TYKERB SIDE EFFECTS
- Generic Name: lapatinib
- Brand Name: Tykerb
- Drug Class: Antineoplastics EGFR Inhibitors, Antineoplastic Tyrosine Kinase Inhibitors, Antineoplastics, Anti-HER2
SIDE EFFECTS
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. 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 (greater than 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 Grades 3 and 4 adverse reactions (NCI CTCAE v3.0) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.
Table 1: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients
| Reactions | TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m2/day (N = 198) |
Capecitabine 2,500 mg/m2/day (N = 191) |
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| All Grades a% | Grade 3% | Grade 4% | All Gradesa % | Grade 3% | Grade 4% | |
| 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 administration 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 NCI CTCAE v3.0. b Grade 3 dermatitis acneiform was reported in less than 1% of patients in the group receiving TYKERB plus capecitabine. |
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Table 2: Selected Laboratory Abnormalities
| Parameters | 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% | |
| 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 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a NCI CTCAE v3.0. |
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Hormone Receptor-Positive, Metastatic Breast Cancer
In a randomized, Phase 3 clinical trial of patients (N = 1286) 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 Greater Than or Equal to 10% of Patients
| Reactions | TYKERB 1,500 mg/day + Letrozole 2.5 mg/day (N = 654) |
Letrozole 2.5 mg/day (N = 624) |
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| All Gradesa% | Grade 3% | Grade 4% | All Gradesa% | Grade 3% | Grade 4% | |
| 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 administration 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 NCI CTCAE v3.0. 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. |
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Table 4: Selected Laboratory Abnormalities
| Hepatic Parameters | 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 % | |
| AST | 53 | 6 | 0 | 36 | 2 | < 1 |
| ALT | 46 | 5 | < 1 | 35 | 1 | 0 |
| Total Bilirubin | 22 | < 1 | < 1 | 11 | 1 | < 1 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a NCI CTCAE v3.0. |
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Hormone Receptor-Positive, HER2+ Metastatic Breast Cancer
In another randomized, Phase 3 clinical trial of postmenopausal patients (N = 355) with hormone receptor positive (HR+), HER2-positive metastatic breast cancer (MBC) which had progressed after prior trastuzumab-containing chemotherapy and endocrine therapies, patients received TYKERB with trastuzumab and an aromatase inhibitor (AI) (letrozole, exemestane, or anastrozole), TYKERB with an AI, or trastuzumab with an AI. In this trial, the safety profile of the treatment groups was consistent with the known safety of these agents. The most frequent study treatment-related AEs (> 10%) in each of the TYKERB-containing treatment arms were diarrhea, rash, paronychia, nausea, stomatitis, dermatitis acneiform, and decreased appetite, which were infrequent to absent in the trastuzumab treatment arm. The frequency of cardiac AEs (mostly decrease in ejection fraction) was 7% in the TYKERB+trastuzumab+AI group, 2% in the TYKERB+AI group and 3% in the trastuzumab+AI group. Adverse reactions which occurred in at least 10% of patients in the treatment arms are shown in Table 5.
Table 5: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients
| Reactions | TYKERB (1,000 mg) + Trastuzumab + AI (N = 118) |
TYKERB (1,500 mg) + AI (N = 119) |
Trastuzumab + AI (N = 116) |
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| All Gradesa(%) | Grade 3 (%) | Grade 4 (%) | All Gradesa(%) | Grade 3(%) | Grade 4 (%) | All Gradesa(%) | Grade 3 (%) | Grade 4 (%) | |
| Gastrointestinal disorders | |||||||||
| Diarrhea | 69 | 13 | 0 | 51 | 6 | 0 | 9 | 0 | 0 |
| Nausea | 22 | 0 | 0 | 22 | 2 | 0 | 9 | 0 | 0 |
| Stomatitis | 17 | 0 | 0 | 13 | < 1 | 0 | 3 | 0 | 0 |
| Vomiting | 10 | 0 | 0 | 14 | 0 | 0 | < 1 | < 1 | 0 |
| Skin and subcutaneous tissue disorders | |||||||||
| Rashb | 54 | 0 | 0 | 44 | 3 | 0 | 5 | 0 | 0 |
| Palmar-plantar erythrodysesthesia | 10 | 0 | 0 | 8 | < 1 | 0 | < 1 | 0 | 0 |
| Alopecia | 10 | 0 | 0 | 7 | 0 | 0 | 2 | 0 | 0 |
| General disorders and administration site conditions | |||||||||
| Fatigue | 12 | < 1 | 0 | 14 | 2 | 0 | 10 | 0 | 0 |
| Musculoskeletal and connective tissue disorders | |||||||||
| Arthralgia | 13 | < 1 | 0 | 14 | 0 | 0 | 12 | 0 | 0 |
| Pain in extremity | 7 | < 1 | 0 | 10 | 0 | 0 | 3 | 0 | 0 |
| Respiratory, thoracic, and mediastinal disorders | |||||||||
| Cough | 8 | 0 | 0 | 8 | 0 | 0 | 15 | 0 | 0 |
| Metabolism and nutrition disorders | |||||||||
| Decreased appetite | 18 | 0 | 0 | 13 | 0 | 0 | 3 | 0 | 0 |
| Infections and infestations | |||||||||
| Paronychia | 30 | 0 | 0 | 15 | 2 | 0 | 0 | 0 | 0 |
| Investigations | |||||||||
| Alanine aminotransferase increased | 7 | 0 | 0 | 15 | 3 | < 1 | 6 | 4 | 0 |
| Aspartate aminotransferase increased | 6 | 0 | 0 | 17 | 5 | 0 | 9 | 4 | 0 |
| Nervous system disorders | |||||||||
| Headache | 5 | 0 | 0 | 16 | 2 | 0 | 10 | < 1 | 0 |
| a NCI CTCAE v3.0. b Includes multiple adverse reaction terms for rash. |
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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 greater than or equal to Grade 3 (NCI CTCAE v3.0), or a greater than or equal to 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 combination treatment with TYKERB/capecitabine, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3.0). Among 654 patients who received combination treatment with TYKERB/letrozole, 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.
Interstitial Lung Disease/Pneumonitis
TYKERB has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies.
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.
Skin And Subcutaneous Tissue Disorders
Nail disorders, including paronychia. Severe cutaneous adverse reactions, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), skin fissures.
Cardiac Disorders
Ventricular arrhythmias/Torsades de Pointes (TdP). Electrocardiogram (ECG) QT prolongation.
SRC: NLM .