Skip to content
SPC Logo

YERVOY 5 mg/ml concentrate for solution for infusion

Last Updated on eMC 16-Dec-2016 View document  | Bristol-Myers Squibb Pharmaceutical Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Updated on 16-Dec-2016 and displayed until Current

Reasons for adding or updating:

  • Change to section 10 - Date of revision of the text
  • Addition of black triangle

Date of revision of text on the SPC: 30-Nov-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

EMEA/H/C/002213/IAIN/0041 - addition of black triangle

Updated on 04-May-2016 and displayed until 16-Dec-2016

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.3 - Shelf life
  • Change to section 6.5 - Nature and contents of container
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text
  • Removal of black triangle

Date of revision of text on the SPC: 21-Apr-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

EC Decision for the Yervoy (ipilimumab) Renewal was granted 21 April 2016. Yervoy is now removed from the list of products under additional monitoring.

Updated on 21-Dec-2015 and displayed until 04-May-2016

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 14-Dec-2015

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

The EC Decision for Yervoy PSUR-8 was granted on 14-Dec-2015 and within this procedure the following change was included in the SmPC:
- section 4.4 to add a warning on the risk ‘Vogt-Koyanagi-Harada syndrome’
- section 4.8 to add this adverse reaction with a frequency unknown.
- Date of revision of the texts: 14 December 2015
Leaflet was not impacted with the PSUR-8 update.

Updated on 07-Jul-2015 and displayed until 21-Dec-2015

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 23-Jun-2015

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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.


4.8     Undesirable effects



Skin and subcutaneous tissue disorders

Very common

rashc, pruritusc

Common

dermatitis, erythema, vitiligo, urticaria, eczemad, alopecia, night sweats, dry skin

Uncommon

toxic epidermal necrolysisb,c, leukocytoclastic vasculitis, skin exfoliation, hair colour changesd

Rare

erythema multiformed, psoriasisd, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)d



10.     DATE OF REVISION OF THE TEXT

 

June 2015


Updated on 07-Apr-2015 and displayed until 07-Jul-2015

Updated on 06-Oct-2014 and displayed until 07-Apr-2015

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 25-Sep-2014

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.8 Undesirable effects

nephritis, myositis/polymyositis, eye oedema, myasthenia gravis, psoriasis, proctitis, erythema multiforme, thyroiditis, blood thyroid hormone decreased, thyroxine decreased, temporal arteritis, autoimmune central neuropathy, hematuria and proteinuria. 

 

5.1 Pharmacodynamic properties

RMP with 1-year safety data from the two observational studies and to update the Yervoy (ipilimumab) product information with overall survival data from the two observational studies and from the chemotherapy-naive patients pooled across Phase 2 and 3 clinical trials.

10. Date of revision of text

September 2014


 

 

Updated on 06-Jan-2014 and displayed until 06-Oct-2014

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 18-Dec-2013

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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.

Table 2: Adverse reactions in patients with advanced melanoma treated with ipilimumab 3 mg/kg (n= 767)a

Infections and infestations

Uncommon

sepsisb, septic shockb, urinary tract infection, respiratory tract infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common

tumour pain

Uncommon

paraneoplastic syndrome

Blood and lymphatic system disorders

Common

anaemia, lymphopenia

Uncommon

haemolytic anaemiab, thrombocytopenia, eosinophilia, neutropenia

Immune system disorders

Uncommon

hypersensitivity

Very rare

anaphylactic reaction

Endocrine disorders

Common

hypopituitarism (including hypophysitis)c, hypothyroidismc

Uncommon

adrenal insufficiencyc, hyperthyroidismc, hypogonadism

Metabolism and nutrition disorders

Very common

decreased appetite

Common

dehydration, hypokalemia

Uncommon

hyponatremia, alkalosis, hypophosphatemia, tumour lysis syndrome

Psychiatric disorders

Common

confusional state

Uncommon

mental status changes, depression, decreased libido

Nervous system disorders

Common

peripheral sensory neuropathy, dizziness, headache, lethargy

Uncommon

Guillain‑Barré syndromeb,c, meningitis (aseptic), syncope, cranial neuropathy, brain oedema, peripheral neuropathy, ataxia, tremor, myoclonus, dysarthria

Eye disorders

Common

blurred vision, eye pain

Uncommon

uveitisc, vitreous haemorrhage, iritisc, reduced visual acuity, foreign body sensation in eyes, conjunctivitis

Cardiac disorders

Uncommon

arrhythmia, atrial fibrillation

Vascular disorders

Common

hypotension, flushing, hot flush

Uncommon

vasculitis, angiopathyb, peripheral ischaemia, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common

dyspnea, cough

Uncommon

respiratory failure, acute respiratory distress syndromeb, lung infiltration, pulmonary oedema, pneumonitis, allergic rhinitis

Gastrointestinal disorders

Very common

diarrhoeac, vomiting, nausea

Common

gastrointestinal haemorrhage, colitisb,c, constipation, gastroesophageal reflux disease, abdominal pain

Uncommon

gastrointestinal perforationb,c, large intestine perforationb,c, intestinal perforationb,c, peritonitisb, gastroenteritis, diverticulitis, pancreatitis, enterocolitis, gastric ulcer, large intestinal ulcer, oesophagitis, ileusd

Hepatobiliary disorders

Common

abnormal hepatic function

Uncommon

hepatic failureb,c, hepatitis, hepatomegaly, jaundice

Skin and subcutaneous tissue disorders

Very common

rashc, pruritusc

Common

dermatitis, erythema, vitiligo, urticaria, alopecia, night sweats, dry skin

Uncommon

 toxic epidermal necrolysisb,c, leukocytoclastic vasculitis, skin exfoliation

Musculoskeletal and connective tissue disorders

Common

arthralgia, myalgia, musculoskeletal pain, muscle spasms

Uncommon

polymyalgia rheumatica, arthritis

Renal and urinary disorders

Uncommon

renal failureb, glomerulonephritisc, renal tubular acidosis

Reproductive system and breast disorders

Uncommon

amenorrhea

General disorders and administration site conditions

Very common

fatigue, injection site reaction, pyrexia

Common

chills, asthenia, oedema, pain

Uncommon

multi‑organ failureb,c, infusion related reaction

Investigations

Common

increased alanine aminotransferasec, increased aspartate aminotransferasec, increased blood bilirubin, weight decreased

Uncommon

increased blood creatinine, increased blood thyroid stimulating hormone, decreased blood cortisol, decreased blood corticotrophin, increased lipasec, increased blood amylasec, decreased blood testosterone

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

 

Updated on 12-Nov-2013 and displayed until 06-Jan-2014

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 31-Oct-2013

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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.

Other organ systemsb:

(e.g. nephritis, pneumonitis, pancreatitis, non-infectious myocarditis)

§ Grade 3 immune-related reactionseventsc

§ Grade 2 for immune-related eye disorders NOT responding to topical immunosuppressive therapy

 

Table 1B When to withholdomit scheduled dose of YERVOY

WithholdOmit YERVOY dosea in patients with the following immune-related adverse reactions. See section 4.4 for detailed management guidelines.

Mild to moderate adverse reactions

Action

Gastrointestinal:

Moderate diarrhoea or colitis that either is not controlled with medical management or that persists (5-7 days) or recurs

1. 1. WithholdOmit dose until an adverse reaction resolves to Grade 1 or Grade 0 (or returns to baseline).

2. 2. If resolution occurs before the next scheduled dose, resume therapy at next scheduled dose.

3. 3. If resolution has not occurred before next scheduled dose, continue to withholdomit doses until resolution then resume treatment schedule.

4. 4. Discontinue YERVOY if resolution to Grade 1 or Grade 0 or return to baseline does not occur.

Hepatic:

Moderate elevations in transaminase (AST or ALT > 5 to 8 x ULN) or total bilirubin (> 3 to 5 x ULN) levels

Skin:

Moderate to severe (Grade 3)b skin rash or widespread/intense pruritus regardless of etiology

Endocrine:

Severe adverse reactions in the endocrine glands, such as hypophysitis and thyroiditis that are not adequately controlled with hormone replacement therapy or high-dose immunosuppressive therapy

Neurological:

Moderate (Grade 2)b unexplained motor neuropathy, muscle weakness, or sensory neuropathy (lasting more than 4 days)

Other moderate adverse reactions

 

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.

Table 2: Adverse reactions in patients with advanced melanoma treated with ipilimumab 3 mg/kg (n= 767)a

Infections and infestations

Uncommon

sepsisb, septic shockb, meningitis, gastroenteritis, diverticulitis, urinary tract infection, upper respiratory tract infection, lower respiratory tract infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common

tumour pain

Uncommon

paraneoplastic syndrome

Blood and lymphatic system disorders

Common

anaemia, lymphopenia

Uncommon

haemolytic anaemiab, thrombocytopenia, eosinophilia, neutropenia

Immune system disorders

Uncommon

hypersensitivity

Endocrine disorders

Common

hypopituitarism (including hypophysitis)c, hypothyroidismc

Uncommon

adrenal insufficiencyc, hyperthyroidismc, hypogonadism

Metabolism and nutrition disorders

Very common

decreased appetite

Common

dehydration, hypokalemia

Uncommon

hyponatremia, alkalosis, hypophosphatemia, tumour lysis syndrome

Psychiatric disorders

Common

confusional state

Uncommon

mental status changes, depression, decreased libido

Nervous system disorders

Common

peripheral sensory neuropathy, dizziness, headache, lethargy

Uncommon

Guillain-Barré syndromeb,c, meningitis (aseptic), syncope, cranial neuropathy, brain oedema, peripheral neuropathy, ataxia, tremor, myoclonus, dysarthria

Eye disorders

Common

blurred vision, eye pain

Uncommon

uveitisc, vitreous haemorrhage, iritisc, reduced visual acuity, foreign body sensation in eyes, conjunctivitis

Cardiac disorders

Uncommon

arrhythmia, atrial fibrillation

Vascular disorders

Common

hypotension, flushing, hot flush

Uncommon

vasculitis, angiopathyb, peripheral ischaemia, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common

dyspnea, cough

Uncommon

respiratory failure, acute respiratory distress syndromeb, lung infiltration, pulmonary oedema, pneumonitis, allergic rhinitis

Gastrointestinal disorders

Very common

diarrhoeac, vomiting, nausea

Common

gastrointestinal haemorrhage, colitisb,c, constipation, gastroesophageal reflux disease, abdominal pain

Uncommon

gastrointestinal perforationb,c, large intestine perforationb,c, intestinal perforationb,c, peritonitisb, gastroenteritis, diverticulitis, pancreatitis, enterocolitis, gastric ulcer, large intestinal ulcer, oesophagitis, ileusd

Hepatobiliary disorders

Common

abnormal hepatic function

Uncommon

hepatic failureb,c, hepatitis, hepatomegaly, jaundice

 

Skin and subcutaneous tissue disorders

Very common

rashc, pruritusc

Common

dermatitis, erythema, vitiligo, urticaria, alopecia, night sweats, dry skin

Uncommon

toxic epidermal necrolysisb,c, leukocytoclastic vasculitis, skin exfoliation

Musculoskeletal and connective tissue disorders

Common

arthralgia, myalgia, musculoskeletal pain, muscle spasms

Uncommon

polymyalgia rheumatica, arthritis

Renal and urinary disorders

Uncommon

renal failureb, glomerulonephritisc, renal tubular acidosis

Reproductive system and breast disorders

Uncommon

amenorrhea

General disorders and administration site conditions

Very common

fatigue, injection site reaction, pyrexia

Common

chills, asthenia, oedema, pain

Uncommon

multi-organ failureb,c, infusion related reaction

Investigations

Common

increased alanine aminotransferasec, increased aspartate aminotransferasec, increased blood bilirubin, weight decreased

Uncommon

abnormal liver function test, increased blood creatinine, increased blood thyroid stimulating hormone, decreased blood cortisol, decreased blood corticotrophin, increased lipasec, increased blood amylasec, decreased blood testosterone

 

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.

Median and estimated rates of OS at 1 year and 2 years are presented in Table 3. Table 3: Overall survival in MDX010-20

Ipilimumab 3 mg/kg n= 137

gp100 a

n= 136

Median Months (95% CI)

10 months (8.0, 13.8)

6 months (5.5, 8.7)

OS at 1 year % (95% CI)

46% (37.0, 54.1)

25% (18.1, 32.9)

OS at 2 years % (95% CI)

24% (16.0, 31.5)

14% (8.0, 20.0)

 

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

 

Updated on 21-Jun-2013 and displayed until 12-Nov-2013

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

Date of revision of text on the SPC: 30-May-2013

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



The following sections of the SmPC are updated as follows:

 

 

 

 

Approved wording SmPC Section 4.4:

Concurrent administration with vemurafenib

In a Phase 1 trial, asymptomatic Grade 3 increases in transaminases and bilirubin (ALT/AST > 5 × ULN or total bilirubin > 3 × ULN) were reported with concurrent administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Based on these preliminary data, the concurrent administration of ipilimumab and vemurafenib is not recommended.


INN update in SmPC section 4.2 to 5.2:

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)

 

 

Updated on 02-Aug-2012 and displayed until 21-Jun-2013

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 8 - MARKETING AUTHORISATION NUMBER(S)
  • Change to section 9 - Date of first Authorisation/renewal of the Authorisation
  • Change to section 10 date of revision of the text
  • Correction of spelling/typing errors

Date of revision of text on the SPC: 02-Jul-2012

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.6     Fertility, pregnancy and lactation

 Pregnancy  

Animal reproduction studies have shown reproductive toxicity (see section 5.3).

Breast‑feeding

 Ipilimumab has been shown to be present at very low levels in milk from cynomolgus monkeys treated during pregnancy.

5.3     Preclinical safety data  

The effects of ipilimumab on prenatal and postnatal development were investigated in a study in cynomolgus monkeys. Pregnant monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through delivery, at exposure (AUC) levels either similar to or higher than those associated with the clinical dose of 3 mg/kg of ipilimumab. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, both ipilimumab groups experienced higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and infant mortality relative to control animals; these findings were dose-dependent. Additionally, developmental external or visceral abnormalities were identified in the urogenital system of 2 infants exposed in utero to ipilimumab. One female infant had unilateral renal agenesis of the left kidney and ureter, and one male infant had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema. The relationship of these malformations to treatment is unclear.

Updated on 28-Jul-2011 and displayed until 02-Aug-2012

Reasons for adding or updating:

  • New SPC for new product

Legal Category:POM

Black Triangle (CHM): YES

Company contact details

Bristol-Myers Squibb Pharmaceutical Limited

Company image
Address

Bristol-Myers Squibb House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex, UB8 1DH, UK

Medical Information Direct Line

+44 (0) 800 731 1736

Telephone

+44 (0)1895 523 000

Medical Information e-mail

Before you contact this company: often several companies will market medicines with the same active ingredient. Please check that this is the correct company before contacting them. Why?

Active ingredients

ipilimumab

Legal categories

POM - Prescription Only Medicine

This site uses cookies. By continuing to browse the site you are agreeing to our policy on the use of cookies. Continue