Rupsulimid^® (Capsules) Instructions for Use

Marketing Authorization Holder

Biocad, JSC (Russia)

ATC Code

L04AX04 (Lenalidomide)

Active Substance

Lenalidomide (Rec.INN registered by WHO)

Dosage Forms

	Rupsulimid®	Capsules 5 mg: 7 or 21 pcs.
		Capsules 7.5 mg: 7 or 21 pcs.
		Capsules 10 mg: 7 or 21 pcs.
		Capsules 15 mg: 7 or 21 pcs.
		Capsules 20 mg: 7 or 21 pcs.
		Capsules 25 mg: 7 or 21 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin size #3 with an opaque white cap and an opaque white body; contents – powder from white to yellowish color.

Excipients : capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide;
capsule cap gelatin, titanium dioxide (E171);
capsule body gelatin, titanium dioxide (E171).

7 pcs. – blister pack (1) – cardboard packs with leaflet.
7 pcs. – blister pack (3) – cardboard packs with leaflet.

Capsules hard gelatin size #3 with an opaque yellow cap and an opaque white body; contents – powder from white to yellowish color.

Excipients : capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide;
capsule cap gelatin, titanium dioxide (E171), yellow iron oxide (E172);
capsule body gelatin, titanium dioxide (E171).

7 pcs. – blister pack (1) – cardboard packs with leaflet.
7 pcs. – blister pack (3) – cardboard packs with leaflet.

Capsules hard gelatin size #2 with an opaque blue-green cap and an opaque yellow body; contents – powder from white to yellowish color.

Excipients : capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide;
capsule cap gelatin, titanium dioxide (E171), yellow iron oxide (E172), indigo carmine (E132);
capsule body gelatin, titanium dioxide (E171), yellow iron oxide (E172).

7 pcs. – blister pack (1) – cardboard packs with leaflet.
7 pcs. – blister pack (3) – cardboard packs with leaflet.

Capsules hard gelatin size #1 with an opaque blue cap and an opaque white body; contents – powder from white to yellowish color.

Excipients : capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide;
capsule cap gelatin, titanium dioxide (E171), yellow iron oxide (E172), indigo carmine (E132);
capsule body gelatin, titanium dioxide (E171).

7 pcs. – blister pack (1) – cardboard packs with leaflet.
7 pcs. – blister pack (3) – cardboard packs with leaflet.

Capsules hard gelatin size #0 with an opaque blue-green cap and an opaque blue body; contents – powder from white to yellowish color.

Excipients : capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide;
capsule cap gelatin, titanium dioxide (E171), yellow iron oxide (E172), indigo carmine (E132);
capsule body gelatin, titanium dioxide (E171), indigo carmine (E132).

7 pcs. – blister pack (1) – cardboard packs with leaflet.
7 pcs. – blister pack (3) – cardboard packs with leaflet.

Capsules hard gelatin size #0 with an opaque white cap and an opaque white body; contents – powder from white to yellowish color.

Excipients : capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide;
capsule cap gelatin, titanium dioxide (E171);
capsule body gelatin, titanium dioxide (E171).

7 pcs. – blister pack (1) – cardboard packs with leaflet.
7 pcs. – blister pack (3) – cardboard packs with leaflet.

Clinical-Pharmacological Group

Immunosuppressant

Pharmacotherapeutic Group

Immunosuppressants; other immunosuppressants

Pharmacological Action

Antineoplastic agent, immunomodulator, which has both immunomodulatory and antiangiogenic properties.

It inhibits the secretion of proinflammatory cytokines, including TNFα, interleukin-1β (IL-1β), IL-6 and IL-12, from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC).

Lenalidomide increases the production of the anti-inflammatory cytokine IL-10 from LPS-stimulated PBMC, resulting in inhibition of expression, but not enzymatic activity of COX-2.

Lenalidomide induces T-cell proliferation and increases the synthesis of IL-2 and interferon gamma-1, and also increases the cytotoxic activity of natural killer cells.

Lenalidomide inhibits the proliferation of cells of various hematopoietic tumor lines, mainly those with cytogenetic defects of chromosome 5.

In a model of erythroid progenitor cell differentiation, Lenalidomide induces fetal hemoglobin expression, as judged by the differentiation of CD34⁺ hematopoietic stem cells.

Lenalidomide inhibits angiogenesis by blocking microvessel and endothelial channel formation, as well as endothelial cell migration in an in vitro angiogenesis model. In addition, Lenalidomide inhibits the synthesis of proangiogenic vascular endothelial growth factor by PC-3 prostate tumor cells.

Pharmacokinetics

Lenalidomide is a racemic mixture of two optically active forms: S(-) and R(+) with a total optical rotation equal to zero.

After oral administration, Lenalidomide is rapidly absorbed. C_max is reached within 0.625-1.5 hours after a single dose. Food intake does not affect the extent of absorption. The pharmacokinetic distribution is linear. C_max and AUC increase proportionally with increasing dose. Repeated administration of the drug does not lead to its accumulation.

In patients with multiple myeloma, Lenalidomide is rapidly absorbed, with C_max reached within 0.5-4 hours after administration, both on day 1 and on day 28. C_max and AUC increase proportionally with both single and repeated administration of the drug. According to C_max and AUC, lenalidomide exposure in patients with multiple myeloma is higher than in healthy volunteers, which is explained by the lower clearance to filtration ratio (CL/F) in patients with multiple myeloma compared to healthy volunteers, 300 and 200 ml/min, respectively.

In vitro binding of (¹⁴C)-lenalidomide to plasma proteins in patients with multiple myeloma and healthy volunteers was 22.7% and 29.2%, respectively.

Approximately 60% of lenalidomide is excreted by the kidneys unchanged. This exceeds the glomerular filtration rate and, therefore, the process is both passive and active. T_1/2 increases with increasing dose, from approximately 3 hours at a dose of 5 mg to approximately 9 hours at a dose of 400 mg. Steady state is reached on day 4.

C_max does not differ between patients with normal and impaired renal function. However, the elimination of lenalidomide slows down in proportion to the degree of renal impairment. A decrease in CC less than 50 ml/min is accompanied by an increase in AUC by 56%. T_1/2 of lenalidomide increases from approximately 3.5 hours (in patients with CC greater than 50 ml/min) to approximately 9 hours (in patients with CC less than 50 ml/min).

Indications

Treatment of multiple myeloma – in combination with dexamethasone in patients who have received at least one line of therapy.

ICD codes

Dosage Regimen

Take orally.

The recommended initial dose is 25 mg once daily on days 1-21 of repeated 28-day cycles. Dexamethasone at a dose of 40 mg is prescribed once daily on days 1-4, 9-12 and 17-20 of each 28-day cycle during the first 4 cycles of therapy, and then – 40 mg once daily on days 1-4 of each subsequent 28-day cycle.

If toxic effects develop, the dosage regimen is adjusted according to a special scheme.

In patients with impaired renal function, adjustment of the dosage regimen is required.

Adverse Reactions

Most frequently with the use of the Lenalidomide/dexamethasone combination: neutropenia (39.4%), muscle weakness (27.2%), asthenia (17.6%), constipation (23.5%), muscle cramps (20.1%), thrombocytopenia (18.4%), anemia (17%), diarrhea (14.2%), rash (10.2%).

Most severe adverse reactions: venous thromboembolism (deep vein thrombosis, pulmonary embolism), grade 4 neutropenia.

From the hematopoietic system very often – neutropenia, thrombocytopenia, anemia; often – leukopenia, lymphopenia.

From the cardiovascular system often – deep vein thrombosis, decreased blood pressure.

Infections and infestations often – pneumonia.

From the musculoskeletal system very often – muscle cramps.

From the nervous system: often – tremor, hypesthesia.

From the respiratory system: often – dyspnea (including exertional dyspnea).

From the skin and subcutaneous tissue: very often – skin rash; often – skin itching.

General reactions: very often – weakness, asthenia.

Contraindications

Pregnancy; lactation period (breastfeeding); childbearing age; inability to comply with necessary contraceptive measures; childhood; hypersensitivity to lenalidomide.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding).

Lenalidomide is a structural analogue of thalidomide, which has a pronounced teratogenic effect. It is known that taking thalidomide by pregnant women causes severe and life-threatening disorders of the internal organs of the fetus (with a frequency of up to 30%). Experimental studies in monkeys showed results similar to those previously described for thalidomide. The risk of developing birth defects is very high if Lenalidomide is used during pregnancy.

Strict adherence to contraception applies to both women and men.

Special Precautions

For the prevention of venous thromboembolism, especially in patients with additional risk factors, it is recommended to use low molecular weight heparins or warfarin. The decision to prescribe antithrombotic therapy should be made after a thorough assessment of individual risk factors.

The risk of developing grade 4 neutropenia in patients with multiple myeloma with simultaneous use of lenalidomide and dexamethasone is very high.

Careful monitoring by both the doctor and the patient of symptoms of increased bleeding, including petechiae and hemoptysis, is recommended.

During the first 2 months of treatment with lenalidomide, it is recommended to perform a complete blood count weekly, including determination of leukocyte count, blood count, platelet count, hemoglobin, and hematocrit. Subsequently, blood tests should be performed monthly.

The manifestations of lenalidomide toxicity that most often limit its use are neutropenia and thrombocytopenia. In this regard, the decision on the combined use of lenalidomide and other immunosuppressive drugs must be clinically justified.

Given the predominant excretion of lenalidomide by the kidneys, in patients with renal failure, it is necessary to carefully monitor renal function and the dose of lenalidomide.

Regular monitoring of thyroid function is necessary due to the possibility of hypothyroidism developing under the influence of lenalidomide.

The possibility of neurotoxic effects of lenalidomide with long-term use cannot be excluded, given the structural similarity of the molecules of lenalidomide and thalidomide, which is known for its pronounced neurotoxic side effect.

Due to the pronounced antineoplastic activity of lenalidomide, tumor lysis syndrome may develop, especially in patients with a large tumor mass. The condition of such patients should be monitored and appropriate prophylaxis should be carried out.

Patients are not allowed to donate blood or sperm as a donor throughout the entire treatment with lenalidomide and for one week after its completion.

Effect on ability to drive vehicles and mechanisms

Some side effects of lenalidomide, such as dizziness, weakness, drowsiness and blurred vision, may adversely affect the ability to drive a car and perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions. In this regard, special care should be taken when driving vehicles and working with machinery.

Drug Interactions

Mutual influence on the metabolism of lenalidomide and other drugs is unlikely due to the fact that Lenalidomide is not metabolized by the cytochrome P450 system.

Concomitant administration of lenalidomide with digoxin is accompanied by an increase in the plasma concentration of digoxin (C_max of digoxin was 114%, AUC – 108%). Thus, during treatment with lenalidomide, it is recommended to monitor the concentration of digoxin.

Dexamethasone, which is a mandatory component of the therapeutic regimen with lenalidomide, may reduce the effectiveness of oral contraceptives.

No mutual influence on the pharmacokinetic parameters of lenalidomide and warfarin was noted. Considering the use of dexamethasone in combination with lenalidomide, the influence of the latter on the effects of warfarin cannot be excluded. Therefore, during combination therapy with lenalidomide and dexamethasone, careful monitoring of the warfarin concentration is recommended.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

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