Myelodest (Capsules) Instructions for Use

Marketing Authorization Holder

Pharmasintez-Nord, JSC (Russia)

ATC Code

L04AX06 (Pomalidomide)

Active Substance

Pomalidomide (Rec.INN registered by WHO)

Dosage Forms

	Myelodest	Capsules 1 mg: 20 or 21 pcs.
		Capsules 2 mg: 20 or 21 pcs.
		Capsules 3 mg: 20 or 21 pcs.
		Capsules 4 mg: 20 or 21 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin No. 3; yellow body, dark blue cap; contents – yellow powder.

Excipients: maltitol (E965), copovidone, colloidal silicon dioxide, glyceryl dibehenate, gelatin, brilliant blue FCF (E133), yellow iron oxide (E172), allura red AC (E129).

5 pcs. – blister pack (4) – cardboard packs.
7 pcs. – blister pack (3) – cardboard packs.
20 pcs. – polyethylene jars (1) – cardboard packs.
21 pcs. – polyethylene jars (1) – cardboard packs.

Capsules hard gelatin No. 3; orange body, dark blue cap; contents – yellow powder.

Excipients: maltitol (E965), copovidone, colloidal silicon dioxide, glyceryl dibehenate, gelatin, yellow iron oxide (E172), brilliant blue FCF (E133), allura red AC (E129), red iron oxide (E172).

5 pcs. – blister pack (4) – cardboard packs.
7 pcs. – blister pack (3) – cardboard packs.
20 pcs. – polyethylene jars (1) – cardboard packs.
21 pcs. – polyethylene jars (1) – cardboard packs.

Capsules hard gelatin No. 2; green body, dark blue cap; contents – yellow powder.

Excipients: maltitol (E965), copovidone, colloidal silicon dioxide, glyceryl dibehenate, gelatin, brilliant blue FCF (E133), allura red AC (E129), tartrazine (E102).

5 pcs. – blister pack (4) – cardboard packs.
7 pcs. – blister pack (3) – cardboard packs.
20 pcs. – polyethylene jars (1) – cardboard packs.
21 pcs. – polyethylene jars (1) – cardboard packs.

Capsules hard gelatin No. 1; bluish-greenish body, dark blue cap; contents – yellow powder.

Excipients: maltitol (E965), copovidone, colloidal silicon dioxide, glyceryl dibehenate, gelatin, brilliant blue FCF (E133), allura red AC (E129).

5 pcs. – blister pack (4) – cardboard packs.
7 pcs. – blister pack (3) – cardboard packs.
20 pcs. – polyethylene jars (1) – cardboard packs.
21 pcs. – polyethylene jars (1) – cardboard packs.

Clinical-Pharmacological Group

Immunomodulator with antitumor activity

Pharmacotherapeutic Group

Immunosuppressants; other immunosuppressants

Pharmacological Action

Pomalidomide has direct anti-myeloma tumoricidal activity, demonstrates immunomodulatory effects, and inhibits stromal cells that support the growth of myeloma tumor cells.

It selectively inhibits the proliferation and induces apoptosis of hematopoietic tumor cells. Furthermore, Pomalidomide inhibits the proliferation of multiple myeloma cell lines resistant to lenalidomide and exhibits synergy with dexamethasone in inducing apoptosis of both lenalidomide-sensitive and resistant tumor cell lines.

Pomalidomide enhances cellular immunity involving T-cells and natural killer cells and inhibits the production of pro-inflammatory cytokines (e.g., TNFα and interleukin-6) by monocytes. Pomalidomide also inhibits angiogenesis by blocking endothelial cell migration and adhesion.

Pharmacokinetics

After a single oral dose, the absorption of pomalidomide is at least 73%, and its C_max in plasma is reached within 2 hours.

The systemic exposure of pomalidomide (by AUC) increases nearly linearly and proportionally with the dose. With multiple dosing, the extent of pomalidomide accumulation is 27-31% based on AUC.

When taken with a high-calorie, high-fat meal, the rate of pomalidomide absorption is slowed, the mean C_max is reduced by approximately 27%, but the overall absorption is practically unchanged, the mean AUC decreases by 8%, so Pomalidomide can be taken regardless of food intake.

The mean apparent V_d of pomalidomide at steady state ranges from 62 to 138 L. After administration of 2 mg/day for 3 days, Pomalidomide was detected in the semen of healthy volunteers at a concentration of approximately 67% of the plasma level, which is reached at 4 hours (approximate T_max) after drug intake. In vitro binding of pomalidomide enantiomers to human plasma proteins ranges from 12% to 44% and is concentration-independent.

In healthy volunteers after a single oral dose of [¹⁴C]-pomalidomide (2 mg), the main radioactive component in blood was Pomalidomide (approximately 70% of plasma radioactivity). The amount of metabolites did not exceed 10% relative to the parent compound or total plasma radioactivity.

Hydroxylation followed by glucuronidation or hydrolysis is the main metabolic pathway for excreted radioactivity. In vitro, CYP1A2 and CYP3A4 isoenzymes were the primary enzymes involved in the hydroxylation of pomalidomide. CYP2C19 and CYP2D6 isoenzymes played a lesser role. Pomalidomide is also a substrate of Pgp in vitro.

The mean T_1/2 of pomalidomide from plasma is 9.5 hours in healthy volunteers and 7.5 hours in patients with multiple myeloma. The mean total clearance of the drug is approximately 7-10 L/h. In healthy volunteers after a single oral dose of [¹⁴C]-pomalidomide (2 mg), approximately 73% and 15% of the radioactive dose was excreted renally and via the intestine, respectively, with about 2% and 8% of the carbon-labeled pomalidomide dose excreted renally and via the intestine unchanged.

Pomalidomide undergoes significant biotransformation, and the resulting metabolites are primarily excreted renally. Three main metabolites formed by hydrolysis or hydroxylation followed by glucuronidation account for 23%, 17%, and 12% of the total metabolite content in urine, respectively. The amount of metabolites formed via cytochrome P450 was approximately 43% of the total radioactivity, and non-CYP-dependent hydrolytic metabolites accounted for 25%. Pomalidomide is excreted 10% unchanged (2% renally and 8% via the intestine).

Indications

In combination with dexamethasone for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and who have demonstrated disease progression on the last therapy.

ICD codes

Dosage Regimen

Take orally. Swallow the capsule whole with water. Do not chew or crush the capsules.

The recommended starting dose is 4 mg once daily. Administer the dose on days 1 to 21 of repeated 28-day treatment cycles.

Take the capsule at approximately the same time each day. Administration with or without food is acceptable.

Perform a complete blood count before initiating therapy. Monitor blood counts weekly for the first 8 weeks and monthly thereafter.

Adjust the dosing regimen based on clinical and laboratory data, particularly for hematological toxicity.

For grade 3 or 4 neutropenia, interrupt treatment and monitor blood counts weekly. Upon recovery to neutrophil count ≥1.0×10⁹/L, resume therapy at a reduced dose of 3 mg daily.

For recurrent grade 4 neutropenia after a dose reduction, interrupt treatment. Upon recovery, resume therapy at a further reduced dose of 2 mg daily.

For grade 3 or 4 thrombocytopenia, interrupt treatment and monitor blood counts weekly. Upon recovery to platelet count ≥50×10⁹/L, resume therapy at a reduced dose of 3 mg daily.

For other grade 3 or 4 toxicities judged to be related to pomalidomide, interrupt treatment until the event resolves to at least grade 2 or baseline. Resume therapy at the physician’s discretion, considering a dose reduction of 1 mg from the previous daily dose.

For patients with severe renal impairment requiring dialysis, administer the 4 mg dose after the dialysis procedure on dialysis days.

For patients receiving a strong CYP1A2 inhibitor (e.g., ciprofloxacin, fluvoxamine), reduce the pomalidomide dose by 50% to 2 mg once daily. Monitor patients closely for adverse reactions.

Continue treatment until disease progression or unacceptable toxicity occurs.

Adverse Reactions

Infections and infestations very common – bacterial, viral, and fungal infections, including opportunistic infections; common – neutropenic sepsis, respiratory tract infections, upper respiratory tract infections, herpes zoster; frequency unknown – reactivation of hepatitis B virus.

Benign, malignant and unspecified neoplasms (including cysts and polyps) uncommon – basal cell carcinoma of the skin, squamous cell carcinoma of the skin.

Blood and lymphatic system disorders very common – neutropenia, thrombocytopenia, leukopenia, anemia; common – febrile neutropenia, pancytopenia.

Allergic reactions common – angioedema, urticaria.

Metabolism and nutrition disorders common – hyperkalemia, hyponatremia, hyperuricemia; uncommon – tumor lysis syndrome.

Psychiatric disorders common – confusion.

Nervous system disorders common – lethargy, peripheral sensory neuropathy, dizziness, tremor, intracranial hemorrhage; uncommon – stroke.

Ear and labyrinth disorders common – vertigo.

Cardiac disorders common – heart failure, atrial fibrillation, myocardial infarction, deep vein thrombosis.

Respiratory, thoracic and mediastinal disorders very common – dyspnea, cough, pneumonia; common – pulmonary embolism, epistaxis, nasopharyngitis, interstitial lung disease, bronchopneumonia, bronchitis.

Gastrointestinal disorders very common – decreased appetite, diarrhea, nausea, constipation; common – vomiting, gastrointestinal hemorrhage, increased ALT; uncommon – hyperbilirubinemia, hepatitis.

Skin and subcutaneous tissue disorders common – rash, pruritus; frequency unknown – DRESS syndrome, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders very common – bone pain, muscle spasms.

Renal and urinary disorders common – renal failure, urinary retention.

General disorders and administration site conditions very common – fatigue, pyrexia, peripheral edema; common – pelvic pain, increased blood uric acid.

Contraindications

Hypersensitivity to pomalidomide; pregnancy, breastfeeding; women of childbearing potential, except when all necessary conditions of the Pregnancy Prevention Program are met; men who are unable or unwilling to adhere to the required contraceptive measures; age under 18 years.

With caution, Pomalidomide should be prescribed to patients with renal and/or hepatic impairment, deep vein thrombosis (including history), advanced stage disease and/or high tumor burden due to the potential risk of tumor lysis syndrome, neuropathy (including history), presence of risk factors for thromboembolism (heart or lung disease, hypertension, hypercholesterolemia, smokers), with concurrent use of drugs that increase the risk of thrombosis (including drugs with erythropoietic activity, hormone replacement therapy).

Use in Pregnancy and Lactation

Contraindicated during pregnancy.

Women of childbearing potential must use one highly effective method of contraception for 4 weeks before starting treatment, during treatment, and for 4 weeks after discontinuation of pomalidomide therapy, even in case of treatment interruption. The exception is patients who have been continuously abstinent for a long period of time, confirmed monthly. If an effective method of contraception has not been selected for the patient, she should be referred to a gynecologist for selection and initiation of a contraceptive method.

In accordance with accepted practice, pregnancy tests with a minimum sensitivity of 25 mIU/mL should be performed under physician supervision for all women of childbearing potential, including those who are completely and continuously abstinent.

Given the potential for adverse effects of pomalidomide on newborns, either breastfeeding or drug administration should be discontinued, taking into account the importance of breastfeeding and treatment for the mother.

Use in Hepatic Impairment

No initial dose adjustment of pomalidomide is required in patients with hepatic impairment.

Use in Renal Impairment

No dose adjustment of pomalidomide is required in patients with renal impairment.

Pediatric Use

Contraindicated in patients under 18 years of age.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Treatment with pomalidomide should be initiated and conducted under the supervision of an experienced hematologist or oncologist.

Strict adherence to all requirements of the Pregnancy Prevention Program must apply to all patients unless the absence of childbearing potential is reliably proven.

The use of combined oral contraceptives is not recommended in patients with multiple myeloma due to the increased risk of thromboembolic complications during treatment with pomalidomide and dexamethasone. The increased risk of thromboembolism persists for 4-6 weeks after discontinuation of combined contraceptives. The effectiveness of hormonal contraceptives may be reduced with concurrent administration of dexamethasone.

The use of subcutaneous hormonal implants or intrauterine systems releasing levonorgestrel is associated with an increased risk of infectious complications at the time of insertion and with irregular vaginal bleeding. Patients with neutropenia using these contraceptive methods should be prophylactically prescribed antibiotics.

The use of copper-releasing intrauterine systems is generally not recommended due to the high risk of infectious complications at implantation and increased blood loss during menstruation, which may exacerbate neutropenia or thrombocytopenia.

Pomalidomide may be present in the patient’s semen during treatment. As a precaution and considering specific patient groups with potentially prolonged elimination, e.g., those with hepatic impairment, all men taking Pomalidomide should consider the potential risk of teratogenic effects of pomalidomide during sexual contact with a pregnant woman or a woman of childbearing potential.

Condoms must be used during sexual contact with a pregnant woman or a woman of childbearing potential not using reliable contraception, during treatment, during treatment interruption, and for 7 days after therapy suspension and/or completion. This recommendation also applies to men who have undergone vasectomy, who must also use a condom during sexual contact with a pregnant woman or a woman of childbearing potential, as even in the absence of sperm, his semen may contain Pomalidomide.

If a partner becomes pregnant during his treatment with pomalidomide or within 7 days after discontinuing pomalidomide therapy, the man must immediately inform his treating physician, and his partner is advised to consult a teratology specialist for examination and counseling.

Patients are not permitted to donate blood, ova, or sperm throughout the treatment period (including treatment interruptions) and for 7 days after completion of pomalidomide intake.

In patients with relapsed/refractory multiple myeloma, the most frequently reported grade 3 or 4 adverse event is neutropenia; the next most frequent are anemia and thrombocytopenia. Patients should be monitored for hematological adverse reactions, especially neutropenia. Patients should be informed to promptly report fever. Physicians should monitor patients for symptoms of increased bleeding, including nosebleeds, especially with concomitant therapy with drugs that increase the risk of bleeding. A complete blood count should be performed before starting treatment, then weekly for the first 8 weeks of treatment, and then once monthly. Dose modification of pomalidomide, use of blood substitutes, and/or growth factor preparations may be required.

Venous thromboembolic events (mainly deep vein thrombosis and pulmonary embolism) and arterial thrombotic events (myocardial infarction and stroke) have developed in patients treated with pomalidomide in combination with dexamethasone. Patients with risk factors for thromboembolism, including prior thrombosis, should be closely monitored. All possible measures should be taken to minimize risk factors (e.g., smoking, hypertension, hyperlipidemia). Patients and physicians should monitor for signs and symptoms of thromboembolism. Patients should be warned to seek medical attention if symptoms such as shortness of breath, chest pain, swelling of the upper and lower extremities occur. In the absence of contraindications, treatment with anticoagulants (such as acetylsalicylic acid, warfarin, heparin, or clopidogrel) is recommended, especially in patients with additional risk factors for thrombosis.

The use of erythropoietic agents is associated with a risk of thrombotic complications, including thromboembolism. Therefore, erythropoietic drugs, as well as other agents that may increase the risk of thromboembolism, should be used with caution.

Complications in the form of heart failure, including congestive heart failure and pulmonary edema, have been noted mainly in patients with pre-existing heart failure or risk factors for heart disease. Caution should be exercised when deciding to prescribe pomalidomide therapy to such patients, including regular check-ups to detect symptoms of heart failure.

The greatest risk of tumor lysis syndrome exists in patients with a high tumor burden at the start of treatment. Close monitoring of such patients with appropriate prophylactic measures is necessary.

The occurrence of primary malignancies of other sites, such as non-melanoma skin cancer, has been reported in patients treated with Pomalidomide. Patients should be thoroughly examined before and during treatment using standard cancer screening methods to detect primary tumors of other sites and, if necessary, appropriate treatment should be prescribed.

During treatment with pomalidomide, angioedema and severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome, have been reported. Patients should be informed about the signs and symptoms of these reactions and warned about the need to seek immediate medical attention if such symptoms appear.

Pomalidomide treatment should be discontinued if exfoliative or bullous rash develops or if Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome is suspected. Treatment should not be resumed after the resolution of the aforementioned reactions.

Patients with a history of serious allergic reactions to thalidomide or lenalidomide may have an increased risk of developing hypersensitivity reactions and should not receive Pomalidomide.

Interruption or discontinuation of pomalidomide treatment should be considered in case of grade 2-3 skin rash.

If angioedema develops, Pomalidomide must be discontinued.

There have been reports of dizziness and confusion during pomalidomide administration.

Patients should avoid situations where dizziness and confusion could pose a problem and should not take other medications that may cause similar disturbances without prior medical consultation.

Interstitial lung disease and other similar phenomena, including cases of pneumonitis, have been observed during treatment with pomalidomide.

Patients with acute symptoms or unexplained worsening of pulmonary symptoms should undergo a thorough examination to rule out interstitial lung disease.

During this examination, pomalidomide treatment should be suspended, and if the diagnosis of interstitial lung disease is confirmed, appropriate therapy should be prescribed.

Pomalidomide treatment may be resumed only after a careful assessment of the benefit and risk.

Marked increases in ALT activity and bilirubin concentration have been observed in patients taking Pomalidomide.

Cases of hepatitis that led to the discontinuation of pomalidomide treatment have also been reported.

Regular monitoring of liver function is recommended during the first 6 months of pomalidomide therapy and thereafter as clinically indicated.

Rare cases of hepatitis B virus reactivation have been reported in patients previously infected with the hepatitis B virus during treatment with pomalidomide in combination with dexamethasone.

In several cases, hepatitis progressed to acute liver failure, resulting in the discontinuation of Pomalidomide.

Before starting treatment with pomalidomide, a test for the presence and activity of the hepatitis B virus must be performed.

For patients with a positive test for the hepatitis B virus, consultation with a physician experienced in treating patients with viral hepatitis B is recommended.

Caution should be exercised when using pomalidomide and dexamethasone concomitantly in patients with a history of viral hepatitis B.

Such patients must be carefully monitored throughout the course of therapy for the timely detection of symptoms and signs of active disease caused by the hepatitis B virus.

Effect on the ability to drive vehicles and operate machinery

Pomalidomide has a minor to moderate influence on the ability to drive vehicles and operate machinery.

Some side effects of pomalidomide, such as fatigue, lethargy, confusion, and dizziness, may adversely affect the ability to drive a car and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

If such adverse events occur, one should refrain from performing these activities.

Drug Interactions

Pomalidomide is partially metabolized by CYP1A2 and CYP3A4/5 isoenzymes and is a substrate for Pgp.

If a strong inhibitor of the CYP1A2 isoenzyme (e.g., ciprofloxacin, enoxacin, or fluvoxamine) is used concomitantly with pomalidomide, the dose of pomalidomide should be reduced by 50%.

It is recommended to monitor the concentration of warfarin during combination therapy.

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.