Managing Side Effects

In addition to providing significantly improved efficacy, tyrosine kinase inhibitors (TKIs) also offer patients a therapeutic option for Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) with a more tolerable side-effect profile than combination therapy with interferon alfa plus low-dose cytarabine.¹GLIVEC^® (imatinib) and TASIGNA^® (nilotinib) were developed to selectively target Bcr-Abl, the key cause of Ph+ CML.¹ This selective targeting has also been associated with more favorable tolerability.¹

TASIGNA^® has a generally well-established safety profile that may allow patients to stay on therapy. Adverse effects from treatment with GLIVEC^® are usually mild to moderate and can generally be managed while continuing treatment. Patients who are intolerant to GLIVEC are unlikely to be intolerant to TASIGNA as there is very low cross intolerance between the 2 drugs.²

For additional information about adverse effects with TASIGNA^® and GLIVEC^®, please click here to view the European Summary of Product Characteristics (SMPC) for complete safety information.

TASIGNA^® (nilotinib) Indication

TASIGNA (nilotinib) is indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase and the treatment of chronic phase (CP) and accelerated phase (AP) Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib.

IMPORTANT SAFETY INFORMATION

Contraindications

Hypersensitivity to the active substance or any of the excipients.

WARNINGS/PRECAUTIONS

Myelosuppression

Treatment with TASIGNA is associated with (National Cancer Institute Common Toxicity Criteria grade 3-4) thrombocytopenia, neutropenia, and anemia. Occurrence is more frequent in patients with accelerated-phase CML. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding TASIGNA temporarily or dose reduction.

QT prolongation

TASIGNA has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner.

TASIGNA should be used with caution in patients who have or who are at significant risk of developing prolongation of QTc, such as those:

• with congenital long QT prolongation
• with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia
• taking anti-arrhythmic medicinal products or other substances that lead to QT prolongation

Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with TASIGNA and as clinically indicated. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be monitored periodically during therapy.

Interactions With Other Medicinal Products

The administration of TASIGNA with agents that are strong CYP3A4 inhibitors (including, but not limited to, ketoconazole, itraconazole, voriconazole, moxifloxacin, clarithromycin, telithromycin, ritonavir) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with TASIGNA be interrupted if possible. If transient interruption of treatment with TASIGNA is not possible, close monitoring of the individual for prolongation of the QT interval is indicated.

Concomitant use of TASIGNA with medicinal products that are potent inducers of CYP3A4 (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital and St. John’s Wort) is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving TASIGNA, coadministration of alternative therapeutic agents with less potential for CYP3A4 induction should be selected.

Food Effect

The bioavailability of nilotinib is increased by food. TASIGNA should not be taken in conjunction with food and should be taken 2 hours after a meal. No food should be consumed for at least one hour after the dose is taken. Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided.

Hepatic Impairment

Metabolism of nilotinib is mainly hepatic. Patients with hepatic impairment might therefore have increased exposure to nilotinib and should be treated with caution.

Serum Lipase

Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis.

Total Gastrectomy

The bioavailability of nilotinib might be reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered.

Lactose

TASIGNA capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Pregnancy and Lactation

Pregnancy

TASIGNA should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the fetus.

Women of childbearing potential must be advised to use effective contraception during treatment with TASIGNA.

Lactation

Women should not breast-feed during treatment with TASIGNA, as a risk to the infant cannot be excluded.

Adverse Reactions (≥5% of all patients, n=438)

Very common: rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, elevated lipase, neutropenia, thrombocytopenia, anemia, hypophosphatemia.

Common: vomiting, myalgia, alopecia, arthralgia, muscle spasms, bone pain, asthenia, abdominal pain, anorexia, peripheral edema, blood amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood glucose increased, weight decreased, weight increased, palpitations, electrocardiogram QT prolonged, febrile neutropenia, pancytopenia, dizziness, paresthesia, vertigo, dyspnea, dyspnea exertional, cough, dysphonia, abdominal discomfort, dyspepsia, flatulence, night sweats, eczema, urticaria, erythema, hyperhidrosis, dry skin, musculoskeletal chest pain, musculoskeletal pain, hypomagnesemia, hyperkalemia, hyperglycemia, hypertension, flushing, pyrexia, insomnia.

Potentially serious: pleural and pericardial effusions, fluid retention and edema, cardiac failure, angina pectoris, myocardial infarction, atrial fibrillation, cardiomegaly, electrocardiogram QT prolongation, pericarditis, ventricular dysfunction, coronary artery disease, cardiac flutter, bradycardia, hypertensive crisis, pneumonia, candidiasis, herpes simplex, sepsis, pancytopenia, thrombocythemia, febrile neutropenia, intracranial hemorrhage, brain edema, peripheral neuropathy, optic neuritis, eye hemorrhage, hypotension, thrombosis, pleurisy, pulmonary edema, pulmonary hypertension, pancreatitis, melena, gastrointestinal ulcer perforation, hematemesis, hepatitis, hepatomegaly, renal failure, bronchitis, hypokalemia, hypomagnesemia, hypocalcemia, diabetes mellitus, shock hemorrhagic, gastrointestinal hemorrhage, retroperitoneal hemorrhage, dehydration.

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

GLIVEC^® (imatinib) Indication

GLIVEC is indicated for the treatment of adult and pediatric patients with newly diagnosed Philadelphia chromosome-(Bcr-Abl) positive (Ph+) chronic myeloid leukemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment, and for adult and pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis.

IMPORTANT SAFETY INFORMATION

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

Adverse reactions:

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.

Next: Common Adverse Events

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