英文药名：Yervoy(Ipilimumab for solution for infusion)
b Any other adverse reactions that are demonstrated or suspected to be immune-related should be graded according to CTCAE. Decision whether to discontinue YERVOY should be based on severity.
c Patients with severe (Grade 3 or 4) endocrinopathy controlled with hormone replacement therapy may remain on therapy.
ULN = upper limit of normal
Table 1B When to withhold dose of YERVOY
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 withhold a dose should be based on severity.
d Until administration of all 4 doses or 16 weeks from first dose, whichever occurs earlier.
ULN = upper limit of normal
The safety and efficacy of YERVOY in children below 18 years of age have not been established. No data are available. YERVOY should not be used in children below 18 years of age.
No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and younger patients (< 65 years). No specific dose adjustment is necessary in this population.
Patients with renal impairment
The safety and efficacy of YERVOY have not been studied in patients with renal impairment. Based on population pharmacokinetic results, no specific dose adjustment is necessary in patients with mild to moderate renal dysfunction (see section 5.2).
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).
Method of administration
The recommended infusion period is 90 minutes.
YERVOY can be used for intravenous administration without dilution or may be diluted in sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection to concentrations between 1 and 4 mg/ml.
YERVOY must not be administered as an intravenous push or bolus injection.
For instructions on the handling of the medicinal product before administration, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Ipilimumab is associated with inflammatory adverse reactions resulting from increased or excessive immune activity (immune-related adverse reactions), likely to be related to its mechanism of action. Immune-related adverse reactions, which can be severe or life-threatening, may involve the gastrointestinal, liver, skin, nervous, endocrine, or other organ systems. While most immune-related adverse reactions occurred during the induction period, onset months after the last dose of ipilimumab has also been reported. Unless an alternate etiology has been identified, diarrhoea, increased stool frequency, bloody stool, LFT elevations, rash and endocrinopathy must be considered inflammatory and ipilimumab-related. Early diagnosis and appropriate management are essential to minimise life-threatening complications.
Systemic high-dose corticosteroid with or without additional immunosuppressive therapy may be required for management of severe immune-related adverse reactions. Ipilimumab-specific management guidelines for immune-related adverse reactions are described below.
Immune-related gastrointestinal reactions
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 resoution 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.
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 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, addition of an alternative immunosuppressive agent to the corticosteroid regimen 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).
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, tumour progression, or concomitant medication 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 withheld, and LFTs must be monitored until resolution. After LFT levels improve (AST and ALT ≤ 5 x ULN and total bilirubin ≤ 3 x ULN), ipilimumab may be resumed (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 LFTs 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.
For patients with significant LFT elevations that are refractory to corticosteroid therapy, addition of an alternative immunosuppressive agent to the corticosteroid regimen may be considered. In clinical trials, mycophenolate mofetil was used in patients without response to corticosteroid therapy, or who had an LFT elevation during corticosteroid tapering that was not responsive to an increase in the dose of corticosteroids (see the Summary of Product Characteristics for mycophenolate mofetil).
Immune-related skin adverse reactions
Ipilimumab is associated with serious skin adverse reactions that may be immune-related. Toxic epidermal necrolysis (including fatal cases) 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.
Ipilimumab-induced rash and pruritus were predominantly mild or moderate (Grade 1 or 2) and responsive to symptomatic therapy. In patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, the median time to onset of moderate to severe or fatal (Grade 2-5) skin adverse reactions was 3 weeks (range 0.9-16 weeks) from start of treatment. With protocol-specified management guidelines, resolution occurred in most cases (87%), with a median time from onset to resolution of 5 weeks (range 0.6 to 29 weeks).
Ipilimumab-induced rash and pruritus should be managed based on severity. Patients with a mild to moderate (Grade 1 or 2) skin adverse reaction may remain on ipilimumab therapy with symptomatic treatment (e.g. antihistamines). For mild to moderate rash or pruritus that persists for 1 to 2 weeks and does not improve with topical corticosteroids, oral corticosteroid therapy should be initiated (e.g. prednisone 1 mg/kg once daily or equivalent).
For patients with a severe (Grade 3) skin adverse reaction, the scheduled dose of ipilimumab should be withheld. If initial symptoms improve to mild (Grade 1) or resolve, ipilimumab therapy may be resumed (see section 4.2).
Ipilimumab must be permanently discontinued in patients with a very severe (Grade 4) rash or severe (Grade 3) pruritus (see section 4.2), and systemic high-dose intravenous corticosteroid therapy (e.g. methylprednisolone 2 mg/kg/day) should be initiated immediately. Once rash or pruritus is controlled, initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month.
Immune-related neurological reactions
Ipilimumab is associated with serious immune-related neurological adverse reactions. Fatal Guillain-Barré syndrome has been reported in clinical trials. 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 should be excluded. For patients with moderate (Grade 2) neuropathy (motor with or without sensory) likely related to ipilimumab, the scheduled dose should be withheld. If neurologic symptoms resolve to baseline, the patient may resume ipilimumab (see section 4.2).
Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) sensory neuropathy suspected to be related to ipilimumab (see section 4.2). Patients must be treated according to institutional guidelines for management of sensory neuropathy, and intravenous corticosteroids (e.g. methylprednisolone 2 mg/kg/day) should be initiated immediately.
Progressive signs of motor neuropathy must be considered immune-related and managed accordingly. Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) motor neuropathy regardless of causality (see section 4.2).
Ipilimumab can cause inflammation of the endocrine system organs, manifesting as 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 immunosuppressive 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 withheld (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.
Once symptoms or laboratory abnormalities are controlled and overall patient improvement is evident, treatment with ipilimumab may be resumed and initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month.
Other immune-related adverse reactions
The following additional adverse reactions suspected to be immune-related have been reported in patients treated with ipilimumab 3 mg/kg monotherapy in MDX010-20: uveitis, eosinophilia, lipase elevation, and glomerulonephritis. In addition, iritis, haemolytic anaemia, amylase elevations, multi-organ failure, and pneumonitis have been reported in patients treated with ipilimumab 3 mg/kg + gp100 peptide vaccine in MDX010-20 (see section 4.8).
If severe (Grade 3 or 4), these reactions may require immediate systemic high-dose corticosteroid therapy and discontinuation of ipilimumab (see section 4.2). For ipilimumab-related uveitis, iritis, or episcleritis, topical corticosteroid eye drops should be considered as medically indicated.
Patients with ocular melanoma, primary CNS melanoma and active brain metastases were not included in the pivotal clinical trial (see section 5.1).
There were isolated reports of severe infusion reactions in clinical trials. In case of a severe infusion reaction, ipilimumab infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may receive ipilimumab with close monitoring. Premedication with antipyretic and antihistamine may be considered.
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, 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. In 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.
Patients on controlled sodium diet
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.
Concurrent administration with vemurafenib
In a Phase 1 trial, asymptomatic grade 3 increases in transaminases (ALT/AST > 5 × ULN) and bilirubin (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.
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.
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).
Other forms of interaction
The use of systemic corticosteroids at baseline, before starting ipilimumab, should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of ipilimumab. However, systemic corticosteroids or other immunosuppressants can be used after starting ipilimumab to treat immune-related adverse reactions. The use of systemic corticosteroids after starting ipilimumab treatment does not appear to impair the efficacy of ipilimumab.
The use of anticoagulants is known to increase the risk of gastrointestinal haemorrhage. Since gastrointestinal haemorrhage is an adverse reaction with ipilimumab (see section 4.8), patients who require concomitant anticoagulant therapy should be monitored closely.
4.6 Fertility, pregnancy and lactation
There are no data on the use of ipilimumab in pregnant women. Animal reproduction studies have shown reproductive toxicity (see section 5.3). Human IgG1 crosses the placental barrier. The potential risk of treatment to the developing foetus is unknown. YERVOY is not recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the clinical benefit outweighs the potential risk.
Ipilimumab has been shown to be present at very low levels in milk from cynomolgus monkeys treated during pregnancy. It is unknown whether ipilimumab is secreted in human milk. Secretion of IgGs in human milk is generally limited and IgGs have a low oral bioavailability. Significant systemic exposure of the infant is not expected and no effects on the breastfed newborn/infant are anticipated. However, because of the potential for adverse reactions in nursing infants, a decision must be made whether to discontinue breast-feeding or to discontinue from YERVOY therapy taking into account the benefit of breast-feeding for the child and the benefit of YERVOY therapy for the woman.
Studies to evaluate the effect of ipilimumab on fertility have not been performed. Thus, the effect of ipilimumab on male and female fertility is unknown.
4.7 Effects on ability to drive and use machines
YERVOY has minor influence on the ability to drive and use machines.
Because of potential adverse reactions such as fatigue (see section 4.8), patients should be advised to use caution when driving or operating machinery until they are certain that ipilimumab does not adversely affect them.
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 two retrospective observational studies (N= 273 and N= 157) 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
a Frequencies are based on pooled data from 9 clinical trials investigating the ipilimumab 3 mg/kg dose in melanoma.
In the ipilimumab 3 mg/kg monotherapy group, median OS was 22 months and 8 months for patients with SD and those with PD, respectively. At the time of this analysis, medians were not reached for patients with CR or PR.
For patients who required re-treatment, 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-treatment can be drawn.
The development or maintenance of clinical activity following ipilimumab treatment was similar with or without the use of systemic corticosteroids.
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= 273 and N= 157) were generally consistent. In the two observational studies, 12.1% and 33.1% of the patients had brain metastases at the time of advanced melanoma diagnosis. In these studies, the estimated 1-year survival rates were 59.2% (95% CI: 53.0 - 64.8) and 46.7% (95% CI: 38.1 - 54.9). The estimated 1-year, 2-year and 3-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), 31.6% (95% CI: 20.7 - 42.9) and 23.7% (95% CI: 14.3 - 34.4) respectively.
The European Medicines Agency has deferred the obligation to submit the results of studies with YERVOY in one or more 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 785 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. Ipilimumab steady-state was reached by the third dose. Based on population pharmacokinetic analysis, the following mean (percent coefficient of variation) parameters of ipilimumab were obtained: terminal half-life of 15.4 days (34.4%); systemic clearance of 16.8 ml/h (38.1%); and volume of distribution at steady-state of 7.47 l (10.1%). The mean (percent coefficient of variation) ipilimumab Cmin achieved at steady-state with a 3 mg/kg induction regimen was 19.4 µg/ml (74.6%).
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 23-88 years), gender, concomitant use of budesonide or dacarbazine, performance status, HLA-A2*0201 status, mild hepatic impairment, renal impairment, immunogenicity, and previous 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.
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.
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.
5.3 Preclinical safety data
In intravenous repeat-dose toxicology studies in monkeys, ipilimumab was generally well tolerated. Immune-mediated adverse reactions were observed infrequently (~3%) and included colitis (which resulted in a single fatality), dermatitis, and infusion reaction (possibly due to acute cytokine release resulting from a rapid injection rate). A decrease in the weight of the thyroid and testes was seen in one study without accompanying histopathologic findings; the clinical relevance of this finding is unknown.
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.
Studies to evaluate the mutagenic and carcinogenic potential of ipilimumab have not been performed. Fertility studies have not been performed.
6. Pharmaceutical particulars
6.1 List of excipients
Tris hydrochloride (2-amino-2-hydroxymethyl-1,3-propanediol hydrochloride)
Pentetic acid (diethylenetriaminepentaacetic acid)
Sodium hydroxide (for pH-adjustment)
Hydrochloric acid (for pH-adjustment)
Water for injections
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
Unopened vial: 3 years
Solution for infusion: From a microbiological point of view, once opened, the medicinal product should be infused or diluted and infused immediately. The chemical and physical in-use stability of the undiluted or diluted concentrate (between 1 and 4 mg/ml) has been demonstrated for 24 hrs at 25°C and 2 to 8°C. If not used immediately, the infusion solution (undiluted or diluted) may be stored for up to 24 hours in a refrigerator (2°C to 8°C) or at room temperature (20°C to 25°C).
6.4 Special precautions for storage
Store in a refrigerator (2°C-8°C).
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions after first opening or dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
10 ml of sterile concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal (aluminium). Pack size of 1.
40 ml of sterile concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal (aluminium). Pack size of 1.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Preparation should be performed by trained personnel in accordance with good practices rules, especially with respect to asepsis.
Calculating the dose:
The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the total dose to be given. More than one vial of YERVOY concentrate may be needed to give the total dose for the patient.
• Each 10 ml vial of YERVOY concentrate provides 50 mg of ipilimumab; each 40 ml vial provides 200 mg of ipilimumab.
• The total ipilimumab dose in mg = the patient's weight in kg × the prescribed dose in mg/kg.
• The volume of YERVOY concentrate to prepare the dose (ml) = the total dose in mg, divided by 5 (the YERVOY concentrate strength is 5 mg/ml).
Preparing the infusion:
Take care to ensure aseptic handling when you prepare the infusion. The infusion should be prepared in a laminar flow hood or safety cabinet using standard precautions for the safe handling of intravenous agents.
YERVOY can be used for intravenous administration either:
• without dilution, after transfer to an infusion container using an appropriate sterile syringe;
• after diluting to up to 5 times the original volume of concentrate (up to 4 parts of diluent to 1 part of concentrate). The final concentration should range from 1 to 4 mg/ml. To dilute the YERVOY concentrate, you can use either:
• sodium chloride 9 mg/ml (0.9%) solution for injection; or
• 50 mg/ml (5%) glucose solution for injection
• Allow the appropriate number of vials of YERVOY to stand at room temperature for approximately 5 minutes.
• Inspect the YERVOY concentrate for particulate matter or discoloration. YERVOY concentrate is a clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) particulates. Do not use if unusual amount of particles and signs of discoloration are present.
• Withdraw the required volume of YERVOY concentrate using an appropriate sterile syringe.
• Transfer the concentrate into a sterile, evacuated glass bottle or IV bag (PVC or non-PVC).
• If applicable, dilute with the required volume of sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucose solution for injection. Gently mix the infusion by manual rotation.
YERVOY infusion must not be administered as an intravenous push or bolus injection.
Administer the YERVOY infusion intravenously over a period of 90 minutes.
YERVOY infusion should not be infused at the same time in the same intravenous line with other agents. Use a separate infusion line for the infusion.
Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 μm to 1.2 μm).
YERVOY infusion is compatible with:
• PVC infusion sets
• Polyethersulfone (0.2 μm to 1.2 μm) and nylon (0.2 μm) in-line filters
Flush the line with sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucose solution for injection at the end of the infusion.
Any unused medicinal product or waste material should be discarded in accordance with local requirements.
7. Marketing authorisation holder
Bristol-Myers Squibb Pharma EEIG
Uxbridge Business Park
Uxbridge UB8 1DH
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 13 July 2011
10. Date of revision of the text
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
Yervoy sBLA的提交，是基于一项随机双盲III期研究CA184-029 （EORTC 18071） 的积极数据。该项研究评估了Yervoy（10mg/kg剂量）作为一种辅助疗法用于已手术切除的高危III阶段黑色素瘤患者以预防或推迟病情复发的潜力。数据表明，在治疗的3年中，Yervoy治疗组有46.5%患者病情无复发，安慰剂组为34.8%（p=0.0013）；平均随访2.7年，Yervoy治疗组无复发生存期（RFS）为26.1个月，安慰剂组为17.1个月，达到了研究的主要终点。