Decitabine-mili

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DECITABIN-MILI (DECITABIN-MILI)

Composition:

Active substance: decitabine;

One vial contains 50 mg of decitabine;

Excipients: potassium dihydrogen phosphate, sodium hydroxide, specially purified acetonitrile, water for injections.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white or almost white lyophilized powder or tablet-like powder.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. Decitabine. ATC code L01B C08.

Pharmacological properties.

Pharmacodynamics.

Decitabine is a deoxycytidine nucleoside analogue that, at low doses, selectively inhibits DNA methyltransferase activity, leading to hypomethylation of the gene promoter region and subsequent reactivation of tumor suppressor genes, induction of cellular differentiation, or cellular senescence followed by programmed cell death.

Decitabine is believed to exert its antineoplastic effect after phosphorylation, through direct incorporation into DNA and inhibition of DNA methyltransferases, resulting in DNA hypomethylation and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro at concentrations that do not cause significant suppression of DNA synthesis. Hypomethylation induced by decitabine in neoplastic cells may restore normal function of genes critical for controlling cellular differentiation and proliferation. In rapidly dividing cells, decitabine cytotoxicity may also result from the formation of covalent bonds between DNA methyltransferases and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.

Pharmacokinetics.

Population pharmacokinetic parameters of decitabine were derived from 3 clinical studies involving 45 patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), using a 5-day treatment regimen. In each study, pharmacokinetic parameters were assessed on day 5 of the first treatment cycle.

Distribution

The pharmacokinetics of decitabine following intravenous administration as a 1-hour infusion were described by a linear two-compartment model, characterized by rapid elimination of the active substance 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 presented in Table 1.

Table 1

Parameter	Predicted value	95% confidence interval
Cmax (ng/mL)	107	88.5–129
AUCcum (ng × h/mL)	580	480–695
t1/2 (min)	68.2	54.2–79.6
Vdss (L)	116	84.1–153
CL (L/h)	298	249–359

The total dose per cycle was 100 mg/m².

Decitabine demonstrates linear pharmacokinetics after intravenous infusion, with steady-state concentrations achieved within 0.5 hours. Modeling showed time-independent pharmacokinetic parameters (unchanged from cycle to cycle), and no accumulation was observed with these dosing regimens. Binding of decitabine to plasma proteins is negligible (<1%). The mean volume of distribution at steady state (Vdss) in oncology patients is high, indicating extensive distribution of the drug into peripheral tissues. No dependence on age, creatinine clearance, total bilirubin levels, or disease stage was observed.

Metabolism

Intracellularly, decitabine is activated through sequential phosphorylation by kinases to its corresponding triphosphate form, which is then incorporated into DNA by DNA polymerase. In vitro metabolism studies and human mass balance studies demonstrated that the cytochrome P450 system is not involved in decitabine metabolism. The primary metabolic pathway is most likely deamination by cytidine deaminase in the liver, kidneys, intestinal epithelium, and blood. Human mass balance studies showed that unchanged decitabine accounts for approximately 2.4% of total radioactivity in plasma. The major circulating metabolites are considered to lack pharmacological activity. The presence of these metabolites in urine, combined with high total clearance and low urinary excretion of unchanged active substance (~4% of dose), indicates that decitabine undergoes extensive in vivo metabolism. 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 via these pathways are not expected. In vitro data also show that decitabine is a weak substrate of P-glycoprotein.

Elimination

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

Results from mass balance studies using radiolabeled 14C-decitabine in cancer patients showed that 90% of the administered dose (4% unchanged) was 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. Pharmacokinetic data in special patient populations were obtained from three clinical trials mentioned above and one study in patients with MDS (n = 14; dose of 15 mg/m² administered as 3-hour infusions every 8 hours for 3 days).

Elderly patients

Population pharmacokinetic analysis showed that decitabine pharmacokinetics are not age-dependent (age range studied: 40 to 87 years, mean age 70 years).

Pediatric patients

Population pharmacokinetic analysis of decitabine showed no difference in pharmacokinetic parameters between pediatric patients with AML compared to adults with AML or MDS.

Sex

Population pharmacokinetic analysis did not reveal any clinically significant difference in decitabine pharmacokinetics between women and men.

Race

The majority of patients in the clinical trials were Caucasian. However, population pharmacokinetic analysis data did not show a clear effect of race on decitabine concentrations.

Hepatic impairment

The pharmacokinetics of decitabine have not been formally studied in patients with hepatic impairment. Mass balance and in vitro studies, as described above, indicate that CYP enzymes are unlikely to be involved in decitabine metabolism. Additionally, some population pharmacokinetic data suggest no significant dependence of pharmacokinetic parameters on total bilirubin levels. Therefore, hepatic dysfunction is not expected to affect plasma concentrations of decitabine.

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, a marker of kidney function. Therefore, renal dysfunction is not expected to affect plasma concentrations of decitabine.

Preclinical safety data

Formal carcinogenicity studies with decitabine have not been conducted. Published scientific literature indicates that decitabine has carcinogenic potential. In vitro and in vivo studies provide sufficient evidence that decitabine exerts genotoxic effects. Scientific literature reports that decitabine adversely affects all aspects of the reproductive cycle, including fertility, embryonic and fetal development, and postnatal development. Repeat-dose toxicity studies in rats and rabbits showed that the primary manifestation of toxicity was myelosuppression, including effects on bone marrow, which was reversible after treatment cessation. Gastrointestinal toxicity was also observed in male rats, and testicular atrophy in these animals did not resolve during the planned recovery periods. Administration of decitabine to neonatal/young rats showed a similar overall toxicity profile as in adult rats. Neurobehavioral development and reproductive capacity were not affected during treatment of neonatal/young rats at doses causing myelosuppression.

Clinical Characteristics.

Indications.

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

Contraindications.

Hypersensitivity to decitabine or to any of the excipients of the medicinal product.

Pregnancy and breastfeeding period (see section "Use during pregnancy or breastfeeding").

Special safety precautions.

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

The medicinal product Decitabine-Mili must not be administered through an intravenous line shared with other medicinal products.

Disposal

The contents of the vial are intended for single use only. Any unused product residue must be disposed of in accordance with national requirements.

Interaction with other medicinal products and other forms of interactions.

Specific studies on the interaction of decitabine with other medicinal products have not been conducted.

Potential interactions may occur with medicinal products that are also activated through sequential phosphorylation (involving intracellular phosphokinases) and/or metabolized by enzymes involved in decitabine inactivation (e.g., cytidine deaminase). Such medicinal products should be administered concomitantly with decitabine with caution.

Effect of other medicinal products on decitabine

CYP-mediated interactions between decitabine and other medicinal products are not expected, since decitabine metabolism is not mediated by the CYP450 cytochrome system, but rather occurs via oxidative deamination.

Effect of decitabine on other medicinal products

Since the plasma protein binding in vitro is low (< 1%), it is unlikely that decitabine will displace other medicinal products from their plasma protein binding sites. In vitro studies indicate that decitabine is a weak inhibitor of P-gp-mediated transport; therefore, an effect on P-gp-mediated transport of other medicinal products is not expected (see section "Pharmacokinetics").

Special precautions for use.

Myelosuppression

Myelosuppression and its complications, including infections and hemorrhage observed in patients with AML, may be exacerbated during treatment with decitabine. Therefore, there is an increased risk of developing serious infections (of any etiology: bacterial, fungal, or viral), with potentially fatal outcomes (see section "Side effects"). Patients should be monitored for signs and symptoms of infection, and treatment should be initiated promptly if necessary.

It is known that during clinical trials the majority of patients had baseline myelosuppression of grade 3/4 severity. Worsening of myelosuppression was observed in most patients who had grade 2 myelosuppression at the start of treatment, more frequently than in patients with baseline grade 1 or 0 myelosuppression. Myelosuppression caused by decitabine is reversible. Complete blood counts and platelet counts should be performed regularly as clinically indicated and prior to each treatment cycle. If worsening of myelosuppression or its complications occurs, decitabine therapy may be discontinued, the dose reduced, or supportive treatment initiated according to recommendations (see sections "Dosage and administration" and "Side effects").

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease (ILD) (including pulmonary infiltrates leading to pneumonia and pulmonary fibrosis) without signs of infectious etiology have been reported in patients receiving decitabine. A careful evaluation of patients with acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. If ILD is confirmed, appropriate treatment should be initiated (see section "Side effects").

Hepatic function impairment

The use of decitabine in patients with hepatic impairment has not been studied. Caution should be exercised when administering decitabine to patients with hepatic impairment or those who develop signs or symptoms of liver dysfunction. Liver function tests should be performed prior to initiation of therapy and before each treatment cycle as clinically indicated (see sections "Pharmacokinetics" and "Dosage and administration").

Renal function impairment

The use of decitabine in patients with severe renal impairment has not been studied. Caution should be exercised when administering decitabine to patients with severe renal impairment (creatinine clearance < 30 mL/min). Renal function testing should be performed prior to initiation of therapy and before each treatment cycle as clinically indicated (see section "Dosage and administration").

Cardiac disorders

Patients with severe congestive heart failure or clinically unstable heart disease were excluded from clinical trials; therefore, the safety and efficacy of decitabine in these patients have not been established. Cases of cardiomyopathy with cardiac decompensation, sometimes reversible after discontinuation of treatment, dose reduction, or corrective therapy, have been reported. 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 receiving decitabine. Differentiation syndrome may lead to fatal outcomes (see section "Side effects"). High-dose intravenous corticosteroids and hemodynamic monitoring should be considered at the first appearance of symptoms or signs suggestive of differentiation syndrome. Temporary discontinuation of the drug should be considered until symptoms resolve, and caution is advised if treatment is resumed.

Excipients

This medicinal product contains 0.5 mmol of potassium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicinal product contains less than 1 mmol (39 mg) of potassium per dose, i.e., practically potassium-free.

This medicinal product contains 0.29 mmol of sodium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicinal product contains between 0.6 mmol and 6 mmol of sodium per dose (depending on the infusion diluent). This product should be used with caution in patients on a controlled sodium intake.

Use during pregnancy or breastfeeding.

Contraception in men and women

Due to the genotoxic potential of decitabine, women of reproductive age should use contraception and avoid becoming pregnant during treatment with decitabine and for 6 months after completion of treatment.

Men should use effective contraception and avoid fathering a child during treatment with decitabine and for 3 months after the last dose of decitabine.

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

Pregnancy

There are insufficient data on the use of decitabine in pregnant women. Studies have shown that decitabine has teratogenic effects in rats and mice. The potential risk in humans is unknown. Given the animal data and mechanism of action, the medicinal product should not be used during pregnancy or in women of childbearing potential who are not using adequate contraceptive methods. A pregnancy test should be performed in all women of reproductive age before initiation of treatment. If a woman becomes pregnant during treatment, she should be informed of the potential risk to the fetus.

Breastfeeding

It is unknown whether decitabine or its metabolites are excreted in human milk. The drug is contraindicated during breastfeeding; if treatment with decitabine is necessary, breastfeeding must be discontinued (see section "Contraindications").

Fertility

There are no data on the effect of decitabine on human fertility. Animal studies have demonstrated effects of decitabine on male fertility and its mutagenic potential. Since there is a risk of infertility associated with decitabine treatment, men should consider sperm cryopreservation, and women should consider oocyte cryopreservation prior to starting decitabine therapy.

Ability to affect reaction speed when driving or operating machinery.

Decitabine may have a moderate influence on the ability to drive or 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 a vehicle or operating machinery.

Dosage and Administration

Decitabine is a cytotoxic medicinal product; therefore, caution must be exercised when handling the drug.

Decitabine 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 over 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 require more than 4 cycles. Treatment may be continued as long as a response, clinical benefit, or disease stability (i.e., absence of overt progression) is observed.

If after 4 treatment courses hematological parameters (platelet count or absolute neutrophil count) have not recovered to pre-treatment levels or if the disease progresses (increased 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.

Pre-medication 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 treated and untreated patients with AML. Complications of myelosuppression include infections and bleeding. For patients who develop myelosuppression and associated complications, treatment may be modified as described below.

Treatment may be delayed at the physician’s discretion if the patient develops any of the following complications:

• Febrile neutropenia (temperature ≥ 38.5 °C, absolute neutrophil count < 1000/μL);
• Active viral, bacterial, or fungal infection (e.g., requiring intravenous antibiotics or systemic supportive therapy);
• Bleeding (gastrointestinal, urogenital, pulmonary with platelet count < 25,000/μL, or hemorrhagic central nervous system lesions).

Resumption of treatment should occur after improvement or stabilization with appropriate management (anti-infective therapy, blood transfusions, or growth factors). In clinical trials, approximately one-third of patients receiving decitabine required treatment delay. Dose reduction is not recommended.

Special Patient Populations

Patients with Hepatic Impairment

Studies in patients with hepatic impairment have not been conducted, and the need for dose adjustment 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

Studies in patients with renal impairment have not been conducted, and the need for dose adjustment has not been established (see sections “Pharmacological Properties” and “Special Warnings and Precautions for Use”).

Administration Method

The medicinal product Decitabine-Mili is administered via intravenous infusion, not necessarily through a central venous catheter.

Reconstitution Procedure

The medicinal product should be reconstituted under aseptic conditions with 10 mL of sterile water for injection at room temperature. After reconstitution, the final concentration of the reconstituted solution is 5 mg/mL with a pH of 6.7 to 7.3. Within 15 minutes after reconstitution, the solution should be further diluted with cool infusion fluids (0.9% sodium chloride injection solution with a concentration of 9 mg/mL or 5% dextrose injection solution) to a final concentration of 0.15–1.0 mg/mL.

Reconstituted and Diluted Solution

Within 15 minutes after reconstitution (in 10 mL of sterile water for injection), the concentrate should be further diluted with cool (2–8 °C) infusion fluids. The resulting diluted solution for intravenous infusion may be stored at 2–8 °C for up to 3 hours and may be kept at room temperature (20–25 °C) for up to 1 hour prior to administration.

Parenteral medicinal products should be visually inspected for particulate matter and discoloration prior to administration. Do not use the solution if particulate matter is present or if the color has changed.

Due to microbiological considerations, the medicinal product should be used within the recommended time period. The user is responsible for adhering to the recommended storage conditions and times and must ensure that reconstitution is performed under aseptic conditions.

Children

The safety and efficacy of the medicinal product in children under 18 years of age with AML have not been established.

Overdose

There is no direct experience of overdose in humans, and no specific antidote exists for overdose. However, clinical studies and scientific publications have reported increased 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, primarily myelosuppression. Management of overdose should be supportive.

Adverse Reactions

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

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

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

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

Adverse reactions observed in 293 patients with AML treated with decitabine are summarized in Table 2. Table 2 includes data from clinical studies and post-marketing experience. Adverse reactions are listed by frequency. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated from the available data).

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

Table 2

Undesirable adverse reactions associated with decitabine

Adverse reactions identified during decitabine use
Organ systems	Frequency (all grades)	Adverse reaction	Frequency
			All gradesa (%)	Grades 3–4a (%)
Infections and infestations	Very common	pneumonia*	24	20
		urinary tract infections*	15	7
		other infections (viral, bacterial, fungal)*, b, c, d	63	39
	Common	septic shock*	6	4
		sepsis*	9	8
		sinusitis	3	1
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Frequency unknown	Differentiation syndrome	Frequency unknown	Frequency unknown
Blood and lymphatic system disorders	Very common	febrile neutropenia*	34	32
		neutropenia*	32	30
		thrombocytopenia*, e	41	38
		anemia	38	31
		leukopenia	20	18
	Uncommon	pancytopenia*	< 1	< 1
Immune system disorders	Common	hypersensitivity, including anaphylactic reactionf	1	< 1
Metabolism and nutrition disorders	Very common	hyperglycemia	13	3
Nervous system disorders	Very common	headache	16	1
Cardiac disorders	Uncommon	cardiomyopathy	< 1	< 1
Respiratory, thoracic and mediastinal disorders	Very common	epistaxis	14	2
	Frequency unknown	interstitial lung disease	Frequency unknown	Frequency unknown
Gastrointestinal disorders	Very common	diarrhea	31	2
		vomiting	18	1
		nausea	33	<1
	Common	stomatitis	7	1
	Frequency unknown	enterocolitis, including neutropenic colitis, cecitis*	Frequency unknown	Frequency unknown
Hepatic disorders	Very common	abnormal liver function	11	3
	Common	hyperbilirubinemiag	5	< 1
Skin and subcutaneous tissue disorders	Uncommon	acute febrile neutrophilic dermatosis (Sweet's syndrome)	< 1	NA
General disorders and administration site conditions	Very common	pyrexia	48	9

a Common terminology criteria for adverse reaction grading of the National Cancer Institute of the United States.

b Except for pneumonia, urinary tract infections, sepsis, septic shock, and sinusitis.

c The most commonly reported "other infections" during the DACO-16 study were oral herpes, oral candidiasis, pharyngitis, upper respiratory tract infections, cellulitis, bronchitis, and nasopharyngitis.

d Including infectious enterocolitis.

e Including hemorrhage associated with thrombocytopenia, including fatal outcomes.

f Including hypersensitivity, hypersensitivity to the active substance, anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock.

g In clinical trials on AML and myelodysplastic syndrome (MDS), the incidence of hyperbilirubinemia was 11% for all grades and 2% for grades 3–4.

* Including adverse reactions with fatal outcome.

NA – not applicable.

Description of individual adverse reactions

Hematologic adverse reactions

The most frequently reported hematologic adverse reactions associated with decitabine treatment included febrile neutropenia, thrombocytopenia, neutropenia, anemia, and leukopenia.

In patients treated with decitabine, severe adverse reactions, some with fatal outcome, such as intracranial hemorrhage (2%) or gastrointestinal bleeding (2%), have been observed due to severe thrombocytopenia.

Management of hematologic adverse reactions should be performed by monitoring complete blood count parameters and, if necessary, early initiation of supportive therapy. Supportive therapy includes prophylactic use of antibiotics and/or administration of growth factors (particularly granulocyte colony-stimulating factor—G-CSF) in case of neutropenia, and blood transfusions in case of anemia or thrombocytopenia, according to institutional guidelines (for situations when decitabine administration should be postponed, see section "Dosage and administration").

Infections and infestations

Severe adverse reactions related to infections with potentially fatal outcomes, such as septic shock, sepsis, pneumonia, and other infections (viral, bacterial, and fungal), have been observed in patients treated with decitabine.

Gastrointestinal disorders

Cases of enterocolitis, including neutropenic colitis and typhlitis, 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 treated with decitabine.

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, and symptoms and clinical manifestations include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary edema, peripheral edema, rapid weight gain, pleural effusion, pericardial effusion, arterial hypotension, and renal dysfunction. Differentiation syndrome may occur with or without concomitant leukocytosis. Capillary leak syndrome and coagulopathy may also occur.

Pediatric population

The 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 adverse reactions

Reporting of adverse reactions after marketing authorization is important. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

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

Packaging.

50 mg of decitabine as lyophilisate in a vial; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Shilpa Medicare Limited / Shilpa Medicare Limited.

Manufacturer's address and location of operations.

Unit 4, Pharmaceutical Formulations SEZ, Plot Nos. S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India /
Unit-4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahabооbnagar, Telangana, 509301, India.

Marketing Authorization Holder.

Mili HealthCare Limited.

Address of Marketing Authorization Holder. 2nd floor, office premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.