Pomalidomide

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# Black Box Warning

# Overview
Pomalidomide is an antineoplastic agent that is FDA approved for the treatment of multiple myeloma. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include peripheral edema, rash, hypercalcemia,constipation, diarrhea, nausea, anemia,neutropenia,thrombocytopenia,dizziness.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
Multiple Myeloma
- Pomalidomide is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

# Dosage
Multiple Myeloma
- Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating Pomalidomide.
- The recommended starting dose of Pomalidomide is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. Pomalidomide may be given in combination with dexamethasone.
- Pomalidomide may be taken with water. Inform patients not to break, chew, or open the capsules. Pomalidomide should be taken without food (at least 2 hours before or 2 hours after a meal).
Dose Adjustments for Toxicities
- 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 physicians discretion.
- To initiate a new cycle of Pomalidomide  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 Pomalidomide.
Dose Adjustment for Strong CYP1A2 Inhibitors in the Presence of Strong CYP3A4 and P-gp Inhibitors
- Avoid co-administration of strong inhibitors of CYP1A2. If necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce Pomalidomide dose by 50%. No clinical efficacy or safety data exist.

# DOSAGE FORMS AND STRENGTHS
- Pomalidomide 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

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pomalidomide in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Pomalidomide in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pomalidomide in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pomalidomide in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Pomalidomide in pediatric patients.

# Contraindications
Pregnancy
Pomalidomide can cause fetal harm when administered to a pregnant female. Pomalidomide 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 hazard to a fetus.

# Warnings
Embryo-Fetal Toxicity
Pomalidomide 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. Pomalidomide is only available through the Pomalidomide REMS program.
Females of Reproductive Potential
- Females of reproductive potential must avoid pregnancy while taking Pomalidomide 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 Pomalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Pomalidomide 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 Pomalidomide therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles, or every 2 weeks in women with irregular menstrual cycles.
Males
- 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 Pomalidomide and for up to 28 days after discontinuing Pomalidomide, even if they have undergone a successful vasectomy. Male patients taking Pomalidomide must not donate sperm.
Blood Donation
- Patients must not donate blood during treatment with Pomalidomide 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 Pomalidomide.
Pomalidomide REMSTM Program
- Because of the embryo-fetal risk, Pomalidomide is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Pomalidomide REMS.
- Required components of the Pomalidomide REMS program include the following:
- Prescribers must be certified with the Pomalidomide REMS program by enrolling and complying with the REMS requirements.
- Patients must sign a Patient-Prescriber 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 Pomalidomide REMS program, must only dispense to patients who are authorized to receive Pomalidomide and comply with REMS requirements.
Further information about the Pomalidomide REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.
Venous Thromboembolism
- Patients receiving Pomalidomide have developed venous thromboembolic events (VTEs) (venous thromboembolism) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patients underlying risk factors.
Hematologic Toxicity
- Neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%.
- 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.
Hypersensitivity Reactions
- Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.
Dizziness and Confusional State
- In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced Grade 3/4 dizziness, and 3% of patients experienced Grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and to not take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy
- In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of Grade 3 or higher neuropathy adverse reactions reported.
Risk of Second Primary Malignancies
- Cases of acute myelogenous leukemia have been reported in patients receiving Pomalidomide as an investigational therapy outside of multiple myeloma.
Tumor Lysis Syndrome
- 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.

# Adverse Reactions

## Clinical Trials Experience
- The following adverse reactions are described in detail in other labeling sections:
- Fetal Risk
- Venous Thromboembolism
- Hematologic Toxicity
- Hypersensitivity Reactions
- Dizziness and Confusional State
- Neuropathy
- Risk of Second Primary Malignancies
- Tumor Lysis Syndrome
Clinical Trials Experience in Multiple Myeloma
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In Clinical Trial 1, data were evaluated from 219 patients (safety population) who received treatment with Pomalidomide + Low-dose Dexamethasone (Low-dose Dex) (112 patients) or Pomalidomide alone (107 patients). Median number of treatment cycles was 5. Sixty-three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty-seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%.
- TABLES 2, 3, and 4 summarize all treatment-emergent adverse reactions reported for the Pomalidomide + Low-dose Dex and Pomalidomide alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug related and those that reflect the patients underlying disease.
Other Adverse Reactions
- Other adverse reactions of Pomalidomide in patients with multiple myeloma, not described above, and considered important:
- Ear and labyrinth disorders: vertigo
- Hepatobiliary disorders: hyperbilirubinemia
- Infections and infestations: Pneumocystis jiroveci pneumonia, respiratory syncytial virus infection, neutropenic sepsis
- Investigations: Alanine aminotransferase increased
- Metabolism and nutritional disorders: hyperkalemia
- Renal and urinary disorders: urinary retention
- Reproductive system and breast disorders: Pelvic pain
- Respiratory, thoracic and mediastinal disorders: Interstitial lung disease

## Postmarketing Experience
- The following adverse drug reactions have been identified from the worldwide post-marketing experience with Pomalidomide: pancytopenia, tumor lysis syndrome.
- 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.

# Drug Interactions
- Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp).
Drugs That May Increase Pomalidomide Plasma Concentrations
- CYP1A2 inhibitors: Pomalidomide exposure is increased when Pomalidomide is co-administered with a strong CYP1A2 inhibitor (fluvoxamine) in the presence of a strong CYP3A4/5 and P-gp inhibitor (ketoconazole). Ketoconazole in the absence of a CYP1A2 inhibitor does not increase pomalidomide exposure. Avoid co-administration of strong CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine). If it is medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, Pomalidomide dose should be reduced by 50%.
The effect of a CYP1A2 inhibitor in the absence of a co-administered CYP3A4 and P-gp inhibitor has not been studied. Monitor for toxicities if CYP1A2 inhibitors are to be co-administered in the absence of a co-administered CYP3A4 and P-gp inhibitor, and reduce dose if needed.
Drugs That May Decrease Pomalidomide Plasma Concentrations
- Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.
- CYP1A2 inducers: Co-administration of Pomalidomide with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Pregnancy Category X
Risk Summary
- Pomalidomide can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Pomalidomide 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. 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 hazard 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 Pomalidomide to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pomalidomide in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Pomalidomide during labor and delivery.

### Nursing Mothers
- It is not known if pomalidomide is excreted in human milk. 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 nursing infants from Pomalidomide  a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
- Safety and effectiveness of Pomalidomide in patients below the age of 18 years have not been established.

### Geriatic Use
- No dosage adjustment is required for Pomalidomide based on age.
- Of the total number of patients in clinical studies of Pomalidomide  41% were aged 65 years and older, while 12% were aged 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients aged greater than or equal to 65 years were more likely to experience pneumonia than patients aged less than or equal to 65 years.

### Gender
Females of Reproductive Potential and Males
- Pomalidomide can cause fetal harm when administered during pregnancy. Females of reproductive potential must avoid pregnancy while taking Pomalidomide and for at least 4 weeks after completing therapy.
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 partners 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  during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of Pomalidomide 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.
- Females of reproductive potential must have 2 negative pregnancy tests before initiating Pomalidomide. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing Pomalidomide  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 treatment must be discontinued during this evaluation.
Males
- Pomalidomide is present in the semen of males who take Pomalidomide  Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Pomalidomide and for up to 28 days after discontinuing Pomalidomide, even if they have undergone a successful vasectomy. Male patients taking Pomalidomide must not donate sperm.

### Race
There is no FDA guidance on the use of Pomalidomide with respect to specific racial populations.

### Renal Impairment
- Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid Pomalidomide in patients with a serum creatinine greater than 3.0 mg/dL.

### Hepatic Impairment
- Pomalidomide is metabolized in the liver. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid Pomalidomide in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pomalidomide in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Pomalidomide in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
There is limited information regarding Monitoring of Pomalidomide in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Pomalidomide in the drug label.

# Overdosage
- No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

# Pharmacology

## 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 (eg, TNF- and IL-6) by monocytes. Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.

## Structure
- Pomalidomide is an immunomodulatory antineoplastic agent. The chemical name is (RS)-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione and it has the following chemical structure:
- The empirical formula for pomalidomide is C13H11N3O4 and the gram molecular weight is 273.24.
- Pomalidomide is a yellow solid powder.  It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL).  Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S(-) enantiomers.
- Pomalidomide is available in 1-mg, 2-mg, 3-mg, and 4-mg capsules for oral administration. Each capsule contains pomalidomide as the active ingredient and the following inactive ingredients: mannitol, pregelatinized starch, and sodium stearyl fumarate. The 1-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink, and black ink. The 2-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, FD&C red 3, and white ink. The 3-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, and white ink. The 4-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 1, FD&C blue 2, and white ink.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pomalidomide in the drug label.

## Pharmacokinetics
Absorption
- Following administration of single oral doses of Pomalidomide  the maximum plasma concentration (Cmax) for pomalidomide occurs at 2 and 3 hours postdose. The systemic exposure (AUC) of pomalidomide increases in an approximately dose proportional manner.
- In patients with multiple myeloma who received Pomalidomide 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC() of 400 ngh/mL and Cmax of 75 ng/mL. Following multiple doses, pomalidomide has an accumulation ratio of 27% to 31%.
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-glycoprotein (P-gp).
Metabolism
- Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. In vitro, CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and CYP2D6.
Elimination
- 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. Pomalidomide has a mean total body clearance (CL/F) of 7-10 L/h.
- Following a single oral administration of -pomalidomide (2 mg) 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.
Drug Interactions
Drugs that Inhibit Pomalidomide Metabolism
- CYP1A2 Inhibitors: The effect of CYP1A2 inhibitors, in the absence of a co-administered CYP3A4 and P-gp inhibitor, is unknown. However, co-administration of fluvoxamine (a strong CYP1A2 inhibitor) in the presence of ketoconazole (a strong CYP3A4 and P-gp inhibitor) to 12 healthy male subjects increased exposure (geometric mean AUCINF) to pomalidomide by 146% compared to pomalidomide administered alone.
- Strong CYP3A4 and P-glycoprotein (P-gp) Inhibitors: Co-administration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) in 16 healthy male subjects resulted in an increased exposure (geometric mean AUCINF) to pomalidomide of 19% compared to pomalidomide administered alone.
Drugs that Induce Pomalidomide Metabolism
- Strong CYP1A2 Inducers: Co-administration of Pomalidomide 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 exposure (geometric mean AUCINF) to pomalidomide by 21% compared to pomalidomide administered alone.
- Dexamethasone: Co-administration of multiple doses of 4 mg Pomalidomide 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 with pomalidomide administered alone.
- In Vitro Inhibition of Drug Metabolizing Enzymes and Transporters by Pomalidomide
- Pomalidomide does not inhibit or induce CYP450 enzymes or transporters in vitro.

## Nonclinical Toxicology
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.

# Clinical Studies
Multiple Myeloma
- Trial 1 was a phase 2, multicenter, randomized open-label study in patients with relapsed multiple myeloma who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. Patients were considered relapsed if they had achieved at least stable disease for at least 1 cycle of treatment to at least 1 prior regimen and then developed progressive disease. Patients were considered refractory if they experienced disease progression on or within 60 days of their last therapy. A total of 221 patients were randomized to receive Pomalidomide alone or Pomalidomide with Low-dose Dex. In Trial 1, the safety and efficacy of Pomalidomide 4 mg, once daily for 21 of 28 days, until disease progression, were evaluated alone and in combination with Low-dose Dex (40 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged 75 years or younger, or 20 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged greater than 75 years). Patients in the Pomalidomide alone arm were allowed to add Low-dose Dex upon disease progression.
- Table 5 summarizes the baseline patient and disease characteristics in Trial 1. The baseline demographics and disease characteristics were balanced and comparable between the study arms.
- Table 6 summarizes the analysis results of overall response rate (ORR) and duration of response (DOR), based on assessments by the Independent Review Adjudication Committee for the treatment arms in Study 1. ORR did not differ based on type of prior anti-myeloma therapy.

# How Supplied
- 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
1 mg bottles of 21        (NDC 59572-501-21) 
1 mg bottles of 100      (NDC 59572-501-00)
- Dark blue opaque cap and orange opaque body, imprinted POML on the cap and 2 mg on the body in white ink
2 mg bottles of 21        (NDC 59572-502-21) 
2 mg bottles of 100      (NDC 59572-502-00)
- Dark blue opaque cap and green opaque body, imprinted POML on the cap and 3 mg on the body in white ink
3 mg bottles of 21        (NDC 59572-503-21) 
3 mg bottles of 100      (NDC 59572-503-00)
- Dark blue opaque cap and blue opaque body, imprinted POML on the cap and 4 mg on the body in white ink
4 mg bottles of 21        (NDC 59572-504-21) 
4 mg bottles of 100      (NDC 59572-504-00)

## Storage
- Store at 20C-25C (68F-77F); excursions permitted to 15C-30C (59F-86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Embryo-Fetal Toxicity
- Advise females of reproductive potential that they must avoid pregnancy while taking Pomalidomide and for at least 4 weeks after completing therapy.
- Initiate Pomalidomide 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 Pomalidomide therapy, during therapy interruption, and for 4 weeks after she has completely finished taking Pomalidomide  Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch, or implants) and a partners vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm, and cervical cap.
- Instruct patient to immediately stop taking Pomalidomide and contact her doctor 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 doctor is not available, she can call 1-888-668-2528 for information on emergency contraception.
- Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Pomalidomide and for up to 28 days after discontinuing Pomalidomide, even if they have undergone a successful vasectomy.
Advise male patients taking Pomalidomide that they must not donate sperm.
- All patients must be instructed to not donate blood while taking Pomalidomide and for 1 month following discontinuation of Pomalidomide.
Pomalidomide REMS Program
- Because of the risk of embryo-fetal toxicity, Pomalidomide is only available through a restricted program called Pomalidomide REMS.
- Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive Pomalidomide  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.
- Pomalidomide is available only from pharmacies that are certified in Pomalidomide REMS. Provide patients with the telephone number and Web site for information on how to obtain the product.
Venous Thromboembolism
- Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment.
Hematologic Toxicities
- 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.
Hypersensitivity
- Inform patients of the potential for a severe hypersensitivity reaction to Pomalidomide if they have had such a reaction in the past to either THALOMID or REVLIMID.
Dizziness and Confusional State
- 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.
Neuropathy
- 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 .
Second Primary Malignancies
- Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with Pomalidomide is unknown.
Tumor Lysis Syndrome
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.
Dosing Instructions
- Inform patients on how to take Pomalidomide
- Pomalidomide should be taken once daily at about the same time each day.
- Pomalidomide should be taken without food (at least 2 hours before or 2 hours after a meal).
- The capsules should not be opened, broken, or chewed. Pomalidomide should be swallowed whole with water.
- Instruct patients that if they miss a dose of Pomalidomide  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 Pomalidomide at the usual time. Warn patients not to take 2 doses to make up for the one that they missed.
Other Information
Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide.

# Precautions with Alcohol
- Alcohol-Pomalidomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- POMALYST

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price