POMALIDOMIDE BIOPHARM

Pomalidomide, an analogue of thalidomide, is an immunomodulatory antineoplastic agent.

FDA approved on

February 8, 2013.

Pomalidomide is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and have demonstrated disease progression on or within 60 days of completion of the last therapy.

It is also indicated for the treatment of Kaposi's sarcoma (KS) in AIDS patients who have failed highly active antiretroviral therapy (HAART) and for the treatment of KS in HIV-negative patients.

Pomalidomide is more potent than thalidomide (100-times) and lenalidomide (10-times).

Protein cereblon Inhibitor Tumor necrosis factor Inhibitor Prostaglandin G/H synthase 2 Inhibitor.

Pomalidomide is generally well absorbed.

The major circulating component is the parent compound.

Tmax, single oral dose = 2-3 hours.

When 4 mg of promalidomide is given to patients with multiple myeloma, the steady-state pharmacokinetic parameters are as follows: AUC(T) = 400 ng.hr/mL Cmax = 75 ng/mL.

Promalidomide accumulates following multiple doses.

Mean apparent volume of distribution (Vd/F), steady-state = 62-138 L.

Promalidomide is hepatically metabolized by

The metabolites are 26-fold less active than the parent compound.

Minor contributions from

CYP2C19 and CYP2D6 have been observed in vitro.

When a single oral dose (2 mg) is given to healthy subjects, 73% of the dose was eliminated in urine. 15% of the dose was eliminated in feces. 2% and 8% of the dose eliminated unchanged as pomalidomide in urine and feces, respectively.

Healthy subjects = 9.4 hours Multiple myeloma patients = 7.5 hours.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

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

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.