Pomalyst

Pomalyst may cause serious side effects, including:

• see "Drug Precautions"
• low white blood cells (neutropenia), low platelets (thrombocytopenia) and low red blood cells (anemia)

The most common side effects of Pomalyst include:

• tiredness and weakness
• constipation
• shortness of breath
• diarrhea
• fever
• back pain
• nausea

This is not a complete list of Pomalyst side effects.  Ask your doctor or pharmacist for more information.

Before receiving Pomalyst, tell your doctor about all of your medical conditions including if you:

• are allergic to thalidomide (Thalomid) or lenalidomide (Revlimid)
• smoke cigarettes
• are breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Store Pomalyst at room temperature, between 59° and 86°F.

Return unused medication to the manufacturer or your healthcare provider.

Keep this and all medications out of the reach of children.

Never use pomalidomide if you are pregnant. Even one dose of pomalidomide can cause severe, life-threatening birth defects or death of a baby if the mother or the father is taking this medicine at the time of conception or during pregnancy.

Use birth control to prevent pregnancy, whether you are a man or a woman. For women: Use two forms of birth control beginning 4 weeks before you start taking pomalidomide and ending 4 weeks after you stop taking it. For men: Use a condom to prevent pregnancy during your treatment, and for up to 28 days after your treatment ends.

Pomalidomide may cause blood clots. Stop using pomalidomide and call your doctor at once if you have symptoms such as chest pain, wheezing, coughing up blood, or if you have pain, swelling, warmth, or redness in one or both legs.

General

• Carefully monitor CBCs during therapy.1 (See Hematologic Effects under Cautions.)

• Do not begin a new treatment cycle until ANC ≥500/mm3 and platelet count ≥50,000/mm3.1

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Restricted Distribution Program

• Distribution of pomalidomide is restricted because it is an analog of thalidomide (a known human teratogen that can cause severe birth defects).1 2 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Must be obtained through a restricted distribution program (Pomalyst Risk Evaluation and Mitigation Strategy [REMS]) to help ensure that fetal exposure to pomalidomide does not occur.1 2 Clinicians, pharmacists, and patients must be registered in the program before they can prescribe, dispense, and receive pomalidomide; compliance with all terms outlined in the program is mandatory.1 2

• The Pomalyst REMS program controls access to pomalidomide; educates participants (clinicians, pharmacists, patients) about the risks associated with pomalidomide and the procedural requirements for safe use; and monitors compliance with the registration, education, and safety requirements of the program.2

• For additional details on program requirements, contact Celgene at 888-423-5436 or visit .1

Administration

Oral Administration

Administer orally with water once daily.1

Administer at least 2 hours before or 2 hours after a meal.1

Swallow capsules whole; do not break, chew, or open capsules.1

Prescribe and dispense no more than a 28-day supply at one time.2

Avoid contact of capsule contents with skin or mucous membranes.1 If such contact occurs, wash affected areas of skin thoroughly with soap and water and rinse affected mucosa thoroughly with water.1

Dosage

Adults

4 mg once daily on days 1–21 of each 28-day cycle; may be used in combination with low-dose dexamethasone (40 mg once daily on days 1, 8, 15, and 22 of each 28-day cycle used in clinical trials).1 15

In the pivotal trial, treatment could be continued until disease progression or unacceptable toxicity occurred.1

Adjust dosage in decrements of 1 mg daily.1

If dosage of 1 mg daily is not tolerated, discontinue therapy.1

For first occurrence of neutropenia (ANC <500/mm3), febrile neutropenia (temperature ≥38.5°C and ANC <1000/mm3), or thrombocytopenia (platelet count <25,000/mm3), withhold therapy and monitor CBC weekly.1 When ANC is ≥500/mm3 and platelet count is ≥50,000/mm3, may resume therapy at reduced dosage of 3 mg daily.1

For subsequent occurrences of neutropenia (ANC <500/mm3) or thrombocytopenia (platelet count <25,000/mm3), interrupt therapy until ANC is ≥500/mm3 and platelet count is ≥50,000/mm3; when resuming therapy following recovery, further reduce dosage by 1 mg daily.1 (See Hematologic Effects under Cautions.)

If grade 3 or 4 toxicities other than neutropenia or thrombocytopenia occur, interrupt therapy until symptoms improve to grade ≤2; resume therapy at reduced dosage of 1 mg daily less than previous dosage.1

Special Populations

Hepatic Impairment

Avoid use in patients with ALT and/or AST >3 times ULN and bilirubin >2 mg/dL.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Avoid use in patients with Scr >3 mg/dL.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No pomalidomide dosage adjustment required.1 Concomitant dexamethasone dosage reduced to 20 mg once daily on days 1, 8, 15, and 22 of each 28-day cycle in patients >75 years of age in multiple myeloma trials.1 15

Absorption

Bioavailability

Peak plasma pomalidomide concentrations are attained about 2–3 hours after oral administration.1

AUC increases in an approximately dose-proportional manner.1

Distribution

Extent

Not known whether pomalidomide is distributed into human milk.1

Distributed into semen.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Plasma Protein Binding

12–44%.1

Elimination

Metabolism

Metabolized primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6.1 13

Elimination Route

Excreted in urine (73%) and feces (15%); minimal amounts of dose are recovered in urine and feces as unchanged drug.1 13 16

Half-life

In healthy individuals, median half-life approximately 9.5 hours.1

In patients with multiple myeloma, median half-life approximately 7.5 hours.1 13 16

In the U.S.

• Pomalyst

Available Dosage Forms:

• Capsule

Use Pomalyst as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Take with a full glass of water.
• Take this medicine at the same time of day.
• Swallow whole. Do not chew, break, or crush.
• Do not open the capsules.
• If you touch a broken capsule, or the drug inside the capsule, wash the area with soap and water.
• If a broken capsule or the drug inside the capsule touches your eyes, rinse your eyes right away with water.
• If you are on dialysis and are taking Pomalyst on the day you get dialysis, take it after your dialysis. If you have questions, talk with your doctor.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it and go back to your normal time.
• If it has been 12 hours or more since the missed dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Multiple Myeloma

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.

Mechanism of Action

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

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 4 and 20 mg.

Pharmacokinetics

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%).

Absorption

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.

Distribution

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.

Elimination

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.

Specific Populations

Age (61 to 85 years old), sex and race had no clinically significant effect on the systemic exposure of pomalidomide. The pharmacokinetics of pomalidomide is unknown in pediatric patients.

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

Hepatic Impairment: Mean exposure (AUC) increased by 51%, 58% and 72% in subjects with mild, moderate or severe hepatic impairment as defined by Child-Pugh criteria, respectively.

Drug Interaction Studies

Co-administration of Pomalyst with the following drugs did not increase pomalidomide exposure to a clinically significant extent: ketoconazole (a strong CYP3A4 and P-gp inhibitor), carbamazepine (a strong CYP3A4 inducer) and dexamethasone (a weak to moderate inducer of CYP3A4). Co-administration of Pomalyst with drugs that are CYP1A2 inducers has not been studied.

CYP1A2 Inhibitors: Co-administration of fluvoxamine (a strong CYP1A2 inhibitor) with Pomalyst increased mean [90% confidence interval] pomalidomide exposure by 125% [98% to 157%] compared to Pomalyst alone in healthy subjects. Co-administration of fluvoxamine in the presence of ketoconazole (a strong CYP3A4 and P-gp inhibitor) with Pomalyst increased mean pomalidomide exposure by 146% [126% to 167%] compared to Pomalyst administered alone in healthy subjects, indicating the predominant effect of CYP1A2 inhibition in the increase of pomalidomide exposure [see Dosage and Administration (2.2) and Drug Interactions (7.1)].

Strong 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 Pomalyst administered alone.

Drugs that Induce Pomalidomide Metabolism

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

Strong 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.

Dexamethasone: Co-administration of multiple doses of 4 mg Pomalyst with 20 mg to 40 mg dexamethasone (a weak to moderate inducer of CYP3A4) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared to when pomalidomide was administered alone.

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

In Vitro Studies

Pomalidomide does not inhibit or induce CYP450 enzymes or transporters in vitro.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 12 monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study.

Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes, and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.

In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males in this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.

Never use Pomalyst if you are pregnant. Even one dose of pomalidomide can cause severe, life-threatening birth defects or death of a baby if the mother or the father is taking this medicine at the time of conception or during pregnancy.

Use birth control to prevent pregnancy, whether you are a man or a woman. For women: Use two forms of birth control beginning 4 weeks before you start taking Pomalyst and ending 4 weeks after you stop taking it. For men: Use a condom to prevent pregnancy during your treatment, and for up to 28 days after your treatment ends.

Pomalyst may cause blood clots. Stop using Pomalyst and call your doctor at once if you have symptoms such as chest pain, wheezing, coughing up blood, or if you have pain, swelling, warmth, or redness in one or both legs.

Taking Pomalyst with other drugs that cause dizziness or confusion can worsen these effects. Ask your doctor before taking Pomalyst with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Other drugs may interact with pomalidomide, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.