POMALIDOMIDE BIOPHARM

Pomalidomide is a thalidomide analog.

The chemical name is ( RS )-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione and it has the following chemical structure: The empirical formula for pomalidomide is C 13 H 11 N 3 O and the gram molecular weight is 273.25.

Pomalidomide is a light yellow to yellow colored powder.

It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL).

Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S(-) enantiomers.

Pomalidomide capsules are available in 1-mg, 2-mg, 3-mg, and 4-mg capsules for oral administration.

Each capsule contains pomalidomide as the active ingredient and the following inactive ingredients: mannitol, pregelatinized starch, croscarmellose sodium and sodium stearyl fumarate.

The 1-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink and black ink.

The 2-mg capsule shell contains gelatin, FD&C Blue #2, titanium dioxide, iron oxide yellow, FD&C Red #3, and white ink.

The 3-mg capsule shell contains gelatin, FD&C Blue #2, titanium dioxide, iron oxide yellow, and white ink.

The 4-mg capsule shell contains gelatin, FD&C Blue #2, titanium dioxide, and white ink.

Black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water.

White ink contains

Shellac, ethanol, isopropyl alcohol, n-butanol, propylene glycol, ammonia solution, purified water, potassium hydroxide, and titanium dioxide. structure.

Pomalidomide capsules are a thalidomide analogue indicated for the treatment of adult patients: in combination with dexamethasone, for patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy. with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART) or in patients with KS who are HIV-negative.

This indication is approved under accelerated approval based on overall response rate.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s) . 1.1 Multiple Myeloma Pomalidomide, in combination with dexamethasone, are indicated for adult patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy. 1.2 Kaposi Sarcoma Pomalidomide capsules are indicated for the treatment of: Adult patients with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART).

Kaposi sarcoma (KS) in adult patients who are HIV-negative.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

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. 12.2 Pharmacodynamics 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 and 20 mg. 12.3 Pharmacokinetics In patients with MM who received pomalidomide 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 pomalidomide 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%).

Following administration of single oral doses of pomalidomide, the maximum plasma concentration (C max ) for pomalidomide occurs at to 3 hours postdose in patients with MM or KS.

Co-administration of pomalidomide capsules with a high-fat meal (approximately 50% of the total caloric content) and high-calorie meal (approximately to 1000 calories) (the meal contained approximately 150, 250, and 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.

Pomalidomide has a mean apparent volume of distribution (Vd/F) between 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

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.

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.

Age (61 to 85 years old), sex and race have no clinically significant effect on the systemic exposure of pomalidomide.

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.

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.

Co-administration of pomalidomide 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 pomalidomide capsules with drugs that are CYP1A2 inducers has not been studied.

CYP1A2 Inhibitors: Co-administration of fluvoxamine (a strong CYP1A2 inhibitor) with pomalidomide increased mean [90% confidence interval] pomalidomide exposure by 125% [98% to 157%] compared to pomalidomide alone in healthy subjects.

Co-administration of fluvoxamine in the presence of ketoconazole (a strong CYP3A4 and P-gp inhibitor) with pomalidomide increased mean pomalidomide exposure by 146% [126% to 167%] compared to pomalidomide administered alone in healthy subjects, indicating the predominant effect of CYP1A2 inhibition in the increase of pomalidomide exposure.

CYP3A4 and P-gp Inhibitors: Co-administration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) in 16 healthy male subjects increased AUC of pomalidomide by 19% compared to pomalidomide administered alone.

CYP1A2 Inducers: Co-administration of pomalidomide capsules with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure.

CYP3A4 Inducers: Co-administration of carbamazepine to 16 healthy male subjects decreased AUC of pomalidomide by 20% with a 90% confidence interval [13% to 27%] compared to when pomalidomide was administered alone.

Co-administration of multiple doses of 4 mg pomalidomide capsules with 20 mg to 40 mg dexamethasone (a weak to moderate inducer of CYP3A4) to patients with MM had no effect on thepharmacokinetics of pomalidomide compared to when pomalidomide was administered alone.

In 14 healthy male subjects who smoked 25 cigarettes per day for a total of 10 days, after single oral dose of 4 mg pomalidomide capsules, C max of pomalidomide increased 14% while AUC of pomalidomide decreased 32%, compared to that in 13 healthy male subjects who were non-smokers.

Pomalidomide does not inhibit or induce cytochrome p450 enzymes or transporters in vitro.

The following clinically significant adverse reactions are described in detail in other labeling sections: Embryo-Fetal Toxicity Venous and Arterial Thromboembolism Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone Hematologic Toxicity Hepatotoxicity Severe Cutaneous Reactions Dizziness and Confusional State Neuropathy Risk of Second Primary Malignancies Tumor Lysis Syndrome Hypersensitivity.

MM: Most common adverse reactions (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia.

KS: Most common adverse reactions including laboratory abnormalities (≥30%) are decreased absolute neutrophil count or white blood cells, elevated creatinine or glucose, rash, constipation, fatigue, decreased hemoglobin, platelets, phosphate, albumin, or calcium, increased ALT, nausea, and diarrhea.

To report SUSPECTED ADVERSE

REACTIONS, contact Breckenridge Pharmaceutical Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Myeloma (MM) In Trial 1, data were evaluated from 219 patients (safety population) who received treatment with Pomalidomide + Low-dose Dex (112 patients) or pomalidomide alone (107 patients).

Median number of treatment cycles was 5.

Sixty-seven percent of patients in the study had a dose interruption of either drug due to adverse reactions.

Forty-two percent of patients in the study had a dose reduction of either drug due to adverse reactions.

The discontinuation rate due to adverse reactions was 11%.

In Trial 2, data were evaluated from 450 patients (safety population) who received treatment with Pomalidomide + Low-dose Dex (300 patients) or High-dose Dexamethasone (High-dose Dex) (150 patients).

The median number of treatment cycles for the Pomalidomide + Low-dose Dex arm was 5.

In the

Pomalidomide + Low-dose Dex arm, 67% of patients had a dose interruption of pomalidomide capsules, the median time to the first dose interruption of pomalidomide was 4.1 weeks.

Twenty-seven percent of patients had a dose reduction of pomalidomide, the median time to the first dose reduction of pomalidomide was 4.5 weeks.

Eight percent of patients discontinued pomalidomide due to adverse reactions.

Tables and 4 summarize the adverse reactions reported in Trials and 2, respectively.

Table 3: Adverse Reactions in Any Pomalidomide Capsules Treatment Arm in Trial 1 Regardless of attribution of relatedness to pomalidomide. a Pomalidomide alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. b Serious adverse reactions were reported in at least 2 patients in any pomalidomide treatment arm.

Data cutoff: 01 March 2013 All Adverse Reactions ≥10% in Either Arm Grade 3 or 4 ≥5% in Either Arm Body System Adverse Reaction Pomalidomide a (N=107) Pomalidomide + Low-dose Dex (N=112) Pomalidomide (N=107) Pomalidomide + Low-dose Dex (N=112) Number (%) of patients with at least one adverse reaction 107 112 98 102 Blood and lymphatic system disorders Neutropenia b 57 55 51 46 Anemia b 41 47 25 24 Thrombocytopenia b 28 26 24 21 Leukopenia 14 22 7 11 Febrile neutropenia b <10% <10% 6 3 Lymphopenia 4 17 2 8 General disorders and administration site conditions Fatigue and asthenia b 62 70 13 19 Edema peripheral 27 19 0 0 Pyrexia b 25 36 <5% <5% Chills 11 14 0 0 Gastrointestinal disorders Nausea b 39 27 <5% <5% Constipation b 38 41 <5% <5% Diarrhea 37 40 <5% <5% Vomiting b 15 16 <5% 0 Musculoskeletal and connective tissue disorders Back pain b 37 36 15 11 Musculoskeletal chest pain 25 22 <5% 0 Muscle spasms 23 22 <5% <5% Arthralgia 18 17 <5% <5% Muscular weakness 15 15 6 4 Bone pain 13 8 <5% <5% Musculoskeletal pain 13 19 <5% <5% Pain in extremity 8 16 0 <5%.

Infections and infestations Upper respiratory tract infection 40 32 <5% <5% Pneumonia b 30 38 21 32 Urinary tract infection b 11 19 2 10 Sepsis b <10% <10% 6 5 Metabolism and nutrition disorders Decreased appetite 25 21 <5% 0 Hypercalcemia b 23 13 11 1 (<1) Hypokalemia 13 13 <5% <5% Hyperglycemia 12 17 <5% <5% Hyponatremia 12 14 <5% <5% Dehydration b <10% <10% 5 6 Hypocalcemia 6 13 0 <5% Respiratory, thoracic and mediastinal disorders Dyspnea b 38 50 8 14 Cough 18 25 0 0 Epistaxis 18 12 <5% 0 Productive cough 10 14 0 0 Oropharyngeal pain 6 12 0 0 Nervous system disorders Dizziness 24 20 <5% <5% Peripheral neuropathy 23 20 0 0 Headache 16 15 0 <5% Tremor 11 15 0 0 Skin and subcutaneous tissue disorders Rash 22 18 0 <5% Pruritus 16 10 0 0 Dry skin 10 12 0 0 Hyperhidrosis 8 18 0 0 Night sweats 5 14 0 0.

Investigations Blood creatinine increased b 20 11 6 3 Weight decreased 16 10 0 0 Weight increased 1 (<1) 12 0 0 Psychiatric disorders Anxiety 14 8 0 0 Confusional state b 13 15 6 3 Insomnia 7 18 0 0 Renal and urinary disorders Renal failure b 16 11 9 8 Table 4: Adverse Reactions in Trial 2 All Adverse Reactions (≥5% in Pomalidomide + Low-dose Dex arm, and at least 2% higher than the High-dose-Dex arm) Grade 3 or 4 (≥1% in Pomalidomide + Low-dose Dex arm, and at least 1% higher than the High-dose-Dex arm) Body System Adverse Reaction Pomalidomide + Low-dose Dex (N=300) High.

• dose Dex (N=150) Pomalidomide + Low-dose Dex (N=300) High-dose Dex (N=150) Number (%) of patients with at least one adverse reaction 297 149 259 127 Blood and lymphatic system disorders Neutropenia b 154 31 145 24 Thrombocytopenia 89 a 44 a 66 a 39 a Leukopenia 38 8 27 5 Febrile neutropenia b 28 0 28 0 General disorders and administration site conditions Fatigue and asthenia 140 64 26 a 18 a Pyrexia b 80 35 9 a 7 a Edema peripheral 52 17 4 a 3 a Pain 11 a 3 a 5 1 (<1).

Infections and infestations Upper respiratory tract infection b 93 19 9 1 (<1) Pneumonia b 58 20 47 15 Neutropenic sepsis b 3 a 0 a 3 0 Gastrointestinal disorders Diarrhea 66 28 3 a 2 a Constipation 65 22 7 0 Nausea 45 17 3 a 2 a Vomiting 23 6 3 0 Musculoskeletal and connective tissue disorders Back pain b 59 24 15 6 Bone pain b 54 21 22 7 Muscle spasms 46 11 1 (<1)a 1 (<1) a Arthralgia 26 7 2 (<1)a 1 (<1) a Pain in extremity 20 a 9 a 6 0 Respiratory, thoracic and mediastinal disorders Dyspnea b 76 25 17 7 Cough 60 15 2 (<1) a 1 (<1) a Chronic obstructive pulmonary disease b 5 a 0 a 4 0 Nervous system disorders Peripheral neuropathy 52 18 5 a 2 a Dizziness 37 14 4 a 2 a Headache 23 8 1 (<1) a 0 a Tremor 17 2 2 (<1) a 0 a Depressed level of consciousness 5 a 0 a 3 0 Metabolism and nutrition disorders Decreased appetite 38 12 3 a 2 a Hypokalemia 28 a 12 a 12 4 Hypocalcemia 12 a 9 a 5 1 (<1) Skin and subcutaneous tissue disorders Rash 23 2 3 0 Pruritus 22 5 0 a 0 a Hyperhidrosis 15 1 (<1) 0 a 0 a.

Investigations Neutrophil count decreased 15 1 (<1) 14 1 (<1) Platelet count decreased 10 a 3 a 8 2 White blood cell count decreased 8 a 1 (<1) a 8 0 Alanine aminotransferase increased 7 a 2 a 5 0 Aspartate aminotransferase increased 4 a 2 a 3 0 Lymphocyte count decreased 3 a 1 (<1) a 3 0 Renal and urinary disorders Renal failure 31 a 18 a 19 8 Injury, poisoning and procedural complications Femur fracture b 5 a 1 (<1) a 5 1 (<1) Reproductive system and breast disorders Pelvic pain 6 a 3 a 4 0 a Percentage did not meet the criteria to be considered as an adverse reaction for pomalidomide for that category of event (i.e., all adverse events or Grade 3 or 4 adverse events). b Serious adverse reactions were reported in at least 3 patients in the POM + Low-dose Dex arm, AND at least 1% higher than the High-dose-Dex arm percentage.

Data cutoff: 01 March 2013 Other Adverse Reactions Other adverse reactions of pomalidomide capsules in patients with MM, not described above, and considered important: Cardiac.

Disorders : Myocardial infarction, Atrial fibrillation, Angina pectoris, Cardiac failure congestive Ear and Labyrinth.

Disorders : Vertigo Gastrointestinal disorders: Abdominal pain General.

Disorders and Administration Site Conditions: General physical health deterioration, Non-cardiac chest pain, Multi-organ failure Hepatobiliary.

Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis, Bacteremia, Pneumonia respiratory syncytial viral, Cellulitis, Urosepsis, Septic shock, Clostridium difficile colitis, Pneumonia streptococcal, Lobar pneumonia, Viral infection, Lung infection.

Investigations : Alanine aminotransferase increased, Hemoglobin decreased Injury, poisoning and procedural complications: Fall, Compression fracture, Spinal compression fracture Metabolism and nutritional disorders: Hyperkalemia, Failure to thrive Nervous system disorders: Depressed level of consciousness, Syncope Psychiatric disorders: Mental status change Renal and urinary disorders: Urinary retention, Hyponatremia Reproductive system and breast disorders: Pelvic pain Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, Pulmonary embolism, Respiratory failure, Bronchospasm Vascular disorders: Hypotension Kaposi Sarcoma (KS) The safety of pomalidomide capsules in patients with KS was evaluated in Trial 12-C-0047.

Twenty-eight patients received pomalidomide capsules 5 mg taken orally once daily on Days 1 through of repeated 28.

• day cycles.

The study excluded patients with procoagulant disorders or a history of venous or arterial thromboembolism.

Patients received

DVT prophylaxis with daily low dose aspirin.

Across all patients treated on

Trial 12-C-0047, 75% were.

Hemodialysis can remove pomalidomide from circulation.

Hypersensitivity 4.1 Pregnancy Pomalidomide capsules are contraindicated in females who are pregnant.

Pomalidomide capsules can cause fetal harm when administered to a pregnant female.

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.

mg per day taken orally on Days 1 through of repeated 28-day cycles until disease progression.

Refer to section 14.1 for dexamethasone dosing.

KS: 5 mg per day taken orally on Days 1 through of repeated 28-day cycles until disease progression or unacceptable toxicity.

Modify the dosage for certain patients with renal impairment or hepatic impairment. 2.1 Pregnancy Testing Prior to Administration Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating pomalidomide capsules. 2.2 Recommended Dosage for Multiple Myeloma The recommended dosage of pomalidomide capsules is 4 mg once daily orally with or without food on Days 1 through of each 28-day cycle until disease progression.

Give pomalidomide capsules in combination with dexamethasone. 2.3 Recommended Dosage for Kaposi Sarcoma The recommended dosage of pomalidomide capsules is 5 mg once daily taken orally with or without food on Days 1 through of each 28-day cycle until disease progression or unacceptable toxicity.

Continue HAART as HIV treatment in patients with AIDS-related Kaposi sarcoma (KS) . 2.4 Dosage Modifications for Hematologic Adverse Reactions Multiple Myeloma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of pomalidomide capsules in patients with multiple myeloma (MM) when the neutrophil count is at least 500 per mcL and the platelet count is at least 50,000 per mcL.

Dosage modification for pomalidomide capsules for hematologic adverse reactions in patients with MM are summarized in Table 1.

Table 1: Dosage Modifications for pomalidomide capsules for Hematologic in MM * Permanently discontinue pomalidomide capsules if unable to tolerate 1 mg once daily.

ANC= absolute neutrophil count Adverse Reaction Severity Dosage Modification Neutropenia ANC less than 500 per mcL or febrile neutropenia (fever greater than or equal to 38.5°C and ANC less than 1,000 per mcL) Withhold pomalidomide capsules until ANC is greater than or equal to 500 per mcL; follow CBC weekly.

Resume pomalidomide capsules dose at 1 mg less than the previous dose. * Thrombocytopenia For each subsequent drop of ANC less than 500 per mcL Withhold pomalidomide capsules until ANC is greater than or equal to 500 mcL.

Resume pomalidomide capsules dose at 1 mg less than the previous dose. * Platelets less than 25,000 per mcL Withhold pomalidomide capsules until platelets are greater than or equal to 50,000 per mcL; follow CBC weekly.

Resume pomalidomide capsules dose at 1 mg less than the previous dose* For each subsequent drop of platelets less than 25,000 per mcL Withhold pomalidomide capsules until platelets are greater than or equal to 50,000 per mcL.

Resume pomalidomide capsules at 1 mg less than the previous dose* Kaposi Sarcoma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of pomalidomide capsules in patients with KS when the neutrophil count is at least 1000 per mcL and the platelet count is at least 75,000 per mcL.

Dose modifications for pomalidomide capsules for hematologic adverse reactions in patients with KS are summarized in Table 2.

Table 2: Dosage Modifications for Pomalidomide Capsules for Hematologic Adverse Reactions in KS * Permanently discontinue pomalidomide capsules if unable to tolerate 1mg once daily.

ANC= absolute neutrophil count Adverse Reaction Severity Dosage Modification Neutropenia ANC to less than1,000 per mcL Day of cycle Withhold pomalidomide capsules until ANC is greater than or equal to 1,000 per mcL.

Resume pomalidomide capsules at the same dose.

During cycle

Continue pomalidomide capsules at the current dose.

ANC less than 500 per mcL Withhold pomalidomide capsules until ANC is greater than or equal to 1,000 per mcL.

ANC less than 1,000 per mcL and single temperature greater than or equal to 38.3°C or ANC less than 1,000 per mcL and sustained temperature greater than or equal to 38°C for more than 1 hour Withhold pomalidomide capsules until ANC is greater than or equal to 1,000 per mcL.

Resume pomalidomide capsules at dose 1 mg less than the previous dose.* Thrombocytopenia Platelet count to less than 50,000 per mcL Day of cycle Withhold pomalidomide capsules until platelet count is greater than or equal to 50,000 per mcL.

Platelet count less than 25,000 per mcL Permanently discontinue pomalidomide capsules. 2.5 Dosage Modifications for Non-Hematologic Adverse Reactions Permanently discontinue pomalidomide capsules for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction.

For other

Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade at the physician’s discretion. 2.6 Dosage Modifications for Strong CYP1A2 Inhibitors Avoid concomitant use of pomalidomide capsules with strong CYP1A2 inhibitors.

If concomitant use of a strong

CYP1A2 inhibitor is unavoidable, reduce pomalidomide capsules dose to 2 mg. 2.7 Dosage Modification for Severe Renal Impairment on Hemodialysis Take pomalidomide capsules after completion of dialysis procedure on hemodialysis days.

For patients with

MM with severe renal impairment requiring dialysis, reduce the recommended dosage to 3 mg orally daily.

KS with severe renal impairment requiring dialysis, reduce the recommended dosage to 4 mg orally daily. 2.8 Dosage Modification for Hepatic Impairment Multiple Myeloma For patients with MM with mild or moderate hepatic impairment (Child-Pugh A or B), reduce the recommended dosage to 3 mg orally daily.

MM with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 2 mg.

Kaposi Sarcoma For patients with

KS with mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C), reduce the recommended dosage to 3 mg orally daily. 2.9 Administration Swallow capsules whole with water.

Do not break, chew, or open the capsules.

Pomalidomide capsules may be taken with or without food.

Dark blue cap and yellow body printed with “NAT’’ with white ink on cap and “1mg” with black ink on body of the capsule 1 mg bottles of 21 (NDC 63850-0131-1) 1 mg bottles of 100 (NDC 63850-0131-2) Dark blue cap and orange body printed with “NAT” with white ink on cap and “2mg” with white ink on body of the capsule 2 mg bottles of 21 (NDC 63850-0132-1) 2 mg bottles of 100 (NDC 63850-0132-2) Dark blue cap and green body printed with “NAT” with white ink on cap and “3mg” with white ink on body of the capsule 3 mg bottles of 21 (NDC 63850-0133-1) 3 mg bottles of 100 (NDC 63850-0133-2) Dark blue cap and blue body printed with “NAT” with white ink on cap and “4mg” with white ink on body of the capsule 4 mg bottles of 21 (NDC 63850-0134-1) 4 mg bottles of 100 (NDC 63850-0134-2) Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) .

Care should be exercised in handling of pomalidomide capsules.

Do not open or crush pomalidomide capsules.

If powder from pomalidomide capsules contacts the skin, wash the skin immediately and thoroughly with soap and water.

If pomalidomide capsules contacts the mucous membranes, flush thoroughly with water.

Follow procedures for proper handling and disposal of hazardous drugs.

There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to pomalidomide capsules during pregnancy as well as female partners of male patients who are exposed to pomalidomide capsules.

This registry is also used to understand the root cause for the pregnancy.

Based on the mechanism of action and findings from animal studies, pomalidomide capsules can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy.

Pomalidomide capsules are a thalidomide analogue.

Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects.

Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants.

Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis.

Pomalidomide crossed the placenta after administration to pregnant rabbits.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug.

Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

The estimated background risk in the

U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis.

In rats, pomalidomide was administered orally to pregnant animals at doses of to 1000 mg/kg/day. Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels.

There was no maternal toxicity observed in this study.

The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day. Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses.

In rabbits, pomalidomide was administered orally to pregnant animals at doses of to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day. Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore - and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs, and a reduced average for ossified tarsals.

No maternal toxicity was observed at the low dose (10 mg/kg/day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg/day. Additional embryo-fetal toxicity included increased resorption.

Following daily oral administration of pomalidomide from Gestation Day 7 through Gestation Day in pregnant rabbits, fetal plasma pomalidomide concentrations were approximately 50% of the maternal C max at all dosages (5 to 250 mg/kg/day), indicating that pomalidomide crossed the placenta.

Females and Males of Reproductive Potential Pregnancy Testing Pomalidomide capsules can cause fetal harm when administered during pregnancy.

Verify the pregnancy status of females of reproductive potential prior to initiating pomalidomide capsules therapy and during therapy.

Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy, while taking pomalidomide capsules, during dose interruptions and for at least 4 weeks after completing therapy.

Females of reproductive potential must have 2 negative pregnancy tests before initiating pomalidomide capsules.

The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing pomalidomide capsules.

Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles.

If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks.

Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding.

Pomalidomide capsules treatment must be discontinued during this evaluation.

Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap.

Contraception must begin 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.

Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.

Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.

Pomalidomide is present in the semen of males who take pomalidomide capsules.

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.

Based on findings in animals, female fertility may be compromised by treatment with pomalidomide capsules.

The safety and effectiveness of pomalidomide capsules have not been established in pediatric patients.

The safety and effectiveness were assessed but not established in two open-label studies: a dose escalation study in 25 pediatric patients aged to <17 with recurrent, progressive or refractory CNS tumors [NCT02415153] and a parallel-group study conducted in 47 pediatric patients aged to <17 years with recurrent or progressive high-grade glioma, medulloblastoma, ependymoma, or diffuse intrinsic pontine glioma (DIPG) [NCT03257631.

No new safety signals were observed in pediatric patients across these studies.

At the same dose by body surface area, pomalidomide exposure in 55 pediatric patients aged to < 17 years old was within the range observed in adult patients with MM but higher than the exposure observed in adult patients with KS.

Of the total number of patients in clinical studies of pomalidomide capsules, 44% were aged older than 65 years, while 10% were aged older than 75 years.

No overall differences in effectiveness were observed between these patients and younger patients.

In these studies, patients older than 65 years were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Of the 28 patients who received pomalidomide capsules, 11% were 65 years or older, and 3.6% were 75 years of age or older.

The clinical study did not include sufficient numbers of patients aged and over to determine whether they respond differently from younger patients.