"The U.S. Food and Drug Administration today approved two new drugs, Tafinlar (dabrafenib) and Mekinist (trametinib), for patients with advanced (metastatic) or unresectable (cannot be removed by surgery) melanoma, the most dangerous type of skin "...
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Depression and Other Neuropsychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
- Cardiovascular Adverse Reactions [see WARNINGS AND PRECAUTIONS]
- Retinopathy and Other Serious Ocular Adverse Reactions [see WARNINGS AND PRECAUTIONS]
- Hepatic Failure [see WARNINGS AND PRECAUTIONS]
- Endocrinopathies [see WARNINGS AND PRECAUTIONS]
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 clinical practice.
The data described below reflect exposure to SYLATRON in 608 patients with surgically resected, AJCC Stage III melanoma. SYLATRON was studied in an open label, multicenter, randomized, observation controlled trial. The median age of the population was 50 years with 10% of patients 65 years or older, and 42% were female. Fourteen percent of patients completed the 5 year treatment schedule.
Patients randomized to SYLATRON were to receive total doses of 48 mcg/kg (6 mcg/kg subcutaneous once weekly for 8 doses), and 780 mcg/kg (3 mcg/kg subcutaneous once weekly until disease recurrence or for up to 5 years), as tolerated. The median total dose received was 42 mcg/kg (range: 6 to 78 mcg/kg) for the first 8 doses, and 136 mcg/kg (range: 1 to 774 mcg/kg) for doses 9 to 260.
Serious adverse events were reported in 199 (33%) patients who received SYLATRON and 94 (15%) patients in the observation group.
The most common adverse reactions experienced by SYLATRON-treated patients were fatigue (94%), increased ALT (77%), increased AST (77%), pyrexia (75%), headache (70%), anorexia (69%), myalgia (68%), nausea (64%), chills (63%), and injection site reaction (62%). The most common serious adverse reactions were fatigue (7%), increased ALT (3%), increased AST (3%), and pyrexia (3%) in the SYLATRON-treated group vs. < 1% in the observation group for these reactions.
Thirty three percent of patients receiving SYLATRON discontinued treatment due to adverse reactions. The most common adverse reactions present at the time of treatment discontinuation were fatigue (27%), depression (17%), anorexia (15%), increased ALT (14%), increased AST (14%), myalgia (13%), nausea (13%), headache (13%), and pyrexia (11%). Adverse events that occurred in the clinical study at ≥ 5% incidence in the SYLATRON-treated group and with a greater incidence in patients receiving SYLATRON as compared to the observation group are presented in Table 3.
Table 4: Incidence of Adverse Reactions(*) Occurring
in ≥ 5% of Melanoma Patients Treated with SYLATRON and with a Greater
Incidence as Compared to Observation
|All Grades (%)||Grade 3 and 4 (%)||All Grades (%)||Grade 3 and 4 (%)|
|Any Adverse Reaction||100||51||82||18|
|General Disorders and Administrative Site Conditions|
|Injection Site Reaction||62||1.8||0||0|
|ALT or AST Increased||77||11||26||1|
|Blood Alkaline Phosphatase Increased||23||0||11||< 1|
|Weight Decreased||11||< 1||1||< 1|
|GGT Increased||8||4||1||< 1|
|Anemia||6||< 1||2||< 1|
|Nervous System Disorders|
|Olfactory Nerve Disorder||23||0||1||0|
|Paraesthesia||21||< 1||14||< 1|
|Metabolism and Nutrition Disorders|
|Musculoskeletal and Connective Tissue Disorders|
|Skin and Subcutaneous Tissue Disorders|
|Respiratory, Thoracic and Mediastinal Disorders|
|* Adverse reactions were graded using NCI CTCAE, V.2.0.|
As with all therapeutic proteins, there is potential for immunogenicity. In a clinical study conducted in patients with melanoma, the incidence of binding antibodies to peg-interferon alfa-2b was approximately 35% (50/144 patients). Among the patients who tested positive for binding antibodies, one patient developed neutralizing antibodies. The impact of antibody formation on pharmacokinetics, safety and efficacy of peg-interferon alfa-2b could not be assessed based on limited available data.
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SYLATRON with the incidence of antibodies to other products may be misleading.
The following adverse reactions have been identified during post-approval use of peginterferon alfa-2b as monotherapy and in combination with ribavirin in chronic hepatitis C (CHC) patients. 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.
Blood and Lymphatic System Disorders
Ear and Labyrinth Disorders
hearing loss, vertigo, hearing impairment
Immune System Disorders
systemic lupus erythematosus, erythema multiforme, thyroiditis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, rheumatoid arthritis, interstitial nephritis, and systemic lupus erythematosus
Metabolism and Nutrition Disorders
Musculoskeletal and Connective Tissue Disorders
Nervous System Disorders
Respiratory, Thoracic and Mediastinal Disorders
Skin and Subcutaneous Tissue Disorders
Read the Sylatron (peginterferon alfa-2b) Side Effects Center for a complete guide to possible side effects
In healthy subjects who were administered peginterferon alfa-2b subcutaneously at 1 mcg/kg once weekly for four weeks with probe drugs of metabolic enzymes administered before the first dose and after the fourth dose, a measure of CYP2C9 activity increased to 125% of baseline, whereas a measure of CYP2D6 activity decreased to 51% of baseline [see CLINICAL PHARMACOLOGY]. When administering SYLATRON with medications metabolized by CYP2C9 or CYP2D6, the therapeutic effect of these drugs may be altered.
The effects of pegylated interferon alfa-2b on the pharmacokinetics of drugs metabolized by cytochrome P-450 enzymes have not been studied at the higher clinical doses for patients with melanoma (3 mcg/kg/week and 6 mcg/kg/week).
Read the Sylatron Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 9/10/2014
This monograph has been modified to include the generic and brand name in many instances.
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