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Tykerb

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Tykerb

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 [see Clinical Studies]. 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 (palmarplantar 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

Reactions TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m²/day
(N = 198)
Capecitabine 2,500 mg/m²/day
(N = 191)
All Gradesa 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 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 the group receiving TYKERB plus capecitabine.

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
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

Reactions TYKERB 1,500 mg/day + Letrozole 2.5 mg/day
(N = 654)
Letrozole 2.5 mg/day
(N = 624)
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 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

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
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 combination treatment with TYKERB/capecitabine, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3) [see WARNINGS AND PRECAUTIONS]. 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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

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].

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].

Skin and Subcutaneous Tissue Disorders

Nail disorders including paronychia.

Read the Tykerb (lapatinib) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems

Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) in vitro at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing TYKERB concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4, CYP2C8, or P-gp. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes in vitro, however, the clinical significance is unknown.

Midazolam

Following coadministration of TYKERB and midazolam (CYP3A4 substrate), 24-hour systemic exposure (AUC) of orally administered midazolam increased 45%, while 24-hour AUC of intravenously administered midazolam increased 22%.

Paclitaxel

In cancer patients receiving TYKERB and paclitaxel (CYP2C8 and P-gp substrate), 24-hour systemic exposure (AUC) of paclitaxel was increased 23%. This increase in paclitaxel exposure may have been underestimated from the in vivo evaluation due to study design limitations.

Digoxin

Following coadministration of TYKERB and digoxin (P-gp substrate), systemic AUC of an oral digoxin dose increased approximately 2.8-fold. Serum digoxin concentrations should be monitored prior to initiation of TYKERB and throughout coadministration. If digoxin serum concentration is > 1.2 ng/mL, the digoxin dose should be reduced by half.

Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes

Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly (see Ketoconazole and Carbamazepine sections, below). Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes [see DOSAGE AND ADMINISTRATION].

Ketoconazole

In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control.

Carbamazepine

In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately 72%.

Drugs That Inhibit Drug Transport Systems

Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If TYKERB is administered with drugs that inhibit P-gp, increased concentrations of lapatinib are likely, and caution should be exercised.

Acid-Reducing Agents

The aqueous solubility of lapatinib is pH dependent, with higher pH resulting in lower solubility. However, esomeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 7 days, did not result in a clinically meaningful reduction in lapatinib steady-state exposure.

Read the Tykerb Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 11/6/2013
This monograph has been modified to include the generic and brand name in many instances.

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