Imatinib Side Effects

Some side effects of imatinib may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

For the Consumer

Applies to imatinib: oral tablet

Get emergency medical help if you have any of these signs of an allergic reaction while taking imatinib: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• fever, chills, body aches, flu symptoms;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• swelling, rapid weight gain, feeling short of breath (even with mild exertion);

• nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• lower back pain, blood in your urine, little or no urinating;

• numbness or tingly feeling around your mouth;

• muscle weakness, tightness, or contraction, overactive reflexes;

• fast or slow heart rate, weak pulse, confusion, fainting; or

• severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• mild nausea or stomach pain, vomiting, diarrhea;

• joint or muscle pain; or

• headache, feeling tired.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

For Healthcare Professionals

Applies to imatinib: oral capsule, oral tablet

General

In general, the most frequent side effects were nausea, vomiting, edema, tumor necrosis, and muscle cramps. Most events were mild to moderate. Causality was difficult to determine due to single arm study designs, disease complications, and concurrent medications. This section lists adverse events regardless of causality.

Hematologic

Occurrence of hematologic toxicity appeared to be dependent on dose and disease stage. The incidence of severe cytopenia was 2 to 3 times higher in blast crisis and accelerated phase than in chronic phase. Neutropenic episodes had a median duration of 2 to 3 weeks and thrombocytopenic episodes had a duration of 3 to 4 weeks. They were treated with dose reduction or imatinib treatment interruption.

Hematologic side effects have been the major toxicity associated with imatinib and have included cytopenias, especially neutropenia (16% to 35% grade 3, 8% to 46% grade 4), thrombocytopenia (16% to 30% grade 3, less than 1% to 31% grade 4), and anemia (4% to 40% grade 3, less than 1% to 10% grade 4). Epistaxis was reported in an average of 3% to 12% of patients. Pancytopenia has been reported infrequently.

In pediatric CML patients the most frequent toxicities observed were grade 3 or 4 cytopenias including neutropenia, thrombocytopenia, and anemia. These generally occurred within the first several months of therapy.

In the newly diagnosed CML trial, 1.1% of patients were reported to have grade 3 or 4 hemorrhage. In the gastrointestinal stromal tumor (GIST) clinical trial, seven patients (5%) had a total of eight events of grade 3 or 4 gastrointestinal bleeds (3 patients), intratumor bleeds (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of the GI bleeds.

Cardiovascular

Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. Unexpected rapid weight gain should be carefully investigated and appropriated treatment should be provided.

One patient in blast crisis died with pleural effusion, congestive heart failure and renal failure.

Cardiovascular side effects have included edema, most frequently in the periorbital area or in the lower limbs. Superficial edema was reported in 51% to 66% of patients. In the chronic myeloid leukemia (CML) studies, the incidence of edema has been higher in patients over 65 years and with higher dosages. Severe superficial edema has been reported in 1.5% to 6% of CML patients. In addition, other severe fluid retention events (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) have been reported in 0.7% of newly diagnosed CML patients, and in 2% to 6% of other adult patients taking imatinib. There have also been postmarketing reports, including fatalities, of cerebral edema, increased intracranial pressure, cardiac tamponade, and papilledema in patients with CML treated with imatinib. Severe congestive heart failure and left ventricular dysfunction have been reported occasionally. Cardiac failure, tachycardia, hypertension, hypotension, flushing, peripheral coldness, subdural hematoma, and increased CPK and LDH have been reported infrequently. Pericarditis, thrombosis, and embolism have been reported rarely.

Hepatic

Hepatic side effects have included laboratory abnormalities with severe bilirubin and enzyme elevations: elevated bilirubin (0.4 to 3.5% grade 3), elevated alkaline phosphatase (0.2% to 5.1% grade 3, 0% to 0.4% grade 4), elevated AST (SGOT) (1.1% to 2.1% grade 3), elevated ALT (SGPT) (1.7% to 3% grade 3, 0% to 0.4% grade 4). These abnormalities were managed with dose reduction or treatment interruption and had a median duration of 1 week.

Severe elevation of transaminases or bilirubin has been reported in approximately 5% of CML patients. Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients.

Fatal liver failure occurred in a study patient who regularly took acetaminophen concurrently.

Imatinib may be potentially hepatotoxic with long-term use. It was associated with severe hepatotoxicity in animal studies, including elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia.

Gastrointestinal

Gastrointestinal side effects have included nausea (47% to 68%), vomiting (20.5% to 49%), diarrhea (33% to 49%), dyspepsia (9% to 19%), abdominal pain (20% to 29.9%), anorexia (3% to 10%), constipation (4% to 13%), and gastrointestinal hemorrhage (0.2% to 5%). Abdominal distention, gastroesophageal reflux, and mouth ulceration have been reported less commonly. Gastric ulcer, gastroenteritis, and gastritis have been reported infrequently. Colitis, ileus/intestinal obstruction, and pancreatitis have been reported rarely. Three cases of splenic rupture have also been reported.

Musculoskeletal

Musculoskeletal side effects have included muscle cramps (25% to 46%), musculoskeletal pain (27% to 39.9%), arthralgia (21% to 28%), myalgia (7% to 22.5%), and weakness (5% to 10%). Joint swelling has been reported less commonly. Sciatica as well as joint and muscle stiffness have been reported infrequently. Rhabdomyolysis has also been reported. In children, growth retardation has been reported.

Nervous system

Nervous system side effects have included headache (24% to 33.6%) and CNS hemorrhage (0.2% to 4%). Paresthesia has been reported less commonly. Syncope, peripheral neuropathy, somnolence, and migraine have been reported infrequently. Confusion, convulsions, increased intracranial pressure, and cerebral edema (including fatalities) have been reported rarely.

Dermatologic

Dermatologic side effects have included skin rash (32% to 39%), pruritus (6% to 10%), and petechiae (0.9% to 10%). Dry skin and alopecia have been less common. Exfoliative dermatitis, psoriasis, bullous eruption, nail disorder, skin pigmentation changes, photosensitivity reaction and purpura have been reported infrequently. Vesicular rash, erythema multiforme, and Stevens-Johnson syndrome have been reported rarely. In one trial (n=133), nine of the patients who had grey hair before treatment had progressive repigmentation of the hair (on the head in eight patients and on the body and the head in one). Three cases of hyperkeratosis and nail dystrophy have been reported in patients with chronic myeloid leukemia. Three cases of skin rashes with a peculiar livedoid pattern that were probably associated with imatinib therapy have also been reported. Two cases of oral and cutaneous lichenoid reaction have been reported. A case of follicular mucinosis and a case of severe pustular eruption have been reported.

In some cases of bullous dermatologic reactions (including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance), a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib therapy after resolution or improvement of the bullous reaction. In these instances, imatinib was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

Hair repigmentation was reported to occur after a median of 5 months.

Respiratory

Respiratory side effects have included nasopharyngitis (5% to 26.9%), cough (9% to 22%), pharyngolaryngeal pain (16.9%), upper respiratory tract infection (16.5%), dyspnea (5% to 16%), and pneumonia (1% to 10%). Interstitial pneumonitis and pulmonary fibrosis have been reported rarely.

Metabolic

Monitoring for SIADH has been recommended for patients receiving high dose imatinib who develop hyponatremia.

Metabolic side effects have included weight increase (4% to 16%) and hypokalemia (2% to 12%). Hypophosphatemia, decreased weight, and gout have been reported infrequently. Hyperkalemia and hyponatremia have been reported rarely. A case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported in a patient receiving high dose imatinib. Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported.

Other

Other side effects have included pyrexia (14% to 38%), fatigue (24% to 37.0%), dizziness (15.8%), insomnia (13.2%), influenza (11.1%), and night sweats (8% to 10%). Infections including sepsis, herpes simplex, and herpes zoster have been reported infrequently. Dehydration, appetite disturbances, vertigo, and tinnitus have been reported infrequently. A case of dental hyperpigmentation and a case of hand-foot syndrome have also been reported.

Renal

Renal side effects have included elevated creatinine (1.2% to 1.3% grade 3). Renal failure, urinary frequency, and hematuria have been reported infrequently.

Imatinib may be potentially nephrotoxic with long term use. It was associated with focal mineralization and dilation of the renal tubules, tubular nephrosis, and increased BUN and creatinine in animal studies.

Hypersensitivity

Hypersensitivity side effects including angioedema have been reported infrequently.

Psychiatric

Psychiatric side effects including depression (12.7%), anxiety, and memory impairment have been reported infrequently.

Genitourinary

Genitourinary side effects including breast enlargement, menorrhagia, and sexual dysfunction have been reported infrequently.

Breast enlargement has been reported in both female and male patients (gynecomastia).

Ocular

Ocular side effects including periorbital edema, epiphora, conjunctivitis, and blurred vision have been reported. Conjunctival hemorrhage and dry eye have been reported infrequently. Macular edema, papilledema, glaucoma, vitreous hemorrhage, and retinal hemorrhage have been reported rarely.

In most cases, periorbital edema and epiphora can be managed conservatively. In severe cases, oral diuretics or topical steroids may improve the signs and symptoms of periorbital edema and epiphora. In unusually severe cases of periorbital edema, surgical excision of periocular soft tissue may be necessary to improve function.

Oncologic

Oncologic side effects have been reported in animal studies including renal adenomas, renal carcinomas, urinary bladder papillomas, and papillomas/carcinomas of the preputial and clitoral gland. A case of eccrine squamous syringometaplasia has also been reported.

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