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GLIVEC (imatinib) DOSING INFORMATION

The following recommendations for appropriate dosing and administration of GLIVEC for Ph+ CML are consistent with the European Summary of Product Characteristics (SmPC).¹ Please refer to local prescribing information for country-specific information.

GLIVEC Tablets¹

• GLIVEC is supplied as 100-mg and 400-mg film-coated tablets

The recommended starting doses for GLIVEC¹

For adult patients in whom GLIVEC therapy is indicated:

• 400 mg/day for chronic-phase (CP) CML
• 600 mg/day for accelerated-phase or blast-crisis (AP/BC) disease

For children with CML in whom GLIVEC therapy is indicated:

• 340 mg/m²/day for CML-CP and advanced-phase CML
• Not to exceed the total dose of 800 mg/day

Please refer to local prescribing information for specific indications.

Dose adjustments—adverse reactions¹

In the event of myelosuppression, dose modifications may be necessary:

What are the advantages
of nilotinib for patients with
Ph+ CML-CP

who are resistant
or intolerant to
GLIVEC?

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When is a patient
response
suboptimal?

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Dose adjustments—suboptimal response

Suboptimal response may be defined as any of the following criteria.²

You may consider switching your patients to nilotinib if they become resistant or intolerant to imatinib.³ To learn more about nilotinib, click on www.tasigna.com.

In the absence of severe adverse drug reactions and severe non-leukemia-related neutropenia or thrombocytopenia, GLIVEC dose may be increased as follows¹ :

• 400 mg/day to 600 mg/day or 800 mg/day in adult patients with CP disease
• 600 mg/day to a maximum of 800 mg/day (given as 400 mg twice daily) in patients in AP/BC

GLIVEC (imatinib) SAFETY INFORMATION

Important Safety Information¹

Contraindications: Hypersensitivity to imatinib or to any of the excipients.

Precautions/warnings: Should be taken with food and a large glass of water to minimize the risk of gastrointestinal disturbances. Beware of severe fluid retention. It is recommended that patients be weighed regularly. Regular monitoring of complete blood counts and liver function tests. Caution in patients with history of cardiac disease. Careful monitoring of patients with cardiac disease or risk factors for cardiac failure. Monitoring of TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Should not be used during pregnancy unless clearly necessary. Should not be used by breast-feeding mothers.

Interactions: Caution with CYP3A4 inhibitors (eg, ketoconazole, clarithromycin). Caution with CYP3A4 inducers (eg, dexamethasone, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's Wort). Caution with substrates of CYP3A4 (eg, triazolo-benzodiazepines, dihydropyridine calcium channel blockers, simvastatin, cyclosporin, pimozide), CYP2C9 (eg, warfarin) or CYP2D6 (eg, metoprolol). Caution with concomitant use of paracetamol/acetaminophen.

Tips for managing
common adverse
events

Learn more

What are the advantages of
nilotinib for patients with chronic

phase Ph+ CML
who are resistant
or intolerant to
GLIVEC?

Read Now

Adverse reactions¹

Very common: headache, nausea, vomiting, diarrhea, dyspepsia, abdominal pain, myalgia, arthralgia, muscle spasm or cramps, bone pain, dermatitis, eczema, rash, fatigue, weight increase.

Common: anorexia, insomnia, dizziness, paresthesia, taste disturbance, hypoesthesia, flushing, photosensitivity reaction, weakness, pyrexia, chills, weight decrease, lacrimation increase, conjunctivitis, dry eye, blurred vision, dyspnea, epistaxis, cough, flatulence, abdominal distension, gastro-esophageal reflux, constipation, dry mouth, gastritis, increased hepatic enzymes, pruritus, dry skin, erythema, alopecia, night sweats, joint swelling.

Potentially serious: fluid retention, anasarca, edema (including brain, eye, pericard, abdomen, and lung), neutropenia, thrombocytopenia or anemia, pancytopenia, hemolytic anemia, hypokalemia, hyperkalemia, sepsis, cellulitis, fungal infection, upper respiratory tract infection, interstitial lung disease, pneumonia, pericardial/pleural effusion, pleuritic pain, pulmonary hypertension/hemorrhage/fibrosis, congestive heart failure, arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericarditis, cardiac tamponade, thrombosis/embolism, ileus/intestinal obstruction, pancreatitis, hepatic failure/necrosis, hepatitis, exfoliative dermatitis, angioneurotic edema, Stevens-Johnson syndrome, erythema multiforme, leukocytoclastic vasculitis, Sweet's syndrome, lichenoid keratosis, lichen planus, toxic epidermal necrolysis, anaphylactic shock, syncope, hypotension, hematoma, acute respiratory failure, acute renal failure, hemorrhage (including brain, eye, kidney, and gastrointestinal tract), melena, hematemesis, diverticulitis, colitis, inflammatory bowel disease, gastrointestinal perforation, ascites, gastric ulcer, tumor hemorrhage/necrosis, hip osteonecrosis/avascular necrosis, sciatica, optic neuritis, cataract, papilledema, glaucoma, hearing loss, Raynaud's phenomenon, increased intracranial pressure, peripheral neuropathy, depression, convulsions.

Note: Before prescribing, please read full Summary of Product Characteristics.

MANAGING ADVERSE EVENTS WITH GLIVEC (imatinib)

While GLIVEC is generally well tolerated, as with any treatment there are risks of adverse events. The following recommendations are provided for your consideration, to help with the management of some common side effects that have been associated with GLIVEC. For additional information, please click here to view the European SmPC.

Hematologic adverse events may be managed by monitoring patient responses

• Treatment with GLIVEC is associated with anemia, neutropenia, and thrombocytopenia¹
• Myelosuppression is generally more frequent and prevalent in patients with chronic myeloid leukemia in the chronic phase (CML-CP) of longer duration²

Steps to manage myelosuppression with GLIVEC¹

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for your GLIVEC-
resistant/intolerant
patient?

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See additional tips
for managing
adverse events

click here

• Withhold GLIVEC if the absolute neutrophil count (ANC) declines to <1.0 x 10⁹/L and/or if the platelet count is <50 x 10⁹/L
• Resume GLIVEC when the ANC recovers to ANC ≥1.5 x 10⁹/L and platelets are ≥75 x 10⁹/L
• See algorithm below for treatment recommendations for patients who experience a recurrence of myelosuppression

Nonhematologic adverse events may be managed with supportive care

Nausea is the most common adverse event with GLIVEC, occurring in 40% to 60% of patients, and is typically mild (Grade 1)^1,2,3

• 45% of patients experience diarrhea as an adverse event of GLIVEC³
• More than 50% of patients develop mild-to-moderate edema as an adverse event of GLIVEC²
  • Peripheral edema is observed most frequently in the legs
  • Excessive central fluid retention occurs in 1% to 3% of patients treated with GLIVEC
  • Periorbital edema is the most common type of tissue swelling and typically requires no specific therapy

ADHERENCE CONSIDERATIONS WITH GLIVEC (imatinib)

Even though GLIVEC offers once-a-day dosing, as with any oral therapy, adherence can still be an issue

Adherence is a complex and multifactorial issue, especially in medical conditions that require chronic, long-term therapy. A combination of personal, treatment, and systemic challenges may lead to reduced patient adherence to long-term therapies, including the following¹ :

Personal Factors¹

Treatment Factors¹

Interaction With System¹

For more information
about patient
adherence

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Importance of adherence

Clinical trials show that adherence to oral Ph+ CML therapy is critical to achieving and maintaining the best response.^2,3

For patients newly diagnosed with Ph+ CML in chronic phase (CP), the estimated overall survival at 8 years is 85% with GLIVEC therapy.⁴ However, Ph+ CML can progress to accelerated phase (AP) and ultimately to blast crisis (BC).⁵ Transition may occur gradually or abruptly. After the development of AP, survival is usually less than 1 year; after blastic transformation, survival is only a few months.⁶ Relapse is characterized by any evidence of progression from a stable remission, which may include⁵ :

• Increasing myeloid or blast cells in the blood or bone marrow
• Cytogenetic positivity after previous cytogenetic negativity
• Fluorescent in situ hybridization (FISH) positivity for BCR-ABL after previous BCR-ABL negativity

Oral TKI therapy has revolutionized treatment for patients with Ph+ CML-CP.⁷ However, to prevent relapse, responding patients must continue therapy indefinitely.⁷ Strict adherence to therapy is also critically important.

Two recent clinical trials, the Hammersmith study and the ADAGIO study, demonstrated that adherence to oral therapy is critical to achieving and maintaining optimal response.^2,3 In fact, evidence demonstrates that missing more than 2 or 3 daily doses each month can negatively impact response.^2,3

The Hammersmith study: summary results²

Study design

• 87 English patients completed the study
• Patients were in complete cytogenetic response (CCyR), had Ph+ CML-CP, and had received oral therapy for at least 2 years
• Adherence was monitored over 90 days

Key findings

• Adherence rate (>90% or ≤90%) was strongly associated with the 6-year probability of major molecular response (MMR) (Figure 1), 4-log reduction in BCR-ABL, complete molecular response (CMR), and response at 18 months

Reproduced from Marin et al.²

• Probability of MMR for the 23 patients with an adherence rate ≤90% was 13.9%; for the 64 patients with an adherence rate >90%, it was 93.7% (P<0.001)²
• 90% adherence is equivalent to missing approximately 2 to 3 tablets per month

Additional findings

• Adherence was poor after dose increase beyond 400 mg per day
• Young patients were more likely to have a lower adherence rate
• Unexplained 5-fold increases in BCR-ABL1 transcript levels were predictive of poor adherence
• Low adherence was also associated with adverse effects—healthcare providers should regularly ask patients if they are experiencing such effects

Conclusions

• Adherence is critical for achieving molecular responses; adherence rate was the only independent factor that predicted CMR
• No CMR was observed when adherence was ≤90%; no MMR was observed when adherence was ≤80%

The ADAGIO study: summary results³

Study design

• 169 Belgian patients completed the study
• Patients had Ph+ CML-CP for an average of 4 years and were receiving oral therapy
• Adherence (taking medicine every day as directed by the physician) was evaluated over 90 days

Results

• Adherence greatly influenced response (Figure 2)

Adapted from Noens et al.³

Additional findings

• Failure to adhere was related to the patient, physician-patient relationship, and treatment center
• Patients who function well and those who have taken oral CML therapy for a long time may become more lax about taking their medication

Conclusions

• More patients failed to adhere to therapy than they, their physicians, and their family members realized
• Poor adherence was related to lower response rates
• Several determinants may serve as alert signals of nonadherence, such as time since diagnosis and median duration of follow-up
• Healthcare providers should carefully assess patient medication behavior as part of their routine care

Healthcare provider role in adherence

Healthcare providers play a critical role in promoting adherence. They are in an ideal position to practice educational strategies to enhance or maintain adherence, such as:

• Understanding the key factors in adherence, such as motivation, habits, health beliefs, and socioeconomic status, and how these factors relate to their patients^8,9
• Clearly stating the purpose of the drug and helping patients establish a routine for taking it¹
• Reinforcing the need for adherence to achieve and maintain an optimal response, such as an MMR³
• Establishing relationships with patients that permit free discussion of adherence problems and solutions⁸
• Inviting patients to talk about their medication routines and asking them about adherence at every visit¹