Pomalyst

Overdose

No specific information is available on the treatment of overdose with pomalidomide. Hemodialysis can remove pomalidomide from circulation.

Contraindications

POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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.

Undesirable effects

The following adverse reactions are described in detail in other labeling sections:

• Fetal Risk
• Venous and Arterial Thromboembolism
• Increased Mortality in Multiple Myeloma when Pembrolizumab Is Added to Dexamethasone and a Thalidomide Analogue
• Hematologic Toxicity
• Hepatotoxicity
• Hypersensitivity Reactions
• Dizziness and Confusional State
• Neuropathy
• Risk of Second Primary Malignancies
• Tumor Lysis Syndrome

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.

In Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dex (112 patients) or POMALYST 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 POMALYST + Low-dose Dex (300 patients) or High-dose Dexamethasone (High-dose Dex) (150 patients). 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.

Tables 2 and 3 summarize the adverse reactions reported in Trials 1 and 2, respectively.

Table 2: Adverse Reactions in Any POMALYST Treatment Arm in Trial 1*

Table 3:Adverse Reactions in Trial 2

Other adverse reactions of POMALYST in patients with multiple myeloma, 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

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

The following adverse reactions have been identified during post approval use of POMALYST. 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: Pancytopenia, tumor lysis syndrome, allergic reactions (e.g., angioedema, urticaria), elevated liver enzymes, hepatic failure (including fatal cases), hepatitis B virus reactivation, herpes zoster, gastrointestinal hemorrhage, basal cell carcinoma and squamous cell carcinoma of the skin.

Therapeutic indications

POMALYST, in combination with dexamethasone, is indicated for patients with multiple myeloma 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.

Pharmacodynamic properties

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.

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.

Pharmacokinetic properties

In patients with multiple myeloma who received POMALYST 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC of 860 ng.h/mL (CV% = 37%) and Cmax of 75 ng/mL (CV% = 32%).

Following administration of single oral doses of POMALYST, the maximum plasma concentration (Cmax) for pomalidomide occurs at 2 and 3 hours postdose.

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 Tmax by 2.5 hours, decreased mean plasma Cmax and AUC in healthy volunteers by about 27% and 8%, respectively.

Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state.

Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours postdose (~Tmax) after 4 days of once-daily dosing at 2 mg.

Human plasma protein binding ranges from 12% to 44% and is not concentration dependent. Pomalidomide is a substrate for P-gp.

Pomalidomide has a mean total body clearance (CL/F) of 7-10 L/h. Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma.

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 [14C]-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.

Date of revision of the text

Fertility, pregnancy and lactation

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 Celgene Corporation at 1-888-4235436.

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. 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. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

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.

Animal Data

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 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 Cmax at all dosages (5 to 250 mg/kg/day), indicating that pomalidomide crossed the placenta.

Qualitative and quantitative composition

POMALYST is available in the following capsule strengths:

• 1 mg: Dark blue opaque cap and yellow opaque body, imprinted “POML” on the cap in white ink and “1 mg” on the body in black ink
• 2 mg: Dark blue opaque cap and orange opaque body, imprinted “POML” on the cap and “2 mg” on the body in white ink
• 3 mg: Dark blue opaque cap and green opaque body, imprinted “POML” on the cap and “3 mg” on the body in white ink
• 4 mg: Dark blue opaque cap and blue opaque body, imprinted “POML” on the cap and “4 mg” on the body in white ink

Dark blue opaque cap and yellow opaque body, imprinted “POML” on the cap in white ink and “1 mg” on the body in black ink

Dark blue opaque cap and orange opaque body, imprinted “POML” on the cap and “2 mg” on the body in white ink

Dark blue opaque cap and green opaque body, imprinted “POML” on the cap and “3 mg” on the body in white ink

Dark blue opaque cap and blue opaque body, imprinted “POML” on the cap and “4 mg” on the body in white ink.

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 POMALYST. POMALYST capsules should not be opened or crushed. If powder from POMALYST contacts the skin, wash the skin immediately and thoroughly with soap and water. If POMALYST contacts the mucous membranes, flush thoroughly with water.

Follow procedures for proper handling and disposal of anticancer drugs. 1

REFERENCES

1. OSHA Hazardous Drugs. OSHA. [Accessed on 29 January 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

Manufactured for: Celgene Corporation, Summit, NJ 07901. Revised: Nov 2017

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. POMALYST is only available through the POMALYST REMS program.

Females of reproductive potential must avoid pregnancy while taking POMALYST 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 POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST 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 POMALYST 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.

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 POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST.

Because of the embryo-fetal risk , POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.”

Required components of the POMALYST REMS program include the following:

• Prescribers must be certified with the POMALYST REMS program 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 and males must comply with contraception requirements.
• Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST, and comply with REMS requirements.

Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.

Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke) have been observed in patients treated with POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST 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 POMALYST 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 POMALYST 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.

No PD-1 or PD-L1 blocking antibodies are approved for the treatment of multiple myeloma. In two randomized clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. In Study KN183 (NCT02576977), patients with relapsed or refractory multiple myeloma were randomized to receive pomalidomide and dexamethasone with (n=125) or without (n=124) pembrolizumab. The hazard ratio for overall survival (OS) was 1.61 (95% CI: 0.91, 2.85), increasing the relative risk of death by more than 50% in the experimental arm containing pembrolizumab. Causes of death in the experimental arm, excluding disease progression, included: myocarditis, Stevens- Johnson syndrome, myocardial infarction, pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis, sepsis, multiple organ dysfunction, and respiratory failure. In Study KN185 (NCT02579863), patients with newly-diagnosed multiple myeloma were randomized to receive lenalidomide and dexamethasone with (n=151) or without (n=150) pembrolizumab. The hazard ratio for OS was 2.06 (95% CI: 0.93, 4.55), increasing the relative risk of death by more than 100% in the experimental arm containing pembrolizumab. Causes of death in the experimental arm, excluding disease progression, included: intestinal ischemia, cardio-respiratory arrest, suicide, pulmonary embolism, cardiac arrest, pneumonia, sudden death, myocarditis, large intestine perforation, and cardiac failure.

The addition of a PD-1 or PD-L1 blocking antibody to a thalidomide analogue is not recommended for the treatment of patients with multiple myeloma outside of controlled clinical trials.

In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 51% of patients in both trials. The rate of Grade 3/4 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.

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

Angioedema and severe dermatologic reactions have been reported. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reactions, and do not resume therapy.

In trials 1 and 2 in patients who received POMALYST + 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.

In trials 1 and 2 in patients who received POMALYST + 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.

Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

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.

See FDA-approved Patient Labeling (PATIENT INFORMATION)

Advise patients that POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue and may cause serious birth defects or death to a developing baby.

• Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy.
• Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test.
• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception, including at least 1 highly effective form, simultaneously during POMALYST therapy, during therapy interruption, and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch, or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm, and cervical cap.
• Instruct patient to immediately stop taking POMALYST and contact her healthcare provider if she becomes pregnant while taking this drug, if she misses her menstrual period or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
• Advise patient that if her healthcare provider is not available, she should call Celgene Customer Care Center at 1-888-423-5436.
• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy.
• Advise male patients taking POMALYST that they must not donate sperm.
• All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST.

Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program called POMALYST REMS.

• Patients must sign a Patient-Physician Agreement Form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements, and participate in monthly telephone surveys. Males must comply with the contraception requirements.
• POMALYST is available only from pharmacies that are certified in POMALYST REMS. Provide patients with the telephone number and Web site for information on how to obtain the product.

Inform females that there is a Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy and that they can contact the Pregnancy Exposure Registry by calling 1-888-423-5436.

Inform patients of the risk of developing DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation.

Inform patients of potential for increased risk of death in people with multiple myeloma when a PD-1 blocking antibody was added to a dexamethasone and thalidomide analogue treatment regimen.

Inform patients on the risks of developing neutropenia, thrombocytopenia, and anemia and the need to report signs and symptoms associated with these events to their healthcare provider for further evaluation.

Inform patients on the risks of developing hepatotoxicity, including hepatic failure and death, and to report signs and symptoms associated with these events to their healthcare provider for evaluation.

Inform patients of the risk for angioedema and severe skin reactions and to report any signs and symptoms associated with these events to their healthcare provider for evaluation.

Inform patients of the potential risk of dizziness and confusional state with the drug, 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.

Inform patients of the risk of neuropathy and to report the signs and symptoms associated with these events to their healthcare provider for further evaluation.

Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown.

Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.

Advise patients that smoking tobacco may reduce the efficacy of POMALYST.

Inform patients on how to take POMALYST

• POMALYST should be taken once daily at about the same time each day.
• Patients on hemodialysis should take POMALYST following hemodialysis, on hemodialysis days.
• POMALYST may be taken with or without food.
• The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water.
• Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed.

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 100fold 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.

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 Celgene Corporation at 1-888-4235436.

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. 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. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

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.

Animal Data

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 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 Cmax at all dosages (5 to 250 mg/kg/day), indicating that pomalidomide crossed the placenta.

There is no information regarding the presence of pomalidomide in human milk, the effects of POMALYST on the breastfed infant, or the effects of POMALYST on milk production. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from POMALYST, advise a nursing woman to discontinue breastfeeding during treatment with POMALYST.

Animal Data

Following a single oral administration of pomalidomide to lactating rats approximately 14 days postpartum, pomalidomide was transferred into milk, with milk to plasma ratios of 0.63 to 1.46.

POMALYST can cause fetal harm when administered during pregnancy. Verify the pregnancy status of females of reproductive potential prior to initiating POMALYST therapy and for at least 4 weeks after completing therapy. Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST.

Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. 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. POMALYST treatment must be discontinued during this evaluation.

Females

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 POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST 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.

Males

Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

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

Safety and effectiveness have not been established in pediatric patients.

No dosage adjustment is required for POMALYST based on age.

Of the total number of patients in clinical studies of POMALYST, 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.

In patients with severe renal impairment requiring dialysis, the AUC of pomalidomide increased by 38% and the rate of SAE increased by 64% relative to patients with normal renal function; therefore, starting dose adjustment is recommended. For patients with severe renal impairment requiring dialysis, POMALYST should be administered after the completion of hemodialysis on dialysis days because exposure of pomalidomide could be significantly decreased during dialysis.

Pomalidomide is metabolized primarily by the liver. Following single dose administration, the AUC of pomalidomide increased 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 compared to subjects with normal liver function. Dose adjustment is recommended in patients with hepatic impairment.

Cigarette smoking reduces pomalidomide AUC by 32% due to CYP1A2 induction. Advise patients that smoking may reduce the efficacy of pomalidomide.

Dosage (Posology) and method of administration

Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST.

The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST should be given in combination with dexamethasone.

POMALYST may be taken with water. Inform patients not to break, chew, or open the capsules. POMALYST may be taken with or without food.

Table 1:Dose Modification Instructions for POMALYST for Hematologic Toxicities

To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL and the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST.

Permanently discontinue POMALYST for angioedema, 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.

Avoid concomitant use of POMALYST with strong inhibitors of CYP1A2. Consider alternative treatments. If a strong CYP1A2 inhibitor must be used, reduce POMALYST dose by 50%.

For patients with severe renal impairment requiring dialysis, the recommended starting dose is 3 mg daily (25% dose reduction). Take POMALYST after completion of dialysis procedure on hemodialysis days..

For patients with mild or moderate hepatic impairment (Child-Pugh classes A or B), the recommended starting dose is 3 mg daily (25% dose reduction). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose is 2 mg (50% dose reduction).

Interaction with other medicinal products and other forms of interaction

The following adverse reactions are described in detail in other labeling sections:

• Fetal Risk
• Venous and Arterial Thromboembolism
• Increased Mortality in Multiple Myeloma when Pembrolizumab Is Added to Dexamethasone and a Thalidomide Analogue
• Hematologic Toxicity
• Hepatotoxicity
• Hypersensitivity Reactions
• Dizziness and Confusional State
• Neuropathy
• Risk of Second Primary Malignancies
• Tumor Lysis Syndrome

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.

In Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dex (112 patients) or POMALYST 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 POMALYST + Low-dose Dex (300 patients) or High-dose Dexamethasone (High-dose Dex) (150 patients). 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.

Tables 2 and 3 summarize the adverse reactions reported in Trials 1 and 2, respectively.

Table 2: Adverse Reactions in Any POMALYST Treatment Arm in Trial 1*

Table 3:Adverse Reactions in Trial 2

Other adverse reactions of POMALYST in patients with multiple myeloma, 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

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

The following adverse reactions have been identified during post approval use of POMALYST. 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: Pancytopenia, tumor lysis syndrome, allergic reactions (e.g., angioedema, urticaria), elevated liver enzymes, hepatic failure (including fatal cases), hepatitis B virus reactivation, herpes zoster, gastrointestinal hemorrhage, basal cell carcinoma and squamous cell carcinoma of the skin.

Pomalidomide is primarily metabolized by CYP1A2 and CYP3A4. Pomalidomide is also a substrate for Pglycoprotein (P-gp).

In healthy volunteers, co-administration of fluvoxamine, a strong CYP1A2 inhibitor, increased Cmax and AUC of pomalidomide by 24% and 125% respectively. Increased pomalidomide exposure increases 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.