Revlimid

lenalidomide

Revlimid

Pharmacologic class: Thalidomide analogue

Therapeutic class: Antineoplastic, immunomodulator

Pregnancy risk category X

FDA Box Warning

• If taken during pregnancy, drug may cause fetal death or severe, life-threatening birth defects. Advise females to avoid pregnancy. Drug is available only under RevAssist distribution program, in which only registered prescribers and pharmacists can prescribe and dispense it to registered patients who meet certain conditions. For information, visit www.REVLIMID.com or call 1-888-423-5436.

• Drug has been linked to hematologic toxicity (including significant neutropenia and thrombocytopenia); 80% of patients with myelodysplastic syndrome (MDS) associated with deletion 5q cytogenic abnormality have required dose delays or dosage reductions. For patients with these syndromes, monitor complete blood count (CBC) weekly for first 8 weeks of therapy and at least monthly thereafter. Patients may require dose delay, dosage reduction, or both and require blood product support, growth factors, or both.

• Drug may increase risk of deep vein thrombosis and pulmonary embolism in patients with multiple myeloma who receive it in combination with dexamethasone. Stay alert for signs and symptoms, such as shortness of breath, chest pain, and arm or leg swelling. Prescriber must consider patient's risk factors when deciding whether to use prophylaxis.

Action

Inhibits secretion of proinflammatory cytokines and increases secretion of anti-inflammatory cytokines from peripheral mononuclear cells

Availability

Capsules: 5 mg, 10 mg, 15 mg, 25 mg

Indications and dosages

Transfusion-dependent anemia caused by low- or intermediate-1-risk MDS associated with deletion 5q cytogenic abnormality (with or without additional cytogenic abnormalities)

Adults: 10 mg P.O. daily

Multiple myeloma, in patients who have received at least one prior therapy given with dexamethasone

Adults: 25 mg P.O. daily with water given as single 25-mg capsule on days 1 to 21 of repeated 28-day cycles. Recommended dexamethasone dosage is 40 mg/day on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for first four cycles of therapy, then 40 mg P.O. daily on days 1 to 4 every 28 days.

Dosage adjustment

• Thrombocytopenia
• Neutropenia
• Moderate to severe renal impairment and patients on dialysis

Contraindications

• Hypersensitivity to drug or its components
• Pregnancy

Precautions

Use cautiously in:
• renal impairment
• history of Grade 4 rash associated with thalidomide treatment (use not recommended)
• elderly patients
• patients with childbearing potential
• breastfeeding patients
• children (safety and efficacy not established).

Administration

• Be aware that patient must be able to reliably follow instructions and must understand conditions of RevAssist program to be eligible for drug.
• Administer drug with water.
• Know that before drug is prescribed, female patient should have two negative pregnancy tests (with sensitivity of at least 50 mIU/ml).

Be aware that patients with history of Grade 4 rash associated with thalidomide treatment shouldn't receive drug.

Adverse reactions

CNS: dizziness, headache, hypoesthesia, peripheral neuropathy, insomnia, depression, rigors, fatigue

CV: hypertension, palpitations, deep vein thrombosis

EENT: epistaxis, rhinitis, pharyngitis, nasopharyngitis, sinusitis

GI: diarrhea, loose stools, constipation, nausea, vomiting, abdominal pain, anorexia, dry mouth, dysgeusia

GU: urinary tract infection, dysuria

Hematologic: anemia, thrombocytopenia, neutropenia, leukopenia, febrile neutropenia, granulocytopenia, pancytopenia

Metabolic: hypokalemia, hypomagnesemia, hypothyroidism

Musculoskeletal: arthralgia, back pain, muscle cramps, limb pain, myalgia

Respiratory: cough, dyspnea, exertional dyspnea, bronchitis, upper respiratory tract infection, pneumonia, respiratory distress, pulmonary embolism

Skin: pruritus, rash, dry skin, contusion, ecchymosis, erythema, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis

Other: fever, peripheral edema, pain, chest pain, cellulitis, night sweats, increased sweating, sepsis, tumor lysis syndrome

Interactions

Drug-drug.Digoxin: increased digoxin level

Drug-diagnostic tests.Magnesium, potassium, thyroid function: decrease in levels or function

Patient monitoring

• Monitor CBC weekly for first 3 months, then at least monthly.
• Watch carefully for electrolyte disorders and abnormal thyroid function tests.

Monitor patient closely for signs and symptoms of serious dermatologic reactions; interrupt therapy for Grade 2 to 3 rash. Discontinue drug for angioedema, Grade 4 rash, or exfoliative or bullous rash, or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected; don't resume drug in these patients.

Monitor patient closely for signs and symptoms of tumor lysis syndrome (irregular heartbeat, shortness of breath, high potassium or uric acid levels, impairment of mental ability, renal failure) and take appropriate measures.

Patient teaching

• Instruct patient to swallow capsules whole with water and not to open, chew, or crush them.
• Advise patient to report unusual symptoms or persistence or worsening of known symptoms.
• Urge female patient to use two effective contraceptive methods simultaneously for at least 4 weeks before starting therapy, during therapy, during dosage interruptions, and for 4 weeks after therapy ends. Emphasize that she must use contraception even if she has a history of infertility (unless she has had a hysterectomy).
• Instruct female patient to stop taking drug if she misses a period, has unusual menstrual bleeding, stops using contraception, or suspects pregnancy.
• Advise patient to immediately report unprotected sexual contact or suspected pregnancy.
• Instruct male patient to use latex condom during sexual contact with female of childbearing potential.
• Inform patients they can't donate blood during therapy.
• Tell male patients they can't donate sperm or semen during therapy.
• As appropriate, review all other significant or life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

lenalidomide

(le-na-lid-o-mide) ,

Revlimid

(trade name)

Classification

Therapeutic: antianemics
Pharmacologic: immune response modifiers
Pregnancy Category: X

Indications

genetic implication Transfusion-dependent anemia due to specific myelodysplastic syndromes associated with deletion 5q cytogenetic abnormality.Treatment of multiple myeloma (with dexamethasone) in patients who have received ≥1 previous therapy.Treatment of mantle cell lymphoma in patients whose disease has relapsed or progressed after 2 prior therapies (including bortezomib)

Action

Lenalidomide is a structural analog of thalidomide.
Inhibits secretion of pro-inflammatory cytokines and increases secretion of anti-inflammatory cytokines.

Therapeutic effects

Decreased anemia in certain myelodysplastic syndromes with a decreased requirement for transfusions.
Slows progression of multiple myeloma.

Pharmacokinetics

Absorption: Well absorbed following oral administration. Levels are higher in multiple myeloma patients.
Distribution: Crosses the placenta.
Metabolism and Excretion: 66% excreted unchanged in urine, some renal excretion involves active secretion.
Half-life: 3 hr.

Time/action profile (↓ need for transfusions)

ROUTEONSETPEAKDURATION
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Contraindications/Precautions

Contraindicated in: Hypersensitivity; Obstetric: Pregnancy (contraception must be used in males and females); Lactation: Lactation.
Use Cautiously in: Obstetric: Patients with childbearing potential; Renal impairment (may ↑ risk of adverse reactions; dose ↓ recommended if CCr <60 mL/min); Geriatric: Consider age-related ↓ in renal function; Pediatric: Safety not established.

Adverse Reactions/Side Effects

Central nervous system

  • dizziness (most frequent)
  • fatigue (most frequent)
  • headache (most frequent)
  • insomnia
  • depression

Respiratory

  • cough (most frequent)
  • pharyngitis (most frequent)

Cardiovascular

  • pulmonary embolism (life-threatening)
  • edema (most frequent)
  • chest pain
  • deep vein thrombosis
  • palpitations

Gastrointestinal

  • hepatotoxicity (life-threatening)
  • abdominal pain (most frequent)
  • constipation (most frequent)
  • diarrhea (most frequent)
  • nausea (most frequent)
  • vomiting (most frequent)
  • abnormal taste
  • anorexia
  • dry mouth

Dermatologic

  • stevens-johnson syndrome (life-threatening)
  • toxic epidermal necrolysis (life-threatening)
  • pruritus (most frequent)
  • rash (most frequent)
  • dry skin
  • sweating

Endocrinologic

  • hypothyroidism

Fluid and Electrolyte

  • hypokalemia
  • hypomagnesemia

Hematologic

  • neutropenia
  • thrombocytopenia

Musculoskeletal

  • arthralgia (most frequent)
  • myalgia

Miscellaneous

  • angioedema (life-threatening)
  • malignancy (life-threatening)
  • fever (most frequent)
  • chills
  • tumor flare reaction
  • tumor lysis syndrome

Interactions

Drug-Drug interaction

Risk of neutropenia and thrombocytopenia may ↑ with antineoplastics, immunosuppressants, and radiation therapy.May ↑ digoxin levels.

Route/Dosage

Myelodysplastic Syndromes
Oral (Adults) 10 mg once daily; dose alteration required for hematologic toxicity.

Renal Impairment

Oral (Adults) CCr 30–60 mL/min—5 mg once daily; CCr <30 mL/min (not on dialysis)—2.5 mg once daily; CCr <30 mL/min (requiring dialysis)—2.5 mg once daily (give after dialysis on dialysis days).
Multiple Myeloma
Oral (Adults) 25 mg once daily on days 1–21 of repeated 28–day cycles; should be used with dexamethasone (40 mg once daily on days 1–4, 9–12, and 17–20 of each 28–day cycle for the first four cycles, then 40 mg once daily on days 1–4 of each 28–day cycle); dose alteration required for hematologic toxicity.

Renal Impairment

Oral (Adults) CCr 30–60 mL/min-10 mg once daily; CCr <30 mL/min (not on dialysis)-15 mg every 48 hr; CCr <30 mL/min (requiring dialysis)-5 mg once daily (give after dialysis on dialysis days).
Mantle Cell Lymphoma
Oral (Adults) 25 mg once daily on days 1–21 of repeated 28–day cycles; continue treatment until disease relapse or unacceptable toxicity develops; dose alteration required for hematologic toxicity.

Renal Impairment

Oral (Adults) CCr 30–60 mL/min-10 mg once daily; CCr <30 mL/min (not on dialysis)-15 mg every 48 hr; CCr <30 mL/min (requiring dialysis)-5 mg once daily (give after dialysis on dialysis days).

Availability

Capsules: 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg

Nursing implications

Nursing assessment

  • Assess pregnancy status prior to therapy. Effective contraception must be used for at least 4 wk prior to initiating therapy, during therapy, during dose interruptions, and for 4 wk following discontinuation of therapy, even with a history of infertility unless due to a hysterectomy or patient has been postmenopausal naturally for 24 consecutive months. Pregnancy tests with a sensitivity of at least 50 mIU/mL) must be done within 10–14 days and within 24 hrs of starting therapy. Once treatment has started pregnancy tests should occur weekly during first 4 wk of use, then every 4 wk in females with a regular menstrual cycle and every 2 wk in females with an irregular cycle. Lenalidomide must be discontinued if pregnancy is suspected or confirmed. Suspected fetal exposure must be reported to FDA via MedWatch at 1-800-FDA-1088 and to manufacturer at 1-888-668–2528.
  • Assess for signs of deep venous thrombosis and pulmonary edema (dyspnea, chest pain, arm or leg swelling) periodically during therapy; risk is greater when lenalidomide is administered with dexamethasone.
  • Assess for skin rash. Discontinue lenalidomide if rash occurs; may cause Stevens-Johnson syndrome or Toxic Epidermal Necrolysis..
  • Monitor for signs and symptoms of tumor flare reaction (tender lymph node swelling, low-grade fever, pain rash) in patients with Mantle Cell Lymphoma; may mimic disease progression.
  • Lab Test Considerations: Monitor CBC with differential, platelet count, hemoglobin and hematocrit weekly for first 8 wk of therapy and at least monthly thereafter. May require dose interruption and/or reduction and use of blood support and/or growth factors.
    • May cause neutropenia with an onset of 42 days (range 4–411 days) and recovery time of 17 days (range 2–170 days). For Mutiple Myeloma starting dose is 25 mg/day — If neutropenia develops and neutrophils fall to <1000/mcl interrupt therapy, add G-CSF, and follow CBC weekly. When neutrophols return to ≥1000/mcl and neutropenia is the only toxicity, resume lenalidomide at 25 mg daily. If neutrophils return to ≥1000/mcl and if other toxicity, resume lenalidomide at 15 mg daily. For each subsequent drop <1000/mcl interrupt therapy. If neutrophils return to ≥1000/mcl, resume at 5 mg less than previous dose. Do not administer doses below 5 mg. For Myelodysplastic Syndrome starting dose is 10 mg/day —if neutropenia develops within 4 wk of starting at a 10 mg/day dose in a patient with a baseline neutrophil count (ANC) ≥1000/mcL and ANC falls to <750/mcL interrupt lenalidomide therapy and resume at 5 mg/day dose when ANC returns to ≥1000/mcL. If baseline ANC is <1000/mcL and ANC falls to <500/mcL, interrupt therapy and resume at 5 mg/day dose when ANC returns to ≥500/mcL. If neutropenia develops after 4 wk of therapy at 10 mg/day dose, and ANC <500/mcL for ≥7 days or <500/mcL associated with fever ≥38.5°C, interrupt therapy and resume at 5 mg/day when ANC returns to ≥500/mcL. If neutropenia develops at 5 mg/day dose and ANC <500/mcL for ≥7 days or <500/mcL associated with fever ≥38.5°C, interrupt therapy and resume at 2.5 mg daily when ANC returns to ≥500/mcL. For Mantle Cell Lymphomastarting dose is 25 mg/day on days 1–21 of repeated 28–day cycles — If neutrophils fall to <1000/mcl for at least 7 days or fall to <1000/mcl with fever ≥38.5°C or fall to <500/mcl, interrupt therapy and follow CBC weekly. If neutrophils return to ≥1000/mcl resume at 5 mg less than previous dose. Do not administer doses below 5 mg.
    • May cause thrombocytopenia with an onset of 28 days (range 8–290 days) and a recovery in 22 days (range 5–224 days). For Multiple Myeloma starting dose is 25 mg/day— If platelets fall to <30,000/mcl interrupt therapy and follow CBC weekly. When platelets return to ≥30,000/mcl restart lenalidomide at 15 mg/day. For each subsequent drop <30,000/mcl interrupt therapy. When platelets return to ≥30,000/mcl resume at 5 mg less than previous dose. Do not administer doses below 5 mg. For Myelodysplastic Syndrome starting dose is 10 mg/day —If thrombocytopenia develops within 4 wk of starting a 10 mg dose in a patient with a baseline of ≥100,000/mcL, and platelets fall to <50,000/mcL interrupt lenalidomide therapy and resume at 5 mg/day dose when platelets return to >50,000/mcL. If baseline was <100,000/mcL and platelets fall to 50% of baseline value interrupt therapy. If baseline ≥60,000/mcL and returns to ≥50,000/mcL or if baseline is <60,000/mcL and returns to ≥30,000/mcL resume therapy at 5 mg/day. If thrombocytopenia develops after 4 wk of treatment at 10 mg/day and platelets are <30,000/mcL or <50,000/mcL with platelet transfusions, interrupt therapy. When platelets return to ≥30,000/mcL without hemostatic failure resume therapy at 2.5 mg/day. For Mantle Cell Lymphomastarting dose is 25 mg/day on days 1–21 of repeated 28–day cycles — If platelets fall to <50,000/mcl interrupt therapy and follow CBC weekly. If platelets return to ≥50,000/mcl resume at 5 mg less than previous dose. Do not administer doses below 5 mg.
    • Monitor liver enzymes periodically during therapy. Stop therapy if enzymes are elevated; may resume when return to normal or decrease dose.
    • May cause anemia and leukopenia.
    • May cause hypokalemia, hypomagnesemia, and ↑ ALT levels.

Potential Nursing Diagnoses

Deficient knowledge, related to medication regimen (Patient/Family Teaching)

Implementation

  • Patients must meet the following conditions before receiving therapy: they must understand the risks and be able to carry out instructions, must be capable of complying with patient registration and patient survey in the Revlimid REMS program, must comply with contraceptive measures, have received both oral and written warnings of the risks of contraception failure and the need for two reliable forms of contraception (females) or the risks of exposing a fetus to the drug and the need to use a latex condom during sexual conduct with a female with childbearing potential (male), acknowledge understanding of these warnings in writing, and if the patient is between 12 and 18 years of age, their parent or legal guardian is to read the educational materials and agree to try to ensure compliance with conditions.
    • Lenalidomide can only be prescribed by health care providers registered in the Revlimide REMS program and only be dispensed by a pharmacy that is registered in the Revlimid REMS program.
  • Oral: Administer once daily, at the same time each day, with water. Capsules should be swallowed whole; do not open, break, or chew.

Patient/Family Teaching

  • Instruct patient to take lenalidomide as directed and to comply with all aspects of the Revlimid REMSprogram. Take missed doses as soon as remembered within 12 hr of dose missed. If more than 12 hrs, skip dose and return to next scheduled dose; do not administer 2 doses within 12 hrs. Inform patient that they are required to participate in a telephone survey and patient registry while taking lenalidomide. Details are available at www.REVLIMID.com.
  • Caution patient not to share lenalidomide with anyone, even someone who has similar symptoms.
  • Advise patient to notify health care professional if rash, shortness of breath, chest pain, or arm or leg swelling occur.
  • May cause dizziness. Caution patient to avoid driving and other activities requiring alertness until response to medication is known.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
  • Inform female patients that they must use one highly effective method (IUD, hormonal contraceptive, tubal ligation, partner's vasectomy) and one additional method (latex condom, diaphragm, cervical cap) AT THE SAME TIME for at least 4 wk before, during therapy and interruptions of therapy, and for 4 wk following discontinuation of therapy.
  • Male patients receiving lenalidomide must always use a latex condom during and for up to 28 days following discontinuation during any contact with females with childbearing potential, even if they have undergone a successful vasectomy.
  • Advise patient that they cannot donate blood and male patients cannot donate sperm while taking lenalidomide.

Evaluation/Desired Outcomes

  • Decreased anemia in deletion 5q myelodysplastic syndromes with a decreased requirement for transfusion.
  • Slowing of multiple myeloma progression.
  • Slowing progression of mantle cell lymphoma.

Revlimid

a trademark for lenalidomide.
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Alexander says that growth opportunities for Revlimid, the company's treatment for multiple myeloma, expanded and led investors to place an even higher valuation on earnings than he had anticipated.
The approval of REVLIMID is based upon the safety and efficacy results of multiple pivotal randomized phase III international clinical trials in patients with relapsed or refractory multiple myeloma.
Patients treated with Kyprolis (carfilzomib) for Injection in combination with Revlimid (lenalidomide) and low-dose dexamethasone (KRd) lived significantly longer without their disease worsening (median 26.