Pomalyst pomalidomide 3 mg Capsule, 21-count — NDC 59572-503-21 (Billing 59572-0503-21)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Pomalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of pomalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos and Ikaros) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects.

In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of lenalidomide-resistant multiple myeloma (MM) cell lines and synergized with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.

12.2Pharmacodynamics Pomalidomide exposure-response analyses showed that there was no relationship between systemic pomalidomide exposure level and efficacy or safety following pomalidomide dose of 4 mg. Cardiac Electrophysiology The QTc prolongation potential of pomalidomide was evaluated in a single center, randomized, double-blind crossover study (N=72) using 4 mg pomalidomide, 20 mg pomalidomide, placebo, and 400 mg moxifloxacin (positive control). No significant QTc prolongation effect of pomalidomide was observed following pomalidomide doses of 4 and 20 mg.

12.3Pharmacokinetics In patients with MM who received POMALYST 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC (CV%) of 860 (37%) ng∙h/mL and C max (CV%) of 75 (32%) ng/mL. In patients with Kaposi sarcoma (KS) who received POMALYST 5 mg daily, pomalidomide steady-state drug exposure was characterized by AUC of 462.3 ng∙h/mL (82%) and C max of 53.1 ng/mL (50%). Absorption Following administration of single oral doses of POMALYST, the maximum plasma concentration (C max ) for pomalidomide occurs at 2 to 3 hours postdose in patients with MM or KS.

Effect of Food Co-administration of POMALYST with a high-fat meal (approximately 50% of the total caloric content) and high-calorie meal (approximately 800 to 1000 calories) (the meal contained approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively) delays the T max by 2.5 hours, decreased mean plasma C max and AUC in healthy subjects by about 27% and 8%, respectively. Distribution Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state in patients with MM or KS.

Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours postdose (~T max ) after 4 days of 2 mg once-daily dosing. Human plasma protein binding of pomalidomide ranges from 12% to 44% and is not concentration dependent. Pomalidomide is a substrate for P-gp.

Elimination Pomalidomide has a mean total body clearance (CL/F) of 7-10 L/h in patients with MM or KS. Pomalidomide is eliminated with a median plasma half-life of 9.5 hours in healthy subjects and 7.5 hours in patients with MM or KS. Metabolism Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4.

Minor contributions from CYP2C19 and CYP2D6 were also observed in vitro . Excretion Following a single oral administration of [ 14 C]-pomalidomide to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as pomalidomide in urine and feces. Specific Populations Age (61 to 85 years old), sex and race have no… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Pomalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of pomalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos and Ikaros) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects.

In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of lenalidomide-resistant multiple myeloma (MM) cell lines and synergized with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.

12.3Pharmacokinetics In patients with MM who received POMALYST 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC (CV%) of 860 (37%) ng∙h/mL and C max (CV%) of 75 (32%) ng/mL. In patients with Kaposi sarcoma (KS) who received POMALYST 5 mg daily, pomalidomide steady-state drug exposure was characterized by AUC of 462.3 ng∙h/mL (82%) and C max of 53.1 ng/mL (50%). Absorption Following administration of single oral doses of POMALYST, the maximum plasma concentration (C max ) for pomalidomide occurs at 2 to 3 hours postdose in patients with MM or KS.

Effect of Food Co-administration of POMALYST with a high-fat meal (approximately 50% of the total caloric content) and high-calorie meal (approximately 800 to 1000 calories) (the meal contained approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively) delays the T max by 2.5 hours, decreased mean plasma C max and AUC in healthy subjects by about 27% and 8%, respectively. Distribution Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state in patients with MM or KS.

Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours postdose (~T max ) after 4 days of 2 mg once-daily dosing. Human plasma protein binding of pomalidomide ranges from 12% to 44% and is not concentration dependent. Pomalidomide is a substrate for P-gp.

Elimination Pomalidomide has a mean total body clearance (CL/F) of 7-10 L/h in patients with MM or KS. Pomalidomide is eliminated with a median plasma half-life of 9.5 hours in healthy subjects and 7.5 hours in patients with MM or KS. Metabolism Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4.

Minor contributions from CYP2C19 and CYP2D6 were also observed in vitro . Excretion Following a single oral administration of [ 14 C]-pomalidomide to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as pomalidomide in urine and feces. Specific Populations Age (61 to 85 years old), sex and race have no clinically significant effect on the systemic exposure of pomalidomide.

Patients with Renal Impairment Pomalidomide pharmacokinetic parameters were not significantly affected in patients with moderate (30 mL/min ≤ CLcr< 60 mL/min) or severe (15 mL/min ≤ CLcr< 30 mL/min) renal impairment relative to patients with normal renal function (CLcr ≥ 60 mL/min). Mean exposure (AUC) to pomalidomide increased by 38% in patients with severe renal impairment requiring dialysis (CLcr< 30 mL/min requiring dialysis) and 40% in patients with end stage renal disease (CLcr< 15 mL/min) on non-dialysis days.

In patients with severe renal impairment requiring dialysis, the estimated dialysis clearance is approximately 12 L/h which is higher than pomalidomide total body clearance, indicating hemodialysis will remove pomalidomide from the blood circulation. Patients with Hepatic Impairment Mean exposure (AUC) of pomalidomide increased by 51%, 58% and 72% in subjects with mild, moderate or severe hepatic impairment as defined by Child-Pugh criteria, respectively. Drug Interaction Studies Clinical Studies Co-administration of POMALYST with the following drugs did not increase pomalidomide exposure to a clinically significant extent: ketoconazole (a strong CYP3A4 and P-gp inhibitor), carbamazepine (a strong CYP3A4 inducer) and dexamethasone (a weak to moderate CYP3A4 inducer).

Co-administration of POMALYST with drugs that are CYP1A2 inducers has not been studied. CYP1A2 Inhibitors: Co-administration of fluvoxamine (a strong CYP1A2 inhibitor) with POMALYST increased mean [90% confidence interval] pomalidomide exposure by 125% [98% to 157%] compared to POMALYST alone in healthy subjects. Co-administration of fluvoxamine in the pr… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Pomalidomide exposure-response analyses showed that there was no relationship between systemic pomalidomide exposure level and efficacy or safety following pomalidomide dose of 4 mg. Cardiac Electrophysiology The QTc prolongation potential of pomalidomide was evaluated in a single center, randomized, double-blind crossover study (N=72) using 4 mg pomalidomide, 20 mg pomalidomide, placebo, and 400 mg moxifloxacin (positive control). No significant QTc prolongation effect of pomalidomide was observed following pomalidomide doses of 4 and 20 mg.

14 CLINICAL STUDIES

14.1Multiple Myeloma Trial 1 Trial 1 was a phase 2, multicenter, randomized open-label study in patients with relapsed multiple myeloma (MM) who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. Patients were considered relapsed if they had achieved at least stable disease for at least 1 cycle of treatment to at least 1 prior regimen and then developed progressive disease. Patients were considered refractory if they experienced disease progression on or within 60 days of their last therapy.

A total of 221 patients were randomized to receive POMALYST alone or POMALYST with Low-dose Dex. In Trial 1, the safety and efficacy of POMALYST 4 mg, once daily for 21 of 28 days, until disease progression, were evaluated alone and in combination with Low-dose Dex (40 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged 75 years or younger, or 20 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged greater than 75 years). Patients in the POMALYST alone arm were allowed to add Low-dose Dex upon disease progression.

Table 7 summarizes the baseline patient and disease characteristics in Trial 1. The baseline demographics and disease characteristics were balanced and comparable between the study arms. Table 7: Baseline Demographic and Disease-Related Characteristics – Trial 1 POMALYST (n=108) POMALYST + Low-dose Dex (n=113) Data cutoff: 01 April 2011 Patient Characteristics Median age, years (range) 61 (37-88) 64 (34-88) Age distribution, n (%) <65 years 65 (60.2) 60 (53.1) ≥65 years 43 (39.8) 53 (46.9) Sex, n (%) Male 57 (52.8) 62 (54.9) Female 51 (47.2) 51 (45.1) Race/ethnicity, n (%) White 86 (79.6) 92 (81.4) Black or African American 16 (14.8) 17 (15) All other race 6 (5.6) 4 (3.6) ECOG Performance, n (%) Status 0-1 95 (87.9) 100 (88.5) Disease Characteristics Number of prior therapies Median (min, max) 5 (2, 12) 5 (2, 13) Prior transplant, n (%) 82 (75.9) 84 (74.3) Refractory to bortezomib and lenalidomide, n (%) 64 (59.3) 69 (61.1) Table 8 summarizes the analysis results of overall response rate (ORR) and duration of response (DOR), based on assessments by the Independent Review Adjudication Committee for the treatment arms in Trial 1.

ORR did not differ based on type of prior antimyeloma therapy. Table 8: Trial 1 Results a Results are prior to the addition of dexamethasone. b ORR = PR + CR per EBMT criteria. CI, confidence interval; NE, not established (the median has not yet been reached).

Data cutoff: 01 April 2011 POMALYST a (n=108) POMALYST + Low-dose Dex (n=113) Response Overall Response Rate (ORR), b n (%) 8 (7.4) 33 (29.2) 95% CI for ORR (%) (3.3, 14.1) (21.0, 38.5) Complete Response (CR), n (%) 0 (0.0) 1 (0.9) Partial Response (PR), n (%) 8 (7.4) 32 (28.3) Duration of Response (DOR) Median, months NE 7.4 95% CI for DOR (months) NE (5.1, 9.2) Trial 2 Trial 2 was a Phase 3 multi-center, randomized, open-label study, where POMALYST + Low-dose Dex therapy was compared to High-dose Dex in adult patients with relapsed and refractory MM, who had received at least two prior treatment regimens, including lenalidomide and bortezomib, and demonstrated disease progression on or within 60 days of the last therapy.

Patients with creatinine clearance ≥ 45mL/min qualified for the trial. A total of 455 patients were enrolled in the trial: 302 in the POMALYST + Low-dose Dex arm and 153 in the High-dose Dex arm. Patients in the POMALYST + Low-dose Dex arm were administered 4 mg POMALYST orally on Days 1 to 21 of each 28-day cycle.

Dexamethasone (40 mg) was administered once per day on Days 1, 8, 15 and 22 of a 28-day cycle. Patients > 75 years of age started treatment with 20 mg dexamethasone using the same schedule. For the High-dose Dex arm, dexamethasone (40 mg) was administered once per day on Days 1 through 4, 9 through 12, and 17 through 20 of a 28-day cycle.

Patients > 75 years of age started treatment with 20 mg dexameth… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 12 monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes, and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.

In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels.

There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males in this study were mated with untreated females, all uterine parameters were comparable to the controls.

Based on these results, the observed effects were attributed to the treatment of females.