Thalidomide-mili

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT THALIDOMIDE-MILI (THALIDOMIDE-MILI)

Composition:

Active substance: thalidomide;

1 capsule contains 50 mg of thalidomide;

Excipients:

Granulated powder: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate;

Composition of hard gelatin capsule (size "4"): titanium dioxide (E 171), gelatin, purified water;

Composition of black ink (BlackInk): shellac (E 904), anhydrous ethanol, isopropyl alcohol, butyl alcohol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide, purified water.

Pharmaceutical form. Hard gelatin capsules.

Main physicochemical properties: hard gelatin capsule consisting of a white opaque body and cap, with "SML" printed on the cap and "28" on the body in black ink, containing granulated powder of white to almost white color.

Pharmacotherapeutic group. Immunosuppressants, other immunosuppressants. ATC code: L04AX02.

Pharmacological Properties

Pharmacodynamics

Thalidomide has a chiral centre and is clinically used as a racemate of (+)-(R)- and (–)-(S)-thalidomide. The full spectrum of thalidomide's activity has not been completely characterized.

Mechanism of action

Thalidomide exerts immunomodulatory, anti-inflammatory, and potential antineoplastic effects.

Data from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory, and antineoplastic effects of thalidomide may be related to inhibition of excessive tumour necrosis factor-alpha (TNF-α) production, reduction in modulation of cell surface adhesion molecules involved in leukocyte migration, and anti-angiogenic activity. Thalidomide is also a non-barbiturate central nervous system depressant with sedative properties. It has no antibacterial activity.

Pharmacokinetics

Absorption. After oral administration, thalidomide is absorbed slowly. Maximum plasma concentration is reached within 1–5 hours. Concomitant administration with food slows absorption but does not alter the overall extent of absorption.

Distribution. Plasma protein binding of the (+)-(R) and (–)-(S) enantiomers has been determined to be 55% and 65%, respectively. Thalidomide is present in semen of male patients at concentrations similar to those in plasma (see section "Special precautions"). Age, sex, renal function, and blood biochemical parameters have no significant effect on thalidomide distribution.

Metabolism. Thalidomide is metabolized almost exclusively via non-enzymatic hydrolysis. Unchanged thalidomide accounts for 80% of circulating components in plasma. Unchanged thalidomide was a minor component (< 3% of dose) in urine. Besides thalidomide, hydrolytic products N-(o-carboxybenzoyl)glutaramide and phthaloyl isoglutamine are present in blood plasma and predominantly in urine, formed through non-enzymatic processes. Oxidative metabolism has no significant impact on the overall metabolism of thalidomide. There is minimal hepatic metabolism of thalidomide catalyzed by cytochrome P450. Some in vitro data suggest that prednisone may induce enzymes, potentially reducing systemic exposure to concomitantly administered drugs. The in vivo relevance of these findings is unknown.

Elimination. The mean plasma half-life of thalidomide after single oral doses ranging from 50 mg to 400 mg was 5.5–7.3 hours. After a single oral dose of 400 mg of radiolabelled thalidomide, the total mean recovery was 93.6% of the administered dose by day 8. The majority of the radioactive dose was excreted within 48 hours after dosing. The primary route of elimination was via urine (> 90%), while faecal excretion was minimal.

There is a linear relationship between body weight and calculated thalidomide clearance; in patients with multiple myeloma weighing 47–133 kg, thalidomide clearance was approximately 6–12 L/h, indicating an increase in thalidomide clearance of 0.621 L/h per 10 kg increase in body weight.

Linearity/Non-linearity. Total systemic exposure (AUC) is dose-proportional following single-dose administration. No time-dependent pharmacokinetics have been observed.

Hepatic and renal impairment. The extent of thalidomide metabolism by the hepatic cytochrome P450 system is minimal, and unchanged thalidomide is not excreted by the kidneys. Parameters of renal function (creatinine clearance [CrCl]) and liver function (blood biochemistry) indicate minimal impact of renal and hepatic function on thalidomide pharmacokinetics. Therefore, changes in thalidomide metabolism are not expected in patients with hepatic or renal impairment. Data in patients with end-stage renal disease support the absence of renal function impact on thalidomide pharmacokinetics.

Clinical Characteristics

Indications

Use as first-line therapy in combination with melphalan and prednisone in patients aged ≥ 65 years with previously untreated multiple myeloma (MM) who are not eligible for high-dose chemotherapy.

THALIDOMIDE-MILI is prescribed and dispensed according to the requirements of the Pregnancy Prevention Program (see section "Special Warnings and Precautions for Use").

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Pregnant women (see section "Use in Pregnancy or Breastfeeding").

Women of childbearing potential if all requirements of the Pregnancy Prevention Program are not met (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy or Breastfeeding").

Men who do not use adequate contraceptive measures (see section "Special Warnings and Precautions for Use").

Interaction with Other Medicinal Products and Other Forms of Interaction

Thalidomide is a poor substrate for cytochrome P450-inducing agents; therefore, clinically significant interactions with medicinal products that are inhibitors and/or inducers of this enzyme system are unlikely. Non-enzymatic hydrolysis of thalidomide, which is the primary clearance mechanism, indicates a low potential for drug-drug interactions involving thalidomide.

Enhancement of sedative effects of other medicinal products. Thalidomide has sedative properties and may therefore enhance the sedative effect caused by anxiolytics, hypnotics, antipsychotics, H1-antihistamines, opioid derivatives, barbiturates, and alcohol. Caution should be exercised when administering thalidomide in combination with medicinal products that cause somnolence.

Bradycardia effect. Since thalidomide may induce bradycardia, caution is advised when co-administering with medicinal products having similar pharmacodynamic effects, particularly those containing substances that induce paroxysmal ventricular tachycardia of the torsade de pointes type, beta-blockers, or anticholinesterase agents.

Medicinal products causing peripheral neuropathy. Medicinal products associated with peripheral neuropathy (e.g., vincristine and bortezomib) should be used with caution in patients receiving thalidomide.

Hormonal contraceptives. Thalidomide does not interact with hormonal contraceptives. In a study of 10 healthy women, pharmacokinetic profiles of norethindrone and ethinyl estradiol were evaluated after a single dose containing 1.0 mg of norethindrone acetate and 0.75 mg of ethinyl estradiol. Results were similar with or without concomitant administration of 200 mg/day thalidomide. However, combined hormonal contraceptives are not recommended due to an increased risk of venous thromboembolism.

Warfarin. Repeated administration of 200 mg thalidomide for 4 days did not affect the international normalized ratio (INR) in healthy volunteers. However, due to the increased risk of thrombosis in cancer patients and the potential for accelerated warfarin metabolism with corticosteroids, careful monitoring of INR values is recommended during combination therapy with thalidomide and prednisone, as well as during the first weeks after discontinuation of this treatment.

Digoxin. Thalidomide does not interact with digoxin. In 18 healthy male volunteers, repeated administration of 200 mg thalidomide had no significant effect on the pharmacokinetics of a single dose of digoxin. Additionally, a single 0.5 mg dose of digoxin had no significant effect on the pharmacokinetics of thalidomide. It is unknown whether the effect would differ in patients with multiple myeloma.

Special precautions for use.

Teratogenic effects Thalidomide has a pronounced teratogenic effect in humans and frequently may cause severe and life-threatening congenital malformations. Thalidomide must in no case be used in pregnant women or women who may become pregnant unless all conditions of the Pregnancy Prevention Program are fulfilled. The conditions of the Pregnancy Prevention Program must be met for all patients, both male and female.

Criteria for women who are not of childbearing potential

Women who are patients or female partners of male patients are considered to be of childbearing potential unless one of the following criteria is met:

• age ≥ 50 years and duration of natural amenorrhea ≥ 1 year (amenorrhea due to oncological therapy or during lactation does not exclude the presence of reproductive potential);
• premature ovarian failure confirmed by a specialist gynecologist;
• history of bilateral salpingo-oophorectomy or hysterectomy;
• XY genotype, Turner syndrome, uterine agenesis.

Recommendations

Thalidomide is contraindicated in women of reproductive age unless all of the following conditions are met:

• the patient understands the expected teratogenic risk to a future child;
• the patient understands the necessity of continuous use of effective contraception for 4 weeks prior to initiation of treatment, throughout the entire treatment period, and for 4 weeks after treatment discontinuation;
• even if a woman of reproductive age has amenorrhea, she must comply with all recommendations regarding effective contraception;
• the patient must be able to use effective contraceptive methods;
• the patient must be informed and understand the possible consequences of pregnancy and the need to seek immediate medical advice if pregnancy is suspected;
• the patient understands the necessity to initiate thalidomide treatment immediately following a negative pregnancy test;
• the patient understands and agrees to undergo pregnancy testing every 4 weeks, except in cases of confirmed tubal sterilization;
• the patient acknowledges that she understands the risks and the necessity of preventive measures associated with thalidomide use.

Since thalidomide is present in semen, all male patients receiving thalidomide must:

• be aware of the teratogenic risk associated with sexual intercourse with a pregnant woman or a woman of reproductive potential;
• understand the necessity of using a condom (even if the man has undergone vasectomy) during sexual intercourse with a pregnant woman or a woman of reproductive potential who is not using effective contraception, during treatment and for 7 days after interruption and/or discontinuation of treatment;
• understand that if his female partner becomes pregnant during his thalidomide treatment or within 7 days after treatment cessation, he must immediately inform his physician, and his partner should be advised to consult a teratology specialist.

The physician prescribing thalidomide to women of reproductive age must ensure that:

• the patient complies with the Pregnancy Prevention Program requirements, including confirmation that she properly understands the risks;
• the patient agrees to comply with all the above-mentioned conditions.

Contraceptive Requirements

Women of reproductive age must use one of the highly effective contraceptive methods for 4 weeks prior to treatment initiation, during the entire treatment course, and for 4 weeks after thalidomide discontinuation, even in cases of temporary treatment interruption, unless the patient agrees to complete and continuous abstinence throughout the month.

If a patient is not using effective contraception, she should be referred to a specialist for selection of an effective contraceptive method.

Effective contraceptive methods include:

• implants;
• intrauterine systems (IUS) releasing levonorgestrel;
• depot medroxyprogesterone acetate preparations;
• tubal sterilization;
• partner vasectomy (confirmed by two negative semen analyses);
• progestin-only ovulation inhibitors (e.g., desogestrel).

Combined oral contraceptives are not recommended for patients with MM due to an increased risk of venous thromboembolism (see section "Interaction with medicinal products and other forms of interaction"). If a patient is using combined oral contraceptives, she should switch to one of the effective methods listed above. The risk of venous thromboembolism persists for 4–6 weeks after discontinuation of combined oral contraceptives.

Pregnancy Testing

Pregnancy testing in women of childbearing age must be performed under medical supervision as specified below, using a test with a minimum sensitivity of 25 mIU/mL. This requirement applies also to women of childbearing age who practice complete and continuous abstinence.

Prior to treatment initiation. A pregnancy test must be performed under medical supervision during the consultation when thalidomide is prescribed, or within 3 days prior to the physician visit if the patient has been using effective contraception for at least the previous 4 weeks. Test results must confirm the absence of pregnancy at the time treatment with thalidomide is initiated.

Subsequent monitoring and treatment completion. Pregnancy testing must be repeated under medical supervision every 4 weeks, including 4 weeks after treatment completion, except in cases of confirmed tubal sterilization. These pregnancy tests should be performed on the day of prescription or within 3 days prior to the physician visit.

Male Patients

Since thalidomide is present in semen, all male patients must use condoms during treatment, during treatment interruptions, and for at least 7 days after treatment discontinuation during sexual intercourse with a pregnant woman or a woman of reproductive age who is not using effective contraception.

Male patients must not donate semen during treatment (including during dose interruptions) and for at least 7 days after discontinuation of thalidomide.

Prescribing and Dispensing Restrictions

The medicinal product should be dispensed to women with preserved fertility for no more than 4 weeks of treatment according to approved regimens for the indication (see section "Indications"), and a new prescription is required for treatment continuation. Ideally, pregnancy testing, prescription issuance, and drug dispensing should occur on the same day. Thalidomide dispensing to women of reproductive age must occur within 7 days after prescription.

For all other patients, prescriptions for thalidomide may be issued for a maximum treatment duration of 12 weeks, and a new prescription is required for treatment continuation.

Additional Precautions

Patients should be instructed never to give this medicinal product to another person, and unused capsules after treatment completion should be returned to their pharmacist.

Patients must not be blood donors during treatment (including during treatment interruptions) and for at least 7 days after discontinuation of thalidomide.

Healthcare professionals and caregivers should wear disposable gloves when handling blisters or capsules. Pregnant women or women who suspect they may be pregnant should not handle blisters or capsules (see section "Storage Conditions").

Educational Materials

To enhance patient safety and reduce the risk of teratogenic effects during thalidomide use, the marketing authorization holder provides physicians with educational materials containing all necessary information on potential teratogenic effects of thalidomide treatment, recommendations for effective contraception before, during, and after therapy, and information on the use of pregnancy tests.

The prescribing physician must inform both male and female patients about the existence of teratogenic risk and the necessity of strict measures to prevent pregnancy (in accordance with the Pregnancy Prevention Program) and provide patients with educational brochures, patient cards, and/or equivalent materials according to the national patient identification card system.

A nationally controlled distribution system is implemented in cooperation with national competent authorities. The controlled distribution system includes the use of patient cards or equivalent documentation to monitor prescription and dispensing of the drug and collection of detailed data on indications to track off-label use within Ukraine. Ideally, pregnancy testing, treatment prescription, and drug dispensing should occur on the same day. Thalidomide dispensing to women of reproductive age should occur within 7 days after treatment prescription and receipt of a negative pregnancy test result performed under medical supervision.

Amenorrhea

Thalidomide use may be associated with menstrual cycle disturbances, including amenorrhea. Amenorrhea during thalidomide therapy should be considered a sign of pregnancy until medically confirmed otherwise. The precise mechanism by which thalidomide may induce amenorrhea is not fully understood. These events occurred in young (premenopausal) women (mean age 36 years) receiving thalidomide for multiple myeloma, began within 6 months of treatment initiation, and resolved after thalidomide discontinuation. In documented cases with hormone assessment, amenorrhea was associated with decreased estradiol levels and increased follicle-stimulating hormone/luteinizing hormone levels. Anti-ovarian antibodies were negative, and prolactin levels were within normal range.

Cardiovascular Disorders

Myocardial Infarction. Myocardial infarction (MI) has been reported in patients receiving thalidomide, particularly in those with risk factors. Patients with known MI risk factors, including history of thrombosis, require careful monitoring and measures to minimize all possible risk factors (e.g., smoking, arterial hypertension, hyperlipidemia).

Venous and Arterial Thromboembolism. Patients receiving thalidomide have an increased risk of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (mainly myocardial infarction and cerebrovascular events) (see section "Adverse Reactions"). The risk is highest during the first 5 months of therapy. Recommendations for thromboprophylaxis and dosing/anticoagulant therapy are provided in the section "Dosage and Administration."

A history of thromboembolism or concomitant use of erythropoietic agents or other agents such as hormone replacement therapy further increases the risk of thromboembolism. Therefore, these agents should be used with caution in patients with multiple myeloma receiving thalidomide with prednisone and melphalan. Erythropoiesis-stimulating agents should be discontinued if hemoglobin concentration exceeds 12 g/dL. Measures should be taken to minimize all possible risk factors (e.g., smoking, arterial hypertension, hyperlipidemia).

Patients and physicians are advised to monitor for signs and symptoms of thromboembolism. Patients should be instructed to seek medical attention if symptoms such as dyspnea, chest pain, or swelling of an arm or leg develop.

Thyroid Disorders

Cases of hypothyroidism have been reported. Concomitant conditions affecting thyroid function should be assessed before treatment initiation. Evaluation of thyroid function is recommended before treatment initiation and regular monitoring during treatment.

Peripheral Neuropathy

Peripheral neuropathy is a very common potentially severe adverse reaction to thalidomide treatment, which may lead to irreversible damage (see section "Adverse Reactions"). In a phase 3 study, the median time to first occurrence of neuropathy was 42.3 weeks. If a patient develops peripheral neuropathy, dose modification and regimen adjustments as described in the section "Dosage and Administration" should be followed.

Careful monitoring of patients for neuropathy symptoms is recommended. These symptoms include paresthesia, dysesthesia, discomfort, coordination disturbances, or weakness.

Clinical and neurological examination is recommended before initiation of thalidomide therapy and regular monitoring during treatment.

Medicinal products associated with neuropathy should be used with caution in patients receiving thalidomide (see section "Interaction with medicinal products and other forms of interaction").

Thalidomide may also exacerbate pre-existing neuropathy; therefore, it should not be used in patients with clinical signs or symptoms of peripheral neuropathy unless clinical benefits outweigh the risks.

Syncope, Bradycardia, and Atrioventricular Block

Patients should be monitored for syncope, bradycardia, and atrioventricular block; dose reduction or treatment discontinuation may be required.

Pulmonary Hypertension

Cases of pulmonary hypertension, some with fatal outcomes, have been reported in patients receiving thalidomide.

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease before and during thalidomide therapy.

Hematological Disorders

Neutropenia. The incidence of grade 3 or 4 neutropenia reported as an adverse reaction was higher in patients with multiple myeloma receiving MPT (melphalan, prednisone, thalidomide) compared to those receiving MP (melphalan, prednisone): 42.7% vs. 29.5%, respectively (IFM 99-06 study). In the post-marketing period, adverse reactions such as febrile neutropenia and pancytopenia have been reported with thalidomide use. Patients should be monitored, and dose delay, dose reduction, or treatment discontinuation may be required (see section "Dosage and Administration").

Thrombocytopenia. Thrombocytopenia, including grade 3 or 4 adverse reactions, has been reported in patients with multiple myeloma receiving MPT. Patients should be monitored, and dose delay, dose reduction, or treatment discontinuation may be required (see section "Dosage and Administration"). Patients and physicians are advised to be vigilant for signs and symptoms of bleeding, including petechiae, epistaxis, and gastrointestinal bleeding, especially when concomitantly using medicinal products that may cause bleeding (see sections "Interaction with medicinal products and other forms of interaction" and "Adverse Reactions").

Hepatic Disorders

Liver function abnormalities, mainly deviations in liver function tests, have been reported. No specific pattern of hepatocellular or cholestatic injury was identified; in some cases, the abnormalities had a mixed pattern.

Most reactions occurred within the first 2 months of therapy and resolved spontaneously without treatment after thalidomide discontinuation. Liver function should be monitored in patients, especially those with pre-existing liver disease or concomitant use of medicinal products that may cause liver function impairment (see section "Adverse Reactions").

Allergic Reactions and Severe Skin Reactions

Cases of allergic reactions, including angioedema, anaphylactic reaction, and severe skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with thalidomide use. Physicians prescribing the drug should inform patients about the signs and symptoms of these reactions; patients should seek immediate medical attention if these symptoms develop.

Discontinuation or interruption of thalidomide should be considered in case of grade 2–3 skin rash.

Thalidomide use should be discontinued in case of angioedema, anaphylactic reaction, grade 4 rash, exfoliative or bullous rash, or suspicion of SJS, TEN, or DRESS syndrome, and re-administration should not be attempted after resolution of these reactions (see sections "Dosage and Administration" and "Adverse Reactions").

Drowsiness

Drowsiness is very commonly caused by thalidomide. Patients should be informed to avoid situations where drowsiness may be problematic and to consult their physician before taking other medicinal products that may also cause drowsiness. Patients should be monitored, as dose reduction may be required.

Patients should be informed about possible impairment of mental and/or physical abilities required for performing hazardous tasks (see section "Ability to affect reaction rate when driving vehicles or operating machinery").

Tumor Lysis Syndrome

The risk of tumor lysis syndrome exists in patients with high tumor burden prior to treatment initiation. Such patients should be closely monitored and appropriate preventive measures taken.

Infections

Patients should be monitored for severe infections, including sepsis and septic shock.

Cases of viral reactivation have been reported in patients receiving thalidomide, including serious cases of herpes zoster reactivation or hepatitis B virus (HBV) reactivation. In some cases, herpes zoster reactivation led to disseminated herpes zoster requiring temporary discontinuation of thalidomide and adequate antiviral treatment.

In some cases, HBV reactivation progressed to acute liver failure and required discontinuation of thalidomide. HBV status should be determined before initiation of thalidomide treatment. Patients with positive HBV infection test are recommended to consult a physician experienced in hepatitis B management.

Previously infected patients should be closely monitored for signs and symptoms of viral reactivation, including active HBV infection, throughout the treatment course.

Progressive Multifocal Leukoencephalopathy (PML)

Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported with thalidomide use. PML occurred several months or years after initiation of thalidomide treatment.

PML typically occurred in patients who were concomitantly receiving dexamethasone or had previously undergone other immunosuppressive chemotherapy. Physicians should regularly monitor patients and consider PML in the differential diagnosis of patients with new neurological symptoms or worsening of existing symptoms, cognitive or behavioral changes. Patients should also be advised to inform their partners or caregivers about their treatment, as they may notice symptoms the patient is unaware of.

PML evaluation should be based on neurological examination, brain magnetic resonance imaging, and analysis of cerebrospinal fluid for John Cunningham virus (JCV) DNA by polymerase chain reaction (PCR) or brain biopsy with JCV analysis. A negative JCV PCR test does not exclude PML. Additional follow-up monitoring and evaluation may be required if an alternative diagnosis cannot be established.

If PML is suspected, further administration of the drug should be discontinued until PML is ruled out. If PML is confirmed, thalidomide should be permanently discontinued.

Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

A statistically significant increase in the incidence of AML and MDS was observed in one clinical trial in patients with previously untreated MM who received a combination of melphalan, prednisone, and thalidomide. The risk increased over time, reaching approximately 2% at 2 years and approximately 4% at 3 years. An increased incidence of other primary malignancies (OPM) was also observed in patients with newly diagnosed MM receiving lenalidomide. Among invasive OPMs, cases of MDS/AML were observed in patients receiving lenalidomide in combination with melphalan or immediately after high-dose melphalan and autologous stem cell transplantation.

The benefits of thalidomide and the risks of AML and MDS should be carefully considered before initiating thalidomide in combination with melphalan and prednisone.

Physicians should carefully evaluate patients before and during treatment using standard cancer screening and initiate treatment according to indications.

Patients with Renal or Hepatic Impairment

Studies in healthy volunteers and patients with multiple myeloma indicate that renal or hepatic function does not significantly affect thalidomide exposure (see section "Pharmacological Properties"). However, this effect has not been formally studied in patients with renal or hepatic impairment; therefore, patients with severe renal or hepatic impairment should be closely monitored for any adverse events.

Use during Pregnancy or Breastfeeding

Women of reproductive age / Contraception in men and women

Women of reproductive age must use an effective contraceptive method for at least 4 weeks before treatment initiation, during treatment (including treatment interruptions), and for at least 4 weeks after thalidomide treatment (see section "Special Precautions for Use"). If a woman receiving thalidomide treatment becomes pregnant, treatment must be discontinued, and the patient should be referred to a physician specializing in or experienced with teratology for risk assessment and recommendations.

Since thalidomide is present in semen, all male patients must use a condom during treatment, during treatment interruptions, and for 7 days after treatment discontinuation during sexual intercourse with a pregnant woman or a woman of reproductive age not using effective contraception. This applies even to men who have undergone vasectomy.

If a woman becomes pregnant from a man receiving thalidomide treatment, she should be referred to a physician specializing in or experienced with teratology for risk assessment and recommendations.

Pregnancy

Thalidomide is contraindicated in pregnant women and women of childbearing potential unless all conditions of the Pregnancy Prevention Program are met (see section "Special Precautions for Use"). Thalidomide is a known human teratogen that frequently (approximately 30%) causes severe, life-threatening congenital malformations such as ectromelia (amelia, phocomelia, hemimelia) of upper and/or lower limbs, microtia with anomalies of the external auditory canal (blind or absent), involvement of the middle and inner ear (less frequently), ocular abnormalities (anophthalmia, microphthalmia), congenital heart defects, and renal anomalies. Other less frequent anomalies have also been described.

Breastfeeding

It is unknown whether thalidomide is excreted in human breast milk. Animal studies have shown that thalidomide crosses into breast milk. Therefore, women should discontinue thalidomide treatment during breastfeeding.

Fertility

Animal studies in rabbits did not show effects on fertility parameters in males or females, although testicular degeneration was observed in males.

Ability to affect reaction rate when driving vehicles or operating machinery

Thalidomide at recommended doses has a negligible or moderate effect on the ability to drive vehicles or operate machinery.

Thalidomide may cause fatigue (very common), dizziness (very common), drowsiness (very common), and blurred vision (common) (see section "Adverse Reactions"). Patients should be instructed not to drive, operate machinery, or perform hazardous tasks during thalidomide treatment if they experience fatigue, dizziness, drowsiness, or blurred vision.

Method of Administration and Dosage

Treatment should be initiated and monitored by a physician experienced in the use of immunomodulatory or chemotherapeutic agents, who fully understands the risks associated with thalidomide therapy and the requirements for monitoring (see section "Special Precautions for Use").

Dosing

The recommended dose of thalidomide is 200 mg orally once daily.

A maximum of 12 cycles of 6 weeks (42 days) each should be administered.

Table 1. Initial doses of thalidomide in combination with melphalan and prednisone

Age (years)	*ANC (/µL)		Platelet count (/µL)	Thalidomide a,b	Melphalan c,d,e	Prednisone
≤ 75	≥ 1,500	and	≥ 100,000	200 mg/day	0.25 mg/kg/day	2 mg/kg/day
≤ 75	< 1,500, but ≥ 1,000	or	< 100,000, but ≥ 50,000	200 mg/day	0.125 mg/kg/day	2 mg/kg/day
> 75	≥ 1,500	and	≥ 100,000	100 mg/day	0.20 mg/kg/day	2 mg/kg/day
> 75	< 1,500, but ≥ 1,000	or	< 100,000, but ≥ 50,000	100 mg/day	0.10 mg/kg/day	2 mg/kg/day

* ANC — absolute neutrophil count.

a Thalidomide once daily at bedtime on days 1–42 of each 42-day cycle.

b Due to the sedative effect associated with thalidomide, administration at bedtime generally improves tolerability.

c Melphalan dose once daily on days 1–4 of each 42-day cycle.

d Melphalan dosing: reduce by 50% in moderate (CrCl: ≥ 30 to < 50 mL/min) or severe (CrCl: < 30 mL/min) renal impairment.

e Maximum daily dose of melphalan: 24 mg (subjects ≤ 75 years of age) or 20 mg (subjects > 75 years of age).

f Prednisone dose once daily on days 1–4 of each 42-day cycle.

Patients should be monitored for the development of thromboembolism, peripheral neuropathy, severe skin reactions, bradycardia, syncope, somnolence, neutropenia, and thrombocytopenia (see sections "Special warnings and precautions" and "Adverse reactions"). Dose delay, dose reduction, or discontinuation of treatment may be required depending on NCI CTC (National Cancer Institute Common Terminology Criteria for Adverse Events) grade.

If a patient misses a dose and less than 12 hours have passed since the missed dose, the patient may take the missed dose. If more than 12 hours have passed since the missed dose, the patient should not take the missed dose and should take the next dose at the regularly scheduled time on the following day.

Thromboembolism

Thrombosis prophylaxis should be administered for at least the first 5 months of treatment, particularly in patients with additional risk factors for thrombosis. Prophylactic antithrombotic agents such as low-molecular-weight heparins or warfarin are recommended. Decisions regarding antithrombotic prophylaxis should be made after careful individual assessment of risk factors (see sections "Special warnings and precautions", "Interaction with other medicinal products and other forms of interaction", and "Adverse reactions").

If a patient develops any thromboembolic event, treatment should be discontinued and standard anticoagulant therapy initiated. After stabilization of the patient on anticoagulant therapy and management of thromboembolic complications, thalidomide treatment may be restarted at the initial dose following a benefit-risk assessment. The patient should continue anticoagulant therapy during thalidomide treatment.

Neutropenia

Leukocyte counts should be monitored regularly according to oncology guidelines, especially in patients who are more susceptible to neutropenia. Dose delay, dose reduction, or discontinuation of treatment may be required depending on the NCI CTC grade.

Thrombocytopenia

Platelet counts should be monitored regularly according to oncology guidelines. Dose delay, dose reduction, or discontinuation of treatment may be required depending on the NCI CTC grade.

Peripheral neuropathy

Dose modifications related to peripheral neuropathy are described in Table 2.

Table 2. Recommended dose modifications for thalidomide-related neuropathy in first-line treatment of multiple myeloma

Neuropathy grade	Dose and schedule modification
Grade 1 (paresthesia, weakness and/or loss of reflexes) without functional impairment	Continue monitoring the patient clinically. Consider dose reduction if symptoms worsen. However, dose reduction does not necessarily lead to improvement in symptoms
Grade 2 (functional impairment, but not in activities of daily living for self-care)	Reduce dose or interrupt treatment and continue monitoring the patient clinically and neurologically. If there is no improvement or neuropathy continues to worsen, discontinue treatment. If neuropathy improves to Grade 1 or better, treatment may be resumed, provided the benefit/risk ratio is favorable
Grade 3 (impairment in activities of daily living for self-care)	Discontinue treatment
Grade 4 (neuropathy rendering the patient unable to work)	Discontinue treatment

Allergic reactions and severe skin reactions

In case of grade 2–3 skin rash, consider the need to interrupt or discontinue thalidomide treatment. Thalidomide must be discontinued in case of angioedema, anaphylactic reaction, grade 4 rash, exfoliative or bullous rash, or suspected Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and must not be restarted after resolution of these reactions.

Elderly patients

No special dose adjustment is recommended for elderly patients ≤ 75 years of age.

For patients over 75 years of age, the recommended starting dose of thalidomide is 100 mg per day. The starting dose of melphalan in patients over 75 years of age should be reduced, taking into account baseline bone marrow reserve and renal function. The recommended starting dose of melphalan is 0.1 to 0.2 mg/kg per day depending on bone marrow reserve, with a further 50% dose reduction in cases of moderate (creatinine clearance: ≥ 30 but < 50 mL/min) or severe (creatinine clearance: < 30 mL/min) renal impairment. The maximum daily dose of melphalan is 20 mg for patients over 75 years of age (see Table 1).

Patients with renal or hepatic impairment

The effect of thalidomide has not been studied in patients with renal or hepatic impairment.

There are no specific dosage recommendations for these patient groups. Patients with severe organ impairment should be closely monitored for adverse reactions.

Method of administration

The medicinal product should be taken once daily at bedtime to minimize the impact of somnolence.

Capsules must not be opened or crushed (see section "Storage conditions").

It is recommended to press only one end of the capsule when removing it from the blister to reduce the risk of capsule deformation or breakage.

Children

There is no information on the use of thalidomide in children with multiple myeloma; therefore, this medicinal product is not indicated for use in children.

Overdose

Eighteen cases of overdose with doses up to 14.4 g are known. In thirteen of these cases, patients took only thalidomide; the amounts ranged from 350 mg to 4000 mg.

In these patients, either no symptoms occurred, or somnolence, irritability, nausea, and headache were observed. In one 2-year-old child who ingested 700 mg, plantar fascia pathology occurred along with somnolence and irritability. No fatal cases were reported, and all patients with overdose recovered without sequelae. There is no specific antidote for thalidomide overdose. In case of overdose, vital signs should be monitored and appropriate supportive therapy provided to maintain blood pressure and respiratory status.

Adverse Reactions

Summary of safety profile

Adverse reactions are expected to occur in the majority of patients taking thalidomide.

The most common adverse reactions associated with the use of thalidomide in combination with melphalan and prednisone are: neutropenia, leukopenia, constipation, somnolence, paresthesia, peripheral neuropathy, anemia, lymphopenia, thrombocytopenia, dizziness, dysesthesia, tremor, and peripheral edema.

In addition to the adverse reactions described above, thalidomide in combination with dexamethasone in other clinical trials very commonly caused fatigue; commonly caused adverse reactions such as transient ischemic attack, syncope, vertigo, arterial hypotension, mood alteration, anxiety, visual disturbances, nausea, and dyspepsia; and uncommonly caused adverse reactions including cerebrovascular disorder, diverticular perforation, peritonitis, orthostatic hypotension, and bronchitis.

The most clinically significant adverse reactions associated with the use of thalidomide in combination with melphalan and prednisone or dexamethasone include: deep vein thrombosis and pulmonary embolism, pulmonary embolism, embolism, peripheral neuropathy, severe skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), syncope, bradycardia, and dizziness (see sections "Dosage and administration", "Special precautions", and "Interaction with medicinal products and other forms of interaction").

List of adverse reactions

Table 3 includes only those adverse reactions for which a causal relationship with thalidomide treatment can reasonably be established. These reactions were observed during the main clinical study and in the post-marketing period. The frequency of adverse reactions was determined during the main comparative clinical trial evaluating thalidomide in combination with melphalan and prednisone in previously untreated patients with multiple myeloma.

The frequency of adverse reactions is classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 3. Adverse reactions (ARs) reported in the main clinical study of thalidomide in combination with melphalan and prednisone, as well as during post-marketing use

System organ classes / types of disorders	Frequency	Adverse reactions
Infections and infestations	Common	Pneumonia
	Frequency unknown	Severe infections (such as fatal sepsis, including septic shock)†, viral infections, including herpes zoster and reactivation of hepatitis B virus†
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Common	Acute myeloid leukemia *^
	Uncommon	Myelodysplastic syndrome *^
	Frequency unknown	Tumour lysis syndrome
Blood and lymphatic system disorders	Very common	Neutropenia, leukopenia, anemia, lymphopenia, thrombocytopenia
	Common	Febrile neutropenia †, pancytopenia †
Immune system disorders	Frequency unknown	Allergic reactions (hypersensitivity, angioedema, anaphylactic reactions, urticaria) †
Endocrine disorders	Frequency unknown	Hypothyroidism†
Psychiatric disorders	Common	Confusion, depression
Nervous system disorders	Very common	Peripheral neuropathy*, tremor, dizziness, paraesthesia, dysaesthesia, somnolence
	Common	Seizures†, coordination disorders
	Frequency unknown	Posterior reversible encephalopathy syndrome (PRES)*†, worsening of Parkinson's disease symptoms†
Ear and labyrinth disorders	Common	Hearing impairment or deafness†
Cardiac disorders	Common	Heart failure, bradycardia
	Uncommon	Myocardial infarction†, atrial fibrillation†, atrioventricular block
Vascular disorders	Common	Deep vein thrombosis*
Respiratory, thoracic and mediastinal disorders	Common	Pulmonary embolism*, interstitial lung disease, bronchopneumopathy, dyspnoea
	Frequency unknown	Pulmonary hypertension†
Gastrointestinal disorders	Very common	Constipation
	Common	Vomiting, dry mouth
	Uncommon	Intestinal obstruction
	Frequency unknown	Gastrointestinal perforation†, pancreatitis†, gastrointestinal haemorrhage†
Hepatic disorders	Frequency unknown	Liver function abnormalities†
Skin and subcutaneous tissue disorders	Common	Toxic skin rashes, rashes, dry skin
	Frequency unknown	Stevens-Johnson syndrome*†, toxic epidermal necrolysis*†, drug reaction with eosinophilia and systemic symptoms (DRESS)*†, leukocytoclastic vasculitis†
Renal and urinary disorders	Common	Renal failure†
Reproductive system and breast disorders	Frequency unknown	Sexual dysfunction†, menstrual disorders including amenorrhoea†
General disorders and administration site conditions	Very common	Peripheral oedema
	Common	Pyrexia, asthenia, malaise

* See "Description of selected adverse reactions" below.

† Identified in the post-marketing period.

^ Acute myeloid leukemia and myelodysplastic syndrome were reported in one clinical trial in patients with previously untreated MM who received the combination of melphalan, prednisone, and thalidomide.

Description of selected adverse reactions

Disorders of blood and lymphatic system

Hematological disorders observed during thalidomide treatment are presented in comparison with concomitantly administered drugs, as they have a significant impact on these disorders (Table 4).

Table 4. Comparison of hematological disorders during treatment with melphalan, prednisone (MP) and the combination of melphalan, prednisone, and thalidomide (MPT) in the IFM 99-06 study (see section "Pharmacological properties").

	Number (%) of patients
	MP (number = 193)	MPT (number = 124)
	Grade 3 and 4*
Neutropenia	57 (29.5)	53 (42.7)
Leukopenia	32 (16.6)	32 (25.8)
Anemia	28 (14.5)	17 (13.7)
Lymphopenia	14 (7.3)	15 (12.1)
Thrombocytopenia	19 (9.8)	14 (11.3)

*WHO criteria.

Additional adverse reactions reported from post-marketing experience with thalidomide, which were not observed in the main study, include febrile neutropenia and pancytopenia.

Teratogenicity

The risk of intrauterine death or severe congenital malformations, primarily phocomelia, is extremely high.

Thalidomide must not be used during pregnancy (see section "Special precautions and warnings").

Venous and arterial thromboembolism

An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (such as myocardial infarction and cerebrovascular events) has been reported in patients receiving thalidomide (see section "Special precautions and warnings").

Peripheral neuropathy

Peripheral neuropathy is a very common, potentially severe adverse reaction of thalidomide therapy, which may lead to irreversible damage (see section "Special precautions and warnings"). Peripheral neuropathy usually occurs after prolonged treatment over several months. However, cases have also been reported following relatively short-term use. The incidence of neuropathy events leading to discontinuation, dose reduction, or interruption increases with higher cumulative doses and longer duration of therapy. Symptoms may appear some time after stopping thalidomide treatment and may resolve slowly or not at all.

Posterior reversible encephalopathy syndrome (PRES) / posterior reversible leukoencephalopathy syndrome (PRLS)

Cases of PRES/PRLS have been reported. Signs and symptoms included visual disturbances, headache, seizures, and altered mental status, with or without hypertension. Diagnosis of PRES/PRLS requires confirmation by brain imaging. In most reported cases, risk factors for PRES/PRLS were present, including hypertension, renal dysfunction, and concomitant use of high-dose corticosteroids and/or chemotherapy.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)

AML and MDS were reported in one clinical trial involving patients with previously untreated multiple myeloma who received a combination of melphalan, prednisone, and thalidomide (see section "Special precautions and warnings").

Allergic reactions and severe skin reactions

Cases of allergic reactions, including angioedema, anaphylactic reaction, and severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and DRESS syndrome, have been reported during thalidomide therapy. If angioedema, anaphylactic reaction, Stevens-Johnson syndrome, TEN, or DRESS syndrome is suspected, thalidomide must not be restarted (see sections "Dosage and administration" and "Special precautions and warnings").

Elderly patients

The adverse reaction profile in patients aged >75 years receiving thalidomide 100 mg once daily was similar to that in patients aged ≤75 years receiving thalidomide 200 mg once daily (see Table 3). However, patients aged >75 years are more likely to experience serious adverse reactions.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmacy 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, in a place inaccessible to children.

Special precautions for disposal

Capsules must not be opened or crushed. If thalidomide powder comes into contact with the skin, the area should be washed immediately and thoroughly with soap and water. If thalidomide contacts mucous membranes, they should be thoroughly rinsed with water.

Healthcare workers and caregivers should wear disposable gloves when handling the blister pack or capsule. Gloves should then be carefully removed, avoiding skin contact, placed into a closable plastic polyethylene bag, and disposed of according to regulatory requirements. Hands should then be thoroughly washed with soap and water. Pregnant women and women who suspect they may be pregnant must not handle the blister pack or capsule (see section "Special precautions and warnings").

All unused capsules should be returned to the pharmacist after completion of treatment.

Packaging. №84: 7 capsules in a blister, 12 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Shilpa Medikem Limited / Shilpa Medicare Limited

Manufacturer's address and place of business. 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, Mahabubnagar, Telangana, 509301, India.

Marketing Authorization Holder. Meilu Healthcare Limited.

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