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Kadcyla

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Kadcyla

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the label:

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 clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis.

The ADRs described in Table 6 were identified in patients with HER2-positive metastatic breast cancer treated in a randomized trial (Study 1) [see Clinical Studies]. Patients were randomized to receive KADCYLA or lapatinib plus capecitabine. The median duration of study treatment was 7.6 months for patients in the KADCYLA-treated group and 5.5 months and 5.3 months for patients treated with lapatinib and capecitabine, respectively. Two hundred and eleven (43.1%) patients experienced ≥ Grade 3 adverse events in the KADCYLA-treated group compared with 289 (59.2%) patients in the lapatinib plus capecitabine-treated group. Dose adjustments for KADCYLA were permitted [see DOSAGE AND ADMINISTRATION]. Thirty-two patients (6.5%) discontinued KADCYLA due to an adverse event, compared with 41 patients (8.4%) who discontinued lapatinib, and 51 patients (10.5%) who discontinued capecitabine due to an adverse event. The most common adverse events leading to KADCYLA withdrawal were thrombocytopenia and increased transaminases. Eighty patients (16.3%) treated with KADCYLA had adverse events leading to dose reductions. The most frequent adverse events leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most frequent adverse events leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases and pyrexia.

Table 6 reports the ADRs that occurred in patients in the KADCYLA-treated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency > 2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

Table 6 : Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

Adverse Drug Reactions (MedDRA) System Organ Class KADCYLA (3.6 mg/kg)
n=490
Frequency rate %
Lapatinib (1250 mg) + Capecitabine (2000 mg/m²)
n=488
Frequency rate %
All grades (%) Grade 3 - 4 (%) All grades (%) Grade 3 - 4 (%)
Blood and Lymphatic System Disorders
Neutropenia 6.7 2.0 9.0 4.3
Anemia 14.3 4.1 10.5 2.5
Thrombocytopenia 31.2 14.5 3.3 0.4
Cardiac Disorders
Left ventricular dysfunction 1.8 0.2 3.3 0.4
Eye Disorders
Lacrimation increased 3.3 0 2.5 0
Dry eye 3.9 0 3.1 0
Vision blurred 4.5 0 0.8 0
Conjunctivitis 3.9 0 2.3 0
Gastrointestinal Disorders
Dyspepsia 9.2 0 11.5 0.4
Stomatitis 14.1 0.2 32.6 2.5
Dry Mouth 16.7 0 4.9 0.2
Abdominal pain 18.6 0.8 17.6 1.6
Vomiting 19.2 0.8 29.9 4.5
Diarrhea 24.1 1.6 79.7 20.7
Constipation 26.5 0.4 11.1 0
Nausea 39.8 0.8 45.1 2.5
General Disorders and Administration
Peripheral edema 7.1 0 8.2 0.2
Chills 7.6 0 3.1 0
Pyrexia 18.6 0.2 8.4 0.4
Asthenia 17.8 0.4 17.6 1.6
Fatigue 36.3 2.5 28.3 3.5
Hepatobiliary Disorders*
Nodular regenerative hyperplasia* 0.4 ND 0 0
Portal hypertension* 0.4 0.2 0 0
Immune System Disorders
Drug hypersensitivity 2.2 0 0.8 0
Injury, Poisoning, and Procedural
Infusion-related reaction 1.4 0 0.2 0
Infections and Infestations
Urinary tract infection 9.4 0.6 3.9 0
Investigations
Blood alkaline phosphatase increased 4.7 0.4 3.7 0.4
Increased transaminases 28.8 8.0 14.3 2.5
Metabolism and Nutrition Disorders
Hypokalemia 10.2 2.7 9.4 4.7
Musculoskeletal and Connective Tissue Disorders
Myalgia 14.1 0.6 3.7 0
Arthralgia 19.2 0.6 8.4 0
Musculoskeletal pain 36.1 1.8 30.5 1.4
Nervous System Disorders
Dysgeusia 8.0 0 4.1 0.2
Dizziness 10.2 0.4 10.7 0.2
Peripheral neuropathy 21.2 2.2 13.5 0.2
Headache 28.2 0.8 14.5 0.8
Psychiatric Disorders
Insomnia 12.0 0.4 8.6 0.2
Respiratory, Thoracic, and Mediastinal Disorders
Pneumonitis 1.2 0 0 0
Dyspnea 12.0 0.8 8.0 0.4
Cough 18.2 0.2 13.1 0.2
Epistaxis 22.5 0.2 8.4 0
Skin and Subcutaneous Tissue Disorders
Pruritus 5.5 0.2 9.2 0
Rash 11.6 0 27.5 1.8
Vascular Disorders
Hemorrhage 32.2 1.8 16.4 0.8
Hypertension 5.1 1.2 2.3 0.4
* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient. ND = Not determined

Table 7 : Selected Laboratory Abnormalities

Parameter KADCYLA (3.6 mg/kg) Lapatinib (1250 mg) + Capecitabine (2000 mg/m²)
All Grade % Grade 3 % Grade 4 % All Grade % Grade 3 % Grade 4 %
Increased bilirubin 17 < 1 0 57 2 0
Increased AST 98 7 < 1 65 3 0
Increased ALT 82 5 < 1 54 3 0
Decreased platelet count 83 14 3 21 < 1 < 1
Decreased hemoglobin 60 4 1 64 3 < 1
Decreased neutrophils 39 3 < 1 38 6 2
Decreased potassium 33 3 0 31 6 < 1

Hepatic failure has been observed in two patients (0.2%) with HER2-positive metastatic breast cancer in clinical trials (n=884) with KADCYLA as single-agent.

Immunogenicity

As with all therapeutic proteins, there is the potential for an immune response to KADCYLA. A total of 836 patients from six clinical studies were tested at multiple time points for anti-therapeutic antibody (ATA) responses to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients tested positive for anti-KADCYLA antibodies at one or more post-dose time points. The presence of KADCYLA in patient serum at the time of ATA sampling may interfere with the ability of this assay to detect anti-KADCYLA antibodies. As a result, data may not accurately reflect the true incidence of anti-KADCYLA antibody development. In addition, neutralizing activity of anti-KADCYLA antibodies has not been assessed.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to KADCYLA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-KADCYLA antibodies is not yet known.

Read the Kadcyla (ado-trastuzumab emtansine injection for iv use) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No formal drug-drug interaction studies with KADCYLA have been conducted. In vitro studies indicate that DM1, the cytotoxic component of KADCYLA, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with KADCYLA should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying KADCYLA treatment until the strong CYP3A4 inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse reactions.

Last reviewed on RxList: 7/29/2014
This monograph has been modified to include the generic and brand name in many instances.

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