Tykerb Side Effects

Generic Name: lapatinib

Please note - some side effects for Tykerb may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Tykerb - for the Consumer

Tykerb

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Tykerb:

Back pain; diarrhea; dry skin; fingernail or toenail changes; headache; indigestion; loss of appetite; mild hair loss or thinning; mouth sores; nausea; nosebleed; redness and tingling of the hands and feet; tiredness; trouble sleeping; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Tykerb:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; dark urine; dizziness or light-headedness; fast or irregular heartbeat; pale stools; persistent loss of appetite; severe or persistent cough; severe pain, redness, or swelling of the hands or feet; severe stomach pain or diarrhea; severe tiredness or weakness; shortness of breath; unusual bruising or bleeding; unusual itching; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Tykerb Side Effects - for the Professional

Tykerb

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.

HER2 Positive Metastatic Breast Cancer: The safety of Tykerb has been evaluated in more than 12,000 patients in clinical trials. The efficacy and safety of Tykerb in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial. [See Clinical Studies (14.1).] Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 1.

The most common adverse reactions (>20%) during therapy with Tykerb plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.

The most common Grade 3 and 4 adverse reactions (NCI CTCAE v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.

Table 1. Adverse Reactions Occurring in ≥10% of Patients

	Tykerb 1,250 mg/day + Capecitabine 2,000 mg/m2/day			Capecitabine 2,500 mg/m2/day
	(N = 198)			(N = 191)
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Reactions	%	%	%	%	%	%
Gastrointestinal disorders
Diarrhea	65	13	1	40	10	0
Nausea	44	2	0	43	2	0
Vomiting	26	2	0	21	2	0
Stomatitis	14	0	0	11	<1	0
Dyspepsia	11	<1	0	3	0	0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia	53	12	0	51	14	0
Rashb	28	2	0	14	1	0
Dry skin	10	0	0	6	0	0
General disorders and administrative site conditions
Mucosal inflammation	15	0	0	12	2	0
Musculoskeletal and connective tissue disorders
Pain in extremity	12	1	0	7	<1	0
Back pain	11	1	0	6	<1	0
Respiratory, thoracic, and mediastinal disorders
Dyspnea	12	3	0	8	2	0
Psychiatric disorders
Insomnia	10	<1	0	6	0	0

a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

b Grade 3 dermatitis acneiform was reported in <1% of patients in Tykerb plus capecitabine group.

Table 2. Selected Laboratory Abnormalities

	Tykerb 1,250 mg/day + Capecitabine 2,000 mg/m2/day			Capecitabine 2,500 mg/m2/day
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Parameters	%	%	%	%	%	%
Hematologic
Hemoglobin	56	<1	0	53	1	0
Platelets	18	<1	0	17	<1	<1
Neutrophils	22	3	<1	31	2	1
Hepatic
Total Bilirubin	45	4	0	30	3	0
AST	49	2	<1	43	2	0
ALT	37	2	0	33	1	0

a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Hormone Receptor Positive, Metastatic Breast Cancer: In a randomized clinical trial of patients (N = 1,286) with hormone receptor positive, metastatic breast cancer, who had not received chemotherapy for their metastatic disease, patients received letrozole with or without Tykerb. In this trial, the safety profile of Tykerb was consistent with previously reported results from trials of Tykerb in the advanced or metastatic breast cancer population. Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 3. Selected laboratory abnormalities are shown in Table 4.

Table 3. Adverse Reactions Occurring in ≥10% of Patients

	Tykerb 1,500 mg/day + Letrozole 2.5 mg/day			Letrozole 2.5 mg/day
	(N = 654)			(N = 624)
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Reactions	%	%	%	%	%	%
Gastrointestinal disorders
Diarrhea	64	9	<1	20	<1	0
Nausea	31	<1	0	21	<1	0
Vomiting	17	1	<1	11	<1	<1
Anorexia	11	<1	0	9	<1	0
Skin and subcutaneous tissue disorders
Rashb	44	1	0	13	0	0
Dry skin	13	<1	0	4	0	0
Alopecia	13	<1	0	7	0	0
Pruritus	12	<1	0	9	<1	0
Nail Disorder	11	<1	0	<1	0	0
General disorders and administrative site conditions
Fatigue	20	2	0	17	<1	0
Asthenia	12	<1	0	11	<1	0
Nervous system disorders
Headache	14	<1	0	13	<1	0
Respiratory, thoracic, and mediastinal disorders
Epistaxis	11	<1	0	2	<1	0

a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

b In addition to the rash reported under "Skin and subcutaneous tissue disorders", 3 additional subjects in each treatment arm had rash under "Infections and infestations"; none were Grade 3 or 4.

Table 4. Selected Laboratory Abnormalities

	Tykerb 1,500 mg/day + Letrozole 2.5 mg/day			Letrozole 2.5 mg/day
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Hepatic Parameters	%	%	%	%	%	%
AST	53	6	0	36	2	<1
ALT	46	5	<1	35	1	0
Total Bilirubin	22	<1	<1	11	1	<1

a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are ≥Grade 3 (NCI CTCAE), or a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received Tykerb/capecitabine combination treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3). [See Warnings and Precautions (5.1).] Among 654 patients who received Tykerb/letrozole combination treatment, 26 patients experienced Grade 1 or 2 and 6 patients had Grade 3 or 4 LVEF adverse reactions.

Hepatotoxicity: Tykerb has been associated with hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.2)].

Interstitial Lung Disease/Pneumonitis: Tykerb has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Warnings and Precautions (5.5)].

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Tykerb. 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.

Immune System Disorders: Hypersensitivity reactions including anaphylaxis [see Contraindications (4)].

Skin and Subcutaneous Tissue Disorders: Nail disorders including paronychia.

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Side Effects by Body System - for Healthcare Professionals

General

All clinical trial data were from trials of lapatinib in combination with capecitabine.

To report suspected adverse reactions, contact GlaxoSmithKline at 1-888-825-5249 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Gastrointestinal

Gastrointestinal side effects including diarrhea (65%), nausea (44%), vomiting (26%), stomatitis (14%), and dyspepsia (11%) have been reported.

Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.

Hematologic

Hematologic side effects have included laboratory abnormalities in hemoglobin (56%), neutrophils (22%), and platelets (18%).

Dermatologic

Dermatologic side effects including palmar plantar erythrodysesthesia (53%) (also called hand-foot syndrome or acral erythema), rash (28%), dry skin (10%), and nail disorders including paronychia have been reported.

Hepatic

Hepatic side effects have included laboratory abnormalities in AST (49%), total bilirubin (45%), and ALT (37%).

Hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with lapatinib should be discontinued and patients should not be retreated with lapatinib. If lapatinib is to be administered to patients with severe preexisting hepatic impairment, dose reduction should be considered. In patients who develop severe hepatotoxicity while on therapy, lapatinib should be discontinued and should not be retreated with lapatinib.

Cardiovascular

Cardiovascular side effects including decreases in left ventricular ejection fraction and QT prolongation have been reported.

Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, left ventricular ejection fraction (LVEF) was monitored in clinical trials at approximately eight-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are grade 3 (NCI CTCAE), or a 20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received lapatinib/capecitabine combination treatment, three experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTC 3.0).

The QT prolongation potential of lapatinib was assessed as part of an uncontrolled, open-label dose escalation study in advanced cancer patients. Eighty-one patients received daily doses of lapatinib ranging from 175 mg/day to 1800 mg/day. Serial ECGs were collected on day 1 and day 14 to evaluate the effect of lapatinib on QT intervals. Thirteen of the 81 subjects were found to have either QTcF (corrected QT by the Friedericia method) greater than 480 msec or an increase in QTcF greater than 60 msec by automated machine-read evaluation of ECG. Analysis of the data suggested a relationship between lapatinib concentration and the QTc interval.

Other

Other side effects including mucosal inflammation (15%), pain in the extremity (12%), dyspnea (12%), back pain (11%), and insomnia (10%) have been reported.

Oncologic

Oncologic side effects including genotoxicity have been reported. An impurity in the drug product was genotoxic when tested alone in both in vitro and in vivo assays.

Respiratory

It is recommended that patients be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. Lapatinib should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are greater than or equal to grade 3 (NCI CTCAE).

Respiratory side effects have been reported including interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies.

Hypersensitivity

Hypersensitivity side effects including anaphylaxis have been reported.

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