LENMID Capsules (Lenalidomide)

Table of Content

Multiple myeloma is a cancer of plasma cells, a type of white blood cell responsible for producing antibodies. It is the 2nd most common form of haematological malignancy after non-Hodgkin lymphoma.

Myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production (or dysplasia) of the myeloid class of blood cells.

Lenalidomide is a derivative of thalidomide, a novel immunomodulator indicated for the treatment of relapsed/refractory multiple myeloma at the dose of 25 mg once-daily on days 1-21 of repeated 28-day cycles. It is also indicated for the treatment of patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities at the dose of 10 mg daily. Lenalidomide can cause fetal harm when administered to a pregnant female and is therefore, contraindicated in pregnancy.

To be sold by retail on prescription of Oncologist only

Black Box Warning

Embryo-Fetal Toxicity, Hematologic Toxicity, And Venous and Arterial Thromboembolism

Embryo-Fetal Toxicity

Do not use Lenalidomide during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting lenalidomide treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after lenalidomide treatment.

Lenalidomide should never be 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.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

Lenalidomide can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism

Lenalidomide has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with Lenalidomide and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

1. Generic Name

Lenalidomide Capsules 5/10/25 mg

2. Qualitative and Quantitative Composition

LENMID 5 Capsules

Each Hard Gelatin Capsule contains

Lenalidomide ….5mg

Approved colour used in the capsule shell.

LENMID 10 Capsules

Each Hard Gelatin Capsule contains:

Lenalidomide ….10 mg

Approved colour used in the capsule shell.

LENMID 25 Capsules

Each Hard Gelatin Capsule contains

Lenalidomide ….25mg

Approved colour used in the capsule shell.

3. Dosage Form and Strength

Hard Gelatin Capsule 5/10/25 mg

4. Clinical Particulars

4.1 Therapeutic Indication

Multiple Myeloma (MM)

LENMID is indicated in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy.

Myelodysplastic Syndromes (MDS)

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

4.2 Posology and Method of Administration

LENMID treatment should be supervised by a physician experienced in the use of anti-cancer therapies.

For all indications described below

Dose is modified based upon clinical and laboratory findings.

Dose adjustments, during treatment and restart of treatment, are recommended to manage Grade 3 or 4 thrombocytopenia, neutropenia, or other Grade 3 or 4 toxicity judged to be related to lenalidomide.

In case of neutropenia, the use of growth factors in patient management should be considered.

If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next dose at the normal time on the following day.

Recommended Dosage for Multiple Myeloma

The recommended starting dose of LENMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg orally once daily on Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. For patients greater than 75 years old, the starting dose of dexamethasone may be reduced. Treatment should be continued until disease progression or unacceptable toxicity.

Prescribing physicians should carefully evaluate which dose of dexamethasone to use, taking into account the condition and disease status of the patient.

Dose Adjustments for Hematologic Toxicities for MM

Dose modification guidelines, as summarized in Table below, are recommended to manage grade 3 or 4 neutropenia or thrombocytopenia or other grade 3 or 4 toxicity, which are judged to be related to lenalidomide.

Platelet counts: Thrombocytopenia in MM

When Platelets

Recommended Course

Days 1-21 of repeated 28-day cycle

Fall to <30,000/mcL

 

Return to ≥30,000/mcL

Interrupt LENMID treatment, follow CBC weekly.

 

Resume LENMID at next lower dose. Do not dose below 2.5 mg daily

For each subsequent drop <30,000/mcL

 

Return to ≥30,000/mcL

Interrupt LENMID treatment

 

Resume LENMID at next lower dose. Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC): Neutropenia in MM

When Neutrophils

Recommended Course

Days 1-21 of repeated 28-day cycle

Fall to <1000/mcL

 

Return to ≥1,000/mcL and neutropenia is the only toxicity

Interrupt LENMID treatment, follow CBC weekly.

 

Resume LENMID at 25 mg daily or initial starting dose.

Return to ≥1,000/mcL and if other toxicity

Resume LENMID at next lower dose. Do not dose below 2.5 mg daily.

For each subsequent drop <1,000/mcL

 

Return to ≥1,000/mcL

Interrupt LENMID treatment.

 

Resume LENMID at next lower dose. Do not dose below 2.5 mg daily.

At the physician's discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide.

Recommended Dosage for Myelodysplastic Syndromes

Lenalidomide treatment must not be started if the ANC < 0.5 x 109/L and/or platelet counts < 25 x 109/L.

The recommended starting dose of lenalidomide is 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment until disease progression or unacceptable toxicity.

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:

Platelet counts

If thrombocytopenia develops within 4 weeks of starting treatment at 10 mg daily in MDS

If baseline ≥100,000/mcL

When Platelets

 Recommended Course

Fall to <50,000/mcL

Return to ≥50,000/mcL

Interrupt LENMID treatment

Resume LENMID at 5 mg daily

If baseline <100,000/mcL

When Platelets

 Recommended Course

Fall to 50% of the baseline value

If baseline ≥60,000/mcL and returns to ≥50,000/mcL

If baseline <60,000/mcL and returns to ≥30,000/mcL

Interrupt LENMID treatment

 

Resume LENMID at 5 mg daily

 

Resume LENMID at 5 mg daily

If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Platelets

Recommended Course

<30,000/mcL or <50,000/mcL with platelet transfusions

Return to ≥30,000/mcL (without hemostatic failure)

Interrupt LENMID treatment

 

Resume LENMID at 5 mg daily

Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows:

If thrombocytopenia develops during treatment at 5 mg daily in MDS

When Platelets

Recommended Course

<30,000/mcL or <50,000/mcL

with platelet transfusions

Return to ≥30,000/mcL(without hemostatic failure)

Interrupt LENMID treatment

 

Resume LENMID at 2.5 mg daily

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

Absolute Neutrophil counts (ANC)

If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline ANC ≥1,000/mcL

 

When Neutrophils

 Recommended Course

Fall to <750/mcL

Return to ≥1,000/mcL

Interrupt LENMID treatment

Resume LENMID at 5 mg daily

If baseline ANC <1,000/mcL

 

When Neutrophils

 Recommended Course

Fall to <500/mcL

Return to ≥500/mcL

Interrupt LENMID treatment

Resume LENMID at 5 mg daily

If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Neutrophils

 Recommended Course

<500/mcL for ≥7 days or <500/mcL

associated with fever (≥38.5°C)

Return to ≥500/mcL

Interrupt LENMID treatment

 

Resume LENMID at 5 mg daily

Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows:

If neutropenia develops during treatment at 5 mg daily in MDS

When Neutrophils

 Recommended Course

<500/mcL for ≥7 days or <500/mcL

associated with fever (≥38.5°C)

Return to ≥500/mcL

Interrupt LENMID treatment

 

Resume LENMID at 2.5 mg daily

Dosage Modifications for Non-Hematologic Adverse Reactions

For non-hematologic Grade 3/4 toxicities judged to be related to LENMID, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has resolved to Grade 2 or below.

Lenalidomide interruption or discontinuation should be considered for Grade 2 or 3 skin rash. Lenalidomide must be discontinued for angioedema, anaphylactic reaction, Grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected and should not be resumed following discontinuation from these reactions.

Special Populations

Paediatric Population

Lenalidomide should not be used in children and adolescents from birth to less than 18 years because of safety concerns.

Elderly

Lenalidomide has been used in clinical trials in multiple myeloma patients up to 91 years of age, in myelodysplastic syndromes patients up to 95 years of age and in mantle cell lymphoma patients up to 88 years of age.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it would be prudent to monitor renal function.

Multiple Myeloma: Patients with At Least One Prior Therapy

The percentage of multiple myeloma patients aged 65 or over was not significantly different between the lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in safety or efficacy was observed between these patients and younger patients, but greater pre-disposition of older individuals cannot be ruled out.

Myelodysplastic Syndromes

For myelodysplastic syndromes patients treated with lenalidomide, no overall difference in safety and efficacy was observed between patients aged over 65 and younger patients.

Patients with Renal Impairment

Lenalidomide is primarily excreted by the kidney; patients with greater degrees of renal impairment can have impaired treatment tolerance. Care should be taken in dose selection and monitoring of renal function is advised.

No dose adjustments are required for patients with mild renal impairment and multiple myeloma, myelodysplastic syndromes.

The following dose adjustments are recommended at the start of therapy and throughout treatment for patients with moderate or severe impaired renal function or end stage renal disease.

There are no phase 3 trial experiences with End Stage Renal Disease (ESRD) (CLcr < 30 mL/min, requiring dialysis).

Multiple Myeloma

Renal Function (CLcr)

Dose Adjustment

Moderate renal impairment (30 ≤ CLcr < 50 mL/min)

10 mg once daily1

Severe renal impairment (CLcr < 30 mL/min, not requiring dialysis)

15 mg every other day

End Stage Renal Disease (ESRD) (CLcr < 30 mL/min, requiring dialysis)

5 mg once daily. On dialysis days, the dose should be administered following dialysis

1 The dose may be escalated to 15 mg once daily after 2 cycles if patient is not responding to treatment and is tolerating the treatment.

Myelodysplastic Syndromes

Renal function (CLcr)

Dose adjustment

Moderate renal impairment (30 ≤ CLcr < 50 mL/min)

Starting dose

5 mg once daily (days 1 to 21 of repeated 28-day cycles)

Dose level -1*

2.5 mg once daily (days 1 to 28 of repeated 28-day cycles)

Dose level -2*

2.5 mg once every other day (days 1 to 28 of repeated 28-day cycles)

Severe renal impairment (CLcr < 30 mL/min, not requiring dialysis)

Starting dose

2.5 mg once daily

(days 1 to 21 of repeated 28-day cycles)

Dose level -1*

2.5 mg every other day (days 1 to 28 of repeated 28-day cycles)

Dose level -2*

2.5 mg twice a week (days 1 to 28 of repeated 28-day cycles)

End Stage Renal Disease (ESRD) (CLcr < 30 mL/min, requiring dialysis) On dialysis days, the dose should be administered following dialysis.

Starting dose

2.5 mg once daily (days 1 to 21 of repeated 28-day cycles)

Dose level -1*

2.5 mg every other day (days 1 to 28 of repeated 28-day cycles)

Dose level -2*

2.5 mg twice a week (days 1 to 28 of repeated 28-day cycles)

* Recommended dose reduction steps during treatment and restart of treatment to manage Grade 3 or 4 neutropenia or thrombocytopenia, or other Grade 3 or 4 toxicity judged to be related to lenalidomide, as described above.

Patients with Hepatic Impairment

Lenalidomide has not formally been studied in patients with impaired hepatic function and there are no specific dose recommendations.

Administration

Advise patients to take LENMID orally at about the same time each day, either with or without food. Advise patients to swallow LENMID capsules whole with water and not to open, break, or chew them.

4.3 Contraindications

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. 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.

Severe Hypersensitivity Reactions

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

4.4 Special Warnings and Precautions for Use

When lenalidomide is given in combination with other medicinal products, the corresponding Summary of Product Characteristics must be consulted prior to initiation of treatment.

Embryo-Fetal Toxicity

Lenalidomide is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy.

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 females with regular menstrual cycles or every 2 weeks in females 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 4 weeks after discontinuing lenalidomide, even if they have undergone a successful vasectomy. Male patients taking lenalidomide must not donate sperm.

Contraception

Women of childbearing potential must use at least one effective method of contraception for at least 4 weeks before therapy, during therapy, and until at least 4 weeks after lenalidomide therapy and even in case of dose interruption unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated.

Blood Donation

Patients must not donate blood during treatment with lenalidomide and for 4 weeks 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. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking lenalidomide should have their complete blood counts assessed periodically as described below.

The combination of lenalidomide with dexamethasone in multiple myeloma patients with at least one prior therapy is associated with a higher incidence of Grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients).

The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of Grade 3 and Grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients).

Monitor complete blood counts (CBC) in patients taking lenalidomide in combination with dexamethasone for MM every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required.

Lenalidomide treatment in myelodysplastic syndromes patients is associated with a higher incidence of Grade 3 and 4 neutropenia and thrombocytopenia compared to patients on placebo.

Monitor complete blood counts (CBC) in patients taking lenalidomide for MDS weekly for the first 8 weeks and at least monthly thereafter. 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).

Co-administration of lenalidomide with other myelosuppressive agents should be undertaken with caution.

Myocardial Infarction

Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors and within the first 12 months when used in combination with dexamethasone. Patients with known risk factors – including prior thrombosis – should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia)

Pulmonary Hypertension

Cases of pulmonary hypertension, some fatal, have been reported in patients treated with lenalidomide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during lenalidomide therapy.

Venous and Arterial Thromboembolism

Venous thromboembolic events (VTE ) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with lenalidomide. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with MM after at least one prior therapy who were treated with lenalidomide, and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies.

Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with MM after at least one prior therapy who were treated with lenalidomide and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials.

Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking).

In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed MM who were treated with lenalidomide, and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone.

Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving lenalidomide.

Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Prophylactic antithrombotic medicines should be recommended, especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's underlying risk factors.

If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, the lenalidomide treatment may be restarted at the original dose dependent upon a benefit risk assessment. The patient should continue anticoagulation therapy during the course of lenalidomide treatment.

Second Primary Malignancies

In clinical trials in patients with MM receiving lenalidomide, an increase of hematologic plus solid tumor second primary malignancies (SPM) notably AML and MDS have been observed.

In patients with relapsed or refractory MM treated with lenalidomide/dexamethasone, the incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM was 2.3% versus 0.6% in the dexamethasone alone arm. Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.1% of patients receiving lenalidomide/dexamethasone, compared to 0.6% in the dexamethasone alone arm.

Patients who received lenalidomide-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration lenalidomide-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.

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 MM and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing 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.

Severe Cutaneous Reactions

Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive lenalidomide. Consider lenalidomide interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue lenalidomide for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS.

Thyroid Disorders

Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before start of lenalidomide treatment and during therapy.

Hypersensitivity

Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to lenalidomide has been reported. Permanently discontinue lenalidomide for angioedema and anaphylaxis.

Excipients with Known Effect

Lenalidomide capsule contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Drug Interactions

Digoxin

When digoxin was co-administered with multiple doses of lenalidomide (10 mg/day) the digoxin Cmax and AUCinf were increased by 14%. Periodically monitor digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, during administration of lenalidomide.

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 after making a benefit-risk assessment in patients receiving Lenalidomide.

Oral Contraceptives

No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme inducer. In an in vitro study with human hepatocytes, lenalidomide, at various concentrations tested did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. Therefore, induction leading to reduced efficacy of medicinal products, including hormonal contraceptives, is not expected if lenalidomide is administered alone. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4 and is likely to also affect other enzymes as well as transporters. It may not be excluded that the efficacy of oral contraceptives may be reduced during treatment. Effective measures to avoid pregnancy must be taken,

Warfarin

Co-administration of multiple doses of lenalidomide (10 mg/day) with a single dose of warfarin (25 mg) had no effect on the pharmacokinetics of 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 patients with MM taking concomitant warfarin.

Statins

There is an increased risk of rhabdomyolysis when statins are administered with lenalidomide, which may be simply additive. Enhanced clinical and laboratory monitoring is warranted notably during the first weeks of treatment.

Dexamethasone

Co-administration of single or multiple doses of dexamethasone (40 mg once daily) has no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg once daily).

Interactions with P-glycoprotein (P-gp) inhibitors

In vitro, lenalidomide is a substrate of P-gp, but is not a P-gp inhibitor. Co-administration of multiple doses of the strong P-gp inhibitor quinidine (600 mg, twice daily) or the moderate P-gp inhibitor/substrate temsirolimus (25 mg) has no clinically relevant effect on the pharmacokinetics of lenalidomide (25 mg). Co-administration of lenalidomide does not alter the pharmacokinetics of temsirolimus.

4.6 Use in Special Populations

Women of Childbearing Potential / Contraception in Males and Females

Women of childbearing potential should use effective method of contraception. If pregnancy occurs in a woman treated with lenalidomide, treatment must be stopped, and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking lenalidomide, it is recommended to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice.

Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after stopping the substance in the healthy subject. As a precaution and taking into account special populations with prolonged elimination time such as renal impairment, all male patients taking lenalidomide should use condoms throughout treatment duration, during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception.

Pregnant Women

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Lenalidomide induced malformation in monkeys similar to those described with thalidomide. Therefore, a teratogenic effect of lenalidomide is expected and lenalidomide is contraindicated during pregnancy.

Lactating Women

It is not known whether lenalidomide is excreted in breast milk. Therefore, breast-feeding should be discontinued during therapy with lenalidomide.

Fertility

A fertility study in rats with lenalidomide doses up to 500 mg/kg (approximately 200 to 500 times the human doses of 25 mg and 10 mg, respectively, based on body surface area) produced no adverse effects on fertility and no parental toxicity.

Paediatric Use

Safety and effectiveness have not been established in paediatric patients.

Geriatric Use

MM After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the lenalidomide/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received lenalidomide/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of lenalidomide. No differences in efficacy were observed between patients over 65 years of age and younger patients.

Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse reactions (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse reactions than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

Renal Impairment

Adjust the starting dose of lenalidomide based on the creatinine clearance value and for patients on dialysis.

4.7 Effects on Ability to Drive and Use Machines

Lenalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have been reported with the use of lenalidomide. Therefore, caution is recommended when driving or operating machines.

4.8 Undesirable Effects

Multiple Myeloma: Patients with at Least One Prior Therapy

In two phase 3 placebo-controlled studies, 353 patients with multiple myeloma were exposed to the lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination.

The most serious adverse reactions observed more frequently in lenalidomide/dexamethasone than placebo/dexamethasone combination were:

Venous thromboembolism (deep vein thrombosis, pulmonary embolism)

Grade 4 neutropenia.

The observed adverse reactions which occurred more frequently with lenalidomide and dexamethasone than placebo and dexamethasone in pooled multiple myeloma clinical trials (MM-009 and MM-010) were fatigue (43.9%), neutropenia (42.2%), constipation (40.5%), diarrhoea (38.5%), muscle cramp (33.4%), anaemia (31.4%), thrombocytopenia (21.5%), and rash (21.2%).

Myelodysplastic Syndromes

The overall safety profile of lenalidomide in patients with myelodysplastic syndromes is based on data from a total of 286 patients from one phase 2 study and one phase 3 study. In the phase 2, all 148 patients were on lenalidomide treatment. In the phase 3 study, 69 patients were on lenalidomide 5 mg, 69 patients on lenalidomide 10 mg and 67 patients were on placebo during the double-blind phase of the study.

Most adverse reactions tended to occur during the first 16 weeks of therapy with lenalidomide.

Serious adverse reactions include:

Venous thromboembolism (deep vein thrombosis, pulmonary embolism)

Grade 3 or 4 neutropenia, febrile neutropenia and Grade 3 or 4 thrombocytopenia

The most commonly observed adverse reactions which occurred more frequently in the lenalidomide groups compared to the control arm in the phase 3 study were neutropenia (76.8%), thrombocytopenia (46.4%), diarrhoea (34.8%), constipation (19.6%), nausea (19.6%), pruritus (25.4%), rash (18.1%), fatigue (18.1%) and muscle spasms (16.7%).

Tabulated list of Adverse Reactions

The adverse reactions observed in patients treated with lenalidomide are listed below by system organ class and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Adverse reactions have been included under the appropriate category in the table below according to the highest frequency observed in any of the main clinical trials.

Adverse Drug Reactions Reported in Clinical Studies in Patients with Multiple Myeloma Treated with Lenalidomide in Combination Therapy

System Organ Class / Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Infections and Infestations

Very Common

Pneumonia, Upper respiratory tract infection, Bacterial, viral and fungal infections (including opportunistic infections), Nasopharyngitis, Pharyngitis, Bronchitis, Rhinitis

Common

Sepsis, Sinusitis

Common

Pneumonia, Bacterial, viral and fungal infections (including opportunistic infections), Cellulitis, Sepsis, Bronchitis, Enterocolitis infectious

Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps)

Uncommon

Basal cell carcinoma, Squamous skin cancer

Common

Acute myeloid leukaemia, Myelodysplastic syndrome,

Uncommon

T-cell type acute leukaemia, Basal cell carcinoma, Tumour lysis syndrome

Blood and Lymphatic System Disorders

Very Common

Neutropenia, Thrombocytopenia, Anaemia, Haemorrhagic disorder, Leucopenia, Lymphopenia

Common

Febrile neutropenia, Pancytopenia

Uncommon

Haemolysis, Autoimmune haemolytic anaemia, Haemolytic anaemia

Very Common

Neutropenia, Thrombocytopenia, Anaemia, Leucopenia, Lymphopenia

Common

Febrile neutropenia, Pancytopenia, Haemolytic anaemia

Uncommon

Hypercoagulation, Coagulopathy

Immune System Disorders

Uncommon

Hypersensitivity

 

Endocrine Disorders

Common

Hypothyroidism

 

Metabolism and Nutrition Disorders

Very Common

Hypokalaemia, Hyperglycaemia, Hypoglycaemia, Hypocalcaemia, Hyponatraemia, Weight decreased

Common

Hypomagnesaemia, Hyperuricaemia, Hypercalcaemia

Common

Hypokalaemia, Hyperglycaemia, Hypocalcaemia, Diabetes mellitus, Hypophosphataemia, Hyponatraemia, Hyperuricaemia, Gout, Weight decreased

Psychiatric Disorders

Very Common

Depression, Insomnia

Uncommon

Loss of libido

Common

Depression, Insomnia

Nervous System Disorders

Very Common

Tremor, Dysgeusia, Headache

Common

Ataxia, Balance impaired, Neuralgia, Dysaesthesia

Common

Cerebrovascular accident, Neuralgia

Uncommon

Intracranial haemorrhage, Transient ischaemic attack, Cerebral ischemia

Eye Disorders

Very Common

Cataracts, Blurred vision

Common

Reduced visual acuity

Common

Cataract

Uncommon

Blindness

Ear and Labyrinth Disorders

Common

Deafness (Including Hypoacusis), Tinnitus

 

Cardiac Disorders

Common

Atrial fibrillation, Bradycardia

Uncommon

Arrhythmia, QT prolongation, Atrial flutter, Ventricular extrasystoles

Common

Myocardial infarction (including acute), Atrial fibrillation, Congestive cardiac failure, Tachycardia, Cardiac failure, Myocardial ischemia

Vascular Disorders

Very Common

Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism, Hypotension

Common

Hypertension, Ecchymosis

Very Common

Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism

Common

Vasculitis, Hypertension

Uncommon

Ischemia, Peripheral ischemia, Intracranial venous sinus thrombosis

Respiratory, Thoracic and Mediastinal Disorders

Very Common

Dyspnoea, Epistaxis, Cough

Common

Dysphonia

Common

Respiratory distress, Dyspnoea, Pleuritic pain, Hypoxia

Gastrointestinal Disorders

Very Common

Diarrhoea, Constipation, Dyspepsia, Dry mouth, Stomatitis

Common

Dysphagia

Uncommon

Colitis, Caecitis

Common

Gastrointestinal Haemorrhage, Constipation,

Nausea

Hepatobiliary Disorders

Very Common

Alanine aminotransferase increased, Aspartate aminotransferase increased

Common

Abnormal liver function tests, Hyperbilirubinaemia

Uncommon

Hepatic failure

Common

Cholestasis, Hepatotoxicity, Alanine aminotransferase increased, Abnormal liver function tests

Uncommon

Hepatic failure

Skin and Subcutaneous Tissue Disorders

Very Common

Pruritus

Common

Urticaria, Hyperhidrosis, Dry skin, Skin hyperpigmentation, Eczema, Erythema

Uncommon

Skin discolouration, Photosensitivity reaction

 

Musculoskeletal and Connective Tissue Disorders

Very Common

Muscle spasms, Bone pain, Musculoskeletal and connective tissue pain and discomfort (including back pain), Pain in extremity, Myalgia, Arthralgia

Common

Joint swelling

Common

Bone pain, Musculoskeletal and connective tissue pain and discomfort (including back pain,)

Uncommon

Joint swelling

Renal and Urinary Disorders

Very Common

Renal failure (including acute)

Common

Haematuria, Urinary retention, Urinary incontinence

Uncommon

Acquired Fanconi syndrome

Uncommon

Renal tubular necrosis

Reproductive System and Breast Disorders

Common

Erectile dysfunction

 

General Disorders and Administration Site Conditions

Very Common

Fatigue, Oedema (including peripheral oedema), Pyrexia, Asthenia, Influenza like illness syndrome (including pyrexia, cough, myalgia, musculoskeletal pain, headache and rigors)

Common

Chest pain, Lethargy

Very Common

Fatigue

Common

Oedema peripheral, Pyrexia, Asthenia

Investigations

Very Common

Blood alkaline phosphatase increased.

Common

C-reactive protein increased

 

Injury, Poisoning and Procedural Complications

Common

Fall, Contusion

 

Adverse Drug Reactions reported in clinical trials in patients with myelodysplastic syndromes treated with lenalidomide:

System Organ Class / Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Infections and Infestations

Very Common

Bacterial, viral and fungal infections (including opportunistic infections)

Very Common

Pneumonia

Common

Bacterial, viral and fungal infections (including opportunistic infections), Bronchitis

Blood and Lymphatic System Disorders

Very Common

Thrombocytopenia^,◊, Neutropenia^,◊, Leucopenia

Very Common

Thrombocytopenia^,◊, Neutropenia^,◊, Leucopenia

Common

Febrile neutropenia^,◊

Endocrine Disorders

Very Common

Hypothyroidism

 

Metabolism and Nutrition Disorders

Very Common

Decreased appetite

Common

Iron overload, Weight decreased

Common

Hyperglycaemia, Decreased appetite

Psychiatric Disorders

 

Common

Altered mood◊,~

Nervous System Disorders

Very Common

Dizziness, Headache

Common

Paraesthesia

 

Cardiac Disorders

 

Common

Acute myocardial infarction^,◊, Atrial fibrillation, Cardiac failure

 

Vascular Disorders

Common

Hypertension, Haematoma

Common

Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism^,◊

Respiratory, Thoracic and Mediastinal Disorders

Very Common

Epistaxis^

 

Gastrointestinal Disorders

Very Common

Diarrhoea, Abdominal pain (including upper), Nausea, Vomiting, Constipation

Common

Dry mouth, Dyspepsia

Common

Diarrhoea, Nausea, Toothache

Hepatobiliary Disorders

Common

Abnormal liver function tests

Common

Abnormal liver function tests

Skin and Subcutaneous Tissue Disorders

Very Common

Rashes, Dry Skin, Pruritus

Common

Rashes, Pruritus

Musculoskeletal and Connective Tissue Disorders

Very Common

Muscle spasms, Musculoskeletal pain (including back pain and pain in extremity), Arthralgia, Myalgia

Common

Back pain

Renal and Urinary Disorders

 

Common

Renal failure

General Disorders and Administration Site Conditions

Very Common

Fatigue, Peripheral oedema, Influenza like illness syndrome (including pyrexia, cough, pharyngitis, myalgia, musculoskeletal pain, headache)

Common

Pyrexia

Injury, Poisoning and Procedural Complications

 

Common

Fall

◊Adverse events reported as serious in myelodysplastic syndromes clinical trials

~Altered mood was reported as a common serious adverse event in the myelodysplastic syndromes phase 3 study; it was not reported as a Grade 3 or 4 adverse event

Algorithm applied for inclusion in the SmPC: All ADRs captured by the phase 3 study algorithm are included in the EU SmPC. For these ADRs, an additional check of the frequency of the ADRs captured by the phase 2 study algorithm was undertaken and, if the frequency of the ADRs in the phase 2 study was higher than in the phase 3 study, the event was included in the EU SmPC at the frequency it occurred in the phase 2 study.

# Algorithm applied for myelodysplastic syndromes:

• Myelodysplastic syndromes phase 3 study (double-blind safety population, difference between lenalidomide 5/10mg and placebo by initial dosing regimen occurring in at least 2 subjects)

o All treatment-emergent adverse events with ≥ 5% of subjects in lenalidomide and at least 2% difference in proportion between lenalidomide and placebo

o All treatment-emergent Grade 3 or 4 adverse events in 1% of subjects in lenalidomide and at least 1% difference in proportion between lenalidomide and placebo

o All treatment-emergent serious adverse events in 1% of subjects in lenalidomide and at least 1% difference in proportion between lenalidomide and placebo

• Myelodysplastic syndromes phase 2 study

o All treatment-emergent adverse events with ≥ 5% of lenalidomide treated subjects.

o All treatment-emergent Grade 3 or 4 adverse\events in 1% of lenalidomide treated subjects.

o All treatment-emergent serious adverse events in 1% of lenalidomide treated subjects.

Description of Selected Adverse Reactions

Teratogenicity

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. In monkeys, lenalidomide induced malformations similar to those described with thalidomide. If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.

Neutropenia and Thrombocytopenia

Multiple myeloma: Patients with at least one prior therapy

The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of Grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients).

The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of Grade 3 and Grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients).

Myelodysplastic Syndromes Patients

In myelodysplastic syndromes patients, lenalidomide is associated with a higher incidence of Grade 3 or 4 neutropenia (74.6% in lenalidomide-treated patients compared with 14.9% in patients on placebo in the phase 3 study). Grade 3 or 4 febrile neutropenia episodes were observed in 2.2% of lenalidomide-treated patients compared with 0.0% in patients on placebo). Lenalidomide is associated with a higher incidence of Grade 3 or 4 thrombocytopenia (37% in lenalidomide-treated patients compared with 1.5% in patients on placebo in the phase 3 study).

Venous Thromboembolism

An increased risk of DVT and PE is associated with the use of the combination of lenalidomide with dexamethasone in patients with multiple myeloma, and to a lesser extent in patients treated with lenalidomide in combination with melphalan and prednisone or in patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma treated with lenalidomide monotherapy (see section 4.5).

Concomitant administration of erythropoietic agents or previous history of DVT may also increase thrombotic risk in these patients.

Myocardial Infarction

Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors.

Haemorrhagic Disorders

Haemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system disorders; nervous system disorders (intracranial haemorrhage); respiratory, thoracic and mediastinal disorders (epistaxis); gastrointestinal disorders (gingival bleeding, haemorrhoidal haemorrhage, rectal haemorrhage); renal and urinary disorders (haematuria); injury, poisoning and procedural complications (contusion) and vascular disorders (ecchymosis).

Allergic Reactions and Severe Skin Reactions

Cases of allergic reactions including angioedema, anaphylactic reaction and severe cutaneous reactions including SJS, TEN and DRESS have been reported with the use of lenalidomide. A possible cross-reaction between lenalidomide and thalidomide has been reported in the literature. Patients with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.

Second Primary Malignancies

In clinical trials in previously treated myeloma patients with lenalidomide/dexamethasone compared to controls, mainly comprising of basal cell or squamous cell skin cancers.

Acute Myeloid Leukaemia

Myelodysplastic Syndromes

Baseline variables including complex cytogenetics and TP53 mutation are associated with progression to AML in subjects who are transfusion dependent and have a Del (5q) abnormality (see section 4.4). The estimated 2-year cumulative risk of progression to AML were 13.8% in patients with an isolated Del (5q) abnormality compared to 17.3% for patients with Del (5q) and one additional cytogenetic abnormality and 38.6% in patients with a complex karyotype.

In a post-hoc analysis of a clinical trial of lenalidomide in myelodysplastic syndromes, the estimated 2-year rate of progression to AML was 27.5 % in patients with IHC-p53 positivity and 3.6% in patients with IHC-p53 negativity (p=0.0038). In the patients with IHC-p53 positivity, a lower rate of progression to AML was observed amongst patients who achieved a transfusion independence (TI) response (11.1%) compared to a non-responder (34.8%).

Hepatic Disorders

The following post-marketing adverse reactions have been reported (frequency unknown): acute hepatic failure and cholestasis (both potentially fatal), toxic hepatitis, cytolytic hepatitis, mixed cytolytic/cholestatic hepatitis.

Rhabdomyolysis

Rare cases of rhabdomyolysis have been observed, some of them when lenalidomide is administered with a statin.

Thyroid Disorders

Cases of hypothyroidism and cases of hyperthyroidism have been reported.

Gastrointestinal Disorders

Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinal perforations may lead to septic complications and may be associated with fatal outcome.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

To report any side effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

4.9 Overdose

There is no specific experience in the management of Lenalidomide overdose in patients with MM and MDS. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.

5 Pharmacological Properties

5.1 Mechanism of Action

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1α) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM and del (5q) myelodysplastic syndromes, in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM. Immunomodulatory properties of lenalidomide include increased number and activation of T cells and natural killer (NK) cells leading to direct and enhanced antibody dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of proinflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In MM cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. The lenalidomide mechanism of action also includes additional activities such as anti-angiogenic and pro-erythropoietic properties. Lenalidomide inhibits angiogenesis by blocking the migration and adhesion of endothelial cells and the formation of micro-vessels, augments foetal haemoglobin production by CD34+ haematopoietic stem cells, and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

5.2 Pharmacodynamic Properties

Cardiac Electrophysiology

The effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in a thorough QT study. At a dose two times the maximum recommended dose, lenalidomide did not prolong the QTc interval. The largest upper bound of the two-sided 90% CI for the mean differences between lenalidomide and placebo was below 10 ms.

5.3 Pharmacokinetic Properties

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 doses of lenalidomide at the recommended dosage does not result in drug accumulation.

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 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 -lenalidomide binding to plasma proteins is approximately 30%. Lenalidomide is present in semen at 2 hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration Lenalidomide 25 mg daily.

Elimination

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

Metabolism

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

Excretion

Elimination is primarily renal. Following a single oral administration of -lenalidomide 25 mg to healthy subjects, approximately 90% and 4% of the radioactive dose was eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose was excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represented 4.6% and 1.8% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate.

Specific Populations

Renal Impairment

Eight subjects with mild renal impairment (creatinine clearance (CLcr) 50 to 79 mL/min calculated using Cockcroft-Gault), 9 subjects with moderate renal impairment (CLcr 30 to 49 mL/min), 4 subjects with severe renal impairment (CLcr < 30 mL/min), and 6 patients with end stage renal disease (ESRD) requiring dialysis were administered a single 25 mg dose of Lenalidomide. Three healthy subjects of similar age with normal renal function (CLcr > 80 mL/min) were also administered a single 25 mg dose of Lenalidomide. As CLcr decreased, half-life increased, and drug clearance decreased linearly. Patients with moderate and severe impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) had an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 30% of the drug in body was removed during a 4-hour hemodialysis session. Adjust the starting dose of Lenalidomide in patients with renal impairment based on the CLcr value.

Hepatic Impairment

Mild hepatic impairment (defined as total bilirubin > 1 to 1.5 times upper limit normal (ULN) or any aspartate transaminase greater than ULN) did not influence the disposition of lenalidomide. No pharmacokinetic data is available for patients with moderate to severe hepatic impairment. Other Intrinsic Factors: Age (39 to 85 years), body weight (33 to 135 kg), sex, race, and type of hematological malignancies (MM or MDS) did not have a clinically relevant effect on lenalidomide clearance in adult patients.

Drug Interactions

Co-administration of a single dose or multiple doses of dexamethasone (40 mg) had no clinically relevant effect on the multiple dose pharmacokinetics of Lenalidomide (25 mg).

Co-administration of Lenalidomide (25 mg) after multiple doses of a P-gp inhibitor such as quinidine (600 mg twice daily) did not significantly increase the Cmax or AUC of lenalidomide.

Co-administration of the P-gp inhibitor and substrate temsirolimus (25 mg),with Lenalidomide (25 mg) did not significantly alter the pharmacokinetics of lenalidomide, temsirolimus, or sirolimus (metabolite of temsirolimus).

In vitro studies demonstrated that lenalidomide is a substrate of P-glycoprotein (P-gp). Lenalidomide is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. Lenalidomide is not an inhibitor of P-gp, bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. Lenalidomide does not inhibit or induce CYP450 isoenzymes. Also, lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes with UGT1A1 genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28.

6 Non-Clinical Properties

6.1 Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with lenalidomide have not been conducted.

Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

7. Description

LENMID, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3- dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:

3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione

The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.

Pharmacotherapeutic group: Other immunosuppressants. ATC code: L04AX04.

8. Pharmaceutical Particulars

8.1 List of Excipients

LENMID is available in, 5 mg, 10 mg and 25 mg capsules for oral administration.

Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

8.2 Incompatibilities

Not applicable.

8.2 Shelf-life

LENMID 5: 24 months

LENMID 10: 24 months

LENMID 25: 24 months

8.3 Packaging Information

LENMID 5: 10 Capsule in a container

LENMID 10: 10 Capsule in a container

LENMID 25: 10 Capsule in a container

8.4 Storage and Handing Instructions

Store in a cool place. Protect from moisture.

Keep the bottle tightly closed.

Keep out of reach of children.

9. Patients Counselling Information

  1. What LENMID is and what it is used for

LENMID contains the active substance ‘lenalidomide’. This medicine belongs to a group of medicines which affect how your immune system works.

LENMID is used in adults for: Multiple myeloma and Myelodysplastic syndromes.

Multiple Myeloma

Multiple myeloma is a type of cancer which affects a certain kind of white blood cell, called the plasma cell. These cells collect in the bone marrow and divide, becoming out of control. This can damage the bones and kidneys.

Multiple myeloma generally cannot be cured. However, the signs and symptoms can be greatly reduced or disappear for a period of time. This is called a ‘response’.

Multiple myeloma – in patients who have had treatment before LENMID is taken together with an anti-inflammatory medicine called ‘dexamethasone’. LENMID can stop the signs and symptoms of multiple myeloma getting worse. It has also been shown to delay multiple myeloma from coming back following treatment.

Myelodysplastic Syndromes (MDS)

MDS are a collection of many different blood and bone marrow diseases. The blood cells become abnormal and do not function properly. Patients can experience a variety of signs and symptoms including a low red blood cell count (anaemia), the need for a blood transfusion, and be at risk of infection.

LENMID is used alone to treat adult patients who have been diagnosed with MDS, when all of the following apply:

  • you need regular blood transfusions to treat low levels of red blood cells (‘transfusion-dependent anaemia’)
  • you have an abnormality of cells in the bone marrow called an ‘isolated deletion 5q cytogenetic abnormality’. This means your body does not make enough healthy blood cells.
  • other treatments have been used before, are not suitable or do not work well enough.

LENMID can increase the number of healthy red blood cells that the body produces by reducing the number of abnormal cells:

  • this can reduce the number of blood transfusions needed. It is possible that no transfusions will be needed.

How LENMID works

LENMID works by affecting the body’s immune system and directly attacking the cancer. It works in a number of different ways

  • by stopping the cancer cells developing
  • by stopping blood vessels growing in the cancer
  • by stimulating part of the immune system to attack the cancer cells.
  1. What you Need to Know Before you take LENMID

You must read the package leaflet of all medicinal products to be taken in combination with LENMID before starting treatment with LENMID

Do not take LENMID:

  • if you are pregnant, think you may be pregnant or are planning to become pregnant, as LENMID is expected to be harmful to an unborn child
  •  if you are able to become pregnant, unless you follow all the necessary measures to prevent you from becoming pregnant.

If you are able to become pregnant, your doctor will record with each prescription that the necessary measures have been taken and provide you with this confirmation.

  • if you are allergic to lenalidomide or any of the other ingredients of this medicine If you think you may be allergic, ask your doctor for advice.

If any of these apply to you, do not take LENMID. Talk to your doctor if you are not sure.

Warnings and Precautions

Talk to your doctor, before taking LENMID if:

  • you have had blood clots in the past - you have an increased risk of developing blood clots in the veins and arteries during treatment.
  • you have any signs of an infection, such as a cough or fever.
  • you have or have ever had previous viral infection, particularly: hepatitis B infection, varicella zoster, HIV. If you are in doubt, talk to your doctor. Treatment with LENMID may cause the virus to become active again, in patients who carry the virus. This results in a recurrence of the infection. Your doctor should check whether you have ever had hepatitis B infection.
  • you have kidney problems - your doctor may adjust your dose of LENMID.
  • you have had a heart attack, have ever had a blood clot, or if you smoke, have high blood pressure or high cholesterol levels.
  • you have had an allergic reaction whilst taking thalidomide (another medicine used to treat multiple myeloma) such as rash, itching, swelling, dizziness or trouble breathing.
  • you have experienced in the past a combination of any of the following symptoms: widespread rash, red skin, high body temperature, flu-like symptoms, liver enzyme elevations, blood abnormalities (eosinophilia), enlarged lymph nodes – these are signs of a severe skin reaction called Drug Reaction with Eosinophilia and Systemic Symptoms which is also known as DRESS or drug hypersensitivity syndrome.

If any of the above apply to you, tell your doctor before starting treatment.

At any time during or after your treatment, tell your doctor or nurse immediately if you:

  • experience blurred, loss of or double vision, difficulty speaking, weakness in an arm or a leg, a change in the way you walk or problems with your balance, persistent numbness, decreased sensation or loss of sensation, memory loss or confusion. These may all be symptoms of a serious and potentially fatal brain condition known as progressive multifocal leukoencephalopathy (PML). If you had these symptoms prior to treatment with LENMID, tell your doctor about any change in these symptoms.
  • experience shortness of breath, tiredness, dizziness, pain in the chest, a faster heartbeat, or swelling in the legs or ankles. These may be symptoms of a serious condition known as pulmonary hypertension

Tests and checks

Before and during the treatment with LENMID you will have regular blood tests. This is because LENMID may cause a fall in the blood cells that help fight infection (white blood cells) and help the blood to clot (platelets). Your doctor will ask you to have a blood test:

  • before treatment
  • every week for the first 8 weeks of treatment
  • then at least every month after that.

You may be evaluated for signs of cardiopulmonary problems before and during the treatment with lenalidomide.

For Patients with MDS taking LENMID

If you have MDS, you may be more likely to get a more advanced condition called acute myeloid leukaemia (AML). In addition, it is not known how LENMID affects the chances of you getting AML. Your doctor may therefore do tests to check for signs which may better predict the likelyhood of you getting AML during your treatment with LENMID.

Your doctor may check you for changes to your skin such as red spots or rashes.

Your doctor may adjust your dose of LENMID or stop your treatment based on the results of your blood tests and on your general condition. If you are newly diagnosed, your doctor may also assess your treatment based on your age and other conditions you already have.

Blood Donation

You should not donate blood during treatment and for at least 7 days after the end of treatment.

Children and Adolescents

LENMID is not recommended for use in children and adolescents under 18 years.

Elderly and People with Kidney Problems

If you are aged 75 years or older or have moderate to severe kidney problems - your doctor will check you carefully before starting treatment.

Other Medicines and LENMID

Tell your doctor or nurse if you are taking or have recently taken any other medicines. This is because LENMID can affect the way some other medicines work. Also, some other medicines can affect the way LENMID works.

Tell your doctor if you are taking any of the following medicines:

  • some medicines used to prevent pregnancy such as oral contraceptives, as they may stop working.
  • some medicines used for heart problems – such as digoxin.
  • some medicines used to thin the blood – such as warfarin.

Pregnancy, breast-feeding and contraception - information for women and men

Pregnancy

For women taking LENMID

  • You must not take LENMID if you are pregnant, as it is expected to be harmful to an unborn baby.
  • You must not become pregnant while taking LENMID. Therefore you must use effective methods of contraception if you are a woman of childbearing potential (see ‘Contraception’).
  • If you do become pregnant during your treatment with LENMID, you must stop the treatment and inform your doctor immediately.

For men taking LENMID

  • If your partner becomes pregnant whilst you are taking LENMID, you should inform your doctor immediately. It is recommended that your partner seeks medical advice.
  • You must also use effective methods of contraception (see ‘Contraception’).

Breast-feeding

You must not breast-feed when taking LENMID, as it is not known if LENMID passes into breast milk.

Contraception

For women taking LENMID

Before starting the treatment, ask your doctor if you are able to become pregnant, even if you think this is unlikely. If you are able to become pregnant

  • you will have pregnancy tests under the supervision of your doctor (before every treatment, at least every 4 weeks during treatment, and at least 4 weeks after the treatment has finished) except where it has been confirmed that the fallopian tubes have been severed and sealed, to stop eggs from reaching the uterus (tubal sterilisation)

AND

  • you must use effective methods of contraception for at least 4 weeks before starting treatment, during treatment, and until at least 4 weeks after stopping treatment. Your doctor will advise you on appropriate methods of contraception.

For men taking LENMID

LENMID passes into human semen. If your female partner is pregnant or able to become pregnant, and she does not use effective methods of contraception, you must use condoms during treatment and for at least 7 days after the end of treatment, even if you have had a vasectomy.

Driving and using machines

Do not drive or operate machines if you feel dizzy, tired, sleepy, have vertigo or blurred vision after taking LENMID.

LENMID contains lactose

LENMID contains lactose. If you have been told by your doctor that you have intolerance to some sugars,

contact your doctor before taking this medicine.

  1. How to take LENMID

LENMID must be given to you by healthcare professionals with experience in treating multiple myeloma, MDS.

  • When LENMID is used to treat multiple myeloma in patients who cannot have a bone marrow transplant or have had other treatments before, it is taken with other medicines.
  • When LENMID is used to treat patients with MDS, it is taken alone.

Always take LENMID exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

If you are taking LENMID in combination with other medicines, you should refer to the package leaflets for these medicines for further information on their use and effects.

Treatment cycle

LENMID is taken on certain days over 3 weeks (21 days).

  • Every 21 days is called a ‘treatment cycle’.
  • Depending on the day of the cycle, you will take one or more of the medicines. However, on some days you do not take any of the medicines.
  • After completing every 21-day cycle, you should start a new ‘cycle’ over the next 21 days.

OR

LENMID is taken on certain days over 4 weeks (28 days).

  • Every 28 days is called a ‘treatment cycle’.
  • Depending on the day of the cycle, you will take one or more of the medicines. However, on some days you do not take any of the medicines.
  • After completing every 28-day cycle, you should start a new ‘cycle’ over the next 28 days.

How much LENMID to take

Before you start treatment, your doctor will tell you:

  • how much LENMID you should take
  • how much of the other medicines you should take in combination with LENMID, if any
  • on what days of your treatment cycle to take each medicine.

How and when to take LENMID

  • swallow the capsules whole, preferably with water.
  • do not break, open or chew the capsules. If powder from a broken LENMID capsule makes contact with the skin, wash the skin immediately and thoroughly with soap and water. Women who are pregnant or suspect they may be pregnant should not handle the blister or capsule.
  • the capsules can be taken either with or without food.
  • you should take LENMID at about the same time on the scheduled days.
  1. Possible Side-effects

Like all medicines, LENMID can cause side effects, although not everybody gets them.

Stop taking LENMID and see a doctor straight away if you notice any of the following serious side effects – you may need urgent medical treatment:

  • Hives, rashes, swelling of eyes, mouth or face, difficulty breathing, or itching, which may be symptoms of serious types of allergic reactions called angioedema and anaphylactic reaction.
  • A serious allergic reaction that may begin as a rash in one area but spread with extensive loss of skin over the whole body (Stevens-Johnson syndrome and/or toxic epidermal necrolysis).
  • Widespread rash, high body temperature, liver enzyme elevations, blood abnormalities (eosinophilia), enlarged lymph nodes and other body organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms which is also known as DRESS or drug hypersensitivity syndrome).

Tell your doctor straight away if you notice any of the following serious side effects:

  • Fever, chills, sore throat, cough, mouth ulcers or any other symptoms of infection including within the bloodstream (sepsis)
  • Bleeding or bruising in the absence of injury
  • Chest pain or leg pain
  • Shortness of breath
  • Bone pain, muscle weakness, confusion or tiredness that might be due to high level of calcium in the blood.

LENMID may reduce the number of white blood cells that fight infection and also the blood cells which help the blood to clot (platelets) which may lead to bleeding disorders such as nosebleeds and bruising.

LENMID may also cause blood clots in the veins (thrombosis).

Other side effects

It is important to note that a small number of patients may develop additional types of cancer, and it is possible that this risk may be increased with LENMID treatment. Therefore, your doctor should carefully evaluate the benefit and risk when you are prescribed LENMID.

Reporting of side effects

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

To report any side effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

  1. How to Store LENMID

Store in a cool place. Protect from moisture.

Keep the bottle tightly closed.

Keep out of reach of children.

  1. Contents of the Pack and Other Information

LENMID 5: 10 Capsule in a container

LENMID 10: 10 Capsule in a container

LENMID 25: 10 Capsule in a container

10. Details of Manufacturer

Cipla House,

Peninsula Business Park,

Ganpatrao Kadam Marg,

Lower Parel, Mumbai - 400 013 INDIA

11. Details of Permission or Licence Number with Date

LENMID 5 & LENMID 10:

Mfg. Lic No. 616 dated 18.03.2009.

LENMID 25

Mfg. Lic No. 616 dated 18.04.2013.

12. Date of Revision

28/06/2021