Revlimid 15 mg

​1.1 Multiple Myeloma

​Revlimid 15 mg in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM).

Myelodysplastic Syndromes

Revlimid 15 mg 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.

Mantle Cell Lymphoma

Revlimid 15 mg is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

Limitations of Use:

Revlimid 15 mg is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials.

Revlimid 15 mg is used to treat anemia (low red blood cells) in patients with a certain type of myelodysplastic syndrome (MDS). Patients with MDS may have very low red blood cell counts and require blood transfusions.

Revlimid 15 mg is also used in combination with dexamethasone to treat multiple myeloma (plasma cell cancer).

Revlimid 15 mg is also used to treat mantle cell lymphoma (MCL) in patients who have been treated previously with bortezomib plus one additional medicine that did not work well.

This medicine is available only with your doctor's prescription and through a special restricted distribution program called the Revlimid 15 mg® REMS program.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, Revlimid 15 mg is used in certain patients with the following medical condition:

• Multiple myeloma, first-line treatment, in combination with dexamethasone (treatment of bone marrow cancer; used together with dexamethasone).

Revlimid 15 mg should be taken orally at about the same time each day, either with or without food. Revlimid 15 mg capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed.

Multiple Myeloma

Multiple Myeloma

​The recommended starting dose of Revlimid 15 mg is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients > 75 years old, the starting dose of dexamethasone may be reduced. Treatment should be continued until disease progression or unacceptable toxicity.

​In patients who are not eligible for autologous stem cell transplantation (ASCT), treatment should continue until disease progression or unacceptable toxicity. For patients who are ASCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a Revlimid 15 mg-containing therapy.

Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment

Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to Revlimid 15 mg.

Table 1: Dose Adjustments for Hematologic Toxicities for MM

Platelet counts

Thrombocytopenia in MM

Absolute Neutrophil counts (ANC)

Neutropenia in MM

Other Toxicities in MM

For other Grade 3/4 toxicities judged to be related to Revlimid 15 mg, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has resolved to ≤ Grade 2.

Starting Dose Adjustment for Renal Impairment in MM:

.

Myelodysplastic Syndromes

The recommended starting dose of Revlimid 15 mg is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings.

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

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

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

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

Other Grade 3 / 4 Toxicities in MDS

For other Grade 3/4 toxicities judged to be related to Revlimid 15 mg, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has resolved to ≤ Grade 2.

Starting Dose Adjustment for Renal Impairment in MDS:

.

Mantle Cell Lymphoma

The recommended starting dose of Revlimid 15 mg is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity.

Treatment is continued, modified or discontinued based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During MCL Treatment

Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to Revlimid 15 mg.

Platelet counts

Thrombocytopenia during treatment in MCL

Absolute Neutrophil counts (ANC)

Neutropenia during treatment in MCL

Other Grade 3 / 4 Toxicities in MCL

For other Grade 3/4 toxicities judged to be related to Revlimid 15 mg, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2.

Starting Dose Adjustment for Renal Impairment in MCL:

.

Starting Dose for Renal Impairment in MM, MDS or MCL

Since Revlimid 15 mg is primarily excreted unchanged by the kidney, adjustments to the starting dose of Revlimid 15 mg 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, Revlimid 15 mg starting dose adjustment is recommended for patients with CLcr < 60 mL/min. The recommendations for initial starting doses for patients with MDS or MCL, and MM are as follows:

​Moderate renal impairment for MM: Consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of Revlimid 15 mg without dose-limiting toxicity.

After initiation of Revlimid 15 mg therapy, subsequent Revlimid 15 mg dose increase or decrease is based on individual patient treatment tolerance, as described elsewhere.

See also:
What is the most important information I should know about Revlimid 15 mg?

Revlimid 15 mg can cause severe, life-threatening birth defects or death of a baby if the mother or the father is taking this medication at the time of conception or during pregnancy. Even one dose of Revlimid 15 mg can cause major birth defects of the baby's arms and legs, bones, ears, eyes, face, and heart. Never use Revlimid 15 mg if you are pregnant.

For Women: You will be required to use two reliable forms of birth control beginning 4 weeks before you start taking Revlimid 15 mg and ending 4 weeks after you stop taking it. Any woman who has not had a hysterectomy or has not been in menopause for at least 24 months in a row must agree in writing to use birth control before, during, and after taking Revlimid 15 mg. Even women with fertility problems are required to use birth control while taking this medication. You must also have a negative pregnancy test at 10 to 14 days before treatment and again at 24 hours before. While you are taking Revlimid 15 mg, you will have a pregnancy test every 4 weeks.

Stop using Revlimid 15 mg and call your doctor at once if you quit using birth control, if your period is late, or if you think you might be pregnant.

For Men: You must not cause a woman to become pregnant while you are taking Revlimid 15 mg because the medicine may affect your sperm and cause birth defects in the baby. You must agree in writing to always use latex condoms when having sex with a woman who is able to get pregnant, even if you have had a vasectomy.

Revlimid 15 mg is available only under a special program called RevAssist. You must be registered in the program and sign documents stating that you understand the dangers of this medication and that you agree to use birth control measures as required by the program.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Never give Revlimid 15 mg to another person, even if he or she has the same disorder for which you are being treated.

Do not donate blood or sperm while you are using Revlimid 15 mg.

Use Revlimid 15 mg as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Revlimid 15 mg comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Revlimid 15 mg refilled.
• Take Revlimid 15 mg by mouth with or without food.
• Swallow Revlimid 15 mg whole with water. Do not break, crush, chew, or open before swallowing.
• Take Revlimid 15 mg at about the same time each day to get the most benefit from it.
• Do not open the capsules or handle them more than needed. If you touch a broken capsule or the medicine inside of the capsule, wash the area with soap and water. If a broken capsule or the medicine inside comes into contact with your eyes, flush thoroughly with water.
• If you miss a dose of Revlimid 15 mg and it has been less than 12 hours since the missed dose, take it as soon as you remember. If it has been more than 12 hours since the missed dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Revlimid 15 mg.

Use: Labeled Indications

Follicular lymphoma (previously treated): Treatment of previously treated follicular lymphoma (in combination with a rituximab product) in adults.

Mantle cell lymphoma (relapsed or progressive): Treatment of mantle cell lymphoma in adults that has relapsed or progressed after 2 prior therapies (one of which included bortezomib).

Marginal zone lymphoma (previously treated): Treatment of previously treated marginal zone lymphoma (in combination with a rituximab product) in adults.

Multiple myeloma: Treatment of multiple myeloma (in combination with dexamethasone) in adults; maintenance therapy following autologous hematopoietic stem cell transplantation in adults.

Myelodysplastic syndromes: Treatment of adults with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q (del 5q) cytogenetic abnormality with or without additional cytogenetic abnormalities.

Limitations of use: Revlimid 15 mg is not indicated and is not recommended for the treatment of chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

Off Label Uses

Chronic lymphocytic leukemia, relapsed or refractory

Data from a phase 2 study in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), support the use of Revlimid 15 mg (in combination with cyclic rituximab) in the treatment of patients with CLL.

See also:
What other drugs will affect Revlimid 15 mg?

Results from human in vitro studies show that Revlimid 15 mg is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that Revlimid 15 mg is not likely to cause or be subject to P450-based metabolic drug interactions.

Digoxin

When digoxin was co-administered with multiple doses of Revlimid 15 mg (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 Revlimid 15 mg.

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 REVLI ID.

Warfarin

Co-administration of multiple dose Revlimid 15 mg (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total Revlimid 15 mg 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 Revlimid 15 mg 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.

See also:
What are the possible side effects of Revlimid 15 mg?

The following adverse reactions are described in detail in other sections of the prescribing information:

• Embryo-Fetal Toxicity
• Neutropenia and thrombocytopenia
• Venous and arterial thromboembolism
• Increased Mortality in Patients with CLL
• Second Primary Malignancies
• Hepatotoxicity
• Allergic Reactions
• Tumor Lysis Syndrome
• Tumor Flare Reactions
• Impaired Stem Cell Mobilization

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience

Specific Populations

Newly Diagnosed Multiple Myeloma

Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of Revlimid 15 mg with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).

In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.

In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of Revlimid 15 mg were infection events (28.8%); overall, the median time to the first dose interruption of Revlimid 15 mg was 7 weeks. The most common adverse reactions leading to dose reduction of Revlimid 15 mg in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of Revlimid 15 mg was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of Revlimid 15 mg were infection events (3.4%).

In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous.

Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Table 4: All Adverse Reactions in ≥ 5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*

The following adverse events which have occurred in other indications and not described above have been reported (5%-10%) in patients treated with Revlimid 15 mg monotherapy for mantle cell lymphoma.

General disorders and administration site conditions: Chills

Musculoskeletal and connective tissue disorders: Pain in extremity

Nervous system disorders: Dysgeusia, headache, neuropathy peripheral

Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis

Skin and subcutaneous tissue disorders: Dry skin, night sweats

The following serious adverse events not described above and reported in 2 or more patients treated with Revlimid 15 mg monotherapy for mantle cell lymphoma.

Respiratory, Thoracic, and Mediastinal Disorders: Chronic obstructive pulmonary disease

Infections and Infestations: Clostridium difficile colitis, sepsis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma

Cardiac Disorder: Supraventricular tachycardia

Postmarketing Experience

The following adverse drug reactions have been identified from the worldwide post-marketing experience with Revlimid 15 mg: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.

Revlimid 15 mg (initially known as CC-5013 and marketed as Revlimid 15 mg® by Celgene) is a derivative of thalidomide introduced in 2004. It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic modality, but has also shown efficacy in the hematological disorders known as the myelodysplastic syndromes. [Wikipedia] FDA approved on December 27, 2005.