Decisan

INSTRUCTION for medical use of the medicinal product DECISUN (DECISUN)

Composition:

Active substance: decitabine;

1 vial contains 50 mg of decitabine;

solvent composition: potassium dihydrogen phosphate, sodium hydroxide, water for injections.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: lyophilized powder from white to almost white.

Solvent: colorless solution.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. ATC code L01B C08.

Pharmacological Properties

Pharmacodynamics

Decitabine (5-aza-2′-deoxycytidine) is a deoxynucleoside analogue of cytidine that, at low doses, selectively inhibits DNA methyltransferases, resulting in hypomethylation of gene promoter regions. This may lead to reactivation of tumor suppressor genes, induction of cellular differentiation or senescence, and subsequent programmed cell death.

Clinical Experience

The use of decitabine was evaluated in an open-label, randomized, multicenter Phase III study (DACO-016) involving patients with newly diagnosed de novo or secondary acute myeloid leukemia (AML) according to WHO classification. Decitabine (n = 242) was compared with treatment choice (TC, n = 243), which consisted of either supportive care only at the physician’s discretion (n = 28, 11.5%) or subcutaneous cytarabine 20 mg/m² once daily for 10 consecutive days, repeated every 4 weeks (n = 215, 88.5%). Decitabine was administered as a 1-hour intravenous infusion of 20 mg/m² once daily for 5 consecutive days, repeated every 4 weeks.

Patients considered candidates for standard induction chemotherapy were not included in the study, as reflected by the following baseline characteristics. The median age in the intent-to-treat (ITT) population was 73 years (range: 64–91 years). Thirty-six percent of patients had low-risk cytogenetics at baseline; the remainder had intermediate-risk cytogenetics. Patients with favorable cytogenetics were excluded from the study. Twenty-five percent of patients had an ECOG performance status ≥ 2. Eighty-one percent of patients had significant comorbidities (e.g., infection, heart failure, respiratory failure). The racial distribution among patients receiving decitabine was 209 (86.4%) Caucasian and 33 (13.6%) Asian.

The primary endpoint of the study was overall survival. Secondary endpoints included complete remission rate, as assessed by independent expert review. Progression-free survival and event-free survival were tertiary endpoints.

Median overall survival in the ITT population was 7.7 months for patients receiving decitabine compared to 5.0 months for patients in the TC group (HR [hazard ratio] = 0.85; 95% CI: 0.69, 1.04; p = 0.1079). The difference did not reach statistical significance; however, a trend toward improved survival was observed, with a 15% reduction in the risk of death for patients in the decitabine group (Fig. 1). When subsequent disease-modifying therapies (e.g., induction chemotherapy or hypomethylating agents) were accounted for in the analysis, overall survival showed a 20% reduction in the risk of death for patients in the decitabine group (HR = 0.80; 95% CI: 0.64, 0.99; p = 0.0437).

Figure 1.

In an analysis incorporating additional 1-year survival data in this elderly population, the effect of decitabine on overall survival demonstrated a clinically meaningful improvement compared to the TC group (7.7 months vs. 5.0 months, respectively; HR = 0.82; 95% CI: 0.68, 0.99; p = 0.0373; Fig. 2).

Figure 2.

Based on the initial analysis in the ITT population, a statistically significant difference in complete remission rate (CR + CRp) was achieved in favor of the decitabine group: 17.8% (43/242) versus 7.8% (19/243) in the TC group; treatment difference 9.9% (95% CI: 4.07, 15.83); p = 0.0011. The median time to best response and median duration of best response among patients achieving CR or CRp were 4.3 months and 8.3 months, respectively. Progression-free survival was significantly longer in the decitabine group: 3.7 months (95% CI: 2.7, 4.6) versus 2.1 months (95% CI: 1.9, 3.1) in the TC group; HR = 0.75; 95% CI: 0.62, 0.91; p = 0.0031. These results, along with other endpoints, are summarized in Table 1.

Table 1

CR – complete remission.

CRp – complete remission with incomplete platelet recovery.

EFS – event-free survival.

PFS – progression-free survival.

OR – odds ratio.

HR – hazard ratio.

• Not evaluable.

a Reported as median number of months.

b 95 % confidence interval.

Overall survival and complete remission rates in predefined disease-related subgroups (i.e., cytogenetic risk, Eastern Cooperative Oncology Group [ECOG] performance status, age, type of AML, and baseline bone marrow blast count) were consistent with the results observed in the overall population.

The use of decitabine as initial therapy was also evaluated in an open-label, single-arm phase II study (DACO-017) involving 55 patients aged ≥60 years with AML according to WHO classification. The primary endpoint was the complete remission (CR) rate, assessed by independent expert review. The secondary endpoint was overall survival. Decitabine was administered as a one-hour intravenous infusion at a dose of 20 mg/m² once daily for 5 consecutive days, repeated every 4 weeks. In the ITT analysis, the CR rate was 23.6 % (95 % CI: 13.2; 37), observed in 13/55 patients receiving Dacogen. The median time to CR was 4.1 months, and the median duration of CR was 18.2 months. Median overall survival in the ITT population was 7.6 months (95 % CI: 5.7; 11.5).

The efficacy and safety of decitabine have not been evaluated in patients with acute promyelocytic leukemia or CNS leukemia.

Pediatric population

An open-label, multicenter phase I/II study evaluated the safety and efficacy of decitabine in combination with cytarabine in children aged 1 month to <18 years with relapsed or refractory AML. A total of 17 patients received decitabine at a dose of 20 mg/m², of whom 9 received cytarabine at 1 g/m² and 8 received cytarabine at the maximum tolerated dose of 2 g/m². All participants discontinued the investigational treatment. Reasons for discontinuation: disease progression – 12 patients (70.6 %); patients proceeded to transplantation – 3 patients (17.6 %); investigator decision – 1 patient (5.9 %); other – 1 patient (5.9 %). Adverse reactions reported were consistent with the known safety profile.

Pharmacokinetics

Population pharmacokinetic parameters for decitabine were derived from three clinical studies involving 45 patients with AML or myelodysplastic syndrome (MDS) using a five-day dosing schedule. In each study, pharmacokinetic parameters were assessed on day 5 of each treatment cycle.

Distribution

The pharmacokinetics of decitabine following intravenous administration as a one-hour infusion were described by a linear two-compartment model, characterized by rapid elimination from the central compartment and relatively slow distribution from the peripheral compartment. Pharmacokinetic parameters for a typical patient (body weight 70 kg, body surface area 1.73 m²) are summarized in Table 2.

Table 2

The total dose per cycle was 100 mg/m².

Decitabine exhibits linear pharmacokinetics following intravenous infusion, and steady-state concentrations are achieved within 30 minutes. Based on modeling calculations, the pharmacokinetic parameters were time-independent (did not change from cycle to cycle), and no accumulation was observed with this dosing regimen. Binding of decitabine to plasma proteins is negligible (< 1%). The Vdss (volume of distribution at steady state) of decitabine in cancer patients is high, indicating distribution of the drug into peripheral tissues. No dependence on age, creatinine clearance, total bilirubin, or disease state was observed.

Metabolism

Intracellularly, decitabine is activated through sequential phosphorylation by phosphokinases to its corresponding triphosphate, which is then incorporated into DNA by DNA polymerase. In vitro metabolism studies and human mass balance study results have demonstrated that the cytochrome P450 system is not involved in the metabolism of decitabine. The primary metabolism occurs via deamination by cytidine deaminase in the liver, kidneys, intestinal epithelium, and blood. Results of human mass balance studies showed that the level of unchanged decitabine in plasma is approximately 2.4% of the total radioactive material in plasma. The major metabolites are considered to lack pharmacological activity. The presence of these metabolites in urine, along with high total clearance and low excretion of the active substance unchanged in urine (~4% of the dose), indicates that decitabine is extensively metabolized in vivo. In vitro studies indicate that decitabine, at concentrations 20 times higher than the maximum therapeutic plasma concentration (Cmax), does not inhibit or induce CYP450 enzymes. Therefore, CYP-mediated drug interactions with agents metabolized by these pathways are not expected. Additionally, in vitro data show that decitabine is a weak substrate of P-glycoprotein.

Elimination

Mean plasma clearance after intravenous administration in cancer patients was > 200 L/h, with moderate inter-subject variability (coefficient of variation (CV) approximately 50%). Excretion of the active substance unchanged plays a minor role in the elimination of decitabine.

Results from mass balance studies using radiolabeled 14C-decitabine in cancer patients showed that 90% of the decitabine dose (4% unchanged) is excreted in urine.

Special patient populations

The impact of renal or hepatic impairment, sex, age, or race on the pharmacokinetics of decitabine has not been formally studied. Information regarding special patient populations was derived from pharmacokinetic data obtained during three clinical trials and a Phase I study in patients with MDS (n = 14).

Elderly patients

Population pharmacokinetic analysis showed that the pharmacokinetics of decitabine are independent of age (age range: 40–87 years, mean age: 70 years).

Pediatric population

Population pharmacokinetic analysis of decitabine demonstrated that, after adjusting for body size, there are no differences in the pharmacokinetic parameters of decitabine between pediatric patients with AML and adult patients with AML or MDS.

Sex

In the population pharmacokinetic analysis, no clinically significant differences between women and men were observed.

Racial background

The majority of patients were Caucasian. Although the population pharmacokinetic analysis did not reveal a significant effect of race on decitabine concentrations.

Hepatic impairment

The pharmacokinetics of decitabine have not been formally studied in patients with hepatic impairment. Results from mass balance studies and in vitro studies described above indicate that CYP enzymes are not involved in the metabolism of decitabine. Additionally, limited data from population pharmacokinetic analysis suggest that the pharmacokinetic parameters of decitabine are independent of total bilirubin levels. Therefore, hepatic impairment is not expected to affect decitabine plasma concentrations.

Renal impairment

The pharmacokinetics of decitabine have not been formally studied in patients with renal impairment. Population pharmacokinetic analysis based on limited data did not reveal a significant dependence of pharmacokinetic parameters on creatinine clearance or renal function parameters. Therefore, renal impairment is not expected to affect decitabine concentrations.

Clinical characteristics.

Indications.

The medicinal product Decyzan is indicated for the treatment of adult patients with newly diagnosed de novo or secondary acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification, who are not candidates for standard induction chemotherapy.

Contraindications.

Known hypersensitivity to decitabine or to any of the excipients of the medicinal product.

Pregnancy.

Breastfeeding period.

Safety precautions.

Contact with the skin should be avoided, and gloves must be worn. Standard procedures for handling and disposal of antineoplastic agents should be followed.

Interaction with other medicinal products and other types of interactions.

No formal studies have been conducted on the interaction of decitabine with other medicinal products.

Possible interactions with other medicinal products that are also activated by sequential phosphorylation (via intracellular phosphokinase activity) and/or metabolized by enzymes involved in decitabine inactivation (e.g., cytidine deaminase) may occur. Therefore, caution should be exercised when co-administering medicinal products with Decyzan.

Effect of other medicinal products on decitabine

Metabolic drug interactions mediated by the cytochrome CYP450 system are not expected, as decitabine metabolism is not mediated by this system but occurs via oxidative deamination.

Effect of decitabine on other medicinal products

Since the in vitro plasma protein binding level is low (< 1%), it is unlikely that decitabine will displace other medicinal products from their plasma protein binding sites. In vitro, decitabine has been shown to be a weak inhibitor of P-gp-mediated transport; therefore, it is not expected to affect P-gp-mediated transport of other medicinal products (see section "Pharmacological properties. Pharmacokinetics").

Special precautions for use.

Myelosuppression

Myelosuppression and complications of myelosuppression, including infections and hemorrhage, observed in patients with MDS and AML, may be exacerbated during treatment with decitabine. Therefore, there is an increased risk of developing severe infections (of any etiology—bacterial, fungal, or viral) with potentially fatal outcomes (see section "Adverse reactions"). Symptoms of infection in patients should be monitored closely, and treatment should be initiated promptly.

In clinical trials, most patients had baseline myelosuppression of Grade III–IV severity. In patients with Grade II myelosuppression at baseline, worsening was observed in most cases and occurred more frequently than in patients with baseline myelosuppression of Grade I or 0. Myelosuppression caused by decitabine is reversible. Complete blood counts and platelet counts should be performed regularly according to clinical indications and prior to each treatment cycle. In cases of myelosuppression or its complications, therapy with Decisan may be interrupted, the dose reduced, or supportive treatment initiated as recommended (see sections "Dosage and administration" and "Adverse reactions").

Respiratory, thoracic, and mediastinal disorders

Cases of interstitial lung disease (ILD), including pulmonary infiltrates, pneumonia, and pulmonary fibrosis without signs of infectious etiology, have been reported in patients treated with decitabine. Patients presenting with acute onset or unexplained worsening of pulmonary symptoms should be thoroughly evaluated to exclude ILD. If ILD is confirmed, appropriate treatment should be initiated (see section "Adverse reactions").

Hepatic impairment

The use of Decisan in patients with hepatic impairment has not been studied. Caution should be exercised when administering Decisan to patients with hepatic impairment; these patients require close monitoring. Liver function tests should be performed before initiation of therapy, before each treatment cycle, and as clinically indicated (see sections "Pharmacological properties. Pharmacokinetics" and "Dosage and administration").

Renal impairment

The use of Decisan in patients with severe renal impairment has not been studied. Caution should be exercised when administering Decisan to patients with severe renal impairment (creatinine clearance < 30 mL/min); such patients require close monitoring. Renal function should be assessed before initiation of therapy, before each treatment cycle, and as clinically indicated (see section "Dosage and administration").

Cardiac disorders

Patients with severe congestive heart failure or clinically unstable cardiac disease were excluded from clinical trials; therefore, the safety and efficacy of Decisan in such patients have not been established. In the post-marketing period, cases of cardiomyopathy with cardiac decompensation have been reported, which in some cases were reversible upon discontinuation of treatment, dose reduction, or adjustment of therapy. Patients, especially those with a history of cardiac disease, should be monitored for signs and symptoms of heart failure.

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients treated with decitabine. Differentiation syndrome can be fatal (see section "Adverse reactions"). High-dose intravenous corticosteroids and hemodynamic support should be considered at the first signs or symptoms suggestive of differentiation syndrome. Temporary discontinuation of decitabine should be considered until symptoms resolve, and if treatment is resumed, caution is advised.

Excipients

After reconstitution, the intravenous solution contains approximately 1–10 mmol of potassium per dose, depending on the diluent used. The medicinal product should be used with caution in patients with renal impairment or in patients requiring potassium restriction.

The amount of sodium in the vial is 0.29 mmol. After reconstitution, the intravenous solution contains approximately 0.6–6 mmol of sodium per dose, depending on the diluent used. Decisan should be used with caution in patients requiring sodium restriction.

Use during pregnancy or breastfeeding.

Contraception in males and females

Females of reproductive potential are advised to use contraception and avoid becoming pregnant during treatment with Decisan and for 6 months after completion of therapy. Males should use effective contraception and avoid fathering a child during treatment with Decisan and for 3 months after the end of therapy.

Concomitant use of Decisan and hormonal contraceptives has not been studied.

Pregnancy

There are insufficient data on the use of Decisan in pregnant women. Studies have shown a teratogenic effect of decitabine in rats and mice. The potential risk to humans is unknown. Given the results of animal studies and the mechanism of action of the drug, decitabine should not be administered to women of reproductive potential who are not using reliable methods of contraception. A pregnancy test should be performed in all women of childbearing age before initiation of therapy. If Decisan was administered during pregnancy or if a woman becomes pregnant during treatment, the patient should be informed of the potential risk to the fetus.

Breastfeeding

It is unknown whether decitabine or its metabolites are excreted in human milk. Decisan is contraindicated during breastfeeding. Breastfeeding must be discontinued if Decisan treatment is initiated.

Fertility

Data on the effect of decitabine on human fertility are lacking. Animal studies have demonstrated effects of decitabine on male fertility and its mutagenic potential. Due to the risk of infertility associated with decitabine treatment, males should consider sperm cryopreservation, and females should consider oocyte cryopreservation prior to starting Decisan therapy.

Ability to drive and use machines.

Decisan may have a moderate influence on the ability to drive and operate machinery. Patients should be informed that adverse reactions such as anemia may occur during treatment. Therefore, patients should be advised to take precautions when driving or operating machinery.

Method of Administration and Dosage

Decisan should be administered under the supervision of a physician experienced in the use of chemotherapeutic agents.

In a treatment cycle, decitabine is recommended to be administered at a dose of 20 mg/m² body surface area via intravenous infusion lasting more than 1 hour for 5 consecutive days (i.e., a total of 5 doses per cycle). The total daily dose should not exceed 20 mg/m², and the total dose per cycle should not exceed 100 mg/m². If a scheduled dose is missed, treatment should be resumed as soon as possible. The cycle should be repeated every 4 weeks, depending on the patient's clinical response and observed toxicity. Patients should be treated for a minimum of 4 cycles; however, complete or partial remission may occur beyond 4 cycles. Treatment may be continued as long as there is a response, clinical benefit, or disease stability, i.e., in the absence of clear disease progression.

If after 4 treatment cycles hematological parameters (such as platelet count or absolute neutrophil count) have not recovered to pre-treatment levels or if the disease progresses (increased number of blast cells in peripheral blood or worsening of bone marrow blast cell parameters), the patient may be considered non-responsive to treatment. Alternative therapy should be considered.

Premedication for the prevention of nausea and vomiting is not recommended as a routine procedure, but may be used if necessary.

Treatment of Myelosuppression and Associated Complications

Myelosuppression and myelosuppression-related adverse reactions (thrombocytopenia, anemia, neutropenia, and febrile neutropenia) are common in both previously treated and treatment-naïve patients. Complications of myelosuppression include infections and bleeding, as well as the following conditions:

• febrile neutropenia (temperature ≥ 38.5 °C, absolute neutrophil count < 1000/µL);
• active viral, bacterial, or fungal infection (e.g., requiring intravenous antimicrobial agents or systemic supportive therapy);
• hemorrhage (gastrointestinal, urogenital, pulmonary with platelet count < 25,000/µL, or CNS hemorrhagic lesions).

Treatment with Decisan may be resumed when the patient's condition improves or stabilizes with appropriate management (anti-infective therapy, blood transfusions, or growth factors).

In clinical studies, approximately one-third of patients receiving decitabine required dose delays. Dose reduction is not recommended.

Paediatric Population

Decisan should not be used in children with AML under 18 years of age, as efficacy has not been established. Currently available data are described in the sections “Pharmacological Properties” and “Adverse Reactions”.

Patients with Hepatic Impairment

Studies in patients with hepatic impairment have not been conducted. The need for dose adjustment in patients with hepatic impairment has not been established. If liver function deteriorates, patients should be closely monitored (see sections “Pharmacological Properties” and “Special Warnings and Precautions for Use”).

Patients with Renal Impairment

The use of Decisan in patients with severe renal impairment has not been studied. The need for dose adjustment in patients with renal impairment has not been evaluated (see sections “Pharmacological Properties” and “Special Warnings and Precautions for Use”).

Method of Administration

Decisan is administered by intravenous infusion. A central venous catheter is not required.

Recommendations for Safe Handling

Contact with skin should be avoided, and protective gloves must be worn. Standard procedures for handling cytotoxic medicinal products should be followed.

Instructions for Reconstitution and Dilution Prior to Administration

Reconstitution Procedure

The powder should be aseptically reconstituted with 10 mL of water for injections. After reconstitution, each milliliter contains approximately 5 mg of decitabine at a pH of 6.7 to 7.3. Within 15 minutes after reconstitution, the solution should be further diluted with cold infusion fluid (sodium chloride 9 mg/mL [0.9%] solution for injection or 5% glucose solution for injection) to a final concentration of 0.15–1.0 mg/mL.

Stability and Storage After Reconstitution

Reconstituted and diluted solution

Within 15 minutes after reconstitution, the concentrate (in 10 mL of sterile water for injections) should be further diluted with cold (2–8°C) infusion fluid. The prepared diluted solution for intravenous infusion may be stored at 2–8°C for up to 3 hours, followed by up to 1 hour at room temperature (20–25°C) prior to administration.

From a microbiological standpoint, the medicinal product should be used within the recommended time period. The user is responsible for ensuring compliance with the recommended storage times and conditions and for confirming that reconstitution was performed under aseptic conditions.

Decisan should not be administered through the same intravenous access line as other medicinal products.

Disposal

This medicinal product is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Children

Decisan should not be used in children with AML under 18 years of age, as efficacy has not been established. Currently available data are described in the sections “Pharmacological Properties” and “Adverse Reactions”.

Overdose

There is no direct experience of human overdose, and there is no specific antidote for overdose. However, data from clinical studies and published literature describe enhanced myelosuppression, including delayed neutropenia and thrombocytopenia, following doses exceeding the current therapeutic dose by 20 times. Toxicity is likely to manifest as an exacerbation of adverse reactions, predominantly myelosuppression. Management of overdose should be supportive.

Adverse reactions.

Safety profile

The most common adverse reactions reported during treatment with decitabine (≥ 35%) are pyrexia, anemia, and thrombocytopenia.

The most common grade 3–4 adverse reactions (≥ 20%) were pneumonia, thrombocytopenia, neutropenia, febrile neutropenia, and anemia.

During clinical studies, adverse reactions resulting in death occurred in 30% of patients receiving decitabine and in 25% of patients in the control group, occurring during treatment or within 30 days after the last dose of the drug.

In the decitabine group, a higher frequency of treatment discontinuation due to adverse reactions was observed in women (43%) compared to men (32%).

Summary of adverse reactions

Adverse reactions observed in 293 patients with AML who received decitabine are summarized in Table 3. The table includes data from clinical studies and post-marketing experience. Adverse reactions are summarized and classified as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated based on available data).

Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Table 3

Description of selected adverse reactions

Hematological adverse reactions

The most common hematological adverse reactions reported in association with decitabine treatment include febrile neutropenia, thrombocytopenia, neutropenia, anemia, and leukopenia.

Severe adverse reactions, some with fatal outcomes, have been observed in patients receiving decitabine, such as intracranial hemorrhage (2%) or gastrointestinal bleeding (2%), due to severe thrombocytopenia.

Management of hematological adverse reactions should be performed by monitoring complete blood count parameters and, if necessary, early initiation of supportive treatment. Supportive treatment measures include prophylactic use of antibiotics and/or administration of growth factors (particularly granulocyte colony-stimulating factor – G-CSF) in neutropenia, and blood transfusions in anemia or thrombocytopenia, according to institutional guidelines (for information on situations in which decitabine administration should be delayed, see section "Dosage and administration").

Infections and infestations

Severe adverse reactions related to infections, some likely fatal, have been reported in patients receiving decitabine, including septic shock, sepsis, pneumonia, and other infections (viral, bacterial, and fungal).

Gastrointestinal disorders

Cases of enterocolitis, including neutropenic colitis and cecitis, have been reported during treatment with decitabine. Enterocolitis may lead to septic complications and may be associated with fatal outcomes.

Respiratory, thoracic, and mediastinal disorders

Cases of interstitial lung disease (including pulmonary infiltrates leading to pneumonia and pulmonary fibrosis) without signs of infectious etiology have been reported in patients receiving decitabine.

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving decitabine. Differentiation syndrome can be fatal, and symptoms and clinical findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary edema, peripheral edema, rapid weight gain, pleural effusion, pericardial effusion, hypotension, and renal dysfunction. Differentiation syndrome may occur with or without concomitant leukocytosis. Capillary leak syndrome and coagulopathy may also occur (see section "Special precautions").

Paediatric population

Safety assessment in children is based on limited data from a phase I/II study evaluating the pharmacokinetics, safety, and efficacy of decitabine in children (aged 1 to 14 years) with relapsed or refractory AML (n = 17) (see section "Pharmacodynamics"). In this pediatric study, no new safety signals were identified.

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Packaging.

1 vial of lyophilisate with 1 vial of solvent (10 ml) in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

San Pharmaceuticals Industries Ltd.

Manufacturer's address and location of its operations.

Baroda Highway, Halol, Gujarat, 389350, India.