Pomalidomide

Usage

Pomalidomide is prescribed in combination with dexamethasone for the treatment of multiple myeloma (MM) in patients who have received at least two prior therapies including lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. It is also used to treat Kaposi sarcoma (KS) in patients with or without HIV infection who have received highly active antiretroviral therapy (HAART) that did not work well. It is classified as an antineoplastic immunomodulatory agent. Pomalidomide’s mechanism of action involves direct cytotoxicity to myeloma cells, inhibition of angiogenesis, enhancement of immune response against myeloma cells, modulation of cytokine production, and inhibition of myeloma cell adhesion to bone marrow stroma.

Alternate Names

Pomalidomide is also known by the International Nonproprietary Name (INN) pomalidomide. Brand names include Pomalyst® and Imnovid®.

How It Works

Pharmacodynamics: Pomalidomide exerts its anti-myeloma effects through various mechanisms: direct anti-proliferative and pro-apoptotic effects on myeloma cells, inhibition of angiogenesis, immunomodulatory effects (enhancing T-cell and natural killer cell activity, inhibiting regulatory T cells), modulation of cytokine production, and disruption of the bone marrow microenvironment.

Pharmacokinetics: Pomalidomide is absorbed orally, reaching peak plasma concentrations within 2 to 3 hours. It is primarily metabolized by CYP1A2 and to a lesser extent by CYP3A4 and CYP2C19. It’s also subject to non-CYP-mediated hydrolysis. Elimination is primarily renal (approximately 73%) with some hepatic excretion. It has a half-life of about 7 to 9 hours.

Mode of Action: At the molecular level, pomalidomide binds to cereblon, a component of the E3 ubiquitin ligase complex. This binding leads to increased ubiquitination and subsequent degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for myeloma cell growth and survival. This ultimately leads to cell cycle arrest and apoptosis of myeloma cells.

Elimination Pathways: Pomalidomide is eliminated through a combination of renal excretion (primarily as unchanged drug) and hepatic metabolism through CYP1A2, CYP3A4, CYP2C19, and non-CYP hydrolysis.

Dosage

Standard Dosage

Adults:

For multiple myeloma: 4 mg orally once daily on days 1-21 of a repeated 28-day cycle, taken in combination with dexamethasone. For Kaposi sarcoma: 5 mg orally once daily on days 1-21 of a repeated 28-day cycle.

Children:

Safety and efficacy have not been established in pediatric patients.

Special Cases:

• Elderly Patients (MM): No dose adjustment for pomalidomide is needed. Dexamethasone dose is typically reduced (20 mg on days 1, 8, 15, and 22 of a 28-day cycle for patients >75 years old). For elderly patients receiving pomalidomide in combination with bortezomib and dexamethasone, a lower dexamethasone starting dose is recommended.
• Patients with Renal Impairment: No dose adjustment is required. Administer after hemodialysis on dialysis days.
• Patients with Hepatic Dysfunction (MM): For mild-to-moderate impairment, the dose is reduced to 3 mg/day. For severe impairment, it is reduced to 2 mg/day. For patients with KS and hepatic impairment, reduce dose to 3 mg/day.
• Patients with Comorbid Conditions: Dosage adjustments may be necessary based on individual patient characteristics and comorbidities.

Clinical Use Cases

Pomalidomide is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. It is specifically used for multiple myeloma and Kaposi sarcoma, as described above.

Dosage Adjustments

Dose reductions may be required for hematologic toxicities (neutropenia, thrombocytopenia) or other adverse effects. Dosage adjustments based on drug interactions should be made as indicated in the drug interaction section.

Side Effects

Common Side Effects:

Fatigue, weakness, anemia, neutropenia, thrombocytopenia, constipation, diarrhea, nausea, vomiting, back pain, muscle pain, peripheral neuropathy, upper respiratory tract infections, and pyrexia.

Rare but Serious Side Effects:

Venous thromboembolism, tumor lysis syndrome, severe allergic reactions (including angioedema and anaphylaxis), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), cardiac arrhythmias (including atrial fibrillation), second primary malignancies, and severe liver injury.

Long-Term Effects:

Increased risk of secondary malignancies (e.g., acute myeloid leukemia) with prolonged use. Peripheral neuropathy can also persist after discontinuation of treatment.

Adverse Drug Reactions (ADR):

Angioedema, anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), tumor lysis syndrome, severe thrombocytopenia, and neutropenia with infections.

Contraindications

• Pregnancy and women of childbearing potential not adhering to the pregnancy prevention program.
• Hypersensitivity to pomalidomide, thalidomide, or lenalidomide.
• Breastfeeding.

Drug Interactions

• Strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin): May increase pomalidomide exposure. Reduce pomalidomide dose or avoid concomitant use.
• Strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin): May decrease pomalidomide exposure. Monitor for reduced efficacy.
• Warfarin: Pomalidomide may enhance the anticoagulant effects of warfarin. Close monitoring of INR is required.
• Other immunomodulatory drugs (e.g., thalidomide, lenalidomide): Increased risk of hematologic toxicity and other adverse effects.
• Strong P-glycoprotein (P-gp) inhibitors (e.g., amiodarone, azithromycin): May increase pomalidomide exposure.

Pregnancy and Breastfeeding

Pomalidomide is contraindicated in pregnancy (Pregnancy Category X) due to its high teratogenic potential. It is structurally related to thalidomide and can cause severe birth defects. Women of childbearing potential must adhere to strict contraception guidelines. Pomalidomide is contraindicated during breastfeeding.

Drug Profile Summary

• Mechanism of Action: Immunomodulatory agent targeting cereblon, leading to degradation of IKZF1 and IKZF3, resulting in myeloma cell death.
• Side Effects: Anemia, neutropenia, thrombocytopenia, fatigue, infections, peripheral neuropathy, thromboembolism.
• Contraindications: Pregnancy, breastfeeding, hypersensitivity to pomalidomide or related drugs.
• Drug Interactions: Strong CYP1A2 inhibitors, strong CYP3A4 inducers, warfarin.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: MM: 4 mg daily on days 1-21 of a 28-day cycle; KS: 5 mg daily on days 1-21 of a 28-day cycle.
• Monitoring Parameters: Complete blood count (CBC) weekly for the first 8 weeks, then monthly; liver function tests monthly; INR if co-administered with warfarin.

Popular Combinations

• Pomalidomide + Dexamethasone: This is the standard regimen for relapsed/refractory multiple myeloma.
• Pomalidomide + Bortezomib + Dexamethasone: This triplet combination may be used in some cases.

Precautions

• General Precautions: Monitor for hematologic toxicities, infections, thromboembolic events, peripheral neuropathy, liver dysfunction.
• Specific Populations:
  • Pregnant Women: Contraindicated.
  • Breastfeeding Mothers: Contraindicated.
  • Children & Elderly: Safety and efficacy not established in children. Elderly patients may require dose adjustments for dexamethasone.
• Lifestyle Considerations: Patients should be advised about potential drug interactions with alcohol and smoking, which can affect pomalidomide metabolism.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Pomalidomide?

A: For multiple myeloma, the recommended dosage is 4 mg orally once daily on days 1-21 of a 28-day cycle. For Kaposi Sarcoma, the recommended dosage is 5 mg orally once daily on days 1-21 of a 28-day cycle. Dose modifications may be required in special populations (elderly, hepatic impairment) or due to adverse events or drug interactions.

Q2: What are the most serious side effects of Pomalidomide?

A: Serious side effects include venous thromboembolism, tumor lysis syndrome, severe allergic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), cardiac arrhythmias, secondary malignancies, and severe liver injury.

Q3: How does Pomalidomide interact with other medications?

A: Strong CYP1A2 inhibitors, such as fluvoxamine and ciprofloxacin, can increase pomalidomide levels. Strong CYP3A4 inducers can decrease levels. Concomitant use of warfarin requires careful monitoring of INR due to enhanced anticoagulant effects.

Q4: Can Pomalidomide be used during pregnancy or breastfeeding?

A: No, Pomalidomide is contraindicated in both pregnancy and breastfeeding due to its teratogenic potential.

Q5: What is the mechanism of action of Pomalidomide?

A: Pomalidomide binds to cereblon, leading to the degradation of IKZF1 and IKZF3 transcription factors, crucial for myeloma cell survival. This induces apoptosis and inhibits myeloma cell growth.

Q6: How should Pomalidomide be administered?

A: Pomalidomide capsules should be swallowed whole with water, with or without food. They should not be broken, chewed, or opened.

Q7: What monitoring is required during Pomalidomide treatment?

A: Complete blood counts (CBCs) should be monitored weekly for the first 8 weeks, then monthly. Liver function tests should be performed monthly. INR should be monitored if co-administered with warfarin.

Q8: Is dose adjustment necessary for patients with renal impairment?

A: No dose adjustment is necessary for renal impairment, but the dose should be administered after hemodialysis on dialysis days.

Q9: What is the role of dexamethasone in combination with Pomalidomide?

A: Dexamethasone is given in combination with pomalidomide to enhance its anti-myeloma activity.

Q10: What should patients be advised regarding lifestyle factors while taking Pomalidomide?

A: Patients should be counseled on potential drug interactions with alcohol and smoking. They should also be advised about the importance of contraception if of childbearing potential.