MYELOMA 5

Each hard gelatin capsule contains:
Lenalidomide………………..5mg
Excipients…………………..q.s
Approved colours used in the capsule shell.

MYELOMA 10

Each hard gelatin capsule contains:
Lenalidomide………………..10mg
Excipients…………………..q.s
Approved colours used in the capsule shell.

MYELOMA 25

Each hard gelatin capsule contains:
Lenalidomide………………..25mg
Excipients…………………..q.s
Approved colours used in the capsule shell.

Mechanism of Action

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including multiple myeloma. Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

Absorption:  Lenalidomide is rapidly absorbed following oral administration. Following single and multiple doses of LENALIDOMIDE in patients with MM or MDS the maximum plasma concentrations occurred between 0.5 and 6 hours post-dose. The single and multiple-dose pharmacokinetic disposition of lenalidomide is linear with AUC and Cmax values increasing proportionally with dose. Multiple dosing at the recommended dose regimen does not result in drug accumulation.

Systemic exposure (AUC) of lenalidomide in MM and MDS patients with normal or mild renal function (CLcr ³ 60 mL/min) is approximately 60% higher as compared to young healthy male subjects.

Administration of a single 25 mg dose of LENALIDOMIDE with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and a 50% decrease in Cmax. In the trials where the efficacy and safety were established for LENALIDOMIDE, the drug was administered without regard to food intake. LENALIDOMIDE can be administered with or without food.

Distribution: In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%.

Metabolism: Lenalidomide -undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.

Elimination: Elimination is primarily renal. Following a single oral administration of [14C]-lenalidomide (25 mg) to healthy subjects, approximately 90% and 4% of the radioactive dose is eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose is excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate.

The mean half-life of lenalidomide is 3 hours in healthy subjects and 3 to 5 hours in patients with MM, MDS or MCL.

Specific Populations

Pregnancy Category X [see Boxed Warnings and Contraindications

LENALIDOMIDE can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. LENALIDOMIDE is a thalidomide analog. 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. Lenalidomide caused thalidomide-type limb defects in monkey offspring. 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 the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Nursing mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, 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.

Females of Reproductive Potential and Males

LENALIDOMIDE can cause fetal harm when administered during pregnancy. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking LENALIDOMIDE, during dose interruptions 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 two 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 one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with LENALIDOMIDE, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of LENALIDOMIDE 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 LENALIDOMIDE. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing LENALIDOMIDE. 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, 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. LENALIDOMIDE treatment must be discontinued during this evaluation.

Males

Lenalidomide is present in the semen of males who take LENALIDOMIDE. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking LENALIDOMIDE, during dose interruptions and for up to 28 days after discontinuing LENALIDOMIDE, even if they have undergone a successful vasectomy. Male patients taking LENALIDOMIDE must not donate sperm.

Renal Impairment

Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of LENALIDOMIDE are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration].

Hepatic Impairment

No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route.

Pediatrics: Clinical data not available in patients below the age of 18 years.

Gender: The effects of gender on the pharmacokinetics of Lenalidomide has not been studied.

Race: Clinical data not available.

Multiple Myeloma : LENALIDOMIDE in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy.

Myelodysplastic Syndromes: LENALIDOMIDE is indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

Multiple Myeloma

The recommended starting dose of LENALIDOMIDE is 25 mg once daily on Days 1-21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg once daily on Days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily orally on Days 1-4 every 28 days. Treatment is continued or modified based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment:

Dose modification guidelines, as summarized below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to LENALIDOMIDE.

Platelet counts

Thrombocytopenia in MM

Absolute Neutrophil counts (ANC)

Neutropenia in MM

Other Grade 3 / 4 Toxicities in MM

For other Grade 3/4 toxicities judged to be related to LENALIDOMIDE, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2.

Myelodysplastic Syndromes

The recommended starting dose of LENALIDOMIDE is 10 mg daily.

Dose Adjustments for Hematologic Toxicities During MDS Treatment

Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows:

Absolute Neutrophil counts (ANC)

Starting Dose Adjustment for Renal Impairment in MM, MDS:

Since LENALIDOMIDE is primarily excreted unchanged by the kidney, adjustments to the starting dose of LENALIDOMIDE are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, LENALIDOMIDE starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with MM, MDS or MCL are as follows:

After initiation of LENALIDOMIDE therapy, subsequent LENALIDOMIDE dose modification is based on individual patient treatment tolerance.

Lenalidomide should never taken by pregnant women or women capable of becoming pregnant as even a single dose can cause severe birth defects or death to an unborn baby.

Embryo-Fetal Toxicity

LENALIDOMIDE is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death.

Females of Reproductive Potential

Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning LENALIDOMIDE therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.

Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with LENALIDOMIDE, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of LENALIDOMIDE 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 LENALIDOMIDE 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

Lenalidomide 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 LENALIDOMIDE and for up to 28 days after discontinuing LENALIDOMIDE, even if they have undergone a successful vasectomy. Male patients taking LENALIDOMIDE must not donate sperm [see Use in Specific Populations.

Blood Donation

Patients must not donate blood during treatment with LENALIDOMIDE 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 LENALIDOMIDE.

Hematologic toxicity

LENALIDOMIDE can cause significant neutropenia and thrombocytopenia. Patients taking LENALIDOMIDE for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking LENALIDOMIDE for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking LENALIDOMIDE for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction [see Dosage and Administration].

Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days [see Boxed Warning and Dosage and Administration].

In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of LENALIDOMIDE and dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions].

Hepatotoxicity

Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Preexisting viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop Lenalidomide upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

Venous Thromboembolism

Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS or MCL treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with LENALIDOMIDE and dexamethasone therapy in a clinical trial. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with LENALIDOMIDE may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

Allergic Reactions

Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive LENALIDOMIDE. LENALIDOMIDE interruption or discontinuation should be considered for Grade 2-3 skin rash. LENALIDOMIDE must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.

Tumor Lysis Syndrome

Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Tumor Flare Reaction

Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL with lenalidomide outside of a well-monitored clinical trial is discouraged.

Laboratory tests

A complete blood cell count (CBC) including white blood cell count with differential count, platelet count, haemoglobin should be performed weekly for the first 8 weeks of Lenalidomide treatment and monthly thereafter to monitor for cytopenias.

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis : Clinical data not available.

Mutagenesis: Lenalidomide does not induce mutation.

Fertility: Animal studies did not reveal any parental toxicity and adverse effects on fertility. Reproductive effects of lenalidomide have not been thoroughly assessed.

The structural similarity of Lenalidomide to Thalidomide, a known human teratogen, suggests a potential risk to the developing fetus.

Adverse events reported in 5% of Lenalidomide treated patients in del 5q MDS clinical study include

• Blood and Lymphatic System Disorders: Thrombocytopenia, Neutropenia, Anemia, Leukopenia, Febrile Neutropenia
• Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Dry Skin , Confusion, Night Sweats, Sweating, Increased Ecchymosis, Erythema
• Gastrointestinal Disorders: Diarrhoea, Constipation, Nausea, Abdominal Pain, Vomiting, Abdominal Pain Upper, Dry Mouth, Loose Stools
• Respiratory, Thoracic and Mediastinal Disorders: Nasopharyngitis, Cough, Dyspnea, Pharyngitis, Epistaxis, Dyspnea Exertional, Rhinitis, Bronchitis
• General Disorders and Administration Site Conditions: Fatigue, Pyrexia, Edema Periphera, Asthenia, Edema, Pain, Rigors, Chest Pain
• Musculoskeletal and Connective Tissue Disorders: Arthralgia, Back Pain, Muscle Cramp, Pain in Limb, Myalgia, Peripheral Swelling
• Nervous System Disorders: Dizziness, Headache, Hypoesthesia, Dysgeusia, Peripheral Neuropathy
• Infections and Infestations: Upper Respiratory Tract Infection, Pneumonia, Urinary Tract Infection, Sinusitis, Cellulitis
• Metabolism and Nutrition Disorders: Hypokalemia, Anorexia, Hypomagnesemia
• Psychiatric Disorders: Insomnia, Depression
• Renal and Urinary Disorders: Dysuria
• Vascular Disorders: Hypertension
• Endocrine Disorders: Acquired Hypothyroidism

Most frequently observed grade 3 & 4 adverse events include: Neutropenia, Thrombocytopenia, rash, anemia, pneumonia, leucopenia

LENALIDOMIDE is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions.

• Digoxin: When digoxin was co-administered with multiple doses of LENALIDOMIDE (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of LENALIDOMIDE.
• Warfarin: Co-administration of multiple dose LENALIDOMIDE (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant LENALIDOMIDE administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin.
• Concomitant Therapies That May Increase the Risk of Thrombosis: Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone.

Pregnancy

LENALIDOMIDE can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. 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 the fetus.

Hypersensitivity

LENALIDOMIDE is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.

Clinical data is not available.

PRESENTATION

MYELOMA 5 – Bottle containing 10 capsules.

MYELOMA 10 – Bottle containing 10 capsules.

MYELOMA 25 – Bottle containing 10 capsules.

STORAGE

Store between 15^oC to 30^oC. Protect from light.

Keep out of reach of children.