Pomalidomide is a structural analog of thalidomide that has immunomodulatory, antiangiogenic, and antineoplastic properties. It is indicated for the treatment of multiple myeloma in patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor, and have demonstrated disease progression on or within 60 days of completion of the last therapy. Additionally, pomalidomide is indicated in adult patients with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART) or in patients with KS who are HIV-negative. Pomalidomide is contraindicated in pregnancy due to a risk for birth defects or embryo-fetal death. All prescribers, pharmacists, and patients must be registered in the POMALYST REMS program to prescribe, dispense, or receive pomalidomide. Routine pregnancy testing is required for females of reproductive capacity. Information about the drug and the program can be found at www.pomalystrems.com or by calling 1-888-423-5436.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
All prescribers, patients, and pharmacists must comply with the conditions of the POMALYST REMS program when prescribing, dispensing, or receiving pomalidomide. Information about the drug and the program can be found at www.CelgeneRiskManagement.com or by calling 1-888-423-5436.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
-Wash the exposed area immediately and thoroughly with soap and water if powder from pomalidomide capsules come into contact with skin; flush thoroughly with water if pomalidomide comes into contact with mucous membranes.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take pomalidomide with or without food at approximately the same time each day.
-Swallow capsules whole; do not crush, break, or chew.
-If a dose is missed, take within 12 hours of missing the dose. If more than 12 hours have passed, skip the dose of the day and take the dose the next day at the scheduled time.
General physical health deterioration and multi-organ failure have been reported with pomalidomide plus low-dose dexamethasone treatment in patients with relapsed and refractory multiple myeloma in 2 clinical trials.
Hematologic toxicity including neutropenia (49% to 96%; grade 3 or 4, 41% to 50%), febrile neutropenia (8% or less; grade 3 or 4, 3% or less), leukopenia (13% to 79%; grade, 3 or 4, 3.6% to 10%), anemia (54% or less; grade 3 or 4, 21% or less), thrombocytopenia (23% to 54%; grade, 3 or 4, 22% or less), and lymphopenia (15% or less; 7% or less) were reported in patients who received pomalidomide in clinical trials. In patients with multiple myeloma, monitor complete blood counts (CBCs) weekly for the first 8 weeks and then monthly thereafter. In patients with Kaposi sarcoma, monitor CBCs every 2 weeks for the first 12 weeks and then monthly thereafter. Therapy interruption, dose reduction, and/or discontinuation may be necessary in patients who develop severe hematologic toxicity. Pancytopenia was reported in pomalidomide-treated patients in postmarketing surveillance.
Fever occurred in 27% (grade 3 or 4, 3%) and 32% (grade 3 or 4, less than 5%) of patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone in 2 randomized trials. Chills were reported in 13% of relapsed or refractory multiple myeloma patients who received pomalidomide plus low-dose dexamethasone (n = 112) in a randomized trial. Additionally, chills occurred in 21% of patients with Kaposi sarcoma who received pomalidomide in a single-arm clinical study (n = 28).
Gastrointestinal (GI) adverse events including nausea (15% to 36%; grade 3 or 4, less than 5%), constipation (22% to 71%; grade 3 or 4, less than 5%), diarrhea (22% to 36%; grade 3 or 4, less than 5%), vomiting (14% or less; grade 3 or 4, 1% or less), and decreased appetite/anorexia (19% or less; grade 3 or 4, 1% or less) occurred in patients who received pomalidomide in clinical trials. Additionally, abdominal pain was reported in relapsed or refractory multiple myeloma patients who received pomalidomide plus low-dose dexamethasone. GI bleeding was reported in postmarketing surveillance of pomalidomide.
Musculoskeletal adverse events including muscle cramps/spasms (15% to 25%; grade 3 or 4, less than 5%) occurred in patients who received pomalidomide in clinical trials. Back pain (32% and 20%; grade 3 or 4, 10% and 5%), musculoskeletal pain in chest (20% or less), musculoskeletal pain (17% or less; grade 3 or 4, less than 5%), arthralgia (15% and 9%; grade 3 or 4, less than 5%), muscular weakness (13% or less; grade 3 or 4, 4% or less), bone pain (7% and 18%; grade 3 or 4, less than 5% and 7%), extremity pain (14% and 7%; grade 3 or 4, less than 5% and 2%), pain (4% or less; grade 3 or 4, 2% or less), and femur bone fractures (grade 3 or 4, 2% or less) occurred in relapsed or refractory multiple myeloma patients who received pomalidomide plus low-dose dexamethasone in 2 randomized trials. Fall, compression fracture fracture, and spinal compression fracture were also reported. Elevated creatine kinase level occurred in 25% of patients with Kaposi sarcoma who received pomalidomide in a single-arm clinical study (n = 28); grade 3 or 4 elevated creatine kinase level was reported in 7% of patients.
Respiratory adverse events including cough (20% to 29%; grade 3 or 4, less than 1%) and dyspnea (25% to 45%; grade 3 or 4, 13% or less) were reported in patients who received pomalidomide in clinical trials. Epistaxis (11%), productive cough (13%), and oropharyngeal pain (11%) occurred in patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone (n = 112) in a randomized trial. Chronic obstructive pulmonary disease (COPD) was reported in 2% of patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone (n = 300) in another randomized trial; grade 3 or 4 COPD occurred in 1% of patients. Interstitial lung disease, respiratory failure, and bronchospasm were reported in relapsed or refractory multiple myeloma patients who received pomalidomide plus low-dose dexamethasone.
Electrolyte abnormalities including hypocalcemia (4% to 50%; grade 3 or 4, less than 5%) were reported in patients who received pomalidomide in clinical trials. Hypercalcemia (12% or less; grade 3 or 4, less than 1%), hypokalemia (12% and 9%; grade 3 or 4, less than 5% and 4%), and hyponatremia (13% or less; grade 3 or 4, less than 5%) occurred in patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone in 2 randomized trials. Hyperkalemia was also reported. Hypoalbuminemia (54%), hypophosphatemia (54%; grade 3 or 4, 25%), and hypomagnesemia (14%) were reported in patients with Kaposi sarcoma who received pomalidomide in a single-arm clinical study (n = 28).
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) were reported postmarketing surveillance of pomalidomide. DRESS may present with a cutaneous reaction (e.g., rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, interstitial nephritis, pneumonitis, myocarditis, and/or pericarditis. Therapy interruption or discontinuation should be considered in patients who develop a grade 2 or 3 skin rash. Permanently discontinue pomalidomide if a patient develops a grade 4 rash, an exfoliative or bullous rash, or SJS, TEN, or DRESS. Rash (16% or less; grade 3 or 4, 3 less than 5%), pruritus (9% or less), dry skin/xerosis (21% or less), hyperhidrosis (16% or less), and night sweats (13% or less) were reported in patients who received pomalidomide in clinical studies. Maculopapular rash was reported in 71% of patients with Kaposi sarcoma who received pomalidomide in a single-arm clinical study (n = 28); grade 3 or 4 maculopapular rash occurred in 3.6% of patients.
Neurological adverse events including dizziness (18 and 12%; grade 3 or 4, less than 5% and 1%), peripheral neuropathy (18% and 17%; grade 3 or 4, 2% or less), headache (13% and 8%; grade 3 or 4, less than 5%), tremor (13% and 6%; grade 3 or 4, 1% or less), and depressed level of consciousness (2% or less; grade 3 or 4, 1% or less) occurred in patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone in 2 randomized trials. Syncope and vertigo were also reported.
Cases of a new primary malignancy (acute myelogenous leukemia) have been reported in patients receiving pomalidomide as an investigational therapy outside of multiple myeloma. Additionally, skin cancer (i.e., basal cell carcinoma and squamous cell carcinoma of the skin) has been reported in postmarketing surveillance of pomalidomide.
Cardiac adverse events such as atrial fibrillation, angina pectoris, hypotension, and congestive heart failure have been reported in patients with relapsed and refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone treatment in 2 clinical trials.
Thromboembolic events/thromboembolism occurred in 8% of patients with multiple myeloma who received pomalidomide plus low-dose dexamethasone (n = 300) in a randomized trial; all patients in this study received thromboprophylaxis. Venous thromboembolic events including deep venous thrombosis and pulmonary embolism were reported in 4.7% of patients who received pomalidomide and dexamethasone therapy. Arterial thromboembolic events including terms for ischemic heart disease (e.g., myocardial infarction) and ischemic cerebrovascular conditions (e.g., stroke) were reported in 3% of patients who received pomalidomide and dexamethasone. Thromboprophylaxis is recommended in all patients; the choice of prophylactic regimen should be based on an assessment of patient underlying risk factors.
Hepatic failure (including fatal cases) and elevated hepatic enzymes were reported in postmarketing surveillance of pomalidomide. Monitor liver function tests monthly. Therapy interruption, dose reduction, and/or discontinuation may be necessary in patients who develop hepatic toxicity. Grade 3 or 4 increased ALT (grade 3 or 4, 2%) and AST (grade 3 or 4, 1%) levels occurred in patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone (n = 300) in a randomized trial. Hyperbilirubinemia was also reported. Increased ALT (32%), AST (35%), and alkaline phosphate (14%; grade 3 or 4, 3.6%) levels were reported in patients with Kaposi sarcoma who received pomalidomide in a single-arm clinical study (n = 28).
In postmarketing surveillance, allergic reactions (e.g., angioedema, urticaria, and anaphylaxis/anaphylactoid reactions) have been reported in patients who received pomalidomide. Permanently discontinue therapy in patients who develop angioedema or anaphylaxis.
Peripheral edema has been reported in 17% to 29% patients who received pomalidomide in clinical trials; grade 3 or 4 peripheral edema occurred in 3.6% or less of patients.
Pelvic pain occurred in 2% of patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone (n = 300) in a randomized trial; grade 3 or 4 pelvic pain was reported in 1% of patients.
Fatigue/asthenia occurred in 63% (grade 3 or 4, 17%) and 47% (grade 3 or 4, 9%) of patients with relapsed and refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone treatment in 2 clinical trials. Fatigue was also reported in 68% of patients with Kaposi sarcoma who received pomalidomide in a single-arm clinical study (n = 28).
Pomalidomide is an analog of thalidomide, a known human teratogen that causes severe, life-threatening human birth defects. Pomalidomide produced malformations in the offspring of female rats and rabbits. It may cause teratogenesis or fetal death if administered during pregnancy. In order to prevent fetal exposure, pomalidomide is only available through a restricted distribution program, the POMALYST REMS program. If pregnancy does occur during treatment, immediately discontinue pomalidomide. Prescribers are encouraged to report all cases of pregnancy to the Celgene Corporation at 1-888-423-5436 or to the FDA MedWatch program at 1-800-FDA-1088. Refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Solid organ transplant rejection was reported in postmarketing surveillance of pomalidomide.
Hypothyroidism occurred in 21% of patients with Kaposi sarcoma who received pomalidomide in a single-arm clinical study (n = 28). Hypothyroidism and hyperthyroidism were reported in pomalidomide-treated patients in postmarketing surveillance.
Infection including upper respiratory tract infection (29% to 31%; grade 3 or 4, less than 5%) was reported in patients who received pomalidomide in clinical trials. Pneumonia (19% and 34%; grade 3 or 4, 16% and 29%), urinary tract infection (17% or less; grade 3 or 4, 9% or less), sepsis (less than 10%; grade 3 or 4, 4% or less), and neutropenic sepsis (grade 3 or 4, 1% or less) were reported in relapsed or refractory multiple myeloma patients who received pomalidomide plus low-dose dexamethasone in 2 randomized trials. Other infections that were reported in patient with multiple myeloma include pneumocystis jiroveci pneumonia, respiratory syncytial virus, neutropenic sepsis, bacteremia, cellulitis, urosepsis, septic shock, clostridium difficile colitis, streptococcal pneumonia, lobar pneumonia, and other viral and lung infections. Hepatitis B virus reactivation resulting in hepatitis B exacerbation, herpes zoster infection, and progressive multifocal leukoencephalopathy were reported in pomalidomide-treated patients in postmarketing surveillance.
Dehydration was reported in less than 10% of patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone (n = 112) in a randomized trial; grade 3 or 4 dehydration occurred in 5.4% of patients.
Weight gain (11%) and weight loss (9%) were reported in patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone (n = 112) in a randomized trial. Failure to thrive was also reported.
Tumor lysis syndrome (TLS) was reported in pomalidomide-treated patients in postmarketing surveillance. Monitor serum electrolytes and uric acid levels in patients at risk for TLS (e.g., high tumor burden prior to treatment); take precautionary measures (e.g., hydration, uric acid lowering therapy) as appropriate to prevent electrolyte imbalances and renal toxicity.
Nephrotoxicity has been reported in patients who received pomalidomide in clinical trials. Renal failure (unspecified) (10% and less; grade 3 or 4, 7% and 6%) and elevated serum creatinine level (10% or less; grade 3 or 4, 3% or less) occurred in patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone in 2 randomized trials. Urinary retention was also reported. Elevated serum creatinine level was also reported in 86% of patients with Kaposi sarcoma who received pomalidomide in a single-arm clinical study (n = 28); grade 3 or 4 elevated serum creatinine level occurred in 3.6% of patients.
Hyperglycemia occurred in 15% of patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone (n = 112) in a randomized trial; grade 3 or 4 hyperglycemia was reported in less than 5% of patients. Elevated glucose level was also reported in 57% of patients with Kaposi sarcoma who received pomalidomide in a single-arm clinical study (n = 28); grade 3 or 4 elevated glucose level occurred in 7% of patients.
Anxiety (7%), confusion (13%; grade 3 or 4, 3%), and insomnia (16%) occurred in patients with relapsed or refractory multiple myeloma who received pomalidomide plus low-dose dexamethasone (n = 112) in a randomized trial. Mental status changes were also reported.
Severe hypersensitivity reactions including serious rash (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with pomalidomide therapy; some cases were fatal. Use is contraindicated in patients who have experienced an allergic reaction (e.g., angioedema or anaphylaxis) to pomalidomide. Therapy interruption or discontinuation should be considered in pomalidomide-treated patients who develop a grade 2 or 3 skin rash. Permanently discontinue pomalidomide if a patient develops angioedema, anaphylaxis, grade 4 rash, exfoliative or bullous rash, or SJS, TEN, or DRESS. Pomalidomide is a thalidomide analog; use caution in patients who have a history of thalidomide hypersensitivity.
Venous (e.g., deep venous thrombosis and pulmonary embolism) thromboembolism and arterial (e.g., myocardial infarction and stroke) thromboembolism have been reported in patients with multiple myeloma who received pomalidomide plus low-dose dexamethasone in clinical trials. A prior history of thrombosis, hyperlipidemia, hypertension, and/or tobacco smoking may increase the risk of thromboembolism with pomalidomide therapy; minimize modifiable risk factors if possible. Thromboprophylaxis is recommended in all patients; the choice of prophylactic regimen should be based on an assessment of a patient's underlying risk factors.
Hepatotoxicity (e.g., elevated hepatic enzymes and hepatic failure) has been reported with pomalidomide therapy; death due to hepatic failure has occurred. Use pomalidomide with caution in patients with hepatic disease; an initial dose reduction is necessary in patients with hepatic impairment. Monitor liver function tests (LFTs) monthly. Therapy interruption, dose reduction, and/or discontinuation may be necessary in patients who develop hepatic toxicity.
Hematologic toxicity (e.g., anemia, neutropenia, thrombocytopenia) has been reported with pomalidomide use. In patients with multiple myeloma, monitor complete blood counts (CBCs) weekly for the first 8 weeks and then monthly thereafter; do not start a new cycle of therapy until the absolute neutrophil count (ANC) is at least 500 cells/microliter (mcL) and the platelet count is at least 50,000 cells/mcL. In patients with Kaposi sarcoma, monitor CBCs every 2 weeks for the first 12 weeks and then monthly thereafter; do not start a new cycle of therapy until the ANC is at least 1,000 cells/mcL and the platelet count is at least 75,000 cells/mcL. Therapy interruption, dose reduction, and/or discontinuation may be necessary in patients who develop severe hematologic toxicity.
Tumor lysis syndrome (TLS) has been reported with pomalidomide therapy. Monitor patients at risk for TLS (e.g., high tumor burden prior to treatment) for hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and decreased urine output. Take precautionary measures (e.g., hydration, uric acid lowering therapy) as appropriate to prevent electrolyte imbalances and renal toxicity.
Blood donation should not be considered by men or women receiving pomalidomide during or for 1 month after therapy because of the risk that this blood might be administered to a pregnant woman whose fetus must not be exposed to pomalidomide.
Renal failure has been reported with pomalidomide therapy. Use pomalidomide with caution in patients with renal disease; an initial dose reduction is necessary in patients with severe renal impairment requiring dialysis.
The use of a PD-1 or PDL1 blocking antibody with a thalidomide analogue plus dexamethasone is not recommended for multiple myeloma treatment outside of a clinical trial. Two clinical trials were halted due to an increased risk of death in patients who received pembrolizumab and dexamethasone in combination with an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of multiple myeloma.
Pomalidomide is contraindicated for use during pregnancy; females of reproductive potential should avoid pregnancy for at least 4 weeks prior to, during, and for at least 4 weeks after pomalidomide therapy. Pomalidomide is an analog of thalidomide, a known human teratogen that causes severe, life-threatening human birth defects. Pomalidomide produced malformations in the offspring of female rats and rabbits. It may cause birth defects or intrauterine fetal death if administered during pregnancy. In order to prevent fetal exposure, pomalidomide is only available through a restricted distribution program, the POMALYST REMS program. This program requires prescribers, pharmacists, and patients to comply with certain conditions prior to prescribing, dispensing, or receiving pomalidomide. It can be prescribed only by licensed prescribers who are registered in the POMALYST REMS program and understand the potential risk of teratogenicity if used during pregnancy. If pregnancy does occur during treatment, immediately discontinue pomalidomide. Prescribers are encouraged to report all cases of pregnancy to the Celgene Corporation at 1-888-423-5436 or to the FDA MedWatch program at 1-800-FDA-1088. Refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Counsel patients about the reproductive risk and contraception requirements during pomalidomide treatment. Do not initiate therapy in females of reproductive potential until pregnancy testing is performed twice with confirmed negative results. Administer the first test within 10 to 14 days and the second test 24 hours prior to prescribing pomalidomide. Once treatment is started, continue pregnancy testing weekly during the first 4 weeks of treatment, then every 4 weeks in females with regular menstrual cycles and every 2 weeks in females with irregular menstrual cycles. Effective contraception must be used by all females of reproductive potential for at least 4 weeks before beginning treatment, during therapy and dosage interruptions, and for 4 weeks following discontinuation of therapy. Women must commit to abstain from heterosexual intercourse or to use 2 methods of reliable birth control, including at least 1 highly effective method (e.g., intrauterine device (IUD), hormonal contraception, tubal ligation, or partner's vasectomy) and 1 additional effective method (e.g., latex condom, diaphragm, or cervical cap). Follow these contraceptive requirements even in patients with a history of infertility, unless a hysterectomy has been performed. Discontinue treatment, test for pregnancy, and counsel any woman of reproductive potential who experiences menstrual irregularity (e.g., dysfunctional uterine bleeding) or misses her period. Advise patients that if her doctor is not available, she can call 1-888-423-5436. Pomalidomide passes into semen and there is potential for male-mediated teratogenicity. Male patients must use barrier contraception (latex condom) during sexual intercourse with a woman of reproductive potential while on therapy, during interruptions, and for 4 weeks after discontinuing therapy, even if he has undergone successful vasectomy. Male patients should be warned against sperm donation during pomalidomide therapy and for 4 weeks after stopping therapy. Female infertility may be possible based on data in animal studies.
It is not known whether pomalidomide is excreted in human milk. Due to the potential for adverse reactions in nursing infants from pomalidomide, a decision should be made whether to discontinue breast-feeding or to discontinue pomalidomide, taking into account the importance of the drug to the mother.
For the treatment of multiple myeloma:
The FDA has designated pomalidomide as an orphan drug for the treatment of multiple myeloma.
-for the treatment of multiple myeloma in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor and who had disease progression within 60 days of completing the last therapy, in combination with dexamethasone:
Oral dosage:
Adults: 4 mg orally daily on days 1 to 21 repeated every 28 days until disease progression; give in combination with dexamethasone. Pomalidomide was administered with low-dose dexamethasone (LoDEX, 40 mg orally on days 1, 8, 15, and 22 of each 28-day cycle) in 2 randomized clinical studies. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Thromboembolism prophylaxis is recommended in all patients. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. At a median follow-up time of 14.2 months, treatment with pomalidomide plus LoDEX resulted in a significantly improved progression-free survival (PFS) time (primary endpoint) compared with pomalidomide monotherapy (4.2 months vs. 2.7 months; hazard ratio (HR) = 0.68; 95% CI, 0.51 to 0.9; p = 0.003) in patients with relapsed or refractory multiple myeloma in a multicenter, randomized, open-label, phase 2 study (MM-003C study; n = 221; age range, 34 to 88 years; median of 5 prior therapies; range, 1 to 13 therapies). Prior to study enrollment, patients had previously received lenalidomide and bortezomib (100%), dexamethasone (99%), thalidomide (67%), and carfilzomib (23%); additionally, 74% of patients had received a stem cell transplant. All patients in this study received aspirin or another form of thromboprophylaxis if aspirin was contraindicated. Upon disease progression, 65 patients in the pomalidomide alone arm were allowed to cross-over to the pomalidomide plus LoDEX arm. The median overall survival (OS) time was not significantly improved with pomalidomide plus LoDEX arm compared with pomalidomide alone (16.5 months vs. 13.6 months; HR = 0.94; 95% CI, 0.7 to 1.28; p = 0.709). Treatment with pomalidomide plus LoDEX (n = 302) was compared with high-dose dexamethasone (HiDEX, given as 40 mg/day PO on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle) (n = 153) in patients with relapsed or refractory multiple myeloma in a multicenter, randomized, open-label, phase 3 trial (MM-003 study; age range, 35 to 87 years). All patients in this study had previously received at least 2 cycles of lenalidomide- and bortezomib-containing therapy and an adequate trial of an alkylating agent-containing regimen (median of 5 prior therapies; range, 2 to 17 therapies). At a median follow-up of 10 months, the median PFS time (primary endpoint) was significantly improved with pomalidomide plus LoDEX (4 months vs. 1.9 months; HR = 0.48; 95% CI, 0.39 to 0.6; p less than 0.0001). Physician's choice of thromboprophylaxis was given in all patients receiving pomalidomide or patients at high risk for developing thrombosis. Upon disease progression, 43 patients in the HiDEX arm were allowed to cross-over to treatment with single-agent pomalidomide. The median OS time was significantly improved with pomalidomide plus LoDEX compared with HiDEX (12.7 months vs. 8.1 months; HR = 0.74; 95% CI, 0.56 to 0.97; p = 0.0285). In a cohort of geriatric patients 76 years or older, treatment with pomalidomide plus LoDEX resulted in significantly increased PFS (HR = 0.36; 95% CI, 0.16 to 0.83) but not OS (HR = 0.4; 95% CI, 0.15 to 1.05) compared with HiDEX.
-for the treatment of multiple myeloma in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor, in combination with daratumumab and dexamethasone*:
NOTE: Daratumumab is FDA approved in combination with pomalidomide and dexamethasone for this indication.
Oral dosage:
Adults: 4 mg orally daily on days 1 to 21 repeated every 28 days until disease progression; give in combination with daratumumab (16 mg/kg of actual body weight IV weekly on weeks 1 to 8 (8 doses), 16 mg/kg IV every other week on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25) and dexamethasone (40 mg orally or IV once weekly or 20 mg orally or IV once weekly in patients older than 75 years or who had a body-mass index less than 18.5). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Thromboembolism prophylaxis is recommended in all patients. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. The overall response rate (ORR) was 60% in patients with relapsed or refractory multiple myeloma who received daratumumab, pomalidomide, and low-dose dexamethasone in a nonrandomized, phase 1b trial (n = 103; EQUULEUS trial); the stringent complete response (CR) rate was 8% and the CR rate was 9%. At a median follow-up time of 13.1 months (range, 0.2 to 25.8 months), the median progression-free survival (PFS) and overall survival (OS) times were 8.8 months and 17.5 months, respectively; the estimated 12-month PFS and OS rates were 42% and 66%, respectively. Patients (median age, 64 years; range, 35 to 86 years) in this study had received a median of 4 prior therapies (range, 1 to 13 therapies); 74% of patients had previously received an autologous stem cell transplantation.
-for the treatment of multiple myeloma in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor, in combination with elotuzumab and dexamethasone*:
NOTE: Elotuzumab is FDA approved in combination with pomalidomide and dexamethasone for this indication.
Oral dosage:
Adults: 4 mg orally daily on days 1 through 21 in combination with elotuzumab 10 mg/kg IV once weekly on cycles 1 and 2 (on days 1, 8, 15, and 22), then 20 mg/kg IV every 4 weeks (on day 1) starting on cycle 3 and oral dexamethasone (age 75 years or less, 28 mg; age over 75 years, 8 mg) at 3 to 24 hours prior to elotuzumab on days 1, 8, 15, and 22 on cycles 1 and 2 and on day 1 of subsequent cycles. Additionally, give oral dexamethasone (age 75 years or less, 40 mg; age over 75 years, 20 mg) at 3 to 24 hours prior to elotuzumab on days 8, 15, and 22 of cycles 3 and beyond. Repeat treatment cycles every 28 days until disease progression. Administer the following premedications 45 to 90 minutes prior to each elotuzumab infusion: acetaminophen 650 to 1,000 mg orally, diphenhydramine 25 to 50 mg orally or IV (or equivalent), an IV or oral H2-blocker, and dexamethasone 8 mg IV. At a minimum follow-up time of 9.1 months, the median investigator-assessed progression-free survival time was significantly improved with elotuzumab plus pomalidomide and dexamethasone (median number of treatment cycles, 9) compared with pomalidomide and dexamethasone alone (10.25 months vs. 4.67 months; hazard ratio (HR) = 0.54; 95% CI, 0.34 to 0.86; p = 0.0078) in patients with relapsed or refractory multiple myeloma in a randomized, phase 2 trial (n = 117; the ELOQUENT-3 trial). In this study, patients had received a median of 3 prior therapies; 70% of patients had refractory disease after both lenalidomide and a proteasome inhibitor and 55% of patients had previously received an autologous stem cell transplantation. Thromboembolism prophylaxis is recommended in all patients. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.
-for the treatment of relapsed or refractory multiple myeloma in patients who have received 1 to 3 prior therapies including lenalidomide, in combination with bortezomib and dexamethasone*:
Oral dosage:
Adults: 4 mg orally daily on days 1 to 14 repeated every 21 days in combination with bortezomib and dexamethasone was evaluated in a randomized, phase 3 trial (n = 559; the OPTIMISMM trial). Bortezomib was administered as follows: 1.3 mg/m2 IV or subcutaneously on days 1, 4, 8, and 11 on cycles 1 to 8 then 1.3 mg/m2 IV or subcutaneously on days 1 and 8 starting on cycle 9. Patients aged 75 years and younger received dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 on cycles 1 to 8 and then 20 mg orally on days 1, 2, 8, and 9 starting on cycle 9; patients older than 75 years received dexamethasone 10 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 on cycles 1 to 8 and then 10 mg orally on days 1, 2, 8, and 9 starting on cycle 9. Treatment cycles were repeated every 21 days until disease progression. All patients received low-dose aspirin, low-molecular-weight heparin, or other equivalent antithrombotic or anticoagulant treatment. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.
-for the treatment of multiple myeloma in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor, in combination with isatuximab and dexamethasone*:
NOTE: Isatuximab is FDA approved in combination with pomalidomide and dexamethasone for this indication.
Oral dosage:
Adults: 4 mg orally daily on days 1 to 21 repeated every 28 days until disease progression. Give in combination with isatuximab 10 mg/kg (actual body weight) IV on days 1, 8, 15, and 22 on cycle 1 and isatuximab 10 mg/kg (actual body weight) IV on days 1 and 15 starting on cycle 2 and dexamethasone 40 mg (or 20 mg in patients older than 75 years) orally or IV on days 1, 8, 15, and 22. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Thromboembolism prophylaxis is recommended in all patients. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. At a median follow-up time of 11.6 months, the median progression-free survival time (evaluated by an independent response committee) was significantly improved in patients with relapsed or refractory multiple myeloma who received isatuximab, pomalidomide, and low-dose dexamethasone compared with pomalidomide and low-dose dexamethasone alone (11.5 months vs. 6.5 months; hazard ratio (HR) = 0.596; 95% CI, 0.44 to 0.81; p = 0.001) in a multinational, randomized, phase 3 trial (the ICARIA-MM trial; n = 307). Patients (median age, 67 years) in this study had received a median of 3 prior therapies including lenalidomide and a proteasome inhibitor; 56% of patients had previously received an autologous stem-cell transplantation. At a second interim analysis (median follow-up, 35.3 months), the median overall survival time was 24.6 months in patients who received isatuximab, pomalidomide, and dexamethasone compared with 17.7 months in patients who received pomalidomide and dexamethasone (HR = 0.76; 95% CI, 0.57 to 1.01). Subsequent therapy was given at disease progression in 60% and 72% of patients in the isatuximab-containing and control arms, respectively. Of patients who received subsequent therapy, fewer patients received daratumumab in the isatuximab-containing arm (24% vs. 58%).
-for the treatment of relapsed or refractory multiple myeloma in patients who have received at least 1 prior therapy including lenalidomide and a proteasome inhibitor, in combination with daratumumab/ hyaluronidase and dexamethasone*:
NOTE: Daratumumab/hyaluronidase is FDA approved in combination with pomalidomide and dexamethasone for this indication.
Oral dosage:
Adults: 4 mg orally daily on days 1 to 21 repeated every 28 days until disease progression; give in combination with daratumumab/hyaluronidase (1,800 mg daratumumab and 30,000 units hyaluronidase subcutaneously weekly on weeks 1 to 8 (8 doses), every other week on weeks 9 to 24 (8 doses), and then every 4 weeks starting on week 25 until disease progression) and dexamethasone (40 mg PO once weekly or 20 mg PO once weekly in patients 75 years or older). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Thromboembolism prophylaxis is recommended in all patients. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. At a median follow-up time of 16.9 months, the median progression-free survival time was significantly improved in patients with relapsed or refractory multiple myeloma who received daratumumab/hyaluronidase plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone alone (12.4 months vs. 6.9 months; hazard ratio (HR) = 0.63; 95% CI, 0.47 to 0.85) in a randomized, phase 3 (APOLLO) trial (n = 304). At a median follow-up time of 39.6 months, the median overall survival time was not significantly improved in the daratumumab/hyaluronidase-containing arm (34.4 months vs. 23.7 months; HR = 0.82; 95% CI, 0.61 to 1.11). In this trial, eligible patients had received at least 1 previous line of therapy with both lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of anti-myeloma therapy, and were refractory to lenalidomide if they had received only 1 previous line of treatment. Patients (median age, 67 years; range, 42 to 86 years) in the daratumumab/hyaluronidase arm had received a median of 2 (range, 1 to 5) prior therapies; 60% of patients had received a prior autologous stem-cell transplantation.
For the treatment of Kaposi's sarcoma:
NOTE: The FDA has designated pomalidomide as an orphan drug for the treatment of Kaposi sarcoma
-for the treatment of AIDS-related Kaposi sarcoma after failure of highly active antiretroviral (HAART) therapy:
Oral dosage:
Adults: 5 mg orally daily on days 1 to 21 repeated every 28 days until disease progression. Continue HAART therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Thromboembolism prophylaxis is recommended in all patients. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. The overall response rate was 67% in 18 patients with AIDS-related Kaposi sarcoma who received pomalidomide in a single-center, phase 2 study. The complete response rate was 17% in these patients. The median duration of response was 12.5 months; 58% and 17% of responding patients had a response that lasted greater than 12 months or greater than 24 months, respectively. At baseline, the median time on antiretroviral therapy was 48 months (range, 7 to 227 months); the median HIV viral load was 50 copies/mL; and the median CD4+ count was 378 cells/mL (range, 135 to 732 cells/mL). Most patients (80%) had received at least 1 prior therapy (other than antiretroviral therapy) in 15 AIDS-related Kaposi sarcoma patients (age range, 32 to 65 years). During the study, all patients continued HAART therapy and aspirin 81 mg once daily was administered for thromboprophylaxis.
-for the treatment of Kaposi sarcoma in HIV-negative patients:
Oral dosage:
Adults: 5 mg orally daily on days 1 to 21 repeated every 28 days until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Thromboembolism prophylaxis is recommended in all patients. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. The overall response rate was 80% in 10 patients with HIV-negative Kaposi sarcoma who received pomalidomide in a single-center, phase 2 study. The complete response rate was 10% in these patients. The median duration of response was 10.5 months; 38% and 25% of responding patients had a response that lasted greater than 12 months or greater than 24 months, respectively. Most patients (71%) had received at least 1 prior therapy in 7 HIV-negative Kaposi sarcoma patients (age range, 38 to 74 years). During the study, all patients received aspirin 81 mg once daily as thromboprophylaxis.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
NOTE: Discontinue pomalidomide in patients who cannot tolerate 1 mg once daily.
Non-Hematologic Toxicity
Angioedema, anaphylaxis, grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction: Permanently discontinue pomalidomide.
Other grade 3 or 4 toxicity: Hold therapy; resume pomalidomide at 1 mg less than the previous dose when toxicity has resolved to grade 2 or less at the physician's discretion.
Hematologic Toxicity
Multiple Myeloma
NOTE: Do not start a new cycle of pomalidomide until the absolute neutrophil count (ANC) is at least 500 cells/microliter (mcL) and the platelet count is at least 50,000 cells/mcL.
Neutropenia
ANC less than 500 cells/mcL (including subsequent drops) OR febrile neutropenia (temperature of 38.5 degrees C or higher and ANC less than 1,000 cells/mcL): Hold therapy; resume pomalidomide at 1 mg less than the previous dose when the ANC is 500 cells/mcL or greater.
Thrombocytopenia
Platelet count less than 25,000 cells/ mcL (including subsequent drops): Hold therapy; resume pomalidomide at 1 mg less than the previous dose when the platelet count of 50,000 cells/mcL or greater.
Kaposi Sarcoma
NOTE: Do not start a new cycle of pomalidomide until the ANC is at least 1,000 cells/mcL and the platelet count is at least 75,000 cells/mcL.
Neutropenia
ANC of 500 to less than 1,000 cells/mcL on day 1 of a cycle OR ANC less than 500 cells/mcL: Hold therapy until the ANC is 1,000 cells/mcL or greater; resume pomalidomide at the same dose.
ANC of 500 to less than 1,000 cells/mcL during a cycle: Continue pomalidomide at the current dose.
Febrile neutropenia (ANC less than 1,000 cells/mcL AND a single temperature of 38.3 degrees C or higher or a sustained temperature of 38 degrees C or higher for more than 1 hour): Hold therapy; resume pomalidomide at 1 mg less than the previous dose when the ANC is 1,000 cells/mcL or greater.
Thrombocytopenia
Platelet count of 25,000 to less than 50,000 cells/mcL on day 1 of a cycle: Hold therapy; resume pomalidomide at the same dose when the platelet count is 50,000 cells/mcL or greater.
Platelet count of 25,000 to less than 50,000 cells/mcL during a cycle: Continue pomalidomide at the current dose.
Platelet count less than 25,000 cells/mcL: Permanently discontinue pomalidomide.
Maximum Dosage Limits:
-Adults
Multiple myeloma, 4 mg/day PO; Kaposi sarcoma, 5 mg/day PO.
-Geriatric
Multiple myeloma, 4 mg/day PO; Kaposi sarcoma, 5 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Multiple Myeloma
Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment at baseline: initial dose, 3 mg once daily.
Severe hepatic impairment (Child-Pugh class C) at baseline: initial dose, 2 mg once daily.
Kaposi Sarcoma
Mild, moderate, and severe (Child-Pugh class C) hepatic impairment at baseline: 3 mg once daily.
Treatment-related toxicity
Elevated hepatic enzymes (e.g., increased AST or ALT levels): Hold therapy; consider resuming pomalidomide at a lower dose when hepatic enzymes levels return to baseline.
Patients with Renal Impairment Dosing
Multiple Myeloma
Severe renal impairment requiring hemodialysis: initial dose, 3 mg once daily; administer after hemodialysis on dialysis days.
Kaposi Sarcoma
Severe renal impairment requiring hemodialysis: initial dose, 4 mg once daily; administer after hemodialysis on dialysis days.
*non-FDA-approved indication
Amobarbital: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Barbiturates: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Butalbital; Acetaminophen: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Butalbital; Acetaminophen; Caffeine: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Carbamazepine: (Minor) A decrease in pomalidomide exposure occurred when pomalidomide and carbamazepine were administered together in a drug interaction study. Pomalidomide is a substrate of CYP3A4 and CYP1A2 and carbamazepine is a strong CYP3A4 and moderate CYP1A2 inducer. In healthy male volunteers, the pomalidomide AUC value was decreased by 20% (90% CI, 13% to 27%) when pomalidomide was co-administered with carbamazepine. The authors did not consider this to be a clinically significant reduction, however it may be prudent to monitor for reduced efficacy of pomalidomide if coadministered with carbamazepine.
Ciprofloxacin: (Major) Avoid the concomitant use of pomalidomide and ciprofloxacin; significantly increased pomalidomide exposure may occur increasing the risk of pomalidomide adverse events. If concomitant use is unavoidable, decrease the pomalidomide dose to 2 mg once daily and monitor for pomalidomide adverse events. Pomalidomide is a CYP1A2 substrate and ciprofloxacin is a strong CYP1A2 inhibitor. In healthy volunteers, the AUC value for pomalidomide was increased by 125% when pomalidomide was co-administered with a strong CYP1A2 inhibitor.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Deferasirox: (Major) Avoid the concomitant use of pomalidomide and deferasirox; significantly increased pomalidomide exposure may occur increasing the risk of pomalidomide adverse events. If concomitant use is unavoidable, decrease the pomalidomide dose by 50% and monitor for pomalidomide adverse events. Pomalidomide is a CYP1A2 substrate and deferasirox inhibits CYP1A2. In healthy volunteers, the Cmax and AUC values for pomalidomide were increased by 24% and 125%, respectively, when pomalidomide was co-administered with a strong CYP1A2 inhibitor. Additionally, the AUC value of a sensitive CYP1A2 substrate about doubled when deferasirox was co-administered with a sensitive CYP1A2 substrate in healthy volunteers.
Denosumab: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
Fluvoxamine: (Major) Avoid the concomitant use of pomalidomide and fluvoxamine; significantly increased pomalidomide exposure occurred when these agents were administered together in a drug interaction study. If concomitant use is unavoidable, decrease the pomalidomide dose to 2 mg once daily and monitor for pomalidomide adverse events. Pomalidomide is a CYP1A2 substrate and fluvoxamine is a strong CYP1A2 inhibitor. In healthy volunteers, the AUC value for pomalidomide was increased by 125% when pomalidomide was co-administered with fluvoxamine.
Fosphenytoin: (Moderate) Use pomalidomide and phenytoin or fosphenytoin together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and phenytoin is a CYP1A2 inducer.
Grapefruit juice: (Major) Pomalidomide is a substrate of CYP1A2, CYP3A, and P-glycoprotein (P-gp). Grapefruit juice is an inhibitor of P-gp. Avoid concomitant use of pomalidomide and grapefruit juice, particularly in combination with both a strong CYP1A2 and a strong CYP3A4 inhibitor. If coadministration of pomalidomide with grapefruit juice and these CYP inhibitors cannot be avoided, decrease the dose of pomalidomide to 2 mg once daily and monitor for efficacy and toxicity. If pomalidomide is co-administered with grapefruit juice in the absence of both a CYP1A2 and CYP3A4 inhibitor, monitor closely for pomalidomide toxicity.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Use pomalidomide and rifampin together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and rifampin is a CYP1A2 inducer.
Isoniazid, INH; Rifampin: (Moderate) Use pomalidomide and rifampin together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and rifampin is a CYP1A2 inducer.
Ketoconazole: (Minor) A clinically insignificant increase in pomalidomide exposure occurred when pomalidomide and ketoconazole were administered together in a drug interaction study. Pomalidomide is a CYP3A4 and P-glycoprotein (P-gp) substrate and ketoconazole is a strong CYP3A4 and P-gp inhibitor. In 16 healthy male volunteers, the pomalidomide AUC value was increased by 19% when pomalidomide was co-administered with ketoconazole.
Levoketoconazole: (Minor) A clinically insignificant increase in pomalidomide exposure occurred when pomalidomide and ketoconazole were administered together in a drug interaction study. Pomalidomide is a CYP3A4 and P-glycoprotein (P-gp) substrate and ketoconazole is a strong CYP3A4 and P-gp inhibitor. In 16 healthy male volunteers, the pomalidomide AUC value was increased by 19% when pomalidomide was co-administered with ketoconazole.
Lopinavir; Ritonavir: (Moderate) Use pomalidomide and ritonavir together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
Methohexital: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Mexiletine: (Moderate) Use pomalidomide and mexiletine together with caution; increased pomalidomide exposure may occur increasing the risk of pomalidomide adverse events. If these drugs are used together, monitor for pomalidomide adverse events; a pomalidomide dose adjustment may be necessary. Pomalidomide is a CYP1A2 substrate and mexiletine is a moderate CYP1A2 inhibitor. In healthy volunteers, the plasma levels of a sensitive CYP1A2 substrate increased by 72% (range 35% to 136%) when mexiletine was co-administered with a sensitive CYP1A2 substrate.
Nirmatrelvir; Ritonavir: (Moderate) Use pomalidomide and ritonavir together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
Pentobarbital: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Phenobarbital: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Phenytoin: (Moderate) Use pomalidomide and phenytoin together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and phenytoin is a CYP1A2 inducer.
Primidone: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Quinine: (Moderate) Use pomalidomide and quinine together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and quinine is a CYP1A2 inducer.
Rifampin: (Moderate) Use pomalidomide and rifampin together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and rifampin is a CYP1A2 inducer.
Ritonavir: (Moderate) Use pomalidomide and ritonavir together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
Secobarbital: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
St. John's Wort, Hypericum perforatum: (Moderate) Use pomalidomide and St. John's Wort, Hypericum perforatum, together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and St. John's Wort is a CYP1A2 inducer.
Tobacco: (Major) Advise patients to avoid smoking tobacco while taking pomalidomide. Smoking tobacco has been observed to decrease pomalidomide exposure by approximately 32% and may decrease efficacy.
Zileuton: (Moderate) Use pomalidomide and zileuton together with caution; increased pomalidomide exposure may occur increasing the risk of pomalidomide adverse events. If these drugs are used together, monitor for pomalidomide adverse events; a pomalidomide dose adjustment may be necessary. Pomalidomide is a CYP1A2 substrate and zileuton is a moderate CYP1A2 inhibitor. The Cmax increased by 73% and the AUC value approximately doubled for a sensitive CYP1A2 substrate when zileuton was co-administered with a sensitive CYP1A2 substrate in healthy volunteers.
The mechanism of action of pomalidomide is not fully understood. Pomalidomide, an analogue of thalidomide, is an immunomodulatory agent with antineoplastic activity. Pomalidomide has been shown in vitro to inhibit the proliferation of hematopoietic tumor cells and induce apoptosis. In addition, it inhibited the proliferation of multiple myeloma cell lines that were resistant to lenalidomide. Synergy with dexamethasone was shown in cell lines that were both lenalidomide-sensitive and lenalidomide-resistant. Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha and interleukin-6) by monocytes. Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.
Pomalidomide is administered orally. It is approximately 12% to 44% bound to plasma proteins; protein binding is not dependent on concentration. At steady state, the mean volume of distribution is 62 to 138 liters (L) in multiple myeloma or Kaposi sarcoma patients. Pomalidomide does pass into semen. Following the administration of pomalidomide 2 mg/day PO for 4 days in healthy male subjects, the pomalidomide concentration in semen was about 67% of the plasma level at 4 hours post-dose. Pomalidomide is metabolized in the liver primarily by CYP1A2 and CYP3A4. The mean total body clearance is 7 to 10 L/hour. Following a radiolabeled dose of pomalidomide in healthy subjects, about 73% of the dose was excreted in the urine and 15% in the feces, with only 2% and 8% eliminated as unchanged drug in urine and feces, respectively. The mean elimination half-life is 9.5 hours in healthy subjects and 7.5 hours in multiple myeloma or Kaposi sarcoma patients.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, P-gp
Pomalidomide is a substrate of CYP1A2, CYP3A4, and P-glycoprotein (P-gp); CYP2C19 and CYP2D6 are minor substrates in vitro. Concurrent use with strong CYP1A2 inhibitors should be avoided; the mean pomalidomide exposure was increased by 125% when pomalidomide was co-administered with a strong CYP1A2 inhibitor (fluvoxamine) in healthy subjects. However, pomalidomide exposure was not increased to a clinically significant extent when pomalidomide was co-administered with a strong CYP3A4 and P-gp inhibitor (ketoconazole), a strong CYP3A4 inducer (carbamazepine), or a weak to moderate inducer of CYP3A4 (dexamethasone) in drug interaction studies.
-Route-Specific Pharmacokinetics
Oral Route
Following the administration of pomalidomide 4 mg/day PO alone or in combination with dexamethasone, the steady-state AUC and Cmax values were 860 nanograms (ng)/mL x hour (coefficient of variance (CV), 37%) and 75 ng/mL (CV, 32%), respectively, in patients with multiple myeloma. Following the administration of pomalidomide 5 mg/day PO, the steady-state AUC and Cmax values were 462.3 ng/mL x hour (CV, 82%) and 53.1 ng/mL (CV, 50%), respectively, in patients with Kaposi sarcoma. The time to maximum plasma concentration (Tmax) is 2 to 3 hours post-dose in patients with multiple myeloma or Kaposi sarcoma.
Effects of food: Compared with the fasted state, the mean AUC and Cmax values were decreased by 8% and 27%, respectively, and the Tmax was delayed by 2.5 hours when pomalidomide was administered with a high-fat (about 50% of the total caloric content), high-calorie (about 800 to 1000 calories) meal in healthy subjects.
-Special Populations
Hepatic Impairment
Following single dose of pomalidomide, the AUC values increased by 51%, 58%, and 72% in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively, compared with subjects who had normal liver function. A dose adjustment is recommended in patients with hepatic impairment.
Renal Impairment
The pharmacokinetic parameters of pomalidomide were not significantly impacted in patients with moderate (creatinine clearance (CrCl) of 30 to 59 mL/min) or severe (CrCl of 15 to 29 mL/min) renal impairment compared with patients who had normal renal function (CrCl of 60 mL/min or greater). On non-dialysis days, the mean AUC values increased by 38% in patients with severe renal impairment requiring dialysis and by 40% in patients with end-stage renal disease (CrCl less than 15 mL/min). The estimated dialysis clearance of 12 L/hour in patients with severe renal impairment requiring dialysis is higher than pomalidomide total body clearance which indicates that hemodialysis will remove pomalidomide from the blood circulation. A dose adjustment is recommended in patients with severe renal impairment; pomalidomide should be administered after dialysis.
Pediatrics
Following the same pomalidomide dose (based on body surface area), the exposure in 55 pediatric patients (age range, 4 years to less than 17 years) was within the range of exposures for adult patients with multiple myeloma; however, pomalidomide exposure was higher in pediatric patients compared with exposures observed in adults with Kaposi sarcoma.
Geriatric
Age (range, 61 to 85 years old) has no clinically significant impact on the systemic exposure of pomalidomide.
Gender Differences
Gender has no clinically significant impact on the systemic exposure of pomalidomide.
Ethnic Differences
Race has no clinically significant impact on the systemic exposure of pomalidomide.
Other
Tobacco Smokers
Compared with healthy male volunteers who did not smoke tobacco (n = 13), the AUC and Cmax values were decreased by 32% and 14%, respectively, following a single pomalidomide 4-mg dose in healthy male subjects who smoked 25 cigarettes per day for 10 days (n = 14).