Gleevec (Imatinib Mesylate) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Chronic Myeloid Leukemia

The majority of Gleevec-treated patients experienced adverse events at some time. Most events were of mild-to-moderate grade, but drug was discontinued for drug-related adverse events in 3.1% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% in blast crisis.

      The most frequently reported drug-related adverse events were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 5 for newly diagnosed CML, Table 6 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec^® (imatinib mesylate). (See DOSAGE AND ADMINISTRATION.) The frequency of severe superficial edema was 1.1%-6%.

      A variety of adverse events represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These events appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These events were usually managed by interrupting Gleevec treatment and with diuretics or other appropriate supportive care measures. However, a few of these events may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure.

      Adverse events, regardless of relationship to study drug, that were reported in at least 10% of the patients treated in the Gleevec studies are shown in Tables 5 and 6.

Table 5      Adverse Experiences Reported in Newly Diagnosed CML Clinical Trial (≥10% of all patients)⁽¹⁾

	All Grades		CTC Grades 3/4
	Gleevec ®	IFN+Ara−C	Gleevec ®	IFN+Ara−C
Preferred Term	N=551 (%)	N=533 (%)	N=551 (%)	N=533 (%)
Fluid Retention	59.2	10.7	1.8	0.9
− Superficial Edema	57.5	9.2	1.1	0.4
− Other Fluid
Retention Events	6.9	1.9	0.7	0.6
Nausea	47	61.5	0.9	5.1
Muscle Cramps	43.2	11.4	1.6	0.2
Musculoskeletal Pain	39.2	44.1	3.4	8.1
Diarrhea	38.5	42	2.0	3.2
Rash and Related Terms	37.2	25.7	2.4	2.4
Fatigue	37.0	66.8	1.6	25.0
Headache	33.6	43.3	0.5	3.6
Joint Pain	30.3	39.4	2.5	7.3
Abdominal Pain	29.9	25.0	2.5	3.9
Nasopharyngitis	26.9	8.4	0	0.2
Hemorrhage	24.1	20.8	1.1	1.5
- GI Hemorrhage	1.3	1.1	0.5	0.2
- CNS Hemorrhage	0.2	0.2	0	0.2
Myalgia	22.5	38.8	1.5	8.1
Vomiting	20.5	27.4	1.5	3.4
Dyspepsia	17.8	9.2	0	0.8
Cough	17.4	23.1	0.2	0.6
Pharyngolaryngeal Pain	16.9	11.3	0.2	0
Upper Repiratory Tract Infection	16.5	8.4	0.2	0.4
Dizziness	15.8	24.2	0.9	3.6
Pyrexia	15.4	42.4	0.9	3.0
Weight Increased	15.2	2.1	1.6	0.4
Insomnia	13.2	18.8	0	2.3
Depression	12.7	35.8	0.5	13.1
Influenza	11.1	6.0	0.2	0.2

⁽¹⁾      All adverse events occurring in ≥10% of patients are listed regardless of suspected relationship to treatment.

Table 6      Adverse Experiences Reported in Other CML Clinical Trials (≥10% of all patients in any trial)⁽¹⁾

	Myeloid Blast		Accelerated		Chronic Phase,
	Crisis		Phase		IFN Failure
	(n= 260)		(n=235)		(n=532)
	%		%		%
	All	Grade	All	Grade	All	Grade
Preferred Term	Grades	3/4	Grades	3/4	Grades	3/4
Fluid Retention	72	11	76	6	69	4
- Superficial Edema	66	6	74	3	67	2
- Other Fluid Retention Events(2)	22	6	15	4	7	2
Nausea	71	5	73	5	63	3
Muscle Cramps	28	1	47	0.4	62	2
Vomiting	54	4	58	3	36	2
Diarrhea	43	4	57	5	48	3
Hemorrhage	53	19	49	11	30	2
- CNS Hemorrhage	9	7	3	3	2	1
- GI Hemorrhage	8	4	6	5	2	0.4
Musculoskeletal Pain	42	9	49	9	38	2
Fatigue	30	4	46	4	48	1
Skin Rash	36	5	47	5	47	3
Pyrexia	41	7	41	8	21	2
Arthralgia	25	5	34	6	40	1
Headache	27	5	32	2	36	0.6
Abdominal Pain	30	6	33	4	32	1
Weight Increased	5	1	17	5	32	7
Cough	14	0.8	27	0.9	20	0
Dyspepsia	12	0	22	0	27	0
Myalgia	9	0	24	2	27	0.2
Nasopharyngitis	10	0	17	0	22	0.2
Asthenia	18	5	21	5	15	0.2
Dyspnea	15	4	21	7	12	0.9
Upper Respiratory Tract Infection	3	0	12	0.4	19	0
Anorexia	14	2	17	2	7	0
Night Sweats	13	0.8	17	1	14	0.2
Constipation	16	2	16	0.9	9	0.4
Dizziness	12	0.4	13	0	16	0.2
Pharyngitis	10	0	12	0	15	0
Insomnia	10	0	14	0	14	0.2
Pruritus	8	1	14	0.9	14	0.8
Hypokalemia	13	4	9	2	6	0.8
Pneumonia	13	7	10	7	4	1
Anxiety	8	0.8	12	0	8	0.4
Liver Toxicity	10	5	12	6	6	3
Rigors	10	0	12	0.4	10	0
Chest Pain	7	2	10	0.4	11	0.8
Influenza	0.8	0.4	6	0	11	0.2
Sinusitis	4	0.4	11	0.4	9	0.4

⁽¹⁾      All adverse events occurring in ≥10% of patients are listed regardless of suspected relationship to treatment.

⁽²⁾      Other fluid retention events include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

Hematologic Toxicity

Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥750 mg (Phase 1 study). However, the occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

      In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 7 and 8). The frequency of grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 7 and 8). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

      These events can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but in rare cases require permanent discontinuation of treatment.

Hepatotoxicity

Severe elevation of transaminases or bilirubin occurred in 3%-6% (see Table 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 0.5% of CML patients. However, one patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the GIST trial, grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

Adverse Reactions in Pediatric Population

The overall safety profile of pediatric patients treated with Gleevec in 39 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported.

Adverse Effects in Other Subpopulations

In older patients (≥65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse events. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen related to race but the subsets were too small for proper evaluation.

Table 7      Lab Abnormalities in Newly Diagnosed CML Trial

	Gleevec ®		IFN+Ara−C
	N=551		N=533
	%		%
CTC Grades	Grade 3	Grade 4	Grade 3	Grade 4
Hematology Parameters
− Neutropenia*	12.3	3.1	20.8	4.3
− Thrombocytopenia*	8.3	0.2	15.9	0.6
− Anemia	3.1	0.9	4.1	0.2
Biochemistry Parameters
− Elevated Creatinine	0	0	0.4	0
− Elevated Bilirubin	0.7	0.2	0.2	0
− Elevated Alkaline       Phosphatase	0.2	0	0.8	0
− Elevated SGOT (AST)	2.9	0.2	3.8	0.4
− Elevated SGPT (ALT)	3.1	0.4	5.6	0

*p<0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups)

Table 8      Lab Abnormalities in Other CML Clinical Trials

	Myeloid Blast		Accelerated		Chronic Phase,
	Crisis		Phase		IFN Failure
	(n=260)		(n=235)		(n=532)
	600 mg n=223		600 mg n=158
	400 mg n=37		400 mg n=77		400 mg
	%		%		%
	Grade	Grade	Grade	Grade	Grade	Grade
CTC Grades	3	4	3	4	3	4
Hematology Parameters
− Neutropenia	16	48	23	36	27	9
− Thrombocytopenia	30	33	31	13	21	<1
− Anemia	42	11	34	7	6	1
Biochemistry Parameters
− Elevated Creatinine	1.5	0	1.3	0	0.2	0
− Elevated Bilirubin	3.8	0	2.1	0	0.6	0
− Elevated Alkaline       Phosphatase	4.6	0	5.5	0.4	0.2	0
− Elevated SGOT (AST)	1.9	0	3.0	0	2.3	0
− Elevated SGPT (ALT)	2.3	0.4	4.3	0	2.1	0

CTC Grades: neutropenia (Grade 3 ≥0.5-1.0 x 10⁹/L, Grade 4 <0.5 x 10⁹/L), thrombocytopenia (Grade 3 ≥10-50 x 10⁹/L, Grade 4 <10 x 10⁹/L), anemia (hemoglobin ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), elevated SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN)

Gastrointestinal Stromal Tumors

The majority of Gleevec-treated patients experienced adverse events at some time. The most frequently reported adverse events were edema, nausea, diarrhea, abdominal pain, muscle cramps, fatigue, and rash. Most events were of mild-to-moderate severity. Drug was discontinued for adverse events in 7 patients (5%) in both dose levels studied. Superficial edema, most frequently periorbital or lower extremity edema, was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec^® (imatinib mesylate). (See DOSAGE AND ADMINISTRATION.) Severe (CTC Grade 3/4) superficial edema was observed in 3 patients (2%), including face edema in one patient. Grade 3/4 pleural effusion or ascites was observed in 3 patients (2%).

      Adverse events, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 9. No major differences were seen in the severity of adverse events between the 400-mg or 600-mg treatment groups, although overall incidence of diarrhea, muscle cramps, headache, dermatitis, and edema was somewhat higher in the 600-mg treatment group.

Table 9      Adverse Experiences Reported in GIST Trial (≥10% of all patients at either dose)⁽¹⁾

	All CTC Grades Initial dose (mg/day)		CTC Grade 3/4 Initial dose (mg/day)
	400 mg (n=73)	600 mg (n=74)	400 mg (n=73)	600 mg (n=74)
Preferred Term	%	%	%	%
Fluid Retention	81	80	7	12
- Superficial Edema	81	77	6	5
- Pleural Effusion or Ascites	15	12	3	8
Diarrhea	59	70	3	7
Nausea	63	74	6	4
Fatigue	48	53	1	1
Muscle Cramps	47	58	0	0
Abdominal Pain	40	37	11	4
Rash and Related Terms	38	53	4	3
Vomiting	38	35	3	5
Musculoskeletal Pain	37	30	6	1
Headache	33	39	0	0
Flatulence	30	34	0	0
Any Hemorrhage	26	34	6	11
- Tumor Hemorrhage	1	4	1	4
- Cerebral Hemorrhage	1	0	1	0
- GI Tract Hemorrhage	4	4	4	3
- Other Hemorrhage(2)	22	27	0	5
Pyrexia	25	16	3	0
Back Pain	23	26	6	0
Nasopharyngitis	21	27	0	0
Insomnia	19	18	1	0
Lacrimation Increased	16	18	0	0
Dyspepsia	15	15	0	0
Upper Respiratory Tract Infection	14	18	0	0
Liver Toxicity	12	12	6	8
Dizziness	12	11	0	0
Loose Stools	12	10	0	0
Operation	12	8	6	4
Pharyngolaryngeal Pain	12	7	0	0
Joint Pain	11	15	1	0
Constipation	11	10	0	1
Anxiety	11	7	0	0
Taste Disturbance	3	15	0	0
All adverse events occurring in ≥10% of patients are listed regardless of suspected relationship to treatment. This category includes conjunctival hemorrhage, blood in stool, epistaxis, hematuria, post-procedural hemorrhage, bruising, and contusion.

      Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values are presented in Table 10.

Table 10      Laboratory Abnormalities in GIST Trial

	400 mg		600 mg
	(n=73)		(n=74)
	%		%
CTC Grades	Grade 3	Grade 4	Grade 3	Grade 4
Hematology Parameters
− Anemia	3	0	8	1
− Thrombocytopenia	0	0	1	0
− Neutropenia	7	3	8	3
Biochemistry Parameters
− Elevated Creatinine	0	0	3	0
− Reduced Albumin	3	0	4	0
− Elevated Bilirubin	1	0	1	3
− Elevated Alkaline Phosphatase	0	0	3	0
− Elevated SGOT (AST)	4	0	3	3
− Elevated SGPT (ALT)	6	0	7	1

CTC Grades: neutropenia (Grade 3 ≥0.5-1.0 x 109/L, Grade 4 <0.5 x 109/L), thrombocytopenia (Grade 3 ≥10 - 50 x 109/L, Grade 4 <10 x 109/L), anemia (Grade 3 ≥65-80 g/L, grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), albumin (Grade 3 <20 g/L)

Additional Data From Multiple Clinical Trials

The following less common (estimated 1%-10%), infrequent (estimated 0.1%-1%), and rare (estimated less than 0.1%) adverse events have been reported during clinical trials of Gleevec. These events are included based on clinical relevance.

Cardiovascular :   Infrequent: cardiac failure, tachycardia, hypertension, hypotension, flushing, peripheral coldness

Rare: pericarditis

Clinical Laboratory Tests :   Infrequent: blood CPK increased, blood LDH increased

Dermatologic :   Less common: dry skin, alopecia

Infrequent: exfoliative dermatitis, bullous eruption, nail disorder, skin pigmentation changes, photosensitivity reaction, purpura, psoriasis

Rare: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome)

Digestive:   Less common: abdominal distention, gastroesophageal reflux, mouth ulceration Infrequent: gastric ulcer, gastroenteritis, gastritis

Rare: colitis, ileus/intestinal obstruction, pancreatitis, diverticulitis, tumor hemorrhage/tumor necrosis, gastrointestinal perforation (see PRECAUTIONS)

General Disorders and Administration Site Conditions:   Rare: tumor necrosis

Hematologic:   Infrequent: pancytopenia

Rare: aplastic anemia  

Hepatobiliary: Uncommon: hepatitis

rare: hepatic failure

Hypersensitivity:   Rare: angioedema

Infections:   Infrequent: sepsis, herpes simplex, herpes zoster

Metabolic and Nutritional:   Infrequent: hypophosphatemia, dehydration, gout, appetite disturbances, weight decreased

Rare: hyperkalemia, hyponatremia

Musculoskeletal:   Less common: joint swelling

Infrequent: sciatica, joint and muscle stiffness  

Rare: avascular necrosis/hip osteonecrosis

Nervous System/Psychiatric:   Less common: paresthesia

Infrequent: depression, anxiety, syncope, peripheral neuropathy, somnolence, migraine, memory impairment

Rare: increased intracranial pressure, cerebral edema (including fatalities), confusion, convulsions

Renal:   Infrequent: renal failure, urinary frequency, hematuria

Reproductive:   Infrequent: breast enlargement, menorrhagia, sexual dysfunction

Respiratory:   Rare: interstitial pneumonitis, pulmonary fibrosis

Special Senses:   Less common: conjunctivitis, vision blurred  

Infrequent: conjunctival hemorrhage, dry eye, vertigo, tinnitus  

Rare: macular edema, papilledema, retinal hemorrhage, glaucoma, vitreous hemorrhage

Vascular Disorders:   Rare: thrombosis/embolism