Revlimid

Immunomodulators, Angiogenesis Inhibitors

Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Wash the exposed area immediately and thoroughly with soap and water if powder from lenalidomide capsules come into contact with skin; flush thoroughly with water if lenalidomide come into contact with mucous membranes.
 
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

Take lenalidomide with or without food at approximately the same time each day.
Swallow capsules whole; do not crush, break, or chew.
If a dose is missed, take within 12 hours of missing the dose. If more than 12 hours have passed, skip the dose of the day and take the dose the next day at the scheduled time.
No more than a 28-day supply should be dispensed at one time.

neutropenia / Delayed / 28.0-59.0
thrombocytopenia / Delayed / 8.0-50.0
leukopenia / Delayed / 4.0-24.0
thromboembolism / Delayed / 0-21.5
anemia / Delayed / 4.0-18.0
lymphopenia / Delayed / 2.8-17.0
hepatotoxicity / Delayed / 0-15.0
new primary malignancy / Delayed / 0.4-14.9
infection / Delayed / 0-12.0
diarrhea / Early / 2.0-10.0
thrombosis / Delayed / 2.0-10.0
heart failure / Delayed / 0-10.0
renal failure (unspecified) / Delayed / 0-9.0
fatigue / Early / 1.0-9.0
asthenia / Delayed / 0-8.0
nausea / Early / 0-7.0
atrial fibrillation / Early / 0-7.0
back pain / Delayed / 0-7.0
hypokalemia / Delayed / 0-7.0
pleural effusion / Delayed / 0-7.0
rash / Early / 1.0-7.0
weakness / Early / 0-6.0
hypophosphatemia / Delayed / 0-6.0
dyspnea / Early / 0-6.0
cataracts / Delayed / 0-6.0
pancytopenia / Delayed / 0-4.0
abdominal pain / Early / 0-4.0
vomiting / Early / 0-4.0
pulmonary embolism / Delayed / 1.0-4.0
peripheral neuropathy / Delayed / 0-4.0
elevated hepatic enzymes / Delayed / 0-4.0
hypocalcemia / Delayed / 0-4.0
anorexia / Delayed / 0-3.0
syncope / Early / 0-3.0
dizziness / Early / 0-3.0
hypotension / Rapid / 0-3.0
bone pain / Delayed / 0-3.0
dehydration / Delayed / 0-3.0
fever / Early / 0-3.0
pruritus / Rapid / 0-2.8
myocardial infarction / Delayed / 0-2.4
stroke / Early / 0-2.3
constipation / Delayed / 0-2.0
headache / Early / 0-2.0
chest pain (unspecified) / Early / 0-2.0
sinus tachycardia / Rapid / 0-2.0
arthralgia / Delayed / 0-2.0
muscle cramps / Delayed / 0-2.0
hyperbilirubinemia / Delayed / 0-2.0
gout / Delayed / 0-2.0
hyponatremia / Delayed / 0-2.0
weight loss / Delayed / 0-2.0
depression / Delayed / 0-2.0
diabetes mellitus / Delayed / 0-2.0
nephrotoxicity / Delayed / 0-1.7
supraventricular tachycardia (SVT) / Early / 0-1.1
cough / Delayed / 0-1.1
tumor lysis syndrome (TLS) / Delayed / 0-1.1
dysgeusia / Early / 0-1.0
dyspepsia / Early / 0-1.0
paresthesias / Delayed / 0-1.0
musculoskeletal pain / Early / 0-1.0
myalgia / Early / 0-1.0
hyperhidrosis / Delayed / 0-1.0
hypoxia / Early / 0-1.0
pulmonary hypertension / Delayed / 0-1.0
epistaxis / Delayed / 0-1.0
pharyngitis / Delayed / 0-1.0
influenza / Delayed / 0-1.0
tumor flare / Delayed / 0-1.0
hyperuricemia / Delayed / 0-1.0
hemolytic anemia / Delayed / 1.0
GI bleeding / Delayed / 1.0
bradycardia / Rapid / 1.0
ocular hypertension / Delayed / 1.0
coagulopathy / Delayed / Incidence not known
intracranial bleeding / Delayed / Incidence not known
GI obstruction / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
biliary obstruction / Delayed / Incidence not known
skin cancer / Delayed / Incidence not known
lymphoma / Delayed / Incidence not known
leukemia / Delayed / Incidence not known
spinal cord compression / Delayed / Incidence not known
cardiac arrest / Early / Incidence not known
cardiomyopathy / Delayed / Incidence not known
pulmonary edema / Early / Incidence not known
respiratory arrest / Rapid / Incidence not known
bone fractures / Delayed / Incidence not known
cholecystitis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
visual impairment / Early / Incidence not known
progressive multifocal leukoencephalopathy / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
erythema multiforme / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
pericarditis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
myocarditis / Delayed / Incidence not known
graft-versus-host disease (GVHD) / Delayed / Incidence not known
organ transplant rejection / Delayed / Incidence not known
fetal death / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known

peripheral edema / Delayed / 0-26.0
blurred vision / Early / 0-17.0
edema / Delayed / 0-10.0
hypertension / Early / 0-8.0
hypothyroidism / Delayed / 0-7.0
dysuria / Early / 0-7.0
hypomagnesemia / Delayed / 0-7.0
hyperglycemia / Delayed / 0-7.0
stomatitis / Delayed / 0-5.0
palpitations / Early / 0-5.0
erythema / Early / 0-5.0
pneumonitis / Delayed / 0-1.0
insomnia / Early / 0-1.0
angina / Early / 1.0
impotence (erectile dysfunction) / Delayed / 1.0
hallucinations / Early / 1.0
hemolysis / Early / Incidence not known
bleeding / Early / Incidence not known
colitis / Delayed / Incidence not known
gastritis / Delayed / Incidence not known
melena / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
phlebitis / Rapid / Incidence not known
dysarthria / Delayed / Incidence not known
migraine / Early / Incidence not known
aphasia / Delayed / Incidence not known
hyperthyroidism / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
hypoglycemia / Early / Incidence not known
hypernatremia / Delayed / Incidence not known
wheezing / Rapid / Incidence not known
interstitial lung disease / Delayed / Incidence not known
confusion / Early / Incidence not known
lymphadenopathy / Delayed / Incidence not known
bullous rash / Early / Incidence not known
impaired stem cell mobilization / Delayed / Incidence not known

ecchymosis / Delayed / 0-55.0
tremor / Early / 0-21.0
rhinitis / Early / 0-15.0
xerosis / Delayed / 0-14.0
sinusitis / Delayed / 0-14.0
hypoesthesia / Delayed / 0-10.0
night sweats / Early / 0-10.0
vertigo / Early / 1.0-10.0
chills / Rapid / 0-10.0
lethargy / Early / 0-10.0
xerostomia / Early / 0-7.0
malaise / Early / 0-7.0
rhinorrhea / Early / 0-5.0
hirsutism / Delayed / 1.0
skin hyperpigmentation / Delayed / 1.0
libido decrease / Delayed / 1.0
gastroesophageal reflux / Delayed / Incidence not known
hoarseness / Early / Incidence not known
pelvic pain / Delayed / Incidence not known

Venous (e.g., deep vein thrombosis, pulmonary embolism) and arterial (e.g., myocardial infarction, stroke) thromboembolism has been reported with lenalidomide use. There was an increased incidence of venous and arterial thrombotic events in patients with multiple myeloma who received lenalidomide in combination with dexamethasone compared with dexamethasone alone in clinical trials. Patients with hyperlipidemia, hypertension, tobacco smoking, or a history of thrombosis may be at greater risk; minimize modifiable risk factors when possible. In clinical trials that did not use thromboprophylaxis, the overall rate of thrombotic events was higher in patients with refractory or relapsed multiple myeloma who received lenalidomide plus dexamethasone compared with dexamethasone alone; the median time to first thrombotic event was 2.8 months. Thromboprophylaxis is recommended in patients with multiple myeloma who receive lenalidomide and dexamethasone; the agent used for prophylaxis may be chosen based on an assessment of the patient’s underlying risks. Monitor for signs of thromboembolism and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.

Hematologic toxicity, including severe thrombocytopenia and neutropenia, has been reported with lenalidomide therapy. Monitor complete blood counts (CBC) in patients receiving lenalidomide therapy as follows: for myelodysplastic syndrome, obtain a CBC weekly for 8 weeks and then monthly thereafter; for multiple myeloma, obtain a CBC weekly for the first 2 cycles, on days 1 and 15 of cycle 3, and then every 4 weeks thereafter; for mantle cell lymphoma, obtain a CBC weekly for the first 4 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter; and for follicular or marginal zone lymphoma, obtain a CBC weekly for the first 3 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter. Monitor neutropenic patients for signs of infection. Advise patients to report unusual bleeding or bruising, especially if they are also receiving other agents that increase the risk of bleeding. Therapy interruption and dose adjustments are necessary in patients who develop significant hematologic toxicity.

Lenalidomide is contraindicated for use during pregnancy. Lenalidomide is structurally similar to thalidomide, which is a known teratogen that causes severe, life-threatening human birth defects. Lenalidomide produced limb malformations in the offspring of pregnant female monkeys. It may cause birth defects or intrauterine fetal death if administered during pregnancy. In order to prevent fetal exposure, it is only available through a restricted distribution program, the Lenalidomide REMS program. This program requires prescribers, pharmacists, and patients to comply with certain conditions prior to prescribing, dispensing, or receiving lenalidomide. It can be prescribed only by licensed prescribers who are registered in the Lenalidomide REMS program and understand the potential risk of teratogenicity if used during pregnancy. If pregnancy does occur during treatment, immediately discontinue lenalidomide. Prescribers are encouraged to report all cases of pregnancy to the REMS Call Center at 1-888-423-5436 or to the FDA MedWatch program at 1-800-332-1088. Refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Counsel patients about the reproductive risk and contraception requirements during lenalidomide treatment. Do not initiate therapy in females of reproductive potential (e.g., sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months) until pregnancy testing is performed twice with confirmed negative results. Administer the first test within 10 to 14 days and the second test 24 hours prior to prescribing lenalidomide. Once treatment is started, continue pregnancy testing weekly during the first 4 weeks of treatment, then every 4 weeks in females with regular menstrual cycles and every 2 weeks in females with irregular menstrual cycles. Effective contraception must be used by all females of reproductive potential for at least 4 weeks before beginning treatment, during therapy and dosage interruptions, and for 4 weeks following discontinuation of therapy. Women must commit to abstain from heterosexual intercourse or to use 2 methods of reliable birth control, including at least 1 highly effective method (e.g., intrauterine device (IUD), hormonal contraception, tubal ligation, or partner's vasectomy) and 1 additional effective method (e.g., latex condom, diaphragm, or cervical cap). Follow these contraceptive requirements even in patients with a history of infertility, unless a hysterectomy has been performed. Discontinue treatment, test for pregnancy, and counsel any woman of reproductive potential who experiences menstrual irregularity (e.g., dysfunctional uterine bleeding) or misses her period. Advise patients that if her doctor is not available, she can call 1-888-423-5436 for information on emergency contraception. Lenalidomide passes into semen and there is potential for male-mediated teratogenicity. Male patients must use barrier contraception (latex condom) during sexual intercourse with a woman of reproductive potential while on therapy, during interruptions, and for 4 weeks after discontinuing therapy, even if he has undergone successful vasectomy. Male patients should be warned against sperm donation during lenalidomide therapy and for up to 4 weeks after stopping it.[58806]

Revlimid

Rx

Biologic response modifier with immunomodulatory, antiangiogenic, and antineoplastic properties
Used for adult patients with myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma
Risk of birth defects or embryo-fetal death if used during pregnancy; routine testing required; prescribers, pharmacies, and patients must register in the Lenalidomide REMS program (1-888-423-5436)

Baseline hepatic impairment: no dosage adjustment is necessary for mild hepatic impairment (defined as total bilirubin level of greater than 1 to 1.5-times upper limit normal (ULN) or any AST level greater than the ULN). Lenalidomide use has not been evaluated in patients with moderate to severe hepatic impairment.
Treatment-related hepatotoxicity: interrupt lenalidomide therapy; when the toxicity resolves to baseline values, may resume therapy at a lower dose.

Adjust the starting dose of lenalidomide in patients with renal impairment based on baseline creatinine clearance (CrCl) values and indication for use. Subsequent dose adjustments are based on individual patient tolerance.
Mantle cell lymphoma (MCL) and Combination Therapy in Multiple Myeloma
CrCl 30 to 60 mL/min: 10 mg PO once daily; in patients with multiple myeloma, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10-mg dose without dose-limiting toxicity. CrCl less than 30 mL/min (not requiring dialysis): 15 mg PO every other day. CrCl less than 30 mL/min (requiring dialysis): 5 mg PO once daily; administer the dose following dialysis on dialysis days.
Myelodysplastic syndromes (MDS) and Maintenance Therapy in Multiple Myeloma
CrCl 30 to 60 mL/min: 5 mg PO once daily. CrCl less than 30 mL/min (not requiring dialysis): 2.5 mg PO once daily. CrCl less than 30 mL/min (requiring dialysis): 2.5 mg PO once daily; administer the dose following dialysis on dialysis days.
Follicular Lymphoma or Marginal Zone LymphomaCrCl 30 to 60 mL/min: 10 mg PO once daily; consider escalating the dose to 15 mg/day after 2 cycles if the patient tolerates 10 mg/day.CrCl less than 30 mL/min (not requiring dialysis): 5 mg PO once daily.CrCl less than 30 mL/min (requiring dialysis): 5 mg PO once daily; administer the dose following dialysis on dialysis days.

Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Darbepoetin Alfa: (Moderate) Concomitant use of lenalidomide with erythropoietic agents such as darbepoetin alfa may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Denosumab: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
Digoxin: (Moderate) Concomitant use of lenalidomide and digoxin may result in increased digoxin levels and exposure; use these drugs together with caution. Monitor digoxin levels periodically and as clinically indicated in patients who require both lenalidomide and digoxin. The Cmax and AUC values of digoxin were increased by 14% in patients who received digoxin following multiple oral doses of lenalidomide 10 mg/day.
Epoetin Alfa: (Moderate) Concomitant use of lenalidomide with erythropoietic agents such as epoetin alfa may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and erythropoietic agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Estrogens: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Warfarin: (Minor) Close monitoring of PT levels and INR in patients with multiple myeloma who require both lenalidomide and warfarin is recommended. According to the manufacturer, the use of warfarin in patients with blood dyscrasias is contraindicated. Therefore, to minimize the bleeding risk, warfarin should be used cautiously in patients receiving antineoplastic agents that cause myelosuppression or blood dyscrasias. In addition, effects of antineoplastic agents on protein synthesis as well as protein binding may lead to transient changes in a patient's INR while receiving warfarin. The INR may increase and/or decrease throughout the chemotherapy cycle leading to supra- or sub-therapeutic values; monitor warfarin therapy closely. There was no change in pharmacokinetic parameters for either agent when a single dose of warfarin 25 mg PO was administered following multiple oral doses of lenalidomide 10 mg/day. Expected PT and INR changes from warfarin use occurred.
Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

Lenalidomide/Revlimid Oral Cap: 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg

25 mg/day PO.

25 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Mechanism of Action: The mechanism of action of lenalidomide is not completely understood. Lenalidomide possesses immunomodulatory properties. Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells. It inhibited cell proliferation with varying effectiveness (IC50s) in some but not all cell lines. Of cell lines tested, lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) but was much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and other cell lines without chromosome 5 deletions. Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.In addition to immunomodulatory properties, lenalidomide possesses antiangiogenic properties. Lenalidomide attenuates growth factor induced angiogenesis and inhibits growth factor induced endothelial cell migration. The antimigratory and thus, antiangiogenic effects of lenalidomide may be a result of Akt phosphorylation inhibition. The inhibition of of growth factor induced Akt phosphorylation correlated with the inhibition of growth factor induced endothelial cell migration. Growth factor induced endothelial cell migration and subsequent tube formation are known to be P13K-Akt-dependent. Activation of the Akt pathway plays a crucial role in malignant transformation, chemoresistance, and invasiveness by inducing angiogenesis and cell survival, growth, and migration. Lenalidomide inhibits the phosphorylation of Akt in response to basic fibroblast growth factor.Lenalidomide appears to cause cytogenetic changes that correlate with hematologic response in patients with myelodysplastic syndromes. Myelodysplastic syndromes associated with a 5q31.1 deletion appear to be very sensitive to lenalidomide. An absence of the pretreatment cytogenetic abnormality on standard metaphase analysis occurred in 9 of 12 patients with del(5)(q31.1) who received lenalidomide 25 mg daily, 10 mg daily, or 10 mg daily for each 21 of 28 days for 4 months. Eight of the nine patients had an isolated del(5)(q31.1); the other patient also had trisomy 21. The one patient in the study with the chromosomal abnormality t(1;22)(q21p11.2) also had a complete cytogenetic response. In addition to a complete cytogenetic response, an additional patient with del(5)(q31.1) had a reduction in abnormal cells by at least 50%. Thus, 10 of the 12 patients with del(5)(q31.1) had a cytogenetic response, and these 10 patients also had an erythroid response defined as at least a sustained hemoglobin concentration increase of 1 g/dl or at least a 50% reduction in transfusion need. Neither of the 2 patients with del (20)(q11.2) nor any of the 5 patients with other chromosomal abnormalities (+19, t(3;3)(q21;q26.3), +8, -X, and complex) had even a 50% reduction in abnormal cells. Three patients with a 5q31.1 deletion acquired new translocations involving chromosome 7 despite the complete suppression of the initial karyotypic abnormality. An additional patient with a normal karyotype before lenalidomide receipt had deletion 20 (q21q13.1). The clinical significance of the acquired translocations is unknown. Although 3 of the 4 patients remained free from the need for transfusion, one patient had cytogenetic and disease progression.

Lenalidomide is administered orally. Lenalidomide is approximately 30% bound to plasma proteins. It does pass into semen. Metabolism is limited with unchanged lenalidomide representing most of the drug present in circulation; 2 metabolites (hydroxy-lenalidomide and N-acetyl-lenalidomide) represent less than 5% of the parent drug found in circulation. Lenalidomide is primarily eliminated renally; the renal clearance exceeds the glomerular filtration rate. Following a radiolabeled dose of lenalidomide 25 mg in healthy subjects, about 82% of the dose was excreted in the urine within 24 hours, and 90% and 4% of the dose was excreted in the urine and feces, respectively, within 10 days. The metabolites hydroxy-lenalidomide and N-acetyl-lenalidomide accounted for 4.6% and 1.8% of the excreted dose, respectively. The mean elimination half-life is 3 hours in healthy subjects and 3 to 5 hours in patients with multiple myeloma, myelodysplastic syndrome, or mantle cell lymphoma. Multiple dosing at the recommended dose does not result in drug accumulation.
 
Affected cytochrome P450 (CYP450) isoenzymes or drug transporters: P-gp
Lenalidomide is not metabolized by the CYP450 pathway; therefore, it is not expected to inhibit or induce CYP450 isoenzymes. In vitro, lenalidomide is a P-glycoprotein (P-gp) substrate but not a P-gp inhibitor. However, the pharmacokinetic values (i.e., Cmax, AUC) of lenalidomide were not significantly altered when lenalidomide 25 mg was administered concurrently with multiple doses of the potent P-gp inhibitor quinidine 600 mg twice daily in healthy volunteers. When lenalidomide 25 mg was administered with the P-gp inhibitor/substrate temsirolimus 25 mg, the pharmacokinetic values of lenalidomide, temsirolimus, and the temsirolimus metabolite (i.e., sirolimus) were not significantly changed. 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 or OATP2); organic cation transporters (OCT) OCT1 and OCT2; multidrug and toxin extrusion protein (MATE) MATE1; and organic cation transporters novel (OCTN) OCTN1 and OCTN2. Additionally, it is not an inhibitor of bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. 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.

Oral lenalidomide is rapidly absorbed with the maximum plasma concentrations occurring 0.5 to 6 hours post-dose following single and multiple doses in patients with multiple myeloma (MM) or myelodysplastic syndromes (MDS). Both the Cmax and AUC values increased proportionally with dose following single and multiple doses. The oral absorption rate in patients with mantle cell lymphoma was similar to that of patients with MM or MDS. In healthy subjects, the administration of a single 25-mg lenalidomide dose with a high-fat meal resulted in a decrease in Cmax by about 20% and a decrease in AUC by about 50%. However, lenalidomide may be taken with or without food.

Lenalidomide is contraindicated for use during pregnancy. Lenalidomide is structurally similar to thalidomide, which is a known teratogen that causes severe, life-threatening human birth defects. Lenalidomide produced limb malformations in the offspring of pregnant female monkeys. It may cause birth defects or intrauterine fetal death if administered during pregnancy. In order to prevent fetal exposure, it is only available through a restricted distribution program, the Lenalidomide REMS program. This program requires prescribers, pharmacists, and patients to comply with certain conditions prior to prescribing, dispensing, or receiving lenalidomide. It can be prescribed only by licensed prescribers who are registered in the Lenalidomide REMS program and understand the potential risk of teratogenicity if used during pregnancy. If pregnancy does occur during treatment, immediately discontinue lenalidomide. Prescribers are encouraged to report all cases of pregnancy to the REMS Call Center at 1-888-423-5436 or to the FDA MedWatch program at 1-800-332-1088. Refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.