Polydover^® (Capsules) Instructions for Use

Marketing Authorization Holder

Veropharm, JSC (Russia)

ATC Code

L04AX06 (Pomalidomide)

Active Substance

Pomalidomide (Rec.INN registered by WHO)

Dosage Form

Polydover®

Capsules 4 mg: 21 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin with an opaque brown body and an opaque red cap; contents – powder from light yellow to yellow.

Excipients: pregelatinized starch, anhydrous lactose, sodium stearyl fumarate.
Composition of the hard gelatin capsule gelatin, purified water, titanium dioxide (E171), yellow iron oxide dye (E172), red iron oxide dye (E172).

21 pcs. – polyethylene jars (1) – cardboard packs with an insert.

Clinical-Pharmacological Group

Immunomodulator with antitumor activity

Pharmacotherapeutic Group

Immunosuppressants; other immunosuppressants

Pharmacological Action

Pomalidomide has direct anti-myeloma tumoricidal activity, demonstrates an immunomodulatory effect 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 has synergy with dexamethasone in inducing apoptosis in 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 almost linearly and proportionally to the dose. With multiple dosing, the extent of pomalidomide accumulation is 27-31% by 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 almost unchanged, the mean AUC is reduced 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 for 3 days at 2 mg/day, 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 main enzymes involved in the hydroxylation of pomalidomide. CYP2C19 and CYP2D6 isoenzymes were of lesser importance. 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 is extensively biotransformed, and the resulting metabolites are primarily excreted renally. The 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 by cytochrome P450 was approximately 43% of the total radioactivity, and non-CYP-dependent hydrolytic metabolites accounted for 25%. Pomalidomide is excreted unchanged at 10% (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

For oral administration.

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

Take capsules with water. Swallow whole; do not chew or open.

Administration is independent of food intake.

Dose adjustments are based on clinical and laboratory parameters, particularly absolute neutrophil count and platelet count.

Monitor complete blood counts weekly for the first 8 weeks, then monthly thereafter.

For grade 3 or 4 hematologic toxicity, interrupt treatment and monitor blood counts weekly.

Upon recovery to specific grade levels, resume treatment at a reduced dose.

For non-hematologic toxicities, treatment interruption and subsequent dose reduction may be required.

Do not crush or break capsules. Avoid direct contact with capsule contents.

If a dose is missed, take it as soon as remembered on the same day. If missed for the entire day, do not double the dose the next day; resume the normal dosing schedule.

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 bleeding, 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 plasma uric acid concentration.

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 comply with 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, high blood pressure, high blood cholesterol, smokers), with concomitant 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 the end of pomalidomide treatment, even in case of treatment interruption. The exception is patients who have been completely abstinent for a long 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 medical supervision for all women of childbearing potential, including those who are completely and long-term 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 adjustment of the initial pomalidomide dose 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 for 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 the concomitant 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 the time of insertion 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 taking into account special patient groups with potentially increased elimination time, e.g., with hepatic impairment, all men taking Pomalidomide should consider the potential risk of teratogenic effects of pomalidomide during sexual intercourse with a pregnant woman or a woman of childbearing potential. Condoms must be used during sexual intercourse with a pregnant woman or a woman of childbearing potential not using reliable contraception, during treatment, treatment interruption, and for 7 days after suspension and/or completion of treatment. This recommendation also applies to men after vasectomy, who should also use a condom during sexual intercourse 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 discontinuation of pomalidomide therapy, the man should immediately inform his treating physician, and his partner is advised to consult a teratologist for examination and counseling.

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

In patients with relapsed/refractory multiple myeloma, grade 3 or 4 adverse events most frequently reported are neutropenia; the next most frequent are anemia and thrombocytopenia. Patients should be monitored for adverse hematological reactions, especially neutropenia. Patients should be informed to report fever promptly. 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, then once a month. 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, were noted mainly in patients with pre-existing heart failure or risk factors for heart disease. Caution should be exercised when deciding to prescribe pomalidomide treatment to such patients, including regular check-ups to detect symptoms of heart failure.

The greatest risk of tumor lysis syndrome is in patients with a high tumor burden at the start of treatment. Close monitoring of such patients with appropriate preventive measures should be carried out.

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

Angioedema and severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome, have been reported during the use of pomalidomide. Patients should be informed about the signs and symptoms of these reactions and warned to seek immediate medical attention if such symptoms occur. Pomalidomide treatment should be discontinued if exfoliative or bullous rash develops or if Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome are suspected. Treatment should not be resumed after resolution of the aforementioned reactions.

Patients with a history of serious allergic reactions to thalidomide or lenalidomide may have an increased risk of 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 are reports of dizziness and confusion during pomalidomide intake. Patients should avoid situations where dizziness and confusion could be a problem and not take other medications that may cause such 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 interstitial lung disease is confirmed, appropriate therapy should be prescribed. Pomalidomide treatment may be resumed only after a careful benefit-risk assessment.

Marked increases in ALT activity and bilirubin concentration have been observed in patients taking Pomalidomide. Cases of hepatitis leading to 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 hepatitis B virus while being treated with pomalidomide in combination with dexamethasone. In several cases, hepatitis progressed to acute liver failure, resulting in the discontinuation of Pomalidomide. Testing for the presence and activity of the hepatitis B virus must be performed prior to initiating treatment with pomalidomide. For patients with a positive test for the hepatitis B virus, consultation with a physician experienced in the management of 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 require careful monitoring throughout the course of therapy for the timely detection of symptoms and signs of active hepatitis B virus disease.

Effect on the Ability to Drive and Operate Machinery

Pomalidomide has minor to moderate influence on the ability to drive and operate machinery. Some adverse reactions of pomalidomide, such as fatigue, somnolence, 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 reactions occur, one should refrain from performing these activities.

Drug Interactions

Pomalidomide is partially metabolized by the 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 warfarin concentration 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.