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Gleevec Side Effects, and Drug Interactions - Imatinib Mesylate

SIDE EFFECTS

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 4% of patients in chronic phase, 5% 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 4 for newly diagnosed CML, Table 5 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 0.9%-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 4 and 5.

Table 4 Adverse Experiences Reported in Newly Diagnosed CML Clinical Trial (>10% of all patients)⁽¹⁾
	All Grades		CTC Grades 3/4
Preferred Term	Gleevec^®N=551 (%)	IFN+Ara-C N=533 (%)	Gleevec™ N=551 (%)	IFN+Ara-C N=533 (%)
Fluid Retention	54.1	10.1	0.9	0.9
- Superficial Edema	53.2	8.8	0.9	0.4
- Other Fluid
Retention Events	3.4	1.5	0	0.6
Nausea	42.5	60.8	0.4	5.1
Muscle Cramps	35.4	9.9	1.1	0.2
Musculoskeletal Pain	33.6	40.5	2.7	7.7
Rash	31.9	25.0	2.0	2.1
Fatigue	30.7	64.7	1.1	24.0
Diarrhea	30.3	40.9	1.3	3.2
Headache	28.5	41.8	0.4	3.2
Joint Pain	26.7	38.3	2.2	6.8
Abdominal Pain	23.4	22.9	2.0	3.6
Myalgia	20.9	38.6	1.5	8.1
Nasopharyngitis	19.2	7.7	0	0.2
Hemorrhage	18.9	19.9	0.7	1.3
Dyspepsia	15.1	9.0	0	0.8
Vomiting	14.7	26.6	0.9	3.4
Pharyngolaryngeal Pain	14.2	11.4	0.2	0
Dizziness	13.2	23.1	0.5	3.4
Cough	12.5	21.6	0.2	0.6
Upper Respiratory
Tract Infection	12.5	7.9	0.2	0.4
Pyrexia	11.8	38.6	0.5	2.8
Weight Increased	11.6	1.5	0.7	0.2
Insomnia	11.4	18.4	0	2.3
⁽¹⁾ All adverse events occurring in >10% of patients are listed regardless of suspected relationship to treatment.

Table 5 Adverse Experiences Reported in Other CML Clinical Trials (>10% of all patients in any trial)⁽¹⁾
	Myeloid last Crisis (n= 260) %		Accelerated Phase (n=235) %		Chronic Phase, IFN Failure (n=532) %
Preferred Term	All Grades	Grade 3/4	All Grades	Grade 3/4	All Grades	Grade 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
- Gastrointestinal 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 6 and 7). 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 6 and 7). 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 5) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1% of patients. However, one patient, who was taking acetaminophen regularly for fever, died of acute liver failure.

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 6 Lab Abnormalities in Newly Diagnosed CML Trial
	Gleevec^®N=551 %		IFN+Ara-C N=533 %
CTC Grades	Grade 3	Grade 4	Grade 3	Grade 4
Hematology Parameters
- Neutropenia*	11.4	2.2	20.3	4.3
- Thrombocytopenia*	6.9	0.2	15.8	0.6
- Anemia	2.7	0.4	4.1	0.2
Biochemistry Parameters
- Elevated Creatinine	0	0	0.4	0
- Elevated Bilirubin	0.2	0.5	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 7 Lab Abnormalities in Other CML Clinical Trials
	Myeloid Blast		Accelerated		Chronic Phase,
	Crisis (n=260) 600 mg n=223 400 mg n=37 %		Phase (n=235) 600 mg n=158 400 mg n=77 %		IFN Failure (n=532) 400 mg %
CTC Grades	Grade 3	Grade 4	Grade 3	Grade 4	Grade 3	Grade 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 10⁹L), 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 6 patients (8%) 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 � 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 8. 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 8 Adverse Experiences Reported in GIST Trial (>10% of all patients at either dose)⁽¹⁾
	All CTC Grades Initial dose (mg/day)		CTC Grade � Initial dose (mg/day)
Preferred Term	400 mg (n=73) %	600 mg (n=74) %	400 mg (n=73) %	600 mg (n=74) %
Fluid Retention	71	76	6	3
- Superficial Edema	71	76	4	0
- Pleural Effusion or Ascites	6	4	1	3
Diarrhea	56	60	1	4
Nausea	53	56	3	3
Fatigue	33	38	1	0
Muscle Cramps	30	41	0	0
Abdominal Pain	37	37	7	3
Skin Rash	26	38	3	3
Headache	25	35	0	0
Vomiting	22	23	1	3
Musculoskeletal Pain	19	11	3	0
Flatulence	16	23	0	0
Any Hemorrhage	18	19	5	8
- Tumor Hemorrhage	1	4	1	4
- Cerebral Hemorrhage	1	0	1	0
- GI Tract Hemorrhage	6	4	4	1
Nasopharyngitis	12	14	0	0
Pyrexia	12	5	0	0
Insomnia	11	11	0	0
Back Pain	11	10	1	0
Lacrimation Increased	6	11	0	0
Upper Respiratory Tract Infection	6	11	0	0
Taste Disturbance	1	14	0	0
⁽¹⁾ All adverse events occurring in >10% of patients are listed regardless of suspected relationship to treatment.

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values are presented in Table 9.

Table 9 Laboratory Abnormalities in GIST Trial
	400 mg (n=73) %		600 mg (n=74) %
CTC Grades	Grade 3	Grade 4	Grade 3	Grade 4
Hematology Parameters
- Anemia	3	0	4	1
- Thrombocytopenia	0	0	1	0
- Neutropenia	3	3	5	4
Biochemistry Parameters
- Elevated Creatinine	0	1	3	0
- Reduced Albumin	3	0	4	0
- Elevated Bilirubin	1	0	1	3
- Elevated Alkaline Phosphatase	0	0	1	0
- Elevated SGOT (AST)	3	0	1	1
- Elevated SGPT (ALT)	3	0	4	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 (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

Digestive

Less common: abdominal distension, gastroesophageal reflux, mouth ulceration Infrequent: gastric ulcer, gastroenteritis, gastritis Rare: colitis, ileus/intestinal obstruction, pancreatitis

General Disorders and Administration Site conditions

Rare: tumor necrosis

Hematologic

Infrequent: pancytopenia Rare: aplastic anemia

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

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

DRUG INTERACTIONS

Drugs that may alter imatinib plasma concentrations

Drugs that may increase imatinib plasma concentrations:

Caution is recommended when administering Gleevec with inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin). Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations. There is a significant increase in exposure to imatinib when Gleevec is coadministered with ketoconazole (CYP3A4 inhibitor).

Drugs that may decrease imatinib plasma concentrations:

Substances that are inducers of CYP3A4 activity may increase metabolism and decrease imatinib plasma concentrations. Co-medications that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital or St. John�s Wort) may significantly reduce exposure to Gleevec. Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean C_max and AUC_(0-∞). In patients where rifampin or other CYP3A4 inducers are indicated, alternative therapeutic agents with less enzyme induction potential should be considered. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Drugs that may have their plasma concentration altered by Gleevec

Gleevec increases the mean ^Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., cyclosporine or pimozide). Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin.

In vitro, Gleevec inhibits the cytochrome P450 isoenzyme CYP2D6 activity at similar concentrations that affect CYP3A4 activity. Systemic exposure to substrates of CYP2D6 is expected to be increased when coadministered with Gleevec. No specific studies have been performed and caution is recommended.

In vitro, Gleevec inhibits the acetaminophen O-glucuronidatuion (K_i value of 58.5 µM) at therapeutic levels. Systemic exposure to acetaminophen is expected to be increased when coadministered with Gleevec. No specific studies in humans have been performed and caution is recommended.

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