Side Effects of Tykerb (lapatinib)

Tykerb (lapatinib) is a cancer medication used in combination with capecitabine to treat patients with advanced or metastatic breast cancer and other specific conditions.

Tykerb is also used in concert with letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer with other conditions present.

Common side effects of Tykerb in combination with capecitabine or letrozole include

• diarrhea,
• red and painful hands and feet,
• nausea,
• rash,
• vomiting,
• tiredness, 
• weakness,
• mouth sores,
• loss of appetite,
• indigestion,
• unusual hair loss or thinning,
• nose bleeds,
• headache,
• dry skin,
• itching, and
• nail disorders such as nail bed changes, nail pain, infection and swelling of the cuticles.

Serious side effects of Tykerb include

• heart problems, including decreased pumping of blood from the heart and an abnormal heartbeat;
• liver problems (symptoms of liver problems include itching, yellowing of skin or eyes, dark urine, and pain or discomfort in the right upper stomach area);
• severe diarrhea that can cause dehydration;
• lung problems (symptoms include a cough that will not go away or shortness of breath); and
• severe skin reactions (symptoms include skin rash, red skin, blistering of the lips, eyes, or mouth, peeling of the skin, fever, or any combination of these).

Drug interactions of Tykerb include

• cimetidine,
• dexamethasone,
• rifabutin,
• rifampin,
• rifapentine,
• St. John's wort,
• midazolam,
• paclitaxel, and digoxin,
• antibiotics,
• antifungals,
• antidepressants,
• calcium channel blockers,
• HIV/AIDS medicines, and
• seizure medications. 

There are no adequate and well-controlled studies with Tykerb in pregnant women. Women should be advised not to become pregnant when taking Tykerb. If this drug is used during pregnancy, or if the patient becomes pregnant while taking Tykerb, the patient should be apprised of the potential hazard to the fetus. 

It is unknown if Tykerb is excreted in breast milk. Because many drugs are excreted in breast milk and because of the potential for serious adverse reactions in nursing infants from Tykerb, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

WARNING

Tykerb may cause serious side effects, including:

• heart problems, including decreased pumping of blood from the heart and an abnormal heartbeat.
• Signs and symptoms of an abnormal heartbeat include:
• feeling like your heart is pounding or racing
• dizziness
• tiredness
• feeling lightheaded
• shortness of breath Your doctor should check your heart function before you start taking Tykerb and during treatment.
• liver problems.
• Liver problems can be severe and deaths have happened. Signs and symptoms of liver problems include:
• itching
• yellowing of your skin or the white part of your eyes
• dark urine
• pain or discomfort in the right upper stomach area Your doctor should do blood tests to check your liver before you start taking Tykerb and during treatment.
• diarrhea. Diarrhea is common with Tykerb and may sometimes be severe. Severe diarrhea can cause loss of body fluid (dehydration) and some deaths have happened. Call your doctor right away if you have a change in bowel pattern or if you have severe diarrhea. Follow your doctor’s instructions for what to do to help prevent or treat diarrhea.
• lung problems. Symptoms of a lung problem with Tykerb include a cough that will not go away or shortness of breath.
• severe skin reactions. Tykerb may cause severe skin reactions. Tell your doctor right away if you develop a skin rash, red skin, blistering of the lips, eyes, or mouth, peeling of the skin, fever, or any combination of these.

As severe skin reactions can be life-threatening, your doctor may tell you to stop taking Tykerb. Call your doctor right away if you have any of the signs or symptoms of the serious side effects listed above.

Common side effects of Tykerb in combination with capecitabine or letrozole include:

• diarrhea
• red, painful hands and feet
• nausea
• rash
• vomiting
• tiredness or weakness
• mouth sores
• loss of appetite
• indigestion
• unusual hair loss or thinning
• nose bleeds
• headache
• dry skin
• itching
• nail disorders such as nail bed changes, nail pain, infection and swelling of the cuticles.

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Tykerb. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also get side effects from the other medicines taken with Tykerb. Talk to your doctor about possible side effects you may get during treatment.

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 Grade 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

Table 2: Selected Laboratory Abnormalities

Hormone Receptor-Positive, Metastatic Breast Cancer

• In a randomized, Phase 3 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 Greater Than or Equal to 10% of Patients

Table 4: Selected Laboratory Abnormalities

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

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) and toxic epidermal necrolysis (TEN).

Cardiac Disorders

• Ventricular arrhythmias/Torsades de Pointes (TdP). Electrocardiogram (ECG) QT prolongation.

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 greater than 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 Tykerb should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes.

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. 7.4 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.