Pomalyst Drug Information

Pregnancy Testing Prior to Administration Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST.

Recommended Dosage for Multiple Myeloma

The recommended dosage of POMALYST is 4 mg once daily orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression. Give POMALYST in combination with dexamethasone.

Recommended Dosage for Kaposi Sarcoma

Continue HAART as HIV treatment in patients with AIDS-related Kaposi sarcoma (KS).

• Dosage Modifications for Hematologic Adverse Reactions Multiple Myeloma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of POMALYST 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 POMALYST for hematologic adverse reactions in patients with MM are summarized in Table 1.
• Table 1: s Initiate a new cycle of POMALYST 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 POMALYST for hematologic adverse reactions in patients with KS are summarized in Table 2.
• Table 2: s Permanently discontinue POMALYST 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 2 at the physician's discretion.

Dosage Modifications for Strong CYP1A2 Inhibitors

Avoid concomitant use of POMALYST with strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce POMALYST dose to 2 mg.

Dosage Modification for Severe Renal Impairment on Hemodialysis Take POMALYST 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. • For patients with KS with severe renal impairment requiring dialysis, reduce the recommended dosage to 4 mg orally daily.

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

Administration

Swallow capsules whole with water. Do not break, chew, or open the capsules. POMALYST may be taken with or without food.

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

In the POMALYST + Low-dose Dex arm, 67% of patients had a dose interruption of POMALYST, the median time to the first dose interruption of POMALYST was 4.1 weeks. Twenty-seven percent of patients had a dose reduction of POMALYST, the median time to the first dose reduction of POMALYST was 4.5 weeks. Eight percent of patients discontinued POMALYST due to adverse reactions.

Table 3: Adverse Reactions in Any POMALYST Treatment Arm in Trial 1* s Other adverse reactions of POMALYST 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 Disorders: Hyperbilirubinemia 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 Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, Pulmonary embolism, Respiratory failure, Bronchospasm Vascular disorders: Hypotension Kaposi Sarcoma (KS) The safety of POMALYST in patients with KS was evaluated in Trial 12-C-0047. Twenty-eight patients received POMALYST 5 mg taken orally once daily on Days 1 through 21 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 exposed to pomalidomide for 6 months or longer and 25% were exposed for greater than one year. Serious adverse reactions occurred in 18% (5/28) of patients who received POMALYST.

The following serious adverse reactions each occurred in 1 patient: anemia, decreased neutrophil count, and hematuria. Permanent discontinuation due to an adverse reaction occurred in 11% (3/28) of patients who received POMALYST. Dosage interruptions due to an adverse reaction occurred in 14% (4/28) of patients who received POMALYST.

The most frequent adverse reaction requiring dosage interruption was decreased neutrophil count, which occurred in 3 patients. The POMALYST dose was reduced due to an adverse reaction in 1 patient due to gout. Tables 5 and 6 summarize the adverse reactions and select laboratory abnormalities reported in Trial 12-C-0047.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Pancytopenia Endocrine Disorders: Hypothyroidism, hyperthyroidism Gastrointestinal Disorders: Gastrointestinal hemorrhage Hepatobiliary Disorders: Hepatic failure (including fatal cases), elevated liver enzymes Immune system Disorders: Allergic reactions (e.g., angioedema, anaphylaxis, urticaria), solid organ transplant rejection Infections and Infestations: Hepatitis B virus reactivation, Herpes zoster, progressive multifocal leukoencephalopathy (PML) Neoplasms benign, malignant and unspecified (incl cysts and polyps): Tumor lysis syndrome, basal cell carcinoma, and squamous cell carcinoma of the skin Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)

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. 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 POMALYST dose.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy as well as female partners of male patients who are exposed to POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436.

Risk Summary Based on the mechanism of action and findings from animal studies, POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is 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 (see Data ).

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. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 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 10 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 20 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.

Pediatric Use The safety and effectiveness of POMALYST 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 5 to <17 with recurrent, progressive or refractory CNS tumors and a parallel-group study conducted in 47 pediatric patients aged 4 to <17 years with recurrent or progressive high-grade glioma, medulloblastoma, ependymoma, or diffuse intrinsic pontine glioma (DIPG). 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 4 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.

Pregnancy POMALYST is contraindicated in females who are pregnant. POMALYST 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.

Hypersensitivity POMALYST is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, anaphylaxis) to pomalidomide or any of the excipients.

Hemodialysis can remove pomalidomide from circulation.