects in pediatric patients were comparable to those in adults, with different frequencies for the dosing regimens recommended in pediatric practice.

Acute otitis media: at the recommended total dosage of 30 mg/kg, the most frequent treatment-related side effects (≥1%) were diarrhea, abdominal pain, vomiting, nausea, and rash.

The frequency of side effects, depending on dosing regimen, for 1-, 3-, and 5-day dosing regimens were: diarrhea, 4.3; 2.6 and 1.8%; abdominal pain, 1.4; 1.7 and 1.2%; vomiting, 4.9; 2.3 and 1.1%; nausea, 1, 0.4 and 0.5%; rash, 1, 0.6 and 0.4%.

Out-of-hospital pneumonia: for the recommended dosing regimen of 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the most common treatment-related side effects were diarrhea/ladder stool (5.8%), abdominal pain (1.9%), vomiting (1.9%), nausea (1.9%), and rash (1.6%).

Pharyngitis/tonsillitis: with a recommended dosing regimen of 12 mg/kg on days 1-5, the most common treatment-related side effects were diarrhea (5.4%), abdominal pain (3.4%), vomiting (5.6%), nausea (1.8%), rash (0.7%), and headache (1.1%).

There were no other treatment-related side effects occurring at a frequency of >1% in pediatric practice with any treatment regimen.

The side effects observed with a frequency of ≤1% included the following.

Cardiovascular side: chest pain.

Gastrointestinal disorders: dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools, oral candidiasis.

With the blood and lymphatic system: anemia, leukopenia.

Nervous system disorders: headache (in case of otitis media), hyperkinesia, dizziness, agitation, nervousness, insomnia.

General: fever, facial swelling, fatigue, fungal infection, malaise, pain.

Allergic: rash and allergic reaction.

Respiratory system: increased cough, pharyngitis, pleural effusion, rhinitis.

Skin and its appendages: eczema, fungal dermatitis, itching, sweating, urticaria, vesiculobulic rash.

Sensory organs: conjunctivitis.

Postmarketing experience

Unwanted reactions reported when taking azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship has not been established include the following.

Allergic reactions: arthralgia, edema, urticaria and angioedema.

Systemic reactions: arrhythmias, including ventricular tachycardia and hypotension. There have been reports of cases of prolonged QT interval and torsade de pointes.

Gastrointestinal disorders: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, rarely leading to dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, gateway stenosis; there have been rare reports of discolored tongue.

General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal).

Urogenital system disorders: interstitial nephritis, acute renal failure and vaginitis.

Hematopoietic disorders: thrombocytopenia.

Liver/biliary tract disorders: adverse reactions associated with liver dysfunction.

Nervous system disorders: seizures, dizziness/vertigo, headache, drowsiness, hyperactivity, nervousness, agitation and fainting.

Mental disorders: aggressive reactions and anxiety.

Skin and skin appendages: itching, severe skin reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome.

Sensory organs: hearing disorders, including hearing loss, deafness and/or tinnitus, as well as reports of perversion and/or loss of taste/sensation.

Laboratory abnormalities

Adults

Clinically significant abnormalities (without regard to drug association) reported during clinical trials with an incidence of greater than 1% have been reported: Decreased Hb, hematocrit, lymphocytes, neutrophils and blood glucose, increased serum CPK, potassium, ALT, GGT, AST, bilirubin, creatinine, blood glucose, platelet count, lymphocytes, neutrophils and eosinophils; with a frequency less than 1%: Leukopenia, neutropenia, decreased sodium, potassium, platelet count, increased monocyte count, basophils, bicarbonate, serum ALP, bilirubin, LDH, and phosphate. Most patients with elevated serum creatinine also had abnormal baseline values.

The changes in laboratory tests were reversible.

In multiple-dose clinical trials involving more than 5,000 patients, 4 patients discontinued azithromycin therapy because of treatment-related liver enzyme abnormalities and 1 because of impaired renal function.

Pediatric patients

One-, three-, and five-day regimens. Laboratory data collected in comparative clinical trials using two 3-day regimens (30 or 60 mg/kg in divided doses for 3 days) or two 5-day regimens (30 or 60 mg/kg) in divided doses for 5 days) were similar in all azithromycin regimens, with the most clinically significant laboratory abnormalities occurring at a rate of 1-5%.

Laboratory data for patients receiving 30 mg/kg as a single dose were collected in a single-center study. In this trial, absolute neutrophil counts between 500-1500 cells/mm3 were observed in 10 of 64 patients receiving 30 mg/kg once, in 9 of 62 patients receiving 30 mg/kg for 3 days, and in 8 of 63 patients in the comparison group. No patient had an absolute neutrophil count < 500 cells/mm3.

In multiple-dose clinical trials involving approximately 4,700 pediatric patients, not one patient had therapy discontinued because of treatment-related laboratory abnormalities.

Overdose

Symptoms: adverse reactions observed at doses higher than recommended were similar to those observed at normal doses, particularly nausea, diarrhea, and vomiting.

Treatment: if necessary, symptomatic and supportive therapy.

Pregnancy use

Pregnancy

The FDA fetal category is B.

Teratogenic effects. Reproduction studies have been performed on rats and mice when administered orally at doses to moderately toxic maternal concentrations (i.e., 200 mg/kg/day). These daily doses for rats and mice, depending on body surface area, are estimated to be 4 and 2 times the daily dose of 500 mg for adults, respectively. No evidence of fetal harm due to the effects of azithromycin has been found in animal studies. However, adequate and well-controlled studies in pregnant women have not been conducted. Because animal studies do not always predict effects in humans, azithromycin should only be used during pregnancy if absolutely necessary.

Breastfeeding

It has been reported that azithromycin is excreted in small amounts into human breast milk. Caution should be exercised when azithromycin is used in breastfeeding women.

Similarities

Azithromycin, Chemomycin, Azitral, Zifactor, Azitrox, Ecomed (Azithromycin), Sumamed, AzitRus, Sumamed forte, Zitrolide forte