Universal reference book for medicines
Product name: ZETAMAX RETARD (ZETAMAX RETARD)

Active substance: azithromycin

Type: Macrolide antibiotic - azalide

Manufacturer: PFIZER PHARMACEUTICALS (Puerto Rico)
Composition, form of production and packaging
Powder for the preparation of a suspension with sustained release for ingestion of
white or almost white color, non-uniform, incl.
microspheres.
1 f.

azithromycin (in the form of dihydrate) 2 g

Excipients: glycerol tribehenate, poloxamer 407.

Fillers: sucrose, sodium phosphate anhydrous, magnesium hydroxide, giprolose, xanthan gum, silicon dioxide colloid, titanium dioxide, cherry flavor, banana flavor.

Plastic bottles (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

Antibiotic, the first representative subclass of macrolide antibiotics, known as azalides.
Azithromycin binds to the 50S subunit of ribosomes of sensitive microorganisms and disrupts the synthesis of proteins, without affecting the synthesis of nucleic acids. Azithromycin accumulates in fibroblasts, epithelial cells, macrophages and circulating neutrophils and monocytes. After a 1-hour incubation, the ratio of intra- and extracellular concentrations in vitro was greater than 30. The results of in vivo studies suggest that the accumulation of the drug in macrophages and circulating leukocytes can contribute to the distribution of the antibiotic into the inflamed tissues.
Azithromycin exhibited activity against most strains of the following microorganisms, both in vitro and in clinical infections.
It is 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 microorganismsChlamydophila pneumoniae, Mycoplasma pneumoniae. The production of β-lactamase by the microorganism does not affect the activity of azithromycin.
In experiments in vitro, at least 90% of the strains of the following microorganisms were marked with MICs indicating sensitivity 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 the 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 microorganismsPeptostreptococcus spp., Prevotella bivia; other microorganisms Ureaplasma urealyticum.
PHARMACOKINETICS

Zetamax retard is a special dosage form containing microspheres providing sustained release of the active substance.
In healthy volunteers, C max azithromycin in serum and AUC 0-24 after a single dose of Zetamax retard oral dose 2.0 g were higher than with the use of azithromycin in tablets at a total dose of 1.5 g for 3 days (500 mg / day) or 5 days (500 mg on the first day, and then 250 mg / day). Given the difference in pharmacokinetics, the Zetamax retard drug is not interchangeable with azithromycin in the form of tablets (3- and 5-day regimens).
Table 1. The average pharmacokinetic parameters of azithromycin on the first day after a single dose of Zetamax retard at a dose of 2.0 g and after the use of azithromycin in tablets at a total dose of 1.5 g for 3 days (500 mg / day) or 5 days (500 mg on the first day , followed by 250 mg / day) in healthy adult volunteers.

Pharmacokinetic parameters Azithromycin

Zetamax retard (n = 41) 1 3 days (n = 12) 2 5 days (n = 12) 2

Cmax (μg / ml) 0.821 (0.281) 0.441 (0.223) 0.434 (0.202)

T max (h) 3 5.0 (2.0-8.0) 2.5 (1.0-4.0) 2.5 (1.0-6.0)

AUC 0-24 (μg · h / ml) 8.62 (2.34) 2.58 (0.84) 2.60 (0.71)

AUC 0-8 (μg · h / ml) 4 20.0 (6.66) 17.4 (6.2) 14.9 (3.1)

T 1/2 (h) 58.8 (6.91) 71.8 (14.7) 68.9 (13.8)

* Pharmacokinetic parameters of the preparation Zetamax retard and azithromycin in the form of tablets (for 3 and 5 days) were obtained in different studies

1 - n = 21 for AUC 0-8 and T 1/2

2 - C max, T max and AUC 0-24 - only on the first day

3 - average value (range)

4 - General AUC for single admission, admission for 3 and 5 days.

SD is the standard deviation.

Suction

In a cross-sectional study, 16 healthy adult volunteers received a single dose of 2.0 g of Zetamax
retard (powder for the preparation of a sustained release suspension for oral administration) and azithromycin in the form of a powder for the preparation of an oral suspension (PIC) (2 bags of 1.0 g). The median C max and AUC 0-tazithromycin with Zetamax retard were respectively 57% and 17% lower than when taking azithromycin PIC. The bioavailability of the Zetamax retard drug in relation to PIC was 83%. After taking Zetamax retard C max azithromycin was achieved on average 2.5 hours later than after taking azithromycin PIC. Thus, doses of Zetamax retard and azithromycin PIC, which are 2.0 g once, are not bioequivalent and interchangeable.
When Zetamax retard was taken at a dose of 2.0 g after fatty foods (150 kcal proteins, 250 kcal carbohydrates and 500-600 kcal fat), the average C max azithromycin increased by 115% in 15 healthy volunteers and the average AUC 0-4 by 23% compared with those on an empty stomach.
When Zetamax retard was used at a dose of 2.0 g after standard food (56 kcal proteins, 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% with those when taken on an empty stomach.
In a cross-sectional study, 39 healthy adult volunteers received Zetamax retard alone at a dose of 2.0 g and Zetamax retard in combination with 20 ml of an antacid containing aluminum and magnesium hydroxides at standard doses.
The use of antacids did not affect the rate and extent of absorption of azithromycin.
Distribution

The degree of binding of azithromycin to serum proteins depends on the concentration 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 into tissues, while V d in the equilibrium state is 31.1 l / kg.
The concentrations of azithromycin in tissues exceeded those in plasma and serum.
The active distribution of the drug in the tissue may be important for its clinical effectiveness. The antimicrobial activity of azithromycin depends on pH and decreases when it decreases. Therefore, high tissue concentrations may not be quantitatively correlated with clinical efficacy. The concentrations of azithromycin in individual tissues (liquids) and their ratio with concentrations in plasma / serum are shown in Table. 2.
Table 2. Concentrations of azithromycin after taking 500 mg in adults *

Time after administration (h) Concentration in tissues or liquids (μg / g or g / ml) Concentration in plasma or serum (μg / ml) Tissue / plasma ratio (serum)

Leather

72-96 0.4 0.012 35

Light 1

72-96 4.0 0.012> 100

Sputum 2

2-4 1.0 0.64 2

10-12 2.9 0.1 30

Tonsils 3

9-18 4.5 0.03> 100

180 0.9 0.006> 100

Cervix of the uterus 4

19 2.8 0.04 70

* The concentrations of azithromycin in tissues were determined after taking 250 mg capsules.

1 - sampling after 2-4 hours after the first dose.

2 - sampling after 10-12 hours after the first dose

3 - dosing regimen - two doses of 250 mg with an interval of 12 hours.

4 - sampling after 19 hours after a single dose of 500 mg.

The active distribution in the tissue was confirmed in the study of additional tissues and liquids, such as bones, ejaculate, prostate, ovaries, uterus, appendages, stomach, liver and gallbladder.
However, the clinical significance of the concentration of the drug in these tissues is not established, the effectiveness of azithromycin in the treatment of infections of this localization in adequate controlled studies has not been studied.
After a 5-day course of using azithromycin in tablets (500 mg on the first day and 250 mg / day for the remaining 4 days), the drug concentrations in the cerebrospinal fluid were very low (less than 0.01 μg / ml) in the absence of inflammation of the meningeal membranes.

Metabolism

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

Excretion

Serum azithromycin concentrations after a single dose of Zetamax retard at a dose of 2.0 g decrease in several phases with T 1/2 59 h. Prolonged T 1/2 is considered a consequence of a large V d .
Azithromycin is excreted mostly unchanged with bile. After a week of therapy in unchanged form, about 6% of the dose taken is excreted in the urine.
Pharmacokinetics in special clinical cases

The pharmacokinetics of azithromycin was studied in 42 adults (21-85 years) with impaired renal function of varying severity.
After a single intake of 1.0 g of azithromycin (4 250 mg capsules) in patients with a glomerular filtration rate (GFR) of 10-80 ml / min, the mean C max and AUC 0-120 were respectively 5.1 and 4.2% higher than in patients with normal kidney function (GFR> 80 mL / min). In patients with terminal renal failure (GFR <10 ml / min), C max and AUC 0-120 were 61% and 35%, respectively, higher than in patients with normal renal function (GFR> 80 ml / min). Based on data on the study of azithromycin pharmacokinetics in patients with renal insufficiency, dose adjustment of Zetamax retard in patients with GFR> 10 ml / min is not required.
The pharmacokinetic parameters of azithromycin in patients with impaired liver function have not been studied.

The effect of sex on the pharmacokinetics of Zetamax retard has not been studied.
However, in previous studies, no significant difference in the pharmacokinetics of azithromycin in men and women has been identified. In this regard, dose adjustment of azithromycin for patients of different sex is not recommended.
The pharmacokinetics of Zetamax retard in elderly people has not been studied.

Zetamax retard is not registered for pediatric use.

INDICATIONS

Treatment of mild to moderate severity of infections of a specific location caused by sensitive strains of these 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 (if oral therapy is possible).

DOSING MODE

A full course of antibacterial therapy with the Zetamax retard drug suggests its single oral intake at a dose of 2 g.

The contents of the vial are dissolved in 60 ml of water.
Before use, shake well and take it once inside. The drug should be taken on an empty stomach at least 1 hour before or 2 hours after a meal.
SIDE EFFECT

When taking Zetamax retard, a single dose of 2.0 g most often shows mild or moderate unwanted reactions from the digestive tract: diarrhea / unstable stool (11.6%), nausea (3.9%), abdominal pain (2.7%), headache (1.3 %) and vomiting (1.1%).
The incidence of gastrointestinal disorders associated with the use of the Zetamax retard drug and comparator drugs was 17.2% and 9.7%, respectively. The incidence of other adverse events associated with therapy 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: heartbeat, chest pain, arrhythmia * (including ventricular tachycardia and arterial hypotension), rarely - prolongation of the QT interval and extrasystole of the pirouette type).

On the part of the digestive system: constipation, dyspepsia, flatulence, gastritis, candidiasis of the oral cavity, unstable stool, anorexia *, vomiting * / diarrhea *, in rare cases leading to dehydration, pseudomembranous colitis *, pancreatitis *, rare cases of discoloration *.

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

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

From the sense organs: distortion of taste, hearing impairment * (including hearing loss, deafness and / or tinnitus).

On the part of the liver and bile ducts: violations of the liver * (including hepatitis and cholestatic jaundice), rare cases of liver necrosis * and liver failure *, which sometimes led to death.

Allergic reactions: rash, itching, urticaria, arthralgia *, swelling *, angioedema, * photosensitivity reactions *;
rarely serious skin reactions * (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), anaphylaxis * (in rare cases, fatal).
On the part of the hematopoiesis system: thrombocytopenia *, mild neutropenia *.

Common reactions: asthenia, paresthesia *, fatigue *, malaise *.

On the part of laboratory indicators : in the clinical studies of the Zetamax retard drug, the following clinically significant deviations in the laboratory indices (irrespective of the relationship with the treatment) were recorded at their normal baseline values: 1% frequency-a decrease in the number of lymphocytes and an increase in the number of eosinophils;
decrease in the level of bicarbonates; frequency <1% - leukopenia, neutropenia, increased bilirubin level, AST, ALT, residual urea nitrogen, creatinine, potassium level changes. In those cases where the results of the observation were known, laboratory abnormalities were reversible.
* undesirable phenomena registered in clinical practice, the relationship of which with azithromycin is not established.

CONTRAINDICATIONS

severe hepatic impairment;

- Hypersensitivity to azithromycin, erythromycin and any macrolide or ketolide antibiotic.

The efficacy and safety of Zetamax retard in children aged 12 years and younger has not been studied.

With caution appoint a drug for violations of liver function (because azithromycin is excreted mainly by the liver), with terminal renal failure (GFR below 10 ml / min), since
the experience of using the drug in such patients is limited, with arrhythmias (possible development of ventricular arrhythmias and prolongation of the QT interval).
PREGNANCY AND LACTATION

Adequate controlled studies of the use of the drug in pregnancy have not been conducted, so azithromycin can be used during pregnancy only in case of obvious need.

There is no information on the isolation of azithromycin with breast milk.
Many drugs are excreted in breast milk, so caution should be exercised when administering azithromycin to breast-feeding women.
APPLICATION FOR FUNCTIONS OF THE LIVER

With caution appoint the drug with terminal renal failure (glomerular filtration rate below 10 ml / min), tk.
the experience of using the drug in such patients is limited.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution appoint a drug for violations of the liver (because azithromycin is excreted mainly liver).
Contraindicated in severe hepatic insufficiency.
APPLICATION FOR CHILDREN

The efficacy and safety of Zetamax retard in children aged 12 years and younger has not been studied.

SPECIAL INSTRUCTIONS

To prevent the formation of resistant strains of bacteria and ensure the preservation of the effectiveness of Zetamax retard, as well as other antibacterial agents, the drug should be used only to treat confirmed or suspected with a high probability of bacterial infections caused by sensitive bacteria.
When selecting or modifying antibacterial therapy, the results of inoculation and sensitivity assessment should be taken into account. If such data are not available, regional information on the distribution of pathogens and their sensitivity may provide some assistance in choosing empirical therapy.
Before starting treatment, bacteriological tests should be performed to identify the pathogen and determine its sensitivity to the Zetamax retard drug.
Therapy with the Zetamax retard drug can be started before the test results are obtained. When they become known, antimicrobial therapy should be adjusted accordingly.
In the treatment with other macrolides, prolongation of repolarization of the heart and QT interval was noted, which increases the risk of arrhythmias, in particular ventricular arrhythmias such as pirouettes.
In patients with an increased risk of prolonging repolarization, a similar effect of azithromycin can not be completely ruled out.
In rare cases, patients who received other forms of azithromycin developed serious allergic reactions, including angioedema, anaphylaxis and skin reactions, including.
Stevens-Johnson syndrome and toxic epidermal necrolysis (although rarely, there have been fatal cases). Despite the effectiveness of primary symptomatic therapy, after its termination in some patients, allergy symptoms soon reappeared, although patients did not receive azithromycin. Such patients need longer follow-up and symptomatic treatment. The relationship between such undesirable phenomena and the long half-life of azithromycin from tissues with subsequent exposure to the antigen is not established.
If any signs of an allergic reaction appear, patients should immediately consult a doctor.
In case of development of an allergic reaction, appropriate therapy should be prescribed. The physician should consider that after the termination of symptomatic treatment it is possible to resume allergy symptoms.
In the treatment of almost all antibacterial agents described cases of pseudomembranous colitis, the severity of which can vary from mild to life-threatening.Therefore, the appearance of diarrhea should be considered the possibility of this disease after administration of antibacterial agents.
Treatment with antibacterial drugs leads to a change of normal microflora of the colon and can cause overgrowth of clostridia. Studies have shown that the primary cause of "colitis associated with antibiotics," is the toxin Clostridium difficile.
If the diagnosis of pseudomembranous colitis, it is necessary to take appropriate measures. In mild cases, usually enough to cancel an antibacterial drug. In the medium-severe and severe cases shown administering fluids and electrolytes, proteins and prescription of antibacterial agents effective in colitis caused by Clostridium difficile.
If within 5 minutes after administration of the drug in the patient develops vomiting, the physician should consider whether more destination antibiotic therapy, because absorption of azithromycin in this case will be minimal. Recorded suction azithromycin in the event of vomiting in the range of 5-60 min after receiving insufficient, so the physician should assess the need for alternative therapies. If vomiting develops within 60 minutes after dosing in patients with normal motility of the stomach, receiving a second dose Zetamaks retard or other antibiotic required.
Zetamaks retard slurry contains 148 mg of sodium.
OVERDOSE

In case of overdose can be expected to develop the above-mentioned side effects in a more pronounced form.
Treatment: symptomatic and supportive therapy.
DRUG INTERACTION

The pharmacokinetic studies have examined the interaction of azithromycin in the form of capsules and tablets (at doses from 500 to 1200 mg) with drugs that could be used simultaneously with them. azithromycin effects on the pharmacokinetics of other drugs given in Table. 1, and the effects of other drugs on the pharmacokinetics of azithromycin - Table.
2.
Use of azithromycin in capsules and tablets at therapeutic doses have little effect on the pharmacokinetics of the drugs listed in Table. 3. Although the interaction Zetamaks retard drug with other drugs has not been studied, it can be assumed absence of potential interactions, since total azithromycin AUC values when using the drug Zetamaks retard and other forms of azithromycin comparable. In connection with this correction doses of drugs are listed in Table. 1, is not recommended when applied simultaneously with the drug Zetamaks retard.
Efavirenz and fluconazole has little effect on the pharmacokinetics of azithromycin is used in form of tablets. Nelfinavir induced a significant increase in the Cmaxand AUC of azithromycin. Similar results can be expected when using the drug Zetamaks retard. Although correction doses Zetamaks retard when applied simultaneously with the preparations listed in Table. 2, is not recommended, however, when combined with nelfinavir prudent to carefully control the known side effects of azithromycin, such as the elevation of liver enzymes and impaired hearing.
Azithromycin has no effect on the change in prothrombin time with single dose of warfarin. However, while the use of azithromycin and warfarin advisable to carefully monitor the prothrombin time. Concomitant use of macrolides and warfarin in clinical practice, accompanied by increased anticoagulant effect.
The pharmacokinetic studies revealed that the therapeutic dose azithromycin has little influence on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (in / and orally), triazolam, trimethoprim / sulfamethoxazole and zidovudine. The simultaneous use of efavirenz or fluconazole has little effect on azithromycin pharmacokinetics. Correction doses of these drugs during their simultaneous use of azithromycin is not required.
Table 1. Pharmacokinetic parameters of drugs used simultaneously with azithromycin.
Dose dose of azithromycin * The ratio (with / without azithromycin) pharmacokinetic parameters drugs used simultaneously (90% CI); no effect = 1.00
The average C max average AUC
Atorvastatin (n = 12)
10 mg / day, 8 days, 500 mg / day orally in 6-8 day 0.83 (0.63-1.08) 1.01 (0.81-1.25)
carbamazepine (n = 7 )
200 mg / day for 2 days, then 200 mg of 2 times / day for 18 days of 500 mg / day orally for 16-18 days 0.97 (0.88-1.06) 0.96 (0.88-1.06)
Cetirizine (n = 14)
20 mg / days 11 days 500 mg orally on day 7, followed by 250 mg / day (days 8-11) 1.03 (0.93-1.14) 1.02 ( 0.92-1.13)
Didanosine (n = 6)
200 mg orally 2 times / day 21 days 1200 mg / day orally for 8-21-day 1.44 (0.85-2.43) 1.14 (0.83-1.57)
Efavirenz (n = 14)
400 mg / day, 7 days 600 mg orally on Day 7 1.04 1 0.95 1
Fluconazole (n = 18)
200 mg single oral dose of 1200 mg single oral dose of 1.04 (0.98-1.11) 1.01 (0.97-1.05)
indinavir (n = 18)
800 mg 3 times / day 5 days 1200 mg inwards on day 5 0.96 (0.86-1.08) 0.90 (0.81-1.00)
Midazolam (n = 12)
15 mg orally on day 3 500 mg / day orally 3 days 1.27 (0.89-1.81) 1.26 (1.01-1.56)
, nelfinavir (n = 14)
750 mg 3 times / day for 11 days 1200 mg inwards on day 9 0.90 (0.81-1.01) 0.85 (0.78-0.93)
Rifabutin (n = 6 )
300 mg / day, 10 days, 500 mg orally on the first day followed by 250 mg (days 2-10) - 2 No data
sildenafil (n = 12)
100 mg and 1 4th day 500 mg / day of the day 3 1.16 (0.86-1.57) 0.92 (0.75-1.12)
Theophylline (n = 10),
4 mg / kg / days 1, 11, 25 to 500 mg po 7th day, followed by 250 mg / day (days 8-11) 1.19 (1.02-1.40) 1.02 ( 0.86-1.22)
Theophylline (n = 8)
300 mg 2 times / days 15 days 500 mg po for 6 minutes day and then 250 mg / day (days 7-10) 1.09 (0.92-1.29) 1.08 ( 0.89-1.31)
triazolam (n = 12),
0.125 mg on the 2nd day, 500 mg orally on the first day, followed by 250 mg / day on day 2 1.06 1 1.02 1
Trimethoprim / sulfamethoxazole (n = 12)
160 mg / 800 mg orally 7 days 1200 mg inwards on day 7 0.85 (0.75-0.97) /0.90 (0.78-1.03) 0.87 (0.80-0.95) /0.96 (0.88-1.03)
Zidovudine (n = 5)
500 mg orally 21 days 600 mg orally 14 days 1.12 (0.42-3.02) 0.94 (0.52-1.70)
Zidovudine (n = 4)
500 mg orally 21 days 1200 mg / day orally 14 days 1.31 (0.43-3.97) 1.30 (0.69- 2.43)
* capsules and tablets of azithromycin, unless otherwise indicated
1 90% confidence interval Unknown
2 mean concentrations of rifabutin 12 hours after the last dose of rifabutin amounted to 60 ng / ml, while the use of azithromycin and 71 ng / ml, while the use of placebo.
Table 2. Pharmacokinetic parameters of azithromycin while the use of other drugs.
Dose dose of azithromycin * The ratio (with / without simultaneously applied PM) pharmacokinetic parameters of azithromycin (90% CI); no effect = 1.00
The average Cmax average AUC
Efavirenz (n = 14)
400 mg / day, 7 days 600 mg orally on Day 7 1.22 (1.04-1.42) 0.92 1
Fluconazole (n = 18)
200 mg single oral 1200 mg single oral 0.82 (0.66-1.02) 1.07 (0.94-1.22)
, nelfinavir (n = 14)
750 mg 3 times / day for 11 days 1200 mg inwards on day 9 2.36 (1.77-3.15) 2.12 (1.8-2.50)
Rifabutin (n = 6)
300 mg / day, 10 days, 500 mg orally on the first day followed by 250 mg / day (days 2-10) - 2 No data
Aluminum and magnesium hydroxide (n = 39)
Once in 20 ml of normal doses of 2 g once Zetamaks 0.99 (0.93-1.06) 0.99 (0.92-1.08)
* azithromycin capsules and tablets, unless otherwise indicated
1 90% confidence interval Unknown
2 mean concentrations of azithromycin 1 day after the last dose is 53 ng / ml, while the use of rifabutin at 300 mg / day and 49 ng / ml, while the use of placebo.
In clinical studies, the following interaction of drugs with azithromycin is not set, but special studies of their interactions was conducted. However, cases of interaction have been reported when applied simultaneously with other macrolides. Before receiving additional data on the interaction with azithromycin while taking drugs listed below recommended careful monitoring of patients:
- digoxin - increasing the concentration of digoxin;
- ergotamine and dihydroergotamine - acute toxicity characterized by severe peripheral vasospasm and dysesthesia;
- monitoring the concentration of cyclosporine, hexobarbital and phenytoin.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at or above 30 ° S.Srok life - 3 years.
Do not use after the expiration date printed on the package.
The finished slurry should be kept out of reach of children at room temperature (15 ° -30 ° C);
Do not freeze. The finished slurry should be used techenie12 hours.
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