Ziromin-Reb

Trade Name: Ziromin-Reb

International Nonproprietary Name: Azithromycin

Drug Form: Powder for oral suspension preparation, 200 mg/5 ml.

Composition:

5 ml suspension contains:

Active substance: Azithromycin (in a form of azithromycin dihydrate) – 200 mg;

Pharmacotherapeutic group

Antibacterial drugs for systemic use. Macrolides.

Code АТC: J01FA10

Pharmacological properties

Pharmacodynamics

Mode of action

Azithromycin is a broad-spectrum antibiotic. Azithromycin is the first representative of new macrolide antibiotics subgroup – azalides. Azithromycin molecule is formed by nitrogen (atom) insertion into the lactone ring of erythromycin A. Azithromycin mechanism of action is expressed by binding to 50S subunit of ribosome, resulted in disruption of bacterial proteins synthesis and peptides translocation.

Azithromycin spectrum of antimicrobial effect

Azithromycin spectrum of antimicrobial effect includes various gram-positive and gram-negative microorganisms, anaerobes, intracellular and clinically atypical pathogens.

Usually sensitive microorganisms:

-aerobic gram-positive microorganisms: Staphylococcus aureus (methicillin-sensitive strains); Streptococcus pneumoniae (penicillin-sensitive strains); Streptococcus pyogenes (group A);

-aerobic gram-negative Pasteurella multocida microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis;

-anaerobic microorganisms: Clostridium perfringens, Fusobacterium spp., Prevotella spp., Porphyromonas spp.;

-other microorganisms: Chlamydia trachomatis.

Microorganisms with secondary resistance may become problematic for treatment:

-aerobic gram-positive microorganisms: Streptococcus pneumoniae (strains with intermediate sensitivity to penicillin and penicillin-resistant strains).

Natural-resistant microorganisms:

-aerobic gram-positive microorganisms: Enterococcus faecalis, staphylococci MRSA*, MRSE*;

-anaerobic microorganisms: strains of Bacteroides fragilis.

* Methicillin-resistant staphylococci are characterized by a high prevalence of secondary resistance to macrolides and included because of their rare case of sensitivity to azithromycin.

Dosage and administration

Ziromin-Reb suspension is indicated for oral administration, once a day, with or without food.

The dose should be measured with a measuring double-sided spoon or a dosing syringe (up to 15 kg – with a dosing syringe, more than 15 kg – with a measuring double-sided spoon).

Ziromin-Reb 200mg/5ml suspension should be used in children with a body weight from 10 to 44 kg. In children with a body weight ≥ 45 kg and in adults Azithromycin should be used in other dosage forms provided with the total dose of active substance necessary for the treatment course. Azithromycin treatment safety and efficacy in children under 6 months old has not been studied.

In case of upper and lower respiratory tract infections, ENT, skin and soft tissue infections: the drug is prescribed at the dose of 10 mg/kg once a day for 3 days; one course dose – 30 mg / kg.

The recommended dosage regimen of Ziromin-Reb depended on the child body weight is presented in the table below:

Azithromycin has been shown to be effective in streptococcal pharyngitis treatment in children when taken once a day at a dose of 10 mg/kg or 20 mg/kg. However, penicillin is a first-line drug for prevention of Streptococcus pyogenes caused pharyngitis and rheumatic fever as a secondary disease.

In case of chronic erythema migraine: on the 1st day at a dose of 20 mg/kg/day, then from the 2nd to the 5th day at a dose of 10 mg/kg/day; course dose – 60 mg/kg.

In case of stomach and duodenum disorders associated with Helicobacter pylori infection: 20 mg/kg of body weight once a day in combination with an antisecretory agent and other drugs recommended by the doctor.

Special categories of patients

Patients with impaired renal function

In patients with mild to moderate renal failure (creatinine clearance 10 - 80 ml/min) dose adjustment is not required. Patients with severe renal impairment should take Azithromycin with caution (creatinine clearance <10 ml/min).

Patients with impaired liver function

The drug should not be prescribed to patients with severely impaired liver function, since Azithromycin is metabolized in the liver and excreted with the bile. Treatment study with Azithromycin in this group of patients has not been conducted.

In case of missed drug dose this dose should be taken as soon as possible and the subsequent doses – at usual treatment regimen. Do not take the double dose to compensate for the missed one or take more than one dose a day.

Suspension preparation:

To prepare 30 ml of suspension, place 15 ml of water into a vial contained 1200 mg of Azithromycin using a measuring cup.

The prepared suspension should be kept at a temperature not higher than 25°C for no longer than 5 days period.

Before each administration, the vial contents should be shaken thoroughly until the homogeneous suspension obtained.

To dispense the final drug suspension use a 5 ml syringe; the bilateral spoon graduated for 1.25 ml, 2.5 ml and 5 ml dose and graduated measuring cup for 15 ml.

Immediately after the drug intake the child should drink some tea or juice to rinse and swallow the remaining dose of suspension presented in the mouth. The measuring cup, the bilateral measuring spoon and the dosing syringe should be washed with running water after use, than dried and stored together with the drug.

Side effect

Side effects frequency parameters mentioned below are defined as follows: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely (from ≥ 1/10000 to <1/1000); very rarely (<1/10000), the frequency is unknown – frequency parameters cannot be estimated based on the data available.

Most of the reported adverse reactions are reversible after the treatment course completion or the therapy discontinuation.

Respiratory, thoracic and mediastinal disorders: infrequently - dyspnea, nosebleeds.

Blood and lymphatic system disorders: infrequently – leukopenia, neutropenia; unknown frequency – thrombocytopenia, hemolytic anemia.

Immune system disorders: infrequently – Quincke's edema, hypersensitivity; unknown frequency – anaphylactic reactions.

Mental disorders: infrequently - neurosis; rarely, anxiety; frequency unknown – aggression, anxiety.

Nervous system disorders: often – dizziness, headache, paresthesia, dysgeusia; infrequently – hypesthesia, drowsiness, insomnia; unknown frequency – syncope, convulsions, psychomotor hyperactivity, anosmia, ageusia, parasomnia, myasthenia gravis.

Eye disorders: often – visual impairment.

Ear and labyrinth disorders: often – deafness; infrequently – hearing impairment, tinnitus; rarely – dizziness.

Heart disease: infrequently – palpitations; unknown frequency – torsade de pointes (pirouette tachycardia), arrhythmia, including ventricular tachycardia.

Vascular disorders: the frequency is unknown - hypotension.

Gastrointestinal tract disorders: very often – nausea, abdominal pain, diarrhea, flatulence; often – vomiting, dyspepsia; infrequently – gastritis, constipation; rarely – cholestatic jaundice, loss of appetite, gastritis; very rarely – candidiasis of the oral mucosa; frequency unknown – pancreatitis, tongue discoloration.

Liver and biliary tract disorders: infrequently – hepatitis; rarely – liver dysfunction; frequency unknown – liver failure, hepatitis, liver necrosis, cholestatic jaundice.

Skin and subcutaneous tissue disorders: often – rash, itching; infrequently – Stevens-Johnson syndrome, photosensitivity, urticaria; frequency unknown – toxic epidermal necrolysis, erythema multiforme.

Reproductive system and breast disorders: metrorrhagia, testicular dysfunction.

Renal and urinary disorders: infrequently – dysuria, renal colic; frequency unknown – acute inflammation of the kidneys, interstitial nephritis.

Metabolic and nutritional disorders: often anorexia.

General disorders and administration site condition: often – fatigue; infrequently – chest pain, swelling, weakness, asthenia.

Deviation in laboratory and instrumental study results: often – lymphocytes count decrease, an eosinophils count increase, serum bicarbonates level decrease; infrequently – aspartate aminotransferase and alanine aminotransferase level increase, serum bilirubin level decrease, serum creatinine and urea increase, deviation in serum potassium concentration; unknown frequency – QT interval prolongation in ECG.

Infectious and parasitic diseases: often - bacterial infection, pharyngitis, rhinitis, gastroenteritis, respiratory infections; infrequently – candidiasis, oral candidiasis, vaginal infection; frequency unknown – pseudomembranous colitis.

Adverse Reaction Report

It is important to report about suspected adverse reactions after drug registration in order to ensure continuous monitoring of the drug benefit-risk ratio.

In case of adverse reactions specified in instructions for medical use or not mentioned in it patients should consult the doctor.

Medical staff is advised to report any suspected adverse drug reaction to the Republican Unitary Enterprise “Center for Expertise and Tests in Health Service” www.rceth.by.

Contraindications

-hypersensitivity to Azithromycin, other macrolides or ketolides or other drug components;

-history of cholestatic jaundice/liver dysfunction caused by Azithromycin administration, severe liver dysfunction;

- combined use with ergotamine derivatives due to theoretical possibility of ergotism.

Precautions

Allergic reactions

Similar to erythromycin and other macrolides, severe allergic reactions, anaphylactic edema and anaphylaxis (rarely fatal) have been reported in rare cases. Some of these symptoms caused by Azithromycin administration led to recurrent symptoms and required longer observation and treatment period.

Impaired liver function

Since Azithromycin is primarily excreted by the liver, the drug should not be prescribed to patients with severe hepatic impairment. Cases of rapid hepatitis development have been reported during Azithromycin administration resulted in a life-threatening condition – liver failure. In case of such liver dysfunction symptoms as: rapidly developed asthenia accompanied by jaundice, dark urine, hemorrhagic tendency, symptoms of hepatic encephalopathy it is necessary to perform laboratory and instrumental investigations to assess the liver function state. In case liver dysfunction test results Azithromycin therapy should be discontinued.

Ergotamine

In patients treated with ergotamine derivatives ergotism accelerated in concomitant use of some macrolide antibiotics. There is no evidence of possible interaction between ergot drugs and Azithromycin. However, since there is a theoretical possibility of ergotism, Azithromycin and ergotamine derivatives should not be used simultaneously.

Secondary infection

Similar to other antibiotics, it is recommended to monitor the signs of secondary infection caused by resistant microorganisms including fungi.

Clostridium difficile associated diarrhea (CDAD)

Diarrhea associated with Clostridium difficile has been observed with almost all antibacterial agents, including Azithromycin. The severity can range from mild diarrhea to acute colitis. Antibacterial therapy modifies the normal intestinal microflora and leads to excessive growth of C. difficile. C. difficile produces toxins A and B, resulted in CDAD development. Hypertoxin produced by C. difficile strains is a major cause of increased morbidity and mortality, as such microorganisms may be refractory to antimicrobial therapy and colectomy may be required. The possibility of CDAD should be considered in all patients with diarrhea after antibiotic therapy. The anamnesis should be carefully considered, as it has been reported that CDAD may occur two months after treatment with antibacterial agents.

Impaired renal function

In patients with severe renal failure (GFR <10 ml/min), an increase in systemic exposure of Azithromycin by 33% was observed.

QT interval prolongation

Cardiac repolarization and QT interval prolongation causing the risk of cardiac arrhythmias and pirouette tachycardia development have been reported with other macrolides. The similar effect cannot be completely excluded with Azithromycin administration in patients at increased risk of cardiac repolarization prolongation; therefore, special care is necessary to treat the patients with:

-hereditary or reported QT interval prolongation;

-concomitant use of other drugs that are known to prolongate the QT interval, for example, antiarrhythmic drugs of IA (procainamide and quinidine) and III (amiodarone, dofetilide and sotalol) classes, cisapride and terfenadine; antipsychotic drugs, such as pimozide; antidepressants (citalopram); fluoroquinolones (moxifloxacin and levofloxacin);

-electrolyte imbalance, especially in case of hypokalemia and hypomagnesemia;

-clinically significant bradycardia, cardiac arrhythmia or severe heart failure

Myasthenia gravis

Myasthenia gravis symptoms exacerbation or the appearance of myasthenic syndrome previously not observed in patients on Azithromycin therapy has been reported.

Streptococcal infections

Penicillin is usually the drug of choice in the treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes and for acute rheumatic fever prophylaxis. Azithromycin is generally effective in acute pharyngitis therapy but there is no evidence of effectiveness in acute rheumatic fever prevention.

Azithromycin safety and efficacy in Mycobacterium Avium Complex treatment in children has not been established.

If you missed one dose of the drug, the missed dose should be taken as soon as possible and the subsequent ones – in 24 hours interval.

When using the drug in patients with diabetes mellitus, as well as in case of low-calorie diet, it is necessary to consider that the suspension contains sucrose (908.3547 mg/g of powder for suspension preparation).

If you are intolerant to certain sugars, you should consult your doctor before the drug intake. The drug is contraindicated in patients with rare congenital fructose intolerance, glucose-galactose malabsorption, or sucrose-isomaltase deficiency.

The drug Ziromin-Reb is for oral administration only.

Effect on ability to drive and operate machinery

It should be kept in mind that possible adverse reactions such as dizziness, drowsiness, delirium, hallucinations, fainting, cramps and visual impairment can adversely affect the ability to drive and work with machinery.

Pediatric use

Azithromycin safety and efficacy in children under 6 months has not been studied. The drug Ziromin-Reb can be prescribed in children with a body weight of at least 10 kg (see section “Dosage and Administration”).

Use in pregnancy and lactation.

Pregnancy

Reproductive toxicity studies in animals have shown that Azithromycin passes through the placenta, but no teratogenic effects have been observed. Azithromycin safety has not been confirmed for pregnant women; therefore, the use of Azithromycin in pregnancy is possible only if the expected benefit to the mother outweighs the potential risk of complications for the fetus.

Lactation

Azithromycin excretion into breast milk has been reported, but there have not been adequately organized clinical trials involved lactating women to characterize azithromycin excretion into breast milk. Therefore, Azithromycin should not be used to treat a nursing woman, unless it is clearly necessary and in case when the potential benefit to the mother outweighs the possible risks to the baby.

Fertility

In studies of fertility in rats, a decrease in the appearance of pregnancy after administration of azithromycin was observed. The potential risk to human health is unknown.

Overdose

Symptoms: nausea, temporary hearing loss, vomiting, diarrhea, abdominal pain, impaired liver function.

Treatment: gastric lavage, symptomatic therapy (activated carbon intake), monitoring of vital functions.

Interaction with other drugs

Antacids: antacids slow the absorption of azithromycin. It is recommended to observe the interval (at least two hours) between taking the drug and antacid.

Cetirizine: concomitant use of Azithromycin and Cetirizine in a dose of 20 mg for 5 days in healthy patients did not lead to a change in pharmacokinetics or significant change in the QT interval.

Didanosine: concomitant use of Azithromycin at a daily dose of 1200 mg and Didanosine in 6 volunteers did not affect pharmacokinetics of didanosine compared with placebo.

Digoxin: since there is evidence of a change in the metabolism of digoxin in patients who take macrolide antibiotics, caution is needed when taking them simultaneously. Many macrolides increase the absorption of digoxin in the intestine, thereby increasing its Cmax.

Zidovudine: single doses of 1000 mg and multiple doses of 1200 mg or 600 mg of Azithromycin had little effect on plasma pharmacokinetics and urinary excretion of Zidovudine or its glucuronide metabolites. However, Azithromycin increased phosphorylated zidovudine (a clinically active metabolite) concentration in peripheral blood mononuclear cells. Clinical relevance of these data is unclear, but may be useful for patients.

Ergotamine derivatives: due to the theoretical possibility of ergotism, Azithromycin cannot be administered together with ergotamine derivatives.

Atorvastatin: in concomitant use of Atorvastatin (10 mg a day) and Azithromycin (500 mg a day), Azithromycin did not affect Atorvastatin plasma concentration.

Carbamazepine: pharmacokinetic studies conducted in healthy volunteers Azithromycin did not significantly affect Carbamazepine or its active metabolite plasma concentration.

Cimetidine: when Cimetidine was taken two hours before Azithromycin, there was no change in Azithromycin pharmacokinetics.

Oral Coumarin anticoagulants: Azithromycin did not change the anticoagulant effect of Warfarin in a single dose of 15 mg prescribed to healthy volunteers. But it is also known about the anticoagulant effect potentiation in case of concomitant use of Azithromycin and oral Coumarin anticoagulants. Although no causal link has been established, it is necessary to frequently monitor prothrombin time when Azithromycin is administered in patients on oral Coumarin anticoagulants.

Cyclosporin: in a Pharmacokinetic interaction Study healthy volunteers used an oral dose of Azithromycin 500 mg once a day and on completion of Azithromycin therapy course (3 days), - a single oral dose of Cyclosporine at a rate of 10 mg/kg. It was noted that maximum concentration of Cyclosporine and AUC_0-5 increased significantly. Therefore, Azithromycin and Cyclosporine combination should be used with caution. If combination treatment is considered reasonable, close monitoring of Cyclosporine plasma concentration and the dose adjustment is necessary.

Efavirenz: co-administration of Azithromycin in a single dose of 600 mg and Efavirenz 400 mg per day for 7 days did not cause a clinically significant pharmacokinetic interaction.

Fluconazole: concomitant use of Azithromycin in a single dose of 1200 mg did not change Fluconazole pharmacokinetics when used in a single dose of 800 mg. The total exposure and elimination half-life of Azithromycin did not change in combined use with Fluconazole. However, a clinically insignificant decrease in Cmax (18%) of Azithromycin was noted.

Indinavir: combined use of Azithromycin in a single dose of 1200 mg did not have a significant effect on Indinavir pharmacokinetics when taken for 5 days at a dose of 800 mg three times a day.

Methylprednisolone: pharmacokinetic drug interactions study in healthy patients did not demonstrate any significant effect of Azithromycin on Methylprednisolone pharmacokinetics.

Midazolam: combined use of Azithromycin in a daily dose of 500 mg for 3 days in healthy patients does not cause clinically significant changes in Midazolam pharmacokinetics and pharmacodynamics when taken 15 mg once a day.

Nelfinavir: concomitant use of Azithromycin (1200 mg) and Nelfinavir (750 mg three times a day) leads to Azithromycin concentration increase. No clinically significant side effects have been observed. It is no need to adjust the dose.

Rifabutin: combined use of Azithromycin and Rifabutin did not affect any of the two drugs serum concentration. In combined use of Azithromycin and Rifabutin neutropenia was observed in patients. Neutropenia was associated with Rifabutin administration; causal link when taken in combination with Azithromycin was not established.

Sildenafil: there was no evidence of Azithromycin effect (when taken in a daily dose of 500 mg for 3 days) on Sildenafil or its main metabolites AUC and C_max values in serum.

Terfenadine: no interaction between Terfenadine and Azithromycin was detected. In some cases such interaction cannot be completely ruled out. And yet there is no evidence of such a reaction. Similar to other macrolides, Azithromycin and Terfenadine combination should be used with caution.

Theophylline: no evidence of clinically significant pharmacokinetic interaction has been obtained in combined use of Azithromycin and Theophylline in healthy volunteers.

Triazolam: concomitant use of Azithromycin 500 mg on the 1st day and 250 mg on the 2nd day and 0.125 mg of Triazolam on the 2nd day of treatment in 14 healthy patients did not significantly affect pharmacokinetic parameters of Triazolam compared with combined administration of Triazolam and placebo.

Trimethoprim/Sulfamethoxazole: concomitant use of Trimethoprim/Sulfamethoxazole DS (160 mg / 800 mg) for 7 days and 1200 mg of Azithromycin on 7^th day did not significantly affect peak concentrations, total exposure, or urinary excretion of both Trimethoprim and Sulfamethoxazole. Azithromycin serum concentrations were similar to those observed in other studies.

Shelf-life and Storage conditions

Store at a temperature not above 25°C. Store the prepared suspension for not longer than 5 days. Shake well before use.

Keep out of reach of children!

Shelf life is 3 years from the production date. Not to be used after the expiration date.

Prescription Status

By prescription

Packaging

24 g of the drug per bottle (contained 1200 mg of Azithromycin) made of high density polyethylene, sealed with a screw-on polypropylene cap with a ring to control the first opening of the bottle.

1 bottle with a measuring syringe, a double-sided measuring spoon and a measuring cup together with a leaflet placed into a cardboard box.

Manufacturer Information

Foreign production and trade unitary enterprise “Reb-Pharma”, 223216, Republic of Belarus, Minsk region, Chervensky district, Smilovichi, Sadovaya Str., 1, tel./fax: (+375) 17 240 26 35,

e-mail: rebpharma@rebpharma.by, http://www.rebpharma.by