TASIGNA SIDE EFFECTS

SIDE EFFECTS

The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of labeling:

• Myelosuppression
• QT Prolongation
• Sudden Deaths
• Cardiac and Arterial Vascular Occlusive Events
• Pancreatitis and Elevated Serum Lipase
• Hepatotoxicity
• Electrolyte Abnormalities
• Hemorrhage
• Fluid Retention

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Adult Patients With Newly Diagnosed Ph+ CML-CP

The data below reflect exposure to Tasigna from a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the Tasigna 300 mg twice daily group was 61 months (range 0.1 to 71 months). The median actual dose intensity was 593 mg/day in the Tasigna 300 mg twice daily group.

The most common (greater than 10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (less than or equal to 10% and greater than 5%) and have been of mild-to-moderate severity, manageable and generally did not require dose reduction.

Increase in QTcF greater than 60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of greater than 500 msec while on study drug.

The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (18%), neutropenia (15%) and anemia (8%). See Table 9 for Grade 3/4 laboratory abnormalities.

Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients.

In Adult Patients With Resistant Or Intolerant Ph+ CML-CP And CML-AP

In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily.

The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1 to 1096) and 264 (range 2 to 1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151 to 1110) and 780 mg/day (range 150 to 1149), respectively and corresponded to the planned 400 mg twice daily dosing.

The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1 to 345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1 to 234).

In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia and anemia.

In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.

Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF greater than 60 msec from baseline was observed in 4.1% of the patients and QTcF of greater than 500 msec was observed in 4 patients (less than 1%).

Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients.

Most Frequently Reported Adverse Reactions

Tables 1 and 2 show the percentage of adult patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of adult patients who received at least 1 dose of Tasigna are listed.

Table 1: Most Frequently Reported Non-Hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Adult Patients with Newly Diagnosed Ph+ CML-CP (Greater than or equal to 10% in Tasigna 300 mg Twice Daily or Imatinib 400 mg Once Daily Groups) 60-Month Analysis^a

Body System and Adverse Reaction		Patients with Newly Diagnosed Ph+ CML-CP
		TASIGNA 300 mg twice daily N=279	Imatinib 400 mg once daily N=280	TASIGNA 300 mg twice daily N=279	Imatinib 400 mg once daily N=280
		All Grades (%)		CTC Gradesb 3/4 (%)
Skin and subcutaneous tissue disorders	Rash	38	19	<1	2
	Pruritus	21	7	<1	0
	Alopecia	13	7	0	0
	Dry skin	12	6	0	0
Gastrointestinal disorders	Nausea	22	41	2	2
	Constipation	20	8	<1	0
	Diarrhea	19	46	1	4
	Vomiting	15	27	<1	<1
	Abdominal pain upper	18	14	1	<1
	Abdominal pain	15	12	2	0
	Dyspepsia	10	12	0	0
Nervous system disorders	Headache	32	23	3	<1
	Dizziness	12	11	<1	<1
General disorders and administration site conditions	Fatigue	23	20	1	1
	Pyrexia	14	13	<1	0
	Asthenia	14	12	<1	0
	Peripheral edema	9	20	<1	0
	Face edema	<1	14	0	<1
Musculoskeletal and connective tissue disorders	Myalgia	19	19	<1	<1
	Arthralgia	22	17	<1	<1
	Muscle spasms	12	34	0	1
	Pain in extremity	15	16	<1	<1
	Back pain	19	17	1	1
Respiratory, thoracic and mediastinal disorders	Cough	17	13	0	0
	Oropharyngeal pain	12	6	0	0
	Dyspnea	11	6	2	<1
Infections and infestations	Nasopharyngitis	27	21	0	0
	Upper respiratory tract infection	17	14	<1	0
	Influenza	13	9	0	0
	Gastroenteritis	7	10	0	<1
Eye disorders	Eyelid edema	1	19	0	<1
	Periorbital edema	<1	15	0	0
Psychiatric disorders	Insomnia	11	9	0	0
Vascular disorder	Hypertension	10	4	1	<1
aExcluding laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0

 

Table 2: Most Frequently Reported Non-Hematologic Adverse Reactions in Adult Patients with Resistant or Intolerant Ph+ CML Receiving TASIGNA 400 mg Twice Daily (Regardless of Relationship to Study Drug) (Greater than or equal to 10% in any Group) 24-Month Analysis^a

Body System and Adverse Reaction		CML-CP N=321		CML-AP N=137
		All Grades (%)	CTC Gradesb 3/4 (%)	All Grades (%)	CTC Gradesb 3/4 (%)
Skin and subcutaneous tissue disorders	Rash	36	2	29	0
	Pruritus	32	<1	20	0
	Night sweat	12	<1	27	0
	Alopecia	11	0	12	0
Gastrointestinal disorders	Nausea	37	1	22	<1
	Constipation	26	<1	19	0
	Diarrhea	28	3	24	2
	Vomiting	29	<1	13	0
	Abdominal pain	15	2	16	3
	Abdominal pain upper	14	<1	12	<1
	Dyspepsia	10	<1	4	0
Nervous system disorders	Headache	35	2	20	1
General disorders and administration site conditions	Fatigue	32	3	23	<1
	Pyrexia	22	<1	28	2
	Asthenia	16	0	14	1
	Peripheral edema	15	<1	12	0
Musculoskeletal and connective tissue disorders	Myalgia	19	2	16	<1
	Arthralgia	26	2	16	0
	Muscle spasms	13	<1	15	0
	Bone pain	14	<1	15	2
	Pain in extremity	20	2	18	1
	Back pain	17	2	15	<1
	Musculoskeletal pain	11	<1	12	1
Respiratory, thoracic and mediastinal disorders	Cough	27	<1	18	0
	Dyspnea	15	2	9	2
	Oropharyngeal pain	11	0	7	0
Infections and infestations	Nasopharyngitis	24	<1	15	0
	Upper respiratory tract infection	12	0	10	0
Metabolism and nutrition disorders	Decreased appetitec	15	<1	17	<1
Psychiatric disorders	Insomnia	12	1	7	0
Vascular disorders	Hypertension	10	2	11	<1
aExcluding laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 cAlso includes preferred term anorexia

 

Laboratory Abnormalities

Table 3 shows the percentage of adult patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 3: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities

	Patient Population
	Newly Diagnosed Adult Ph+ CML-CP		Resistant or Intolerant Adult Ph+
			CML-CP	CML-AP
	TASIGNA 300 mg twice daily N=279 (%)	Imatinib 400 mg once daily N=280 (%)	TASIGNA 400 mg twice daily N=321 (%)	TASIGNA 400 mg twice daily N=137 (%)
Hematologic Parameters
Thrombocytopenia	10	9	301	423
Neutropenia	12	22	312	424
Anemia	4	6	11	27
Biochemistry Parameters
Elevated lipase	9	4	18	18
Hyperglycemia	7	<1	12	6
Hypophosphatemia	8	10	17	15
Elevated bilirubin (total)	4	<1	7	9
Elevated SGPT (ALT)	4	3	4	4
Hyperkalemia	2	1	6	4
Hyponatremia	1	<1	7	7
Hypokalemia	<1	2	2	9
Elevated SGOT (AST)	1	1	3	2
Decreased albumin	0	<1	4	3
Hypocalcemia	<1	<1	2	5
Elevated alkaline phosphatase	0	<1	<1	1
Elevated creatinine	0	<1	<1	<1
*NCI Common Terminology Criteria for Adverse Events, version 3.0 1CML-CP: Thrombocytopenia: 12% were Grade 3, 18% were Grade 4 2CML-CP: Neutropenia: 16% were Grade 3, 15% were Grade 4 3CML-AP: Thrombocytopenia: 11% were Grade 3, 32% were Grade 4 4CML-AP: Neutropenia: 16% were Grade 3, 26% were Grade 4

 

Elevated total cholesterol (all grades) occurred in 28% (Tasigna 300 mg twice daily) and 4% (imatinib). Elevated triglycerides (all grades) occurred in 12% and 8% of patients in the Tasigna and imatinib arms, respectively. Hyperglycemia (all Grades) occurred in 50% and 31% of patients in the Tasigna and imatinib arms, respectively.

Most common biochemistry laboratory abnormalities (all grades) were alanine aminotransferase increased (72%), blood bilirubin increased (59%), aspartate aminotransferase increased (47%), lipase increased (28%), blood glucose increased (50%), blood cholesterol increased (28%), and blood triglyceride increased (12%).

Treatment Discontinuation In Ph+ CML-CP Patients Who Have Achieved A Sustained Molecular Response (MR4.5)

In eligible patients who discontinued Tasigna therapy after attaining a sustained molecular response (MR4.5), musculoskeletal symptoms (e.g. myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain), were reported more frequently than before treatment discontinuation in the first year, as noted in Table 10. The rate of new musculoskeletal symptoms generally decreased in the second year after treatment discontinuation.

In the newly diagnosed population in whom musculoskeletal symptoms occurred at any time during the TFR phase, 23/53 (43.4%) had not resolved by the TFR end date or data cut-off date. In the population previously treated with imatinib in whom musculoskeletal events occurred at any time during the TFR phase, 32/57 (56.1%) had not resolved by the data cut-off date.

The rate of musculoskeletal symptoms decreased in patients who entered the Tasigna treatment reinitiation (NTRI) phase, at 11/88 (12.5%) in the newly diagnosed population and 14/56 (25%) in the population previously treated with imatinib. Other adverse reactions observed in the Tasigna re-treatment phase were similar to those observed Tasigna use in patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP.

Table 4: Musculoskeletal symptoms occurring upon treatment discontinuation in the context of treatment-free remission (TFR)

Ph+ CML-CP patients	Entire TFR period in all TFR patients				By time interval, in subset of patients in TFR greater than 48 weeks
	N	Median follow-up in TFR	Patients with musculoskeletal symptoms		N	Year prior to TASIGNA discontinuation		1st year after TASIGNA discontinuation		2nd year after TASIGNA discontinuation
			All Grades	Grade 3/4		All Grades	Grade 3/4	All Grades	Grade 3/4	All Grades	Grade 3/4
Newly Diagnosed	190	76 weeks	28%	1%	100	17%	0%	34%	2%	9%	0%
Previously treated with imatinib	126	99 weeks	45%	2%	73	14%	0%	48%	3%	15%	1%

 

Additional Data From Clinical Trials

The following adverse drug reactions were reported in adult patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (greater than or equal to 1% and less than 10%), uncommon (greater than or equal to 0.1% and less than 1%), and unknown frequency (single events). For laboratory abnormalities, very common events (greater than or equal to 10%), which were not included in Tables 7 and 8, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category, obtained from 2 clinical studies:

1. Adult patients with newly diagnosed Ph+ CML-CP 60 month analysis and,
2. Adult patients with resistant or intolerant Ph+ CML-CP and CMP-AP 24 months’ analysis.

Infections And Infestations

Common: folliculitis. Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis). Unknown frequency: hepatitis B reactivation, sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.

Neoplasms Benign, Malignant, And Unspecified

Common: skin papilloma. Unknown frequency: oral papilloma, paraproteinemia.

Blood And Lymphatic System Disorders

Common: leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythemia, leukocytosis.

Immune System Disorders

Unknown frequency: hypersensitivity.

Endocrine Disorders

Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis.

Metabolism And Nutrition Disorders

Very Common: hypophosphatemia. Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia. Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, hypoglycemia.

Psychiatric Disorders

Common: depression, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria.

Nervous System Disorders

Common: peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, ischemic stroke, transient ischemic attack, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: basilar artery stenosis, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome.

Eye Disorders

Common: eye hemorrhage, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation, conjunctival hemorrhage. Unknown frequency: papilledema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease.

Ear And Labyrinth Disorders

Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus.

Cardiac Disorders

Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur, coronary artery stenosis, myocardial ischemia, pericardial effusion, cyanosis. Unknown frequency: ventricular dysfunction, pericarditis, ejection fraction decrease.

Vascular Disorders

Common: flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, hematoma, arteriosclerosis. Unknown frequency: shock hemorrhagic, hypotension, thrombosis, peripheral artery stenosis.

Respiratory, Thoracic And Mediastinal Disorders

Common: dyspnea exertional, epistaxis, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.

Gastrointestinal Disorders

Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth, gastritis, sensitivity of teeth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis.

Hepatobiliary Disorders

Very Common: hyperbilirubinemia. Common: hepatic function abnormal. Uncommon: hepatotoxicity, toxic hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly.

Skin And Subcutaneous Tissue Disorders

Common: eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform). Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis.

Musculoskeletal And Connective Tissue Disorders

Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain, muscular weakness. Uncommon: musculoskeletal stiffness, joint swelling. Unknown frequency: arthritis.

Renal And Urinary Disorders

Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia.

Reproductive System And Breast Disorders

Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling.

General Disorders And Administration Site Conditions

Common: pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise. Uncommon: gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema.

Investigations

Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, lipoprotein cholesterol (including very low density and high density) increased, total cholesterol increased, blood triglycerides increased. Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased, globulins decreased. Uncommon: blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, insulin C-peptide decreased, blood parathyroid hormone increased.

In Pediatric Patients With Newly Diagnosed Ph+ CML-CP Or Resistant Or Intolerant Ph+ CML-CP

The data below reflect exposure to Tasigna from two studies in pediatric patients from 2 to less than 18 years of age with either newly diagnosed Ph+ CML-CP or imatinib/dasatinib resistant or intolerant Ph+ CML-CP treated at the recommended dose of 230 mg/m² twice daily (n=69). The median time on treatment with Tasigna was 13.8 months (range: 0.7 to 30.9 months). The median actual dose intensity was 435.5 mg/m²/day (range: 149 to 517 mg/m²/day), and the median relative dose intensity was 94.7% (range: 32 to 112%). Forty patients (58.0%) had relative dose intensity superior to 90%.

In pediatric patients with Ph+ CML-CP, the most common (greater than 20%) non-hematologic adverse drug reactions were headache, rash, hyperbilirubinemia, alanine aminotransferase increased, pyrexia, nausea, upper respiratory tract infection, aspartate aminotransferase increased, and vomiting. The most common (greater than 5%) Grade 3/4 non-hematologic adverse drug reactions were alanine aminotransferase increased and hyperbilirubinemia.

Laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 13%) and transaminase elevation (AST Grade 3/4: 1%, ALT Grade 3/4: 9%), were reported at a higher frequency than in adult patients.

The most common hematological adverse drug reactions (greater than or equal to 30% of patients, of all grades) were decreases in total white blood cells (54%), platelet count (44%), absolute neutrophils (41%), absolute lymphocytes (32%), and hemoglobin (30%).

Discontinuation due to adverse reactions occurred in 9 patients (13%). The adverse reactions leading to discontinuation were hyperbilirubinemia (6%) and rash (4%).

Increase in QTcF greater than 30 msec from baseline was observed in 17 patients (25%). No patient had an absolute QTcF of greater than 500 msec or QTcF increase of greater than 60 msec from baseline.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Tasigna. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood And Lymphatic System Disorders: thrombotic microangiopathy.

 

SRC: NLM .