Gleevec


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imatinib mesylate

Gleevec, Glivec (UK)

Pharmacologic class: Protein-tyrosine kinase inhibitor

Therapeutic class: Antineoplastic

Pregnancy risk category D

Action

Inhibits proliferation of Bcr-Abl tyrosine kinase, an abnormal chromosome protein found in most patients with chronic myeloid leukemia (CML). This inhibition suppresses tumor growth.

Availability

Tablets: 100 mg, 400 mg

Indications and dosages

Philadelphia chromosome-positive (Ph+) CML

Adults: During chronic phase, 400 mg P.O. daily as a single dose; during accelerated phase or blast crisis, 600 mg P.O. daily as a single dose. May increase to 600 mg P.O. daily during chronic phase or to 800 mg P.O. daily (400 mg b.i.d.) during accelerated phase or blast crisis in absence of severe adverse drug reaction and severe non-leukemia-related neutropenia or thrombocytopenia in following circumstances: disease progression at any time, failure to achieve satisfactory hematologic response after at least 3 months of treatment, failure to achieve cytogenetic response after 6 to 12 months of treatment, or loss of previously achieved hematologic or cytogenetic response.

Newly diagnosed Ph+ CML

Children: 340 mg/m2/day P.O. as once-daily dose; or, daily dose may be split into two (once in morning and once in evening). Daily dose not to exceed 600 mg.

Ph+ chronic-phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy

Children: 260 mg/m2/day P.O. as once-daily dose; or, daily dose may be split into two (once in morning and once in evening).

Relapsed/refractory Ph+ acute lymphoblastic leukemia

Adults: 600 mg P.O. daily as single dose

Myelodysplastic/myeloproliferative diseases

Adults: 400 mg P.O. daily as single dose

Aggressive systemic mastocytosis (ASM)

Adults: Recommended dosage is 400 mg P.O. daily as single dose for patients without D816V c-Kit mutation. If c-Kit mutational status is unknown or unavailable, 400 mg daily may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a starting dose of 100 mg P.O. daily is recommended. Dosage increase from 100 to 400 mg for these patients may be considered in absence of adverse drug reactions if assessments show insufficient response to therapy.

Hypereosinophilic syndrome/chronic eosinophilic leukemia

Adults: Recommended dosage is 400 mg P.O. daily as single dose

Dermatofibrosarcoma protuberans

Adults: Recommended dosage is 800 mg P.O. daily (given as 400 mg twice daily)

Kit (CD117)-positive unresectable or metastatic malignant GI stromal tumors

Adults: 400 to 600 mg P.O. daily

Dosage adjustment

• Hepatic or hematologic impairment
• Concurrent use of potent CYP3A4 inducers, such as rifampin or phenytoin

Contraindications

• Hypersensitivity to drug or its components

Precautions

Use cautiously in:
• renal or hepatic impairment
• pregnant or breastfeeding patients
• children younger than age 2 (safety and efficacy not established).

Administration

• Give with meal and large glass of water.
• Disperse tablets in glass of water or apple juice for patients unable to swallow tablets. Place required number of tablets in appropriate volume of beverage (approximately 50 ml for 100-mg tablet, and 200 ml for 400-mg tablet) and stir with spoon. Administer suspension immediately after complete disintegration of tablets.

Adverse reactions

CNS: headache, fatigue, asthenia, malaise, insomnia, headache, cerebral hemorrhage

CV: heart failure, ventricular dysfunction

GI: nausea, vomiting, diarrhea, constipation, anorexia, abdominal pain or cramps, dyspepsia, GI hemorrhage

Hematologic: anemia, hemorrhage, neutropenia, thrombocytopenia, gastrointestinal perforation

Hepatic: hepatotoxicity

Metabolic: hypokalemia, fluid retention

Musculoskeletal: myalgia, muscle cramps, musculoskeletal or joint pain

Respiratory: cough, dyspnea, pneumonia

Skin: rash, pruritus, night sweats, petechiae bullous dermatitis, reactions (erythema multiforme, Stevens-Johnson syndrome)

Other: weight gain, edema, fever

Interactions

Drug-drug.Cyclosporine, dihydropyridine calcium channel blockers, pimozide, some HMG-CoA reductase inhibitors, triazolobenzodiazepines: increased blood levels of these drugs

CYP450-3A4 inducers (such as carbamazepine, dexamethasone, phenobarbital, phenytoin): increased metabolism and decreased blood level of imatinib

CYP450-3A4 inhibitors (such as clarithromycin, erythromycin, itraconazole, ketoconazole): decreased metabolism and increased blood level of imatinib

Warfarin: altered warfarin metabolism

Drug-diagnostic tests.Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, creatinine, hepatic enzymes: increased values

Hemoglobin, neutrophils, platelets, potassium: decreased values

Drug-herbs.St. John's wort: decreased imatinib effects

Patient monitoring

• Monitor for GI distress. Provide small, frequent meals; consult dietitian if nausea and vomiting persist.

Monitor CBC before therapy starts and regularly during therapy. Expect to adjust dosage if bone marrow depression occurs.

Evaluate for signs and symptoms of bleeding, edema, and fluid retention.
• Measure daily weight and fluid intake and output.
• Monitor liver function tests.

Patient teaching

• Advise patient to take with a meal and a large glass of water.
• Instruct patient to avoid potential sources of infection, such as crowds and people with known infections.
• Tell patient drug may cause sudden weight gain and fluid retention. Instruct him to weigh himself daily.

Advise patient to immediately report sudden weight gain, swelling, difficulty breathing, signs or symptoms of infection, unusual bleeding or bruising, or jaundice.
• Tell patient he'll undergo frequent blood testing to monitor drug effects.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and herbs mentioned above.

imatinib

(i-mat-i-nib) ,

Gleevec

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: enzyme inhibitors
Pregnancy Category: D

Indications

genetic implication Newly diagnosed Philadelphia positive (Ph+) chronic myeloid leukemia (CML).CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha treatment.genetic implication Kit (CD117) positive metastatic/unresectable malignant gastrointestinal stomal tumors (GIST).Adjuvant treatment following resection of Kit (CD117) positive GIST.genetic implication Pediatric patients with Ph+ CML after failure of bone marrow transplant or resistance to interferon-alpha.genetic implication Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL).genetic implication Newly diagnosed Ph+ ALL (in combination with chemotherapy).genetic implication Myelodysplastic/myelyproliferative disease (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.genetic implication Aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown.Hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CEL).Unresectable, recurrent, or metastatic dermatofibrosarcoma protuberans (DFSP).

Action

Inhibits kinases which may be produced by malignant cell lines.

Therapeutic effects

Inhibits production of malignant cell lines with decreased proliferation of leukemic cells in CML, HES/CEL, and ALL and malignant cells in GIST, MDS/MPD, ASM, and DFSP.

Pharmacokinetics

Absorption: Well absorbed (98%) following oral administration.
Distribution: Unknown.
Protein Binding: 95%.
Metabolism and Excretion: Mostly metabolized by the CYP3A4 enzyme system to N-demethyl imatinib, which is as active as imatinib. Excreted mostly in feces as metabolites. 5% excreted unchanged in urine.
Half-life: Imatinib—18 hr; N-desmethyl imatinib—40 hr.

Time/action profile (blood levels of imatinib)

ROUTEONSETPEAKDURATION
POunknown2–4 hr24 hr

Contraindications/Precautions

Contraindicated in: Hypersensitivity; Obstetric: Potential for fetal harm; Lactation: Potential for serious adverse reactions in nursing infants; breast feeding should be avoided.
Use Cautiously in: Hepatic impairment (dose ↓ recommended if bilirubin >3 times normal or liver transaminases >5 times normal);Cardiac disease (severe HF and left ventricular dysfunction may occur); Pediatric: Children <1 yr (safety not established); Geriatric: ↑ risk of edema.

Adverse Reactions/Side Effects

Central nervous system

  • fatigue (most frequent)
  • headache (most frequent)
  • weakness (most frequent)
  • dizziness
  • somnolence

Ear, Eye, Nose, Throat

  • epistaxis (most frequent)
  • nasopharyngitis (most frequent)
  • blurred vision

Respiratory

  • cough (most frequent)
  • dyspnea (most frequent)
  • pneumonia (most frequent)

Gastrointestinal

  • hepatotoxicity (life-threatening)
  • abdominal pain (most frequent)
  • anorexia (most frequent)
  • constipation (most frequent)
  • diarrhea (most frequent)
  • dyspepsia (most frequent)
  • nausea (most frequent)
  • vomiting (most frequent)

Dermatologic

  • petechiae (most frequent)
  • pruritus (most frequent)
  • skin rash (most frequent)

Fluid and Electrolyte

  • edema (including pleural effusion, pericardial infusion, anasarca, superficial edema and fluid retention) (most frequent)
  • hypokalemia (most frequent)

Endocrinologic

  • ↓ growth (in children)
  • hypothyroidism

Hematologic

  • bleeding (life-threatening)
  • neutropenia (life-threatening)
  • thrombocytopenia (life-threatening)

Metabolic

  • weight gain (most frequent)

Musculoskeletal

  • arthralgia (most frequent)
  • muscle cramps (most frequent)
  • musculoskeletal pain (most frequent)
  • myalgia (most frequent)

Miscellaneous

  • tumor lysis syndrome (life-threatening)
  • fever (most frequent)
  • night sweats (most frequent)

Interactions

Drug-Drug interaction

Blood levels and effects are ↑ by concurrent use of potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavor, telithromycin, or voriconazole ).Blood levels and effects may be ↓ by potent CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, and phenobarbital ; if used concurrently, ↑ dose of imatinib by 50%.↑ blood levels of simvastatin.Imatinib inhibits the following enzyme systems: CYP2C9, CYP2D6, CYP3A4/5 and may be expected to alter the effects of other drugs metabolized by these systems.Blood levels and effects are ↑ by grapefruit juice; concurrent use should be avoided.

Route/Dosage

Chronic Myeloid Leukemia

Oral (Adults) Chronic phase—400 mg once daily, may be ↑ to 600 mg once daily; accelerated phase or blast crisis—600 mg once daily; may be ↑ to 800 mg/day given as 400 mg twice daily based on response and circumstances.
Oral (Children) Newly diagnosed Ph+ CML—340 mg/m2/day (not to exceed 600 mg); CML recurrent after failure of bone marrow transplant or resistance to interferon-alpha—260 mg/m2/day.

Gastrointestinal Stromal Tumors

Oral (Adults) Metastatic or unresectable—400 mg/day; may be ↑ to 400 mg twice daily if well tolerated and response insufficient; Adjuvant treatment after resection—400 mg/day.

Ph+ Acute Lymphoblastic Leukemia

Oral (Adults) 600 mg/day.
Oral (Children) 340 mg/m2/day (not to exceed 600 mg).

Myelodysplastic/Myeloproliferative Diseases

Oral (Adults) 400 mg/day.

Aggressive Systemic Mastocytosis

Oral (Adults) 400 mg/day. For patients with eosinophilia—100 mg/day; ↑ to 400 mg/day if well tolerated and response insufficient.

Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia

Oral (Adults) 400 mg/day. For patients with FIP1L1–PDGFRa fusion kinase 100 mg/day; increase to 400 mg/day if well tolerated and response insufficient.

Dermatofibrosarcoma Protuberans

Oral (Adults) 800 mg/day.

Hepatic Impairment

Oral (Adults) ↓ dose by 25% in severe hepatic impairment.

Renal Impairment

Oral (Adults) CCr 40–59 mL/min—Do not exceed dose of 600 mg/day; CCr 20–39 mL/min—↓ initial dose by 50%; ↑ as tolerated.

Availability

Tablets: 100 mg, 400 mg

Nursing implications

Nursing assessment

  • Monitor for fluid retention. Weigh regularly, and assess for signs of pleural effusion, pericardial effusion, pulmonary edema, ascites (dyspnea, periorbital edema, swelling in feet and ankles, weight gain). Evaluate unexpected weight gain. Edema is usually managed with diuretics. General fluid retention is usually dose related, more common in accelerated phase or blast crisis, and is more common in the elderly. Treatment usually involves diuretics, supportive therapy, and interruption of imatinib.
  • Monitor growth rate in children and adolescents; may cause decrease in growth.
  • Monitor vital signs; may cause fever.
  • Monitor for tumor lysis syndrome (malignant disease progression, high WBC counts, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcamia, and/or dehydration). Prevent by maintain adequate hydration and correcting uric acid levels prior to starting imatinib.
  • Lab Test Considerations: Monitor liver function before and monthly during treatment or when clinically indicated. May cause ↑ transamininases and bilirubin which usually lasts 1 wk and may require dose reduction or interruption. If bilirubin is >3 times the upper limit of normal or transaminases are >5 times the upper limit of normal withhold dose until bilirubin levels return to <1.5 times the upper limit of normal and transaminase levels to <2.5 times the upper limit of normal. Treatment may then be continued at reduced levels (patients on 400 mg/day should receive 300 mg/day and patients receiving 600 mg/day should receive 400 mg/day).
    • Monitor CBC weekly for the first month, biweekly for the second month, and periodically during therapy. May cause neutropenia and thrombocytopenia, usually lasting 2–3 wk or 3–4 wk, respectively, and anemia. Usually requires dose reduction, but may require discontinuation (see Implementation).
    • Patients receiving chronic phase, myelodysplastic/myeloproliferative disease, aggressive systemic mastocytosis, and hypereosinophilic syndrome and/or chronic eosinophilic leukemia treatment who develop an ANC <1.0 × 109/L and/or platelets <50 × 109L should stop imatinib until ANC ≥1.5 × 109/L and platelets are ≥75 × 109/L. Then resume imatinib treatment at 400 mg or 600 mg/day.
    • Patients receiving accelerated phase and blast crisis treatment or Ph+ acute lymphoblastic leukemia who develop an ANC <0.5 × 109/L and/or platelets <10 × 109/L should determine if cytopenia is related to leukemia via marrow aspirate or biopsy. If cytopenia is unrelated to leukemia, reduce dose to 400 mg/day. If cytopenia persists for 2 wk, reduce dose to 300 mg/day. If cytopenia persists for 4 wk and is still unrelated to leukemia, stop imatinib until ANC ≥1 × 109/L and platelets are ≥20 × 109/L. Then resume imatinib treatment at 300 mg/day.
    • Patients receiving aggressive systemic mastocytosis with eosinophilia or hypereosinohpilic syndrome and/or chronic eosinophilic leukemia with FIP1L1–PDGFRa fusion kinase—who develop ANC <1.0 × 109/L and platelets <50 × 109/L should stop imatinib until ANC ≥1.5 × 109/L and platelets ≥75 × 109/L. Resume treatment at previous dose.
    • May cause hypokalemia.

Potential Nursing Diagnoses

Risk for injury (Adverse Reactions)

Implementation

  • high alert: Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify all ambiguous orders; double check single, daily, and course-of-therapy dose limits; have second practitioner independently double check original order and dose calculations. Therapy should be initiated by physician experienced in the treatment of patients with chronic myeloid leukemia.
  • Patients requiring anticoagulation should receive low-molecular-weight or standard heparin, not warfarin.
    • Treatment should be continued as long as patient continues to benefit.
  • Oral: Administer with food and a full glass of water to minimize GI irritation.
    • Tablets may be dispersed in water or apple juice (50 mL for the 100 mg and 100 mL for the 400 mg tablet) and stirred with a spoon for patients unable to swallow pills. Administer immediately after suspension.
    • Doses for children may be given once daily or divided into two doses, one in morning and one in evening.
    • Administer doses >800 mg/day as 400 mg twice daily to decrease exposure to iron.

Patient/Family Teaching

  • Explain purpose of imatinib to patient.
  • Advise patient to avoid grapefruit and grapefruit juice during therapy.
  • May cause drowsiness or dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
  • Advise female patient to notify health care professional if pregnancy is planned or suspected; avoid breast feeding.

Evaluation/Desired Outcomes

  • Decrease in production of leukemic cells in patients with CML, HES/CEL, and ALL and malignant cells in GIST, MDS/MPD, ASM, and DFSP.

Gleevec

(glē′vĕk)
A trademark for the mesylate form of imatinib.

Gleevec

Imatinib mesylate Oncology An anticancer monoclonal antibody that blocks signaling of defective proteins, which may be effective against CML, brain tumors, GI and lung CAs
References in periodicals archive ?
I was put on Gleevec for six months to reduce the tumour to an operable size.
According to the company, the Imatinib Mesylate Tablets in 100 mg and 400 mg is the generic version of Novartis's Gleevec Tablets.
These could be combined with Gleevec to overcome allosteric mutations to shift Abl into an inhibited state.
Gleevec is commonly used to treat specific types of blood cancer, bone marrow disorders, skin cancer, and some tumors involving the stomach and digestive system.
Pharmaceutical company Teva Pharmaceutical Industries (NYSE:TEVA)(TASE:TEVA) revealed on Friday the availability of the the US FDA approved generic equivalent to Gleevec (imatinib mesylate) tablets, 100 mg and 400 mg, in the US for multiple indications.
While Gleevec and many other drugs were less efficient at killing leukemia cells in soft gels, several other drugs were impervious to gel stiffness.
Instead of the previous first-line treatment of bone marrow transplant which we cannot afford (P4 million to 8 million here in the Philippines), Gleevec, as with other tyrosine kinase inhibitor drugs, is long-considered as the gold-standard for CML care worldwide.
Novartis argued that it invested years of research into Gleevec, specifically on modifying the molecule imatinib, to make it a safe treatment for leukemia.
Now, with Gleevec and the newer and better drugs called "super-Gleevecs" that followed, the survival rate is better than 90 percent.
The study at Rex Cancer Center of Wakefield will assess the use of eMedonline, a cellphone-based, personalised drug management system, to help manage patients' compliance with Gleevec and also help identify and manage side effects.
According to a report in the June 22 online edition of Nature Medicine, Gleevec blocks key receptors, preventing bleeding.
They respond to Gleevec in standard doses in only about 35%-40% of cases, which suggests to some the need to increase the dosage given to patients with this mutation.