POMALIDOMIDE Drug Interactions: What You Need to Know

INTERACTIONS Strong CYP1A2 Inhibitors: Avoid concomitant use of strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce pomalidomide capsules dose to 2 mg ( 2.6 , 7.1 , 12.3 ).

7.1 Drugs That Affect Pomalidomide Plasma Concentrations CYP1A2 inhibitors: In healthy subjects, co-administration of fluvoxamine, a strong CYP1A2 inhibitor, increased C max and AUC of pomalidomide by 24% and 125% respectively <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3 )]</span>. Increased pomalidomide exposure may increase the risk of exposure related toxicities. Avoid co-administration of strong CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine). If co-administration is unavoidable, reduce the pomalidomide capsules dose <span class="opacity-50 text-xs">[see Dosage and Administration (2.6 )]</span>.

Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 )

4.1 Pregnancy Pomalidomide capsules are contraindicated in females who are pregnant. Pomalidomide capsules can cause fetal harm when administered to a pregnant female <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Use in Specific Populations (8.1 )]</span>. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.

4.2 Hypersensitivity Pomalidomide Capsules are contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, anaphylaxis) to pomalidomide or any of the excipients <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7 ), Description (11) ]</span>.

AND PRECAUTIONS Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue ( 5.4 ).

Hematologic

Toxicity: Neutropenia was the most frequently reported Grade 3/4 adverse event. Monitor patients for hematologic toxicities, especially neutropenia ( 5.5 ). Hepatotoxicity: Hepatic failure including fatalities; monitor liver function tests monthly ( 5.6 ).

Severe Cutaneous

Reactions: Discontinue pomalidomide capsules for severe reactions ( 5.7 ).

Tumor Lysis

Syndrome (TLS): Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions ( 5.11 ). Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue pomalidomide capsules for angioedema and anaphylaxis ( 5.12 ).

5.1 Embryo-Fetal Toxicity Pomalidomide capsules are a thalidomide analogue and are contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span>. Pomalidomide capsules are only available through PS-Pomalidomide REMS <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2 )]</span>. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning Pomalidomide Capsules therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with pomalidomide capsules, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of pomalidomide capsules therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing pomalidomide capsules therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles, or every 2 weeks in females with irregular menstrual cycles <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3 )]</span>.

Males

Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking pomalidomide capsules and for up to 4 weeks after discontinuing pomalidomide capsules, even if they have undergone a successful vasectomy. Male patients taking pomalidomide capsules must not donate sperm [see Use in Specific Populations (8.3) ].

Blood Donation

Patients must not donate blood during treatment with pomalidomide capsules and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to pomalidomide capsules.

5.2 PS-Pomalidomide REMS Because of the embryo-fetal risk <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>, pomalidomide capsules are available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), “PS-Pomalidomide REMS”. Required components of PS-Pomalidomide REMS include the following: Prescribers must be certified with PS-Pomalidomide REMS by enrolling and complying with the REMS requirements. Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span> and males must comply with contraception requirements <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span>. Pharmacies must be certified with PS-Pomalidomide REMS, must only dispense to patients who are authorized to receive pomalidomide capsules and comply with REMS requirements. Further information about PS-Pomalidomide REMS is available at www.PS-PomalidomideREMS.com or by telephone at 1-888-423-5436.

5.3 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke) have been observed in patients treated with pomalidomide capsules.

In Trial

2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with pomalidomide capsules and low dose-dexamethasone (Low-dose Dex), and 3.3% of patients treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with pomalidomide capsules and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with pomalidomide capsules and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient's underlying risk factors.

5.4 Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

5.5 Hematologic Toxicity Multiple Myeloma In trials 1 and 2 in patients who received pomalidomide + Low-dose Dex, neutropenia was the most frequently reported Grade 3 or 4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 51% of patients in both trials. The rate of Grade 3 or 4 neutropenia was 46%. The rate of febrile neutropenia was 8%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span>.

Kaposi Sarcoma In Trial

12-C-0047, hematologic toxicities were the most common (all grades and Grade 3 or 4) adverse reactions [see Adverse Reactions (6.1) ]. Fifty percent of patients had Grade 3 or 4 neutropenia. Monitor patients for hematologic toxicities, especially decreased neutrophils. Monitor complete blood counts every 2 weeks for the first 12 weeks and monthly thereafter. Withhold, reduce the dose, or permanently discontinue pomalidomide based on the severity of the reaction [see Dosage and Administration (2.4) ].

5.6 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with pomalidomide capsules. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with pomalidomide capsules. Monitor liver function tests monthly. Stop pomalidomide capsules upon elevation of liver enzymes and evaluate. After return to baseline values, treatment at a lower dose may be considered.

5.7 Severe Cutaneous Reactions Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These reactions can be fatal. Consider pomalidomide capsules interruption or discontinuation for Grade 2 or 3 skin rash. Permanently discontinue pomalidomide capsules for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>.

5.8 Dizziness and Confusional State In trials 1 and 2 in patients who received pomalidomide capsules + Low-dose Dex, 14% of patients experienced dizziness and 7% of patients experienced a confusional state; 1% of patients experienced Grade 3 or 4 dizziness, and 3% of patients experienced Grade 3 or 4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.

5.9 Neuropathy In trials 1 and 2 in patients who received pomalidomide capsules + Low-dose Dex, 18% of patients experienced neuropathy, with approximately 12% of the patients experiencing peripheral neuropathy. Two percent of patients experienced Grade 3 neuropathy in trial 2. There were no cases of Grade 4 neuropathy adverse reactions reported in either trial.

5.10 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving pomalidomide capsules as an investigational therapy outside of MM.

5.11 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

5.12 Hypersensitivity Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to pomalidomide capsules have been reported. Permanently discontinue pomalidomide capsules for angioedema or anaphylaxis <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>.