Zetamax Retard (Powder) Instructions for Use

Marketing Authorization Holder

Pfizer Pharmaceuticals, LLC (Puerto Rico)

ATC Code

J01FA10 (Azithromycin)

Active Substance

Azithromycin (Rec.INN registered by WHO)

Dosage Form

Zetamax Retard

Powder for the preparation of prolonged-release oral suspension 2 g: 1 pc.

Dosage Form, Packaging, and Composition

Powder for the preparation of prolonged-release oral suspension white or almost white, heterogeneous, incl. microspheres.

Excipients : glyceryl tribehenate, poloxamer 407.

Fillers sucrose, anhydrous sodium phosphate, magnesium hydroxide, hypromellose, xanthan gum, colloidal silicon dioxide, titanium dioxide, cherry flavor, banana flavor.

Plastic bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antibiotic of the macrolide group – azalide

Pharmacotherapeutic Group

Antibiotic-azalide

Pharmacological Action

Antibiotic, the first representative of the subclass of macrolide antibiotics known as azalides. Azithromycin binds to the 50S ribosomal subunit of susceptible microorganisms and disrupts protein synthesis, without affecting nucleic acid synthesis. Azithromycin accumulates in fibroblasts, epithelial cells, macrophages, and circulating neutrophils and monocytes. After 1 hour of incubation, the ratio of intracellular to extracellular concentrations in vitro exceeded 30. Results of in vivo studies suggest that accumulation of the drug in macrophages and circulating leukocytes may contribute to the distribution of the antibiotic to inflamed tissues.

Azithromycin demonstrated activity against most strains of the microorganisms listed below both in vitro and in clinical infections. Active against aerobic and facultative gram-positive microorganisms Streptococcus pneumoniae (gram-positive microorganisms resistant to erythromycin and penicillin may exhibit cross-resistance to azithromycin); aerobic and facultative gram-negative microorganisms Haemophilus influenzae, Moraxella catarrhalis; other microorganisms Chlamydophila pneumoniae, Mycoplasma pneumoniae. Production of β-lactamases by the microorganism does not affect the activity of azithromycin.

In in vitro experiments, at least 90% of strains of the following microorganisms had MICs indicating susceptibility to azithromycin. However, the safety and efficacy of azithromycin in the treatment of infections caused by these microorganisms have not been established in adequate controlled studies. These include aerobic and facultative gram-positive microorganisms Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococci (groups C, F, G), Streptococcus viridans; aerobic and facultative gram-negative microorganisms Bordetella pertussis, Legionella pneumophila; anaerobic microorganisms Peptostreptococcus spp., Prevotella bivia; other microorganisms Ureaplasma urealyticum.

Pharmacokinetics

Zetamax Retard is a special dosage form containing microspheres that provide prolonged release of the active substance. In healthy volunteers, the C_max of azithromycin in serum and AUC_0-24 after a single oral dose of Zetamax Retard 2.0 g were higher than with azithromycin tablets in a total dose of 1.5 g over 3 days (500 mg/day) or 5 days (500 mg on the first day, then 250 mg/day). Given the difference in pharmacokinetics, Zetamax Retard is not interchangeable with azithromycin in tablet form (3- and 5-day regimens).

Table 1. Mean pharmacokinetic parameters of azithromycin on the first day after a single dose of Zetamax Retard 2.0 g and after administration of azithromycin tablets in a total dose of 1.5 g over 3 days (500 mg/day) or 5 days (500 mg on the first day, then 250 mg/day) in healthy adult volunteers.

*Pharmacokinetic parameters of Zetamax Retard and azithromycin in tablet form (over 3 and 5 days) were obtained in different studies

¹ – n=21 for AUC_0-8and T_1/2

² – C_max,T_maxand AUC_{0-24 –}only on the first day

³– mean (range)

⁴ – Total AUC for single dose, 3-day and 5-day administration.

SD – standard deviation.

Absorption

In a crossover study, 16 healthy adult volunteers received a single 2.0 g dose of Zetamax Retard (powder for the preparation of prolonged-release oral suspension) and Azithromycin as a powder for oral suspension (POS) (2 sachets of 1.0 g each). The mean C_max and AUC_0-t of azithromycin when taking Zetamax Retard were 57% and 17% lower, respectively, than when taking azithromycin POS. The bioavailability of Zetamax Retard relative to POS was 83%. After taking Zetamax Retard, the C_max of azithromycin was reached on average 2.5 hours later than after taking azithromycin POS. Thus, doses of Zetamax Retard and azithromycin POS of 2.0 g as a single dose are not bioequivalent and are not interchangeable.

When taking Zetamax Retard at a dose of 2.0 g after a high-fat meal (150 kcal protein, 250 kcal carbohydrates and 500-600 kcal fat) in 15 healthy volunteers, the mean C_max of azithromycin increased by 115%, and the mean AUC_0-4 – by 23% compared to those on an empty stomach. When using Zetamax Retard at a dose of 2.0 g after a standard meal (56 kcal protein, 316 kcal carbohydrates and 207 kcal fat) in 88 adults, the mean C_max of azithromycin increased by 119%, and the mean AUC_{0-72 h} – by 12% compared to those when taken on an empty stomach.

In a crossover study, 39 healthy adult volunteers took only Zetamax Retard at a dose of 2.0 g and Zetamax Retard in combination with 20 ml of an antacid containing aluminum and magnesium hydroxides in standard doses. The use of the antacid did not affect the rate and extent of absorption of azithromycin.

Distribution

The degree of binding of azithromycin to serum proteins is concentration-dependent and decreases from 51% at a concentration of 0.02 µg/ml to 7% at 2.0 µg/ml. After oral administration, Azithromycin is widely distributed in tissues, with a V_d at steady state of 31.1 L/kg.

Azithromycin concentrations in tissues exceeded those in plasma and serum. Active distribution of the drug into tissues may be important for its clinical efficacy. The antimicrobial activity of azithromycin is pH-dependent and decreases with decreasing pH. Therefore, high tissue concentrations may not quantitatively correlate with clinical efficacy. Azithromycin concentrations in individual tissues (fluids) and their ratio to plasma/serum concentrations are shown in Table 2.

Table 2. Azithromycin concentrations after a 500 mg dose in adults*

* Azithromycin tissue concentrations were determined after taking 250 mg capsules.

¹ – sample collection 2-4 hours after the first dose.

² – sample collection 10-12 hours after the first dose

³ – dosing regimen – two doses of 250 mg with a 12-hour interval.

⁴ – sample collection 19 hours after a single 500 mg dose.

Active distribution into tissues was confirmed by studying additional tissues and fluids, such as bone, ejaculate, prostate, ovaries, uterus, appendages, stomach, liver, and gallbladder. However, the clinical significance of the drug concentration in these tissues has not been established, since the efficacy of azithromycin in the treatment of infections of this localization has not been studied in adequate controlled studies.

After a 5-day course of azithromycin tablets (500 mg on the first day and 250 mg/day for the remaining 4 days), drug concentrations in the cerebrospinal fluid in the absence of meningeal inflammation were very low (less than 0.01 µg/ml).

Metabolism

The metabolism of azithromycin has not been studied in in vitro and in vivo studies.

Excretion

Serum concentrations of azithromycin after a single dose of Zetamax Retard 2.0 g decrease in several phases with a T_1/2 of 59 h. The long T_1/2 is considered a consequence of the large V_d. Azithromycin is excreted mainly unchanged in the bile. After a week-long course of therapy, approximately 6% of the administered dose is excreted unchanged in the urine.

Pharmacokinetics in special clinical cases

The pharmacokinetics of azithromycin were studied in 42 adults (21-85 years) with varying degrees of renal impairment. After a single oral dose of 1.0 g of azithromycin (4 capsules of 250 mg) in patients with a glomerular filtration rate (GFR) of 10-80 ml/min, the mean C_max and AUC_0-120 were 5.1% and 4.2% higher, respectively, than in patients with normal renal function (GFR>80 ml/min). In patients with end-stage renal disease (GFR<10 ml/min), C_max and AUC_0-120 were 61% and 35% higher, respectively, than in patients with normal renal function (GFR>80 ml/min). Based on pharmacokinetic data for azithromycin in patients with renal impairment, no dose adjustment of Zetamax Retard is required in patients with GFR>10 ml/min.

The pharmacokinetic parameters of azithromycin in patients with hepatic impairment have not been studied.

The effect of gender on the pharmacokinetics of Zetamax Retard has not been studied. However, in previous studies, no significant difference in the pharmacokinetics of azithromycin between men and women was found. Therefore, dose adjustment of azithromycin for patients of different genders is not recommended.

The pharmacokinetics of Zetamax Retard in the elderly have not been studied.

Zetamax Retard is not registered for use in pediatrics.

Indications

Treatment of mild to moderate infections of certain locations caused by susceptible strains of the listed microorganisms

• Acute bacterial sinusitis caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae;
• Community-acquired pneumonia caused by Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae (when oral therapy is possible).

ICD codes

Dosage Regimen

Administer the full course of antibacterial therapy as a single oral dose of 2 g.

Take the drug on an empty stomach, at least one hour before or two hours after a meal.

Prepare the suspension immediately before use by adding 60 ml of water to the powder in the bottle.

Shake the bottle vigorously until the powder is completely dispersed to form a heterogeneous suspension.

Ingest the entire prepared suspension immediately as a single dose; do not store the prepared suspension for later use.

Do not administer this formulation to children under 12 years of age, as safety and efficacy have not been established.

This prolonged-release formulation is not interchangeable with other azithromycin tablet or suspension regimens.

If vomiting occurs within one hour of administration, contact a physician to consider the need for an alternative antibiotic dose.

Adverse Reactions

When taking Zetamax Retard as a single 2.0 g dose, the most frequently observed are mild or moderate adverse reactions from the gastrointestinal tract: diarrhea/loose stools (11.6%), nausea (3.9%), abdominal pain (2.7%), headache (1.3%) and vomiting (1.1%). The frequency of gastrointestinal disorders associated with the use of Zetamax Retard and comparator drugs was 17.2% and 9.7%, respectively. The frequency of other therapy-related adverse reactions in patients receiving Zetamax Retard did not exceed 1%.

Adverse events occurring with a frequency of less than 1% in patients taking Zetamax Retard are listed below.

From the cardiovascular system: palpitations, chest pain, arrhythmias* (including ventricular tachycardia and arterial hypotension), rarely – QT interval prolongation* and torsades de pointes).

From the digestive system: constipation, dyspepsia, flatulence, gastritis, oral candidiasis, loose stools, anorexia*, vomiting*/diarrhea*, in rare cases leading to dehydration, pseudomembranous colitis*, pancreatitis*, rare cases of tongue discoloration*.

From the genitourinary system vaginitis, interstitial nephritis*, acute renal failure*, candidiasis*.

From the central and peripheral nervous system dizziness, seizures*, headache*, drowsiness*, hyperactivity*, nervousness*, agitation* and fainting*, aggressive reactions* and anxiety*.

From the senses taste perversion, hearing disorders* (including hearing loss, deafness and/or tinnitus).

From the liver and biliary tract: liver function disorders* (including hepatitis and cholestatic jaundice), rare cases of liver necrosis* and liver failure*, which were sometimes fatal.

Allergic reactions: rash, itching, urticaria, arthralgia*, edema*, angioedema*, photosensitivity reactions*; rarely – serious skin reactions* (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), anaphylaxis* (in rare cases with fatal outcome).

From the hematopoietic system: thrombocytopenia*, mild neutropenia*.

General reactions asthenia, paresthesia*, fatigue*, malaise*.

From laboratory parameters : in clinical studies of Zetamax Retard, the following clinically significant deviations in laboratory parameters (regardless of relationship to treatment) with their normal baseline values were recorded: frequency ≥1% – decrease in lymphocyte count and increase in eosinophil count; decrease in bicarbonate level; frequency <1% – leukopenia, neutropenia, increase in bilirubin level, AST, ALT, blood urea nitrogen, creatinine, changes in potassium level. In cases where follow-up results were known, the laboratory deviations were reversible.

* adverse events reported in clinical practice, the relationship of which with azithromycin has not been established.

Contraindications

• Severe hepatic insufficiency;
• Hypersensitivity to azithromycin, erythromycin and any macrolide or ketolide antibiotics.

The efficacy and safety of Zetamax Retard in children aged 12 years and under have not been studied.

With caution the drug should be prescribed for liver dysfunction (since Azithromycin is excreted primarily by the liver), for end-stage renal failure (GFR below 10 ml/min), because experience with the drug in such patients is limited, for arrhythmias (ventricular arrhythmias and QT interval prolongation may develop).

Use in Pregnancy and Lactation

Adequate controlled studies of the use of the drug during pregnancy have not been conducted, therefore Azithromycin can be used during pregnancy only in case of clear necessity.

There is no information on the excretion of azithromycin in breast milk. Many drugs are excreted in breast milk, so caution should be exercised when prescribing azithromycin to nursing women.

Use in Hepatic Impairment

With caution the drug should be prescribed for liver dysfunction (since Azithromycin is excreted primarily by the liver). Contraindicated in severe hepatic insufficiency.

Use in Renal Impairment

With caution the drug should be prescribed for end-stage renal failure (glomerular filtration rate below 10 ml/min), because experience with the drug in such patients is limited.

Pediatric Use

The efficacy and safety of Zetamax Retard in children aged 12 years and under have not been studied.

Special Precautions

To prevent the development of resistant bacterial strains and to maintain the effectiveness of Zetamax Retard, as well as other antibacterial agents, the drug should be used only for the treatment of confirmed or highly suspected bacterial infections caused by susceptible bacteria. When selecting or modifying antibacterial therapy, the results of culture and susceptibility testing should be taken into account. If such data are not available, regional information on the prevalence of pathogens and their susceptibility may provide some assistance in the selection of empirical therapy.

Before starting treatment, bacteriological studies should be conducted to identify the pathogen and determine its sensitivity to Zetamax retard. Therapy with Zetamax retard can be initiated before the test results are available. Once they become known, antimicrobial therapy should be adjusted accordingly.

Treatment with other macrolides has been associated with prolongation of cardiac repolarization and the QT interval, which increases the risk of arrhythmias, particularly ventricular arrhythmias of the ‘torsades de pointes’ type. A similar effect of azithromycin cannot be completely ruled out in patients at increased risk of repolarization prolongation.

In rare cases, patients receiving other forms of azithromycin have developed serious allergic reactions, including angioedema, anaphylaxis, and skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (although rare, fatalities have occurred). Despite the effectiveness of initial symptomatic therapy, after its discontinuation, allergy symptoms reappeared shortly in some patients, even though they did not receive Azithromycin. Such patients require longer observation and symptomatic treatment. The relationship between such adverse events and the long tissue half-life of azithromycin with subsequent antigen exposure has not been established.

If any signs of an allergic reaction appear, patients should immediately consult a doctor. If an allergic reaction develops, adequate therapy should be prescribed. The physician should be aware that allergy symptoms may recur after discontinuation of symptomatic treatment.

Cases of pseudomembranous colitis have been reported with almost all antibacterial agents, with severity ranging from mild to life-threatening. Therefore, the possibility of this disease should be considered if diarrhea occurs after the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.

If the diagnosis of pseudomembranous colitis is established, appropriate measures should be taken. In mild cases, discontinuation of the antibacterial drug is usually sufficient. In moderate to severe cases, administration of fluids and electrolytes, protein supplementation, and the prescription of antibacterial agents effective against Clostridium difficile colitis are indicated.

If vomiting occurs within 5 minutes of taking the drug, the physician should consider the advisability of prescribing additional antibiotic therapy, as the absorption of azithromycin in this case will be minimal. Data on the absorption of azithromycin if vomiting occurs within the 5-60 minute interval after its intake are insufficient; therefore, the physician should assess the need for alternative therapy. If vomiting occurs more than 60 minutes after taking the drug in patients with normal gastric motility, a second dose of Zetamax retard or another antibiotic is not required.

Zetamax retard suspension contains 148 mg of sodium.

Overdose

In case of overdose, the aforementioned adverse events may occur in a more pronounced form.

Treatment symptomatic and supportive therapy.

Drug Interactions

Pharmacokinetic studies have investigated the interaction of azithromycin in capsule and tablet form (in doses from 500 to 1200 mg) with drugs that could be used concomitantly. The effects of azithromycin on the pharmacokinetics of other drugs are presented in Table 1, and the effects of other drugs on the pharmacokinetics of azithromycin are presented in Table 2.

The use of azithromycin capsules and tablets at therapeutic doses had a minor effect on the pharmacokinetics of the drugs listed in Table 3. Although the interaction of Zetamax retard with other drugs has not been studied, the absence of a potential interaction can be assumed, as the total AUC values of azithromycin when using Zetamax retard and other forms of azithromycin are comparable. Therefore, dose adjustment of the drugs listed in Table 1 when used concomitantly with Zetamax retard is not recommended.

Efavirenz and fluconazole had a small effect on the pharmacokinetics of azithromycin used in tablet form. Nelfinavir caused a significant increase in C_max and AUC of azithromycin. Similar results can be expected with the use of Zetamax retard. Although dose adjustment of Zetamax retard when used concomitantly with the drugs listed in Table 2 is not recommended, careful monitoring of known side effects of azithromycin, such as increased liver enzyme activity and hearing impairment, is advisable when combined with nelfinavir.

Azithromycin did not affect the change in prothrombin time with a single dose of warfarin. Nevertheless, when azithromycin is used concomitantly with warfarin, it is advisable to carefully monitor the prothrombin time. Concomitant use of macrolides and warfarin in clinical practice has been accompanied by an enhancement of the anticoagulant effect.

Pharmacokinetic studies have established that at therapeutic doses, Azithromycin has a weak effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (IV and oral), triazolam, trimethoprim/sulfamethoxazole, and zidovudine. Concomitant use of efavirenz or fluconazole had a small effect on the pharmacokinetics of azithromycin. Dose adjustment of these drugs when used concomitantly with azithromycin is not required.

Table 1. Pharmacokinetic parameters of drugs used concomitantly with azithromycin.

* azithromycin capsules and tablets, unless otherwise specified

¹ 90% confidence interval not reported

²mean rifabutin concentrations 12 hours after the last rifabutin dose were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo.

Table 2. Pharmacokinetic parameters of azithromycin when co-administered with other drugs.

* azithromycin capsules and tablets, unless otherwise specified

¹ 90% confidence interval not reported

²mean azithromycin concentrations 1 day after the last dose were 53 ng/mL when co-administered with rifabutin 300 mg/day and 49 ng/mL when co-administered with placebo.

Clinical interaction studies of the following drugs with azithromycin have not been conducted; however, no interactions have been observed in clinical trials. Nevertheless, interaction cases have been reported during their concomitant use with other macrolides. Until further interaction data with azithromycin are available, careful monitoring of patients is recommended when the following drugs are used concomitantly:

• Digoxin – increased digoxin concentrations;
• Ergotamine and dihydroergotamine – acute toxicity characterized by severe peripheral vasospasm or dysesthesia;
• Monitoring of cyclosporine, hexobarbital, and phenytoin concentrations.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the packaging.

The prepared suspension should be stored out of the reach of children at room temperature (15°-30°C (59°-86°F)); do not freeze. The prepared suspension should be used within 12 hours.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.