May 26, 2016
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Yervoy

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Yervoy




Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

  • Immune-mediated enterocolitis [see WARNINGS AND PRECAUTIONS].
  • Immune-mediated hepatitis [see WARNINGS AND PRECAUTIONS].
  • Immune-mediated dermatitis [see WARNINGS AND PRECAUTIONS].
  • Immune-mediated neuropathies [see WARNINGS AND PRECAUTIONS].
  • Immune-mediated endocrinopathies [see WARNINGS AND PRECAUTIONS].
  • Other immune-mediated adverse reactions, including ocular manifestations [see WARNINGS AND PRECAUTIONS].

In patients receiving YERVOY 3 mg/kg for unresectable or metastatic melanoma in Trial 1, 15% of patients receiving monotherapy and 12% of patients treated in combination with gp100 peptide vaccine experienced Grade 3 to 5 immune-mediated reactions. In patients receiving YERVOY 10 mg/kg for adjuvant treatment of melanoma in Trial 2, 41% experienced Grade 3 to 5 immune-mediated reactions.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to YERVOY 3 mg/kg in Trial 1, a randomized trial in patients with unresectable or metastatic melanoma and to YERVOY 10 mg/kg in Trial 2, a randomized trial in patients with resected Stage IIIA ( > 1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma.

Clinically significant adverse reactions were evaluated in a total of 982 patients treated in Trials 1 and 2 and in 21 dose-ranging trials (n=2478) administering YERVOY at doses of 0.1 to 20 mg/kg [see WARNINGS AND PRECAUTIONS].

Unresectable or Metastatic Melanoma

The safety of YERVOY was evaluated in Trial 1, a randomized, double-blind clinical trial in which 643 previously treated patients with unresectable or metastatic melanoma received YERVOY 3 mg/kg for 4 doses given by intravenous infusion as a single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (gp100) (n=380), or gp100 peptide vaccine as a single agent (n=132) [see Clinical Studies]. Patients in the trial received a median of 4 doses (range: 1 to 4 doses).

Trial 1 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation.

The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% white, and baseline ECOG performance status 0 (56%).

YERVOY was discontinued for adverse reactions in 10% of patients.

Table 2 presents selected adverse reactions from Trial 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3 to 5 events.

Table 2: Selected Adverse Reactions in Trial 1

System Organ Class/ Preferred Term Percentage (%) of Patientsa
YERVOY 3 mg/kg
n=131
YERVOY 3 mg/kg + gp100
n=380
gp100
n=132
Any Grade Grade 3 to 5 Any Grade Grade 3 to 5 Any Grade Grade 3 to 5
General Disorders and Administration-Site Conditions
  Fatigue 41 7 34 5 31 3
Gastrointestinal Disorders
  Diarrhea 32 5 37 4 20 1
  Colitis 8 5 5 3 2 0
Skin and Subcutaneous Tissue Disorders
  Pruritus 31 0 21 < 1 11 0
  Rash 29 2 25 2 8 0
a Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 3 presents the per-patient incidence of severe, life-threatening, or fatal immunemediated adverse reactions from Trial 1.

Table 3: Severe to Fatal Immune-Mediated Adverse Reactions in Trial 1

  Percentage (%) of Patients
YERVOY 3 mg/kg
n=131
YERVOY 3 mg/kg + gp100
n=380
Any Immune-Mediated Adverse Reaction 15 12
Enterocolitisa,b 7 7
Hepatotoxicitya 1 2
Dermatitisa 2 3
Neuropathya 1 < 1
Endocrinopathy 4 1
  Hypopituitarism 4 1
  Adrenal insufficiency 0 1
Other
  Pneumonitis 0 < 1
  Meningitis 0 < 1
  Nephritis 1 0
  Eosinophiliac 1 0
  Pericarditisac 0 < 1
a Including fatal outcome.
b Including intestinal perforation.
c Underlying etiology not established.

Adjuvant Treatment of Melanoma

The safety of YERVOY was evaluated in Trial 2, a randomized (1:1), double-blind, placebo-controlled trial in which 945 patients with resected Stage IIIA ( > 1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma received YERVOY 10 mg/kg (n=471) or placebo (n=474) administered as an intravenous infusion for 4 doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at Week 24 up to a maximum of 3 years [see Clinical Studies]. In this trial, 36% of patients received YERVOY for longer than 6 months and 26% of patients received YERVOY for longer than 1 year. YERVOY-treated patients in the trial received a median of 4 doses (range: 1 to 16).

Trial 2 excluded patients with prior systemic therapy for melanoma, autoimmune disease, a condition requiring systemic immunosuppression, or a positive test for hepatitis B, hepatitis C, or HIV.

The trial population characteristics were: median age 51 years (range: 18 to 84 years), 62% male, 99% white, and baseline ECOG performance status 0 (94%).

YERVOY was discontinued for adverse reactions in 52% of patients.

Table 4 presents selected adverse reactions from Trial 2 which occurred in at least 5% of YERVOY-treated patients and with at least 5% increased incidence over the placebo group for all-grade events.

Table 4: Selected Adverse Reactions in Trial 2

System Organ Class/ Preferred Term Percentage (%) of Patientsa
YERVOY 10 mg/kg
n=471
Placebo
n=474
Any Grade Grade 3 to 5 Any Grade Grade 3 to 5
Skin and Subcutaneous Tissue Disorders
  Rash 50 2.1 20 0
  Pruritus 45 2.3 15 0
Gastrointestinal Disorders
  Diarrhea 49 10 30 2.1
  Nausea 25 0.2 18 0
  Colitisb 16 8 1.5 0.4
  Vomiting 13 0.4 6 0.2
Investigations
  Weight Decreased 32 0.2 9 0.4
General Disorders and Administration-Site Conditions
  Fatigue 46 2.3 38 1.5
  Pyrexia 18 1.1 4.9 0.2
Nervous System Disorders
  Headache 33 0.8 18 0.2
Metabolism and Nutrition Disorders
  Decreased Appetite 14 0.2 3.4 0.2
Psychiatric Disorders 
  Insomnia 10 0 4.4 0
a Incidences presented in this table are based on reports of adverse events regardless of causality.
b Includes 1 death.

Table 5 presents selected laboratory abnormalities from Trial 2 which occurred in at least 10% of YERVOY-treated patients at a higher incidence compared to placebo.

Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 10% of YERVOY-Treated Patients (Trial 2)a

Test Percentage of Patients with Worsening
Laboratory Test from Baselinea
YERVOY Placebo
All Grades Grade 3 to 4 All Grades Grade 3 to 4
Chemistry
  Increased ALT 46 10 16 0
  Increased AST 38 9 14 0.2
  Increased lipaseb 26 9 17 4.5
  Increased amylaseb 17 2.0 7 0.6
  Increased alkaline phosphatase 17 0.6 6 0.2
  Increased bilirubin 11 1.5 9 0
  Increased creatinine 10 0.2 6 0
Hematology
  Decreased hemoglobin 25 0.2 14 0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Excluding lipase and amylase, YERVOY group (range: 466 to 470 patients) and placebo group (range: 472 to 474 patients).
b For lipase and amylase, YERVOY group (range: 447 to 448 patients) and placebo group (range: 462 to 464 patients).

Table 6 presents the per-patient incidence of severe, life-threatening, or fatal immunemediated adverse reactions from Trial 2.

Table 6: Severe to Fatal Immune-Mediated Adverse Reactions in Trial 2

  Percentage (%) of Patients
YERVOY 10 mg/kg
n=471
Any Immune-Mediated Adverse Reaction 41
Enterocolitisa,b 16
Hepatitis 11
Dermatitis 4.0
Neuropathya 1.7
Endocrinopathy 8
  Hypopituitarism 7
  Primary hypothyroidism 0.2
  Hyperthyroidism 0.6
Other
  Myocarditisa 0.2
  Meningitis 0.4
  Pericarditisc 0.2
  Pneumonitis 0.2
  Uveitis 0.2
a Including fatal outcome.
b Including intestinal perforation.
c Underlying etiology not established.

Other Clinical Experience

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of YERVOY. 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.

Skin and Subcutaneous Tissue Disorders

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.

Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab (TE-ADAs) in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of 144 patients receiving ipilimumab and 7 (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for TE-ADAs using an ECL assay with improved drug tolerance. No patients tested positive for neutralizing antibodies. No infusion-related reactions occurred in patients who tested positive for TE-ADAs.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ipilimumab with the incidences of antibodies to other products may be misleading.

Read the Yervoy (ipilimumab injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.

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

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 11/5/2015

Side Effects
Interactions

Yervoy - User Reviews

Yervoy User Reviews

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