Yervoy 5mg per ml concentrate for solution for infusion

Addition of cytokine release syndrome.

Change to sections 1, 2 and 3.

Update to Sections 4.1, 4.2, 4.8, 5.1, 5.2 and 10.

sec

To update of the efficacy analyses based upon 7.5 years of minimum follow-up for all subjects from study CA209067.

extension of indication, change in ipi infusion time

Worksharing TYII RCC 1L CA209214 60-month data, SmPc update

Yervoy EU PSUR 14, covering the period from 25 Mar 2020 to 24 Mar 2021, update on SmPC/PIL

Addition of 'cystitis non infective' to the warnings and uundesirable effects for YERVOY in combination with OPDIVO

Extension of indication to include the treatment of mismatch repair deficient or microsatellite instability high (MSI-H) metastatic colorectal cancer (CRC) after prior fluoropyrimidine based combination chemotherapy

Product information updated to include Opdivo (nivolumab) plus Yervoy (ipilimumab) with two cycles of chemotherapy for first-line treatment of metastatic non-small cell lung cancer

4.       Clinical particulars
4.1     Therapeutic indications

Non-Small Cell Lung Cancer (NSCLC)

YERVOY in combination with nivolumab and 2 cycles of platinum-based chemotherapy is indicated for the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have no sensitising EGFR mutation or ALK translocation.

4.2     Posology and method of administration

YERVOY in combination with nivolumab and chemotherapy

Non-Small Cell Lung Cancer

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with 360 mg nivolumab administered intravenously over 30 minutes every 3 weeks, and platinum-based chemotherapy administered every 3 weeks. After completion of 2 cycles of chemotherapy, treatment is continued with 1 mg/kg ipilimumab every 6 weeks in combination with 360 mg nivolumab administered intravenously every 3 weeks. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

4.4     Special warnings and precautions for use

 Ipilimumab in combination with nivolumab

When ipilimumab is administered in combination with nivolumab, refer to the Summary of Product Characteristics for nivolumab of the other combination therapy components prior to initiation of treatment. For additional information on warnings and precautions associated with nivolumab treatment, please refer to the nivolumab SmPC. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications (see section 4.2). Immune-related adverse reactions have occurred at higher frequencies when nivolumab was administered in combination with ipilimumab compared with nivolumab as monotherapy.

Disease specific precautions

Non-Small Cell Lung Cancer

Patients with active autoimmune disease, symptomatic interstitial lung disease, medical conditions requiring systemic immunosuppression, active (untreated) brain metastasis, who received prior systemic treatment for advanced disease, or who had sensitising EGFR mutations or ALK translocations were excluded from the pivotal trial in first-line treatment of NSCLC (see sections 4.5 and 5.1). Limited data are available in elderly patients (≥ 75 years) (see section 5.1). In these patients, ipilimumab in combination with nivolumab and chemotherapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis.

4.8     Undesirable effects

Ipilimumab in combination with nivolumab and chemotherapy

Table 6:           Adverse reactions with ipilimumab in combination with nivolumab and chemotherapy

Immune-related colitis

In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and chemotherapy in NSCLC, the incidence of diarrhoea or colitis was 22.3% (80/358). Grade 2, Grade 3, Grade 4, and Grade 5 cases were reported in 7% (25/358), 5% (18/358), 0.3% (1/358), and 0.3% (1/358) of patients, respectively. Median time to onset was 5.1 weeks (range: 0.1-53.6). Resolution occurred in 70 patients (87.5%) with a median time to resolution of 1.4 weeks (range: 0.1-76.9⁺).

Immune-related pneumonitis

In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and chemotherapy in NSCLC, the incidence of pneumonitis including interstitial lung disease was 5.3% (19/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 1.1% (4/358),and 0.6% (2/358) of patients, respectively. Median time to onset was 18.1 weeks (range: 0.6-52.4). Resolution occurred in 14 patients (74%) with a median time to resolution of 4.3 weeks (range: 0.7-27.9⁺).

Immune‑related hepatotoxicity

In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and chemotherapy in NSCLC, the incidence of liver function test abnormalities was 13.4% (48/358). Grade 2, Grade 3, and Grade 4 cases were reported in 3.1% (11/358), 3.4% (12/358), and 1.1% (4/358) of patients, respectively. Median time to onset was 10.6 weeks (range: 1.1-68.3). Resolution occurred in 37 patients (80.4%) with a median time to resolution of 5 weeks (range: 0.3⁺-45.0⁺).

Immune‑related skin adverse reactions

In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and chemotherapy in NSCLC, the incidence of rash was 37.7% (135/358). Grade 2, Grade 3, and Grade 4 cases were reported in 11.5% (41/358), 4.2% (14/358), and 0.3% (1/358) of patients, respectively. Median time to onset was 3.3 weeks (range: 0.1-83.1). Resolution occurred in 96 patients (71.6%) with a median time to resolution of 9.4 weeks (range: 0.1⁺-84.1⁺).

Immune-related nephritis and renal dysfunction

In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and chemotherapy in NSCLC, the incidence of nephritis or renal dysfunction was 7% (25/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 1.7% (6/358), and 0.6 (2/358) of patients, respectively. Median time to onset was 10.6 weeks (range: 0.1-51.3). Resolution occurred in 14 patients (56%) with a median time to resolution of 6.3 weeks (range: 0.1⁺-82.9⁺).

Immune‑related endocrinopathy

In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and chemotherapy in NSCLC, the incidence of thyroid disorders was 24% (86/358). Grade 2 and Grade 3 thyroid disorders were reported in 12.3% (44/358) and 0.3% (1/358) of patients, respectively. Hypophysitis occurred in 1.4% (5/358) of patients. Grade 2 and Grade 3 cases were reported in 0.6% (2/358) and 0.8% (3/358) of patients, respectively. Grade 2 hypopituitarism occurred in 0.3% (1/358) of patients. Grade 2 and Grade 3 adrenal insufficiency occurred in 1.7% (6/358) and 1.4% (5/358) of patients, respectively. Diabetes mellitus including Type 1 diabetes mellitus was not reported. Median time to onset of these endocrinopathies was 12.1 weeks (range:1.9-58.3). Resolution occurred in 30 patients (35.3%). Time to resolution ranged from 1.4 to 72.4⁺ weeks.

Infusion reactions

In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and chemotherapy in NSCLC, the incidence of hypersensitivity/infusion reactions was 4.7% (17/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 0.3% (1/358), and 0.3% (1/358) of patients, respectively.

Immunogenicity

Of the patients who were treated with ipilimumab in combination with nivolumab and evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged from 6.3 to 8.4%. Of the patients who were treated with ipilimumab in combination with nivolumab and chemotherapy and evaluable for the presence of anti-ipilimumbab antibodies or neutralising antibodies against ipilimumab, the incidence of anti-ipilimumab antibodies was 7.5% and neutralising antibodies against ipilimumab was 1.6%. Of patients evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks,  37.8% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks, and 33.8% with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy. The incidence of neutralising antibodies against nivolumab was 0.5% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 4.6% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks and 2.6% with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy.

Laboratory abnormalities with ipilimumab in combination with nivolumab

In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and chemotherapy in NSCLC, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 9.2% for anaemia, 4.3% for thrombocytopaenia, 9.8% for leucopoenia, 5.8% for lymphopaenia, 14.7% for neutropaenia, 1.2% for increased alkaline phosphatase, 3.5% for increased AST, 4.3% for increased ALT, 0% for increased total bilirubin, 1.2% for increased creatinine, 7.1% for hyperglycaemia, 0% for hypoglycaemia, 6.7% for increased amylase, 11.9% for increased lipase, 1.4% for hypocalcaemia, 1.2% for hypercalcaemia, 1.7% for hyperkalemia, 0.3% for hypermagnesaemia, 1.2% for hypomagnesaemia 3.5% for hypokalaemia, and 10.7% for hyponatraemia.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

First-line treatment of Non-Small Cell Lung Cancer

Randomised phase 3 study of ipilimumab in combination with nivolumab and 2 cycles of platinum-based chemotherapy vs. 4 cycles of platinum-based chemotherapy (CA2099LA)

5.2     Pharmacokinetic properties

Yervoy in combination with nivolumab and chemotherapy: When ipilimumab 1 mg/kg every 6 weeks was administered in combination with nivolumab 360 mg every 3 weeks and with 2 cycles of chemotherapy, the CL of ipilimumab increased approximately 22% and the CL of nivolumab decreased approximately 10%, which was not considered clinically relevant.

10.     DATE OF REVISION OF THE TEXT

05 November 2020

Product information updated to include Opdivo (nivolumab) plus Yervoy (ipilimumab) with two cycles of chemotherapy for first-line treatment of metastatic non-small cell lung cancer

This SmPC revision includes:

1. Updated efficacy data i.e. updated overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Safety data and analysis in terms of the type, frequency and severity of reported events have also been updated. Variation approved 23 Jul 2020.

2. Updated shelf-life section 6.3 to reflect extended in-use stability. This variation was approved on the 14th of July.

Section 4.4. of the SmPC was updated to include the standard biologics traceability statement, in line with GVP EMA/168402/2014 Corr* .

Minor revisions were also made to the sodium content section (section 4.4) as follows:

Patients on controlled sodium diet

 This medicinal product contains 23 mg sodium per 10 ml vial and 92 mg sodium per 40 mg vial, respectively equivalent to 1.15% and 4.60% of the WHO recommended maximum daily intake of 2 g sodium for an adult.Each ml of this medicinal product contains 0.1 mmol (or 2.30 mg) sodium. To be taken into consideration when treating patients on a controlled sodium diet.

Update to date of revision

7.       MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb Pharma EEIG
Plaza 254
Blanchardstown Corporate Park 2
Dublin 15, D15 T867

Ireland

Update to date of revision.

Please see reasons for change

Immune‑related gastrointestinal reactions

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune‑related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in a Phase 3 study of advanced (unresectable or metastatic) melanoma (MDX010‑20, see section 5.1), the median time to onset of severe or fatal (Grade 3‑5) immune‑related gastrointestinal reactions was 8 weeks (range 5 to 13 weeks) from the start of treatment. With protocol‑specified management guidelines, resolution (defined as improvement to mild [Grade 1] or less or to the severity at baseline) occurred in most cases (90%), with a median time from onset to resolution of 4 weeks (range 0.6 to 22 weeks).

Patients must be monitored for gastrointestinal signs and symptoms that may be indicative of immune‑related colitis or gastrointestinal perforation. Clinical presentation may include diarrhoea, increased frequency of bowel movements, abdominal pain, or haematochezia, with or without fever. Diarrhoea or colitis occurring after initiation of ipilimumab must be promptly evaluated to exclude infectious or other alternate etiologies. In clinical trials, immune‑related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration. Post‑marketing cases of cytomegalovirus (CMV) infection/reactivation have been reported in patients with corticosteroid‑refractory immune‑related colitis. Stool infections work-up should be performed upon presentation of diarrhoea or colitis to exclude infectious or other alternate etiologies.

Management recommendations for diarrhoea or colitis are based on severity of symptoms (per NCI‑CTCAE v4 severity grading classification). Patients with mild to moderate (Grade 1 or 2) diarrhoea (an increase of up to 6 stools per day) or suspected mild to moderate colitis (e.g. abdominal pain or blood in stools) may remain on ipilimumab. Symptomatic treatment (e.g. loperamide, fluid replacement) and close monitoring are advised. If mild to moderate symptoms recur or persist for 5‑7 days, the scheduled dose of ipilimumab should be withheld and corticosteroid therapy (e.g. prednisone 1 mg/kg orally once daily or equivalent) should be initiated. If resolution to Grades 0‑1 or return to baseline occurs, ipilimumab may be resumed (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) diarrhoea or colitis (see section 4.2), and systemic high‑dose intravenous corticosteroid therapy should be initiated immediately. (In clinical trials, methylprednisolone 2 mg/kg/day has been used). Once diarrhoea and other symptoms are controlled, the initiation of corticosteroid taper should be based on clinical judgment. In clinical trials, rapid tapering (over periods < 1 month) resulted in recurrence of diarrhoea or colitis in some patients. Patients must be evaluated for evidence of gastrointestinal perforation or peritonitis.

The experience from clinical trials on the management of corticosteroid‑refractory diarrhoea or colitis is limited. However, aAddition of an alternative immunosuppressive agent to the corticosteroid regimen should be considered in corticosteroid‑refractory immune‑related colitis if other causes are excluded (including Cytomegalovirus (CMV) infection/reactivation evaluated with viral PCR on biopsy, and other viral, bacterial and parasitic etiology)may be considered. In clinical trials, a single dose of infliximab 5 mg/kg was added unless contraindicated. Infliximab must not be used if gastrointestinal perforation or sepsis is suspected (see the Summary of Product Characteristics for infliximab).

10.     DATE OF REVISION OF THE TEXT

22 November 2018

• To provide an update on the following important key messages:

- That side effects need to be addressed immediately, regardless of severity to avoid their worsening

- Patients should inform their doctor of all known medical conditions and medicines they are taking, or have recently taken, before receiving treatment with ipilimumab

- To pay attention to side effects even after the end of their treatment

• Editorial updates

The purpose of this variation is to reflect updated efficacy and safety data from the final CSRs for studies CA184332 and CA184338 in the YERVOY SmPC section 5.1.

This variation is to align the YERVOY and OPDIVO labels in terms of clarity on the treatment options (monotherapy + combination therapy) for patients and prescribers.

·        Inclusion of Steven Johnson Syndrome (SJS) in the Warnings section as potential fatal skin reaction

·        Addition of statement to specify that patients with ocular melanoma were not included in study 169. However patients with brain metastasis were included subject to defined criteria

·        Addition of a statement to specify that overall safety profile of ipilimumab 3 mg/kg in study 169 was consistent with that established for ipilimumab in patients treated for advanced melanoma.

·        Inclusion of study 169 efficacy results in section 5.1 – Pharmacodynamic properties
- Removal of black triangle 

-Revision of the current warning on concurrent administration with vemurafenib to enhance awareness of the potential of  hypersensitivity reactions when ipilimumab is administered following prior vemurafenib
-Update to the posology section information for hepatic irARs in line with CTCAE (Common Terminology Criteria for Adverse Events) v.4

-Amendment of the frequency of the ADR ' Vogt-Konyanagi-Harada syndrome from ‘unknown’ to ‘rare’

4.4     Special warnings and precautions for use

Immune‑related skin adverse reactions

Ipilimumab is associated with serious skin adverse reactions that may be immune‑related. Fatal tToxic epidermal necrolysis (including fatal cases) has been reported in clinical trials and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported in clinical trials and during post-marketing use (see section 4.8).

DRESS presents as a rash with eosinophilia associated with one or more of the following features: fever, lymphadenopathy, facial oedema, and internal organ involvement (hepatic, renal, pulmonary). DRESS may be characterized by a long latency (two to eight weeks) between drug exposure and disease onset.

Caution should be used when considering the use of Yervoy in a patient who has previously experienced a severe or life-threatening skin adverse reaction on a prior cancer immune stimulatory therapy.

4.4     Special warnings and precautions for use

Immune‑related skin adverse reactions

Ipilimumab is associated with serious skin adverse reactions that may be immune‑related. Fatal toxic epidermal necrolysis has been reported in < 1% of patients who received ipilimumab in combination with gp100 (see section 5.1). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been rarely reported with Ipilimumab in clinical studies and during post-marketing use.

10.     DATE OF REVISION OF THE TEXT

June 2015

5.1     Pharmacodynamic properties

4.8     Undesirable effects

Summary of safety profile

Ipilimumab has been administered to approximately 10,000 patients in a clinical program evaluating its use with various doses and tumour types. Unless otherwise specified, the data below reflect exposure to ipilimumab at 3 mg/kg in clinical trials of melanoma. In the Phase 3 study MDX010‑20, (see section 5.1), patients received a median of 4 doses (range 1‑4).

Ipilimumab is most commonly associated with adverse reactions resulting from increased or excessive immune activity. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of ipilimumab (see section 4.4 for management of immune-related adverse reactions).

In patients who received 3 mg/kg ipilimumab monotherapy in MDX010‑20, the most frequently reported adverse reactions (≥ 10% of patients) were diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. The majority were mild to moderate (Grade 1 or 2). Ipilimumab therapy was discontinued for adverse reactions in 10% of patients.

Tabulated list of adverse reactions

Adverse reactions reported in patients with advanced melanoma who were treated with ipilimumab 3 mg/kg in clinical trials (n= 767) are presented in Table 2.

These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Rates of immune-related adverse reactions in HLA‑A2*0201 positive patients who received ipilimumab in MDX010‑20 were similar to those observed in the overall clinical program.

The safety profile of ipilimumab 3 mg/kg in chemotherapy‑naive patients pooled across Phase 2 and 3 clinical trials (N= 75; treated) and in treatment‑naive patients in a retrospective observational study (N= 120) was similar to that in previously‑treated advanced melanoma.

a          Frequencies are based on pooled data from 9 clinical trials investigating the ipilimumab 3 mg/kg dose in melanoma.

b          Including fatal outcome.

c           Additional information about these potentially inflammatory adverse reactions is provided in “Description of selected adverse reactions” and section 4.4. Data presented in those sections primarily reflect experience from a Phase 3 study, MDX010‑20.

d          Reported in recent studies outside the completed clinical trials in melanoma.

10.     DATE OF REVISION OF THE TEXT

18 December 2013

4.1 Therapeutic indications

YERVOY is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy.

4.2 Posology and method of administration

Permanent discontinuation of treatment or withholdingomission of doses

Management of immune-related adverse reactions may require withholding omission of a dose or permanent discontinuation of YERVOY therapy and institution of systemic high-dose corticosteroid. In or, in some cases, the addition of other immunosuppressive therapy may be considered (see section 4.4).

Dose reduction is not recommended. Doses that are omitted due to an adverse reaction must not be replaced.

Guidelines for permanent discontinuation or withholdingomission of scheduled doses are described in Tables 1A and 1B. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

a No dose reduction of YERVOY is recommended. Doses that are omitted due to an adverse reaction must not be replaced.

b Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 3.0 (NCI-CTCAE v3).

c Any other organ system adverse reactions that are considered immune-related should be graded according to CTCAE. Decision whether to withholdomit a scheduled dose should be based on severity.

d Until administration of all 4 doses or 16 weeks from first dose, whichever occurs earlier.

Special populations

Patients with hepatic impairment

The safety and efficacy of YERVOY have not been studied in patients with hepatic impairment. Based on the population pharmacokinetic results, no specific dose adjustment is necessary in patients with  mild hepatic impairment (see section 5.2). YERVOY must be administered with caution in patients with transaminase levels ≥ 5 x ULN or bilirubin levels > 3 x ULN at baseline (see section 5.1).

4.4 Special warnings and precautions for use

Management recommendations for diarrhoea or colitis are based on severity of symptoms (per NCI-CTCAE v3 severity grading classification). Patients with mild to moderate (Grade 1 or 2) diarrhoea (an increase of up to 6 stools per day) or suspected mild to moderate colitis (e.g. abdominal pain or blood in stools) may remain on ipilimumab. Symptomatic treatment (e.g. loperamide, fluid 6 replacement) and close monitoring are advised. If mild to moderate symptoms recur or persist for 5-7 days, the scheduled dose of ipilimumab should be withheldomitted and corticosteroid therapy (e.g. prednisone 1 mg/kg orally once daily or equivalent) should be initiated. If resolution to Grades 0-1 or return to baseline occurs, ipilimumab may be resumed at the next scheduled dose. Doses omitted due to an adverse reaction must not be replaced (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) diarrhoea or colitis (see section 4.2), and systemic high-dose intravenous corticosteroid therapy should be initiated immediately. (In clinical trials, methylprednisolone 2 mg/kg/day has been used). Once diarrhoea and other symptoms are controlled, the initiation of corticosteroid taper should be based on clinical judgment. In clinical trials, rapid tapering (over periods < 1 month) resulted in recurrence of diarrhoea or colitis in some patients. Patients must be evaluated for evidence of gastrointestinal perforation or peritonitis.

Immune-related hepatotoxicity

Ipilimumab is associated with serious immune-related hepatotoxicity. Fatal hepatic failure has been reported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, time to onset of moderate to severe or fatal (Grade 2-5) immune-related hepatotoxicity ranged from 3 to 9 weeks from the start of treatment. With protocol-specified management guidelines, time to resolution ranged from 0.7 to 2 weeks.

Hepatic transaminase and bilirubin must be evaluated before each dose of ipilimumab, as early laboratory changes may be indicative of emerging immune-related hepatitis (see section 4.2). Elevations in LFTs may develop in the absence of clinical symptoms. Increases in AST and ALT or total bilirubin should be evaluated to exclude other causes of hepatic injury, including infections, tumourdisease progression, or concomitant medicationmedicinal products and monitored until resolution. Liver biopsies from patients who had immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

For patients with elevated AST or ALT in the range of -> 5-≤ 8 x ULN or total bilirubin in the range of -> 3-≤ 5 x ULN that is suspected to be related to ipilimumab, the scheduled dose of ipilimumab should be omittedwithheld, and LFTs must be monitored until resolution. After LFT levels improves (AST and ALT- ≤ 5 x ULN and total bilirubin -≤ 3 x ULN), ipilimumab may be resumed at the next scheduled dose. Doses omitted due to an adverse reaction must not be replaced (see section 4.2).

For patients with AST or ALT elevations > 8 x ULN or bilirubin > 5 x ULN that are suspected to be related to ipilimumab, treatment must be permanently discontinued (see section 4.2), and systemic high-dose intravenous corticosteroid therapy (e.g. methylprednisolone 2 mg/kg daily or equivalent) should be initiated immediately. In such patients, LFTs must be monitored until normalization. Once symptoms have resolved and LFT elevations are normalizedLFT show sustained improvement or return to baseline, the initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month. Elevations in LFTs during taper may be managed with an increase in the dose of corticosteroid and a slower taper.

Immune-related skin adverse reactions

For patients with a severe (Grade 3) skin adverse reaction, the scheduled dose of ipilimumab should be withheldomitted. If initial symptoms improve to mild (Grade 1) or resolve, ipilimumab therapy may be resumed at the next scheduled dose. Doses omitted due to an adverse reaction must not be replaced (see section 4.2).

Immune-related neurological reactions

Ipilimumab is associated with serious immune-related neurological adverse reactions. Fatal Guillain-Barré syndrome has been reported in clinical trials (see section 4.8). Myasthenia gravis-like symptoms have also been reported (see section 4.8). Patients may present with muscle weakness. Sensory neuropathy may also occur.

Unexplained motor neuropathy, muscle weakness, or sensory neuropathy lasting > 4 days must be evaluated, and non-inflammatory causes such as disease progression, infections, metabolic syndromes and concomitant medication medicinal products should be excluded. For patients with moderate (Grade 2) neuropathy (motor with or without sensory) likely related to ipilimumab, the scheduled dose should be withheldomitted. If neurologic symptoms resolve to baseline, the patient may resume ipilimumab at the next scheduled dose. Doses omitted due to an adverse reaction must not be replaced (see section 4.2).

Immune-related endocrinopathy

Ipilimumab can cause inflammation of the endocrine system organs, manifesting asspecifically hypophysitis, hypopituitarism, adrenal insufficiency, and hypothyroidism (see section 4.8), and patients may present with nonspecific symptoms, which may resemble other causes such as brain metastasis or underlying disease. The most common clinical presentation includes headache and fatigue. Symptoms may also include visual field defects, behavioural changes, electrolyte disturbances, and hypotension. Adrenal crisis as a cause of the patient’s symptoms must be excluded. Clinical experience with ipilimumab-associated endocrinopathy is limited.

For patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, time to onset of moderate to very severe (Grade 2-4) immune-related endocrinopathy ranged from 7 to nearly 20 weeks from the start of treatment. Immune-related endocrinopathy observed in clinical trials was generally controlled with immunosuppressiveant therapy and hormone replacement therapy.

If there are any signs of adrenal crisis such as severe dehydration, hypotension, or shock, immediate administration of intravenous corticosteroids with mineralocorticoid activity is recommended, and the patient must be evaluated for presence of sepsis or infections. If there are signs of adrenal insufficiency but the patient is not in adrenal crisis, further investigations should be considered including laboratory and imaging assessment. Evaluation of laboratory results to assess endocrine function may be performed before corticosteroid therapy is initiated. If pituitary imaging or laboratory tests of endocrine function are abnormal, a short course of high-dose corticosteroid therapy (e.g. dexamethasone 4 mg every 6 hrs or equivalent) is recommended to treat the inflammation of the affected gland, and the scheduled dose of ipilimumab should be withheldomitted (see section 4.2). It is currently unknown if the corticosteroid treatment reverses the gland dysfunction. Appropriate hormone replacement should also be initiated. Long-term hormone replacement therapy may be necessary.

Patients with autoimmune disease

Patients with a history of autoimmune disease (other than vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism), including those who require systemic immunosuppressive therapy for pre-existing active autoimmune disease or for organ transplantation graft maintenance,9

were not evaluated in clinical trials. Ipilimumab is a T-cell potentiator that enables the immune response (see section 5.1) and may interfere with immunosuppressive therapy, resulting in an exacerbation of the underlying disease or increased risk of graft rejection. Ipilimumab should be avoided in patients with severe active autoimmune disease where further immune activation is potentially imminently life threatening and used with caution. Iin other patients with a history of autoimmune disease, ipilimumab should be used with caution after careful consideration of the potential risk-benefit on an individual basis.

4.5 Interaction with other medicinal products and other forms of interaction

Ipilimumab is a human monoclonal antibody that is not metabolized by cytochrome P450 enzymes (CYPs) or other drug metabolizing enzymes.., and is not expected to have an effect on CYPs or other drug metabolizing enzymes in terms of inhibition or induction. Therefore, ipilimumab is not expected to have pharmacokinetic-based interactions.
A drug-interaction study of ipilimumab administered alone and in combination with chemotherapy (dacarbazine or paclitaxel/carboplatin) was conducted evaluating interaction with CYP isozymes (particularly CYP1A2, CYP2E1, CYP2C8, and CYP3A4) in patients with treatment-naive advanced melanoma. No clinically relevant pharmacokinetic drug-drug interaction was observed between ipilimumab and paclitaxel/carboplatin, dacarbazine or its metabolite, 5-aminoimidazole-4-carboxamide (AIC).

4.8 Undesirable effects

Summary of safety profile

Ipilimumab has been administered to approximately 10> 3,000 patients in a clinical program evaluating its use with various doses and tumour types. Unless otherwise specified, the data below reflect exposure to ipilimumab at 3 mg/kg in clinical trials of melanoma. In the Phase 3 study MDX010-20, (see section 5.1), patients received a median of 4 doses (range 1-4).

Tabulated list of adverse reactions

Adverse reactions reported in patients with advanced melanoma who were treated with ipilimumab 3 mg/kg in clinical trials (n= 767) are presented in Table 2.

These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Rates of immune-related adverse reactions in HLA-A2*0201 positive patients who received ipilimumab in MDX010-20 were similar to those observed in the overall clinical program.

The safety profile of ipilimumab 3 mg/kg in chemotherapy-naive patients pooled across Phase 2 and 3 clinical trials (N= 75; treated) and in treatment-naive patients in a retrospective observational study (N= 120) was similar to that in previously-treated advanced melanoma.

a Frequencies are based on pooled data from 9 clinical trials investigating the ipilimumab 3 mg/kg dose in melanoma.

b Including fatal outcome.

c Additional information about these potentially inflammatory adverse reactions is provided in "Description of selected adverse reactions" and section 4.4. Data presented in those sections primarily reflect experience from a Phase 3 study, MDX010-20.

d Reported in recent studies outside the completed clinical trials in melanoma.

Additional adverse reactions not listed in Table 2 have been reported in patients who received other doses (either < or > 3 mg/kg) of ipilimumab in clinical trials of melanoma. These additional reactions all occurred at a frequency of < 1% unless otherwise noted: meningism, myocarditis, pericardial effusion, cardiomyopathy, autoimmune hepatitis, erythema multiforme, erythema nodosum, hair colour changes, autoimmune nephritis, autoimmune pancreatitis, myasthenia gravis-like symptoms, muscular weakness, autoimmune thyroiditis, hyperpituitarism, secondary adrenocortical insufficiency, hypoparathyroidism, thyroiditis, systemic inflammatory response syndrome, influenza-like illness (4%), mucosal inflammation, infectious peritonitis, episcleritis, blepharitis, eye oedema, scleritis, temporal arteritis, Raynaud’s phenomenon, proctitis, palmar-plantar erythrodysaesthesia syndrome, eczema, psoriasis, cytokine release syndrome, sarcoidosis, haematuria, proteinuria, increased blood alkaline phosphatase (4%), increased gamma-glutamyltransferase, decreased blood thyroid stimulating hormone, decreased blood gonadotrophin, decreased thyroxine, positive antinuclear antibody, abnormal blood prolactin, hypocalcaemia, leukopenia, and polycythaemia, lymphocytosis, polymyositis, ocular myositis, myositis, neurosensory hypoacusis, and autoimmune central neuropathy (encephalitis).

Description of selected adverse reactions

Immune-related gastrointestinal reactions

Ipilimumab is associated with serious immune-related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in < 1% of patients who received ipilimumab 3 mg/kg in combination with gp100.

In the ipilimumab 3 mg/kg monotherapy group, diarrhoea and colitis of any severity were reported in 27% and 8%, respectively. The frequency of severe (Grade 3 or 4) diarrhoea and severe (Grade 3 or 4) colitis was 5% each. The median time to onset of severe or fatal (Grade 3 to 5) immune-related gastrointestinal reactions was 8 weeks (range 5 to 13 weeks) from the start of treatment. With protocol-specified management guidelines, resolution occurred in most cases (90%), with a median time from onset to resolution (defined as improvement to mild [Grade 1] or less or to the severity at baseline) occurred in most cases (90%), with a median time from onset to resolution of 4 weeks (range 0.6 to 22 weeks). In clinical trials, immune-related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration.

Immune-related hepatotoxicity

Ipilimumab is associated with serious immune-related hepatotoxicity. Fatal hepatic failure has been reported in < 1% of patients who received ipilimumab 3 mg/kg monotherapy.

Increases in AST and ALT of any severity were reported in 1% and 2% of patients, respectively. There were no reports of severe (Grade 3 or 4) AST or ALT elevation. Time to onset of moderate to severe or fatal (Grade 2 to 5) immune-related hepatotoxicity ranged from 3 to 9 weeks from the start of treatment. With protocol-specified management guidelines, time to resolution ranged from 0.7 to 2 weeks. In clinical trials, liver biopsies from patients who had immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

In patients receiving ipilimumab at a higher than recommended dose in combination with dacarbazine, immune-related hepatotoxicity occurred more frequently than in patients receiving ipilimumab 3 mg/kg monotherapy.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Clinical trials

Overall survival (OS) advantage The efficacy of ipilimumab at the recommended dose of 3 mg/kg in patients with previously- treated advanced (unresectable or metastatic) melanoma was demonstratedinvestigated in a Phase 3 study (MDX010-20). Patients with ocular melanoma, primary CNS melanoma, active brain metastases, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C were not included in the pivotal clinical trial. Clinical trials excluded patients with ECOG performance status > 1 and mucosal melanoma. Patients without liver metastasis who had a baseline AST > 2.5 x ULN, patients with liver metastasis who had a baseline AST > 5 x ULN, and patients with a baseline total bilirubin ≥ 3 x ULN were also excluded.

For patients with a history of autoimmune disease, see also section 4.4.

MDX010-20

A Phase 3, double-blind study enrolled patients with advanced (unresectable or metastatic) melanoma who had previously been treated with regimens containing one or more of the following: IL-2, dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to receive ipilimumab 3 mg/kg + an investigational gp100 peptide vaccine (gp100), ipilimumab 3 mg/kg monotherapy, or gp100 alone. All patients were HLA-A2*0201 type; this HLA type supports the immune presentation of gp100. Patients were enrolled regardless of their baseline BRAF mutation status. Patients received ipilimumab every 3 weeks for 4 doses as tolerated (induction therapy). Patients with apparent tumour burden increase before completion of the induction period were continued on induction therapy as tolerated if they had adequate performance status. Assessment of tumour response to ipilimumab was conducted at approximately Week 12, after completion of induction therapy.

Additional treatment with ipilimumab (re-treatmentinduction therapy) was offered to those who developed PD after initial clinical response (PR or CR) or after SD (per the modified WHO criteria) > 3 months from the first tumour assessment. The primary endpoint was overall survival (OS) in the ipilimumab+ gp100 group vs. the gp100 group. Key secondary endpoints were OS in the ipilimumab+ gp100 group vs. the ipilimumab monotherapy group and in the ipilimumab monotherapy group vs. the gp100 group. Other secondary endpoints included best overall response rate (BORR) up to Week 24 and duration of response.

A total of 676 patients were randomized: 137 to the ipilimumab monotherapy group, 403 to the ipilimumab + gp100 group, and 136 to the gp100 alone group. The majority had received all 4 doses during induction. Thirty-two patients received a re-treatmentinduction dose: 8 in the ipilimumab monotherapy group, 23 in the ipilimumab + gp100 group, and 1 in the gp100 group. Duration of follow-up ranged up to 55 months. Baseline characteristics were well balanced across groups. The median age was 57 years. The majority (71-73%) of patients had M1c stage disease and 37-40% of patients had an elevated lactate dehydrogenase (LDH) at baseline. A total of 77 patients had a history of previously treated brain metastases.

The ipilimumab-containing regimens demonstrated a statistically significant advantage over the gp100 control group in OS. The hazard ratio (HR) for comparison of OS between ipilimumab monotherapy and gp100 was 0.66 (95% CI: 0.51, 0.87; p = 0.0026).

By subgroup analysis, it has been shown that the observed OS benefit was consistent within most of the subgroups of patients (M [metastases]-stage, prior interleukin-2, baseline LDH, age, and sex, and the type and number of prior therapy). However, for women above 50 years of age, the data supporting an OS benefit of ipilimumab treatment were limited. The efficacy of ipilimumab for women above 50 years of age is therefore uncertain. As the subgroups analysis includes only small numbers of patients, no definitive conclusions can be drawn from these data.

For patients who required re-treatmentinduction therapy, the BORR was 38% (3/8 patients) in the ipilimumab monotherapy group, and 0% in the gp100 group. The disease control rate (DCR) (defined as CR+PR+SD) was 75% (6/8 patients) and 0%, respectively. Because of the limited number of patients in these analyses, no definitive conclusion regarding the efficacy of ipilimumab re--treatmentinduction can be drawn.

The development or maintenance of clinical activity following ipilimumab treatment was similar with or without the use of systemic corticosteroids.

Other studies

OS of ipilimumab 3 mg/kg monotherapy in chemotherapy-naive patients pooled across Phase 2 and 3 clinical trials (N= 78; randomised) and in treatment-naive patients in two retrospective observational studies (N= 120 and N= 61) were generally consistent. The estimated 1-year survival rates were 59.5% (95% CI: 50.1 - 67.8) and 49.3% (95% CI: 35.6 - 61.6) in the two retrospective observational studies. The estimated 1-year and 2-year survival rates for chemotherapy-naive patients (N= 78) pooled across Phase 2 and 3 clinical trials were 54.1% (95% CI: 42.5 - 65.6) and 32% (95% CI: 20.7 - 42.9), respectively.

The European Medicines Agency has deferredwaived the obligation to submit the results of studies with YERVOY in one or moreall subsets of the paediatric population in the treatment of melanoma (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of ipilimumab was studied in 785498 patients with advanced melanoma who received induction doses ranging from 0.3 to 10 mg/kg administered once every 3 weeks for 4 doses. Cmax, Cmin and AUC of ipilimumab were found to be dose proportional within the dose range examined. Upon repeated dosing of ipilimumab administered every 3 weeks, clearance was found to be time-invariant, and minimal systemic accumulation was observed as evident by an accumulation index 1.5 fold or less for Cmax, Cmin and AUC. Ipilimumab steady-state was reached by the third dose administered once every 3 weeks. Based on population pharmacokinetic analysis, the following mean (percent coefficient of variation) pharmacokinetic parameters of ipilimumab were obtained: a mean (SD) terminal half-life of 15.4 (4.62) days (34.4%); a geometric mean systemic clearance of 16.85.3 ml/h (38.1%); and with percent coefficient of variation (CV%) of 38.5%; and a geometric mean volume of distribution at steady-state of 7.22 47 l (10.1%)with CV% of 10.5%. The mean (percent coefficient of variation) ipilimumab Cminaverage (±SD) ipilimumab serum trough concentrations achieved at steady-state with a 3 mg/kg induction regimen was 19.4-21.8 μg/ml (74.6%± 11.2).

Ipilimumab clearance increased with increasing body weight and with increasing LDH at baseline; however, no dose adjustment is required for elevated LDH or body weight after administration on a mg/kg basis. Clearance was not affected by age (range 236-886 years), gender, hepatic function (as measured by albumin and alkaline phosphatase), concomitant use of budesonide or dacarbazine,, renal function (estimated GFR 22 ml/min or greater), performance status, HLA-A2*0201 status, mild hepatic impairment, renal impairment, immunogenicity, and previous prior use of systemic anticancer therapy. The effect of race was not examined as there was insufficient data in non-Caucasian ethnic groups. No controlled studies have been conducted to evaluate the pharmacokinetics of ipilimumab in the paediatric population or in patients with hepatic or renal impairment.

Based on an exposure-response analysis in 497 patients with advanced melanoma, OS was independent of prior systemic anti-cancer therapy and increased with higher ipilimumab Cminss plasma concentrations.

Renal impairment
In the population pharmacokinetic analysis of data from clinical studies in patients with metastatic melanoma, pre-existing mild and moderate renal impairment did not influence the clearance of ipilimumab. Clinical and pharmacokinetic data with pre-existing severe renal impairment are limited; the potential need for dose adjustment cannot be determined.

Hepatic impairment
In the population pharmacokinetic analysis of data from clinical studies in patients with metastatic melanoma, pre-existing mild hepatic impairment did not influence the clearance of ipilimumab. Clinical and pharmacokinetic data with pre-existing moderate hepatic impairment are limited; the potential need for dose adjustment cannot be determined. No patients with pre-existing severe hepatic impairment were identified in clinical studies.

10. DATE OF REVISION OF THE TEXT

31 October 2013

Approved wording SmPC Section 4.4:

Concurrent administration with vemurafenib

The Invented name is replaced by the  International Non-proprietary Name (INN) when referring to properties of the active substance(s) rather than those of the product.

QRD 9 update  

implement the black symbol + additional monitoring statement + encouragement to report ADRs statement + other QRD changes (annex II update)

Pregnancy

Breast‑feeding