Consumer medicine information

Yervoy

Ipilimumab

BRAND INFORMATION

Brand name

Yervoy

Active ingredient

Ipilimumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Yervoy.

SUMMARY CMI

YERVOY®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I given YERVOY?

YERVOY contains the active ingredient ipilimumab. YERVOY is used to treat various kinds of cancer.

For more information, see Section 1. Why am I using YERVOY? in the full CMI.

2. What should I know before I am given YERVOY?

Do not use if you have ever had an allergic reaction to YERVOY or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use YERVOY? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with YERVOY and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given YERVOY?

  • YERVOY will be given to you in hospital or clinic under the supervision of an experienced doctor and/or nurse
  • It will be given to you as an infusion (a drip) into a vein (intravenously)
  • Your doctor will decide how many treatments you should be given

More instructions can be found in Section 4. How do I use YERVOY? in the full CMI.

5. What should I know while receiving YERVOY?

Things you should do
  • Tell any other doctors, dentists, and pharmacists who are treating you that you are being given YERVOY
  • Ensure you tell your doctor if you have autoimmune disease, any history of inflammation of the lungs, if you take anticoagulant therapy, if you have previously experienced a severe skin reaction on prior cancer therapy or if you are taking any medicines that suppress your immune system, such as corticosteroids
  • YERVOY acts on your immune system and may cause inflammation in parts of your body which may be life threatening and need treatment or withdrawal of YERVOY
  • Tell your doctor immediately if you have any signs or symptoms of possible side effects or if they get worse despite medical care or management
Things you should not do
  • Do not try to treat your symptoms with other medicines on your own without telling your doctor. Your doctor may give you other medicines to prevent complications and reduce your symptoms, your doctor may withhold the next dose of YERVOY, or stop your treatment with YERVOY altogether
Driving or using machines
  • Do not drive or use machines after you have been given YERVOY unless you are sure that you are not affected
  • Notify your doctor if you notice any changes to your ability to drive or use machines

For more information, see Section 5. What should I know while receiving YERVOY? in the full CMI.

6. Are there any side effects?

Like all medicines, YERVOY can cause side effects. Your doctor will discuss potential side effects with you and will explain the risks and benefits of your treatment. Some side effects can be serious and you may require medical attention. Contact your doctor immediately or go to the Emergency Department at your nearest hospital if you have any signs or symptoms (changes to your normal self), particularly if they are getting worse or do not go away.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

Both YERVOY and nivolumab act on your immune system and may cause inflammation in parts of your body. Inflammation may cause serious damage to your body and some inflammatory conditions may be life-threatening.

These side effects are most likely to begin during treatment, however, side effects can show up months after your last infusion.

IT IS IMPORTANT TO TELL YOUR DOCTOR IMMEDIATELY IF YOU HAVE, OR DEVELOP, ANY OF THE SYMPTOMS LISTED UNDER POSSIBLE SIDE EFFECTS.



FULL CMI

YERVOY® (yure-voy)

Active ingredient(s): ipilimumab (ipi-lim-u-mab)

Consumer Medicine Information (CMI)

This leaflet provides important information about using YERVOY. You should also speak to your doctor, nurse or pharmacist if you would like further information or if you have any concerns or questions about using YERVOY.

Where to find information in this leaflet:

1. Why am I given YERVOY?
2. What should I know before I am given YERVOY?
3. What if I am taking other medicines?
4. How am I given YERVOY?
5. What should I know while receiving YERVOY?
6. Are there any side effects?
7. Product details

1. Why am I given YERVOY?

YERVOY contains the active ingredient ipilimumab. YERVOY is a protein which helps your immune system to attack and destroy cancer cells.

YERVOY as a single therapy is used to treat:

  • Advanced skin cancer (unresectable or metastatic melanoma)

YERVOY in combination with nivolumab is used to treat:

  • Advanced melanoma (unresectable or metastatic melanoma)
  • A type of advanced kidney cancer (renal cell carcinoma)
  • A type of cancer that affects the lining of the lung (Malignant pleural mesothelioma)
  • A type of cancer of the food pipe (oesophageal squamous cell cancer)

YERVOY in combination with nivolumab and chemotherapy is used to treat:

  • A type of lung cancer (non-small cell lung cancer without certain biological markers)

2. What should I know before I am given YERVOY?

Warnings

You should not be given YERVOY if:

Always check the ingredients or talk to your doctor to make sure you can use this medicine.

Check with your doctor if you:

  • have an autoimmune disease (a condition where the body attacks its own cells) like Crohn's, ulcerative colitis or lupus
  • have any history of inflammation of the lungs
  • if you take anticoagulant therapy. These are medicines which increase the risk of bleeding in the stomach and gut
  • if you have previously experienced a severe skin reaction on prior cancer therapy
  • are taking any medicines that suppress your immune system, such as corticosteroids, since these medicines may interfere with the effect of YERVOY. However, once you are treated with YERVOY, your doctor may give you corticosteroids to reduce any possible side effects that you may have during your treatment and this will not impact the effect of the medicine.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant, intend to become pregnant, or if you are breast-feeding.

You must not use YERVOY if you are pregnant unless your doctor specifically recommends it.

The effects of YERVOY in pregnant women are not known, but it is possible that the active substance, ipilimumab, could harm an unborn baby.

  • You must use effective contraception while you are being treated with YERVOY if you are a woman who could become pregnant
  • If you become pregnant while using YERVOY, tell your doctor

You should stop breast-feeding if you are being treated with YERVOY.

It is not known whether ipilimumab gets into breast milk. A risk to the breast-fed infant cannot be excluded.

Use in children or adolescents

  • It is not recommended to use this medicine in children or an adolescent (below 18 years) until further information becomes available

Important information about some of the ingredients of YERVOY

  • Tell your doctor if you are on a low-sodium (low-salt) diet before you are given YERVOY. This medicine contains 2.3 mg sodium per mL of concentrate.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription (over the counter) from your pharmacy, supermarket or health food shop.

Ask your doctor for advice before taking any medicine or dietary supplement/vitamin during your treatment.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect YERVOY.

4. How am I given YERVOY?

How is YERVOY given

  • YERVOY will be given to you in hospital or clinic under the supervision of an experienced doctor
  • It will be given to you as an infusion (a drip) into a vein (intravenously)
  • Your doctor will decide how many treatments you should be given

Dosage and frequency of administration of YERVOY

  • The recommended dose (amount) and frequency (timing) of YERVOY can be different depending on the type of cancer it is being used to treat
  • Some types of cancer are treated with YERVOY in combination with other prescription anti-cancer medicines
  • Your doctor will advise you which treatments you will be given and will tell you about the dose and frequency of these treatments
  • Please refer to the Consumer Medicine Information of the other prescription anti-cancer medicines in order to understand the use of these other prescription anti-cancer medicines. If you have questions about these medicines, please ask your doctor

If you miss a dose of YERVOY

It is very important for you to keep all appointments to receive YERVOY. If you miss an appointment, ask your doctor when to schedule your next dose.

If you are given too much YERVOY

As YERVOY is given to you under the supervision of your doctor, it is unlikely that you will be given too much. However, if you experience any side effects after being given YERVOY, tell your doctor immediately.

5. What should I know while receiving YERVOY?

Things you should do

Tell any other doctors, dentists, nurses and pharmacists who are treating you that you are being given YERVOY.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given YERVOY.

Call your doctor straight away if you:

  • Have any signs or symptoms of possible side effects or if they get worse. See Section 6. Are there any side effects?
  • Develop symptoms of an allergic reaction. These symptoms may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin.

Things you should not do

Do not try to treat your symptoms with other medicines on your own without telling your doctor.

Your doctor may:

  • Give you other medicines in order to prevent complications and reduce your symptoms
  • Withhold the next dose of YERVOY
  • Or stop your treatment with YERVOY altogether

Please note that these signs and symptoms are sometimes delayed, and may develop weeks or months after your last dose. Before treatment, your doctor will check your general health. You will also have blood tests during treatment.

Take special care with YERVOY

  • YERVOY is a medicine that influences your immune system and may cause inflammation in parts of your body. Inflammation may cause serious damage to your body and some inflammatory conditions may be life threatening and need treatment or withdrawal of YERVOY
  • Tell your doctor immediately if you have any of the symptoms of inflammation listed in Section 6. Are there any side effects?

Driving or using machines

Do not drive or use machines after you have been given YERVOY unless you are sure that you are not affected. Notify your doctor if you notice any changes to your ability.

Feeling tired or weak is a very common side effect of YERVOY. This can affect your ability to drive or operate any machinery. Patients should therefore be cautious after having received YERVOY.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effectsWhat to do
Lung problems:
  • Problems with your lungs such as breathing difficulties, shortness of breath, or cough. These may be signs of inflammation of the lungs (pneumonitis or interstitial lung disease)
Stomach and Intestinal problems:
  • Inflammation of the intestines (colitis), stomach (gastritis) and duodenum (duodenitis) which can worsen to bleeding or bowel perforation
  • Symptoms may include diarrhoea (watery, loose or soft stools), an increased number of bowel movements (an increase by two or more per day), constipation, vomiting, nausea, mucus and blood in your stools, or darker-coloured stools, stomach pain or tenderness in your stomach area
Liver problems:
  • Inflammation of the liver (hepatitis)
  • Symptoms may include yellowing of the eye or skin (jaundice), pain on the right side of your stomach area or tiredness
Kidney problems:
  • Inflammation in the kidney (nephritis)
  • Signs and symptoms may include abnormal kidney function tests, decreased volume of urine and kidney failure (including abrupt loss of kidney function)
Hormone gland problems:
  • Damage or inflammation of hormone producing glands. Symptoms may include headaches, blurry or double vision, fatigue, decreased sexual drive, behavioural changes.
  • Underactive function of the pituitary gland
  • Underactive function of the thyroid gland which can cause tiredness or weight gain
  • Overactive function of the thyroid which can cause rapid heart rate, sweating and weight loss
  • Decreased function of the adrenal glands caused by an underactive hypothalamus part of the brain) or an overactive pituitary gland (a small gland at the base of the brain)
  • Defect in gland producing sex hormones
  • Acid in the blood produced by diabetes (diabetic ketoacidosis)
  • Excessive thirst, the passing of a greatly increased amount of urine, increase in appetite with a loss of weight, feeling tired, drowsy, weak, depressed, irritable and generally unwell (diabetes)
Skin problems:
  • Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis, Steven-Johnson syndrome) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
  • Signs and symptoms of severe skin reaction may include skin rash with or without itching, peeling of the skin, dry skin, fever, fatigue, swelling of the face or lymph glands, increase of eosinophils (type of white blood cells) and effects on liver, kidneys or lungs
  • Severe condition of the skin that causes red, often itchy spots, similar to rash of measles, which starts on the limbs and sometimes on the face and the rest of the body (erythema multiforme), skin disease with thickened patches of red skin, often silvery scales (psoriasis), hives (itchy, bumpy rash)
Brain and nervous system problems:
  • Damage to nerves causing numbness and weakness (polyneuropathy)
  • Inflammation of the brain (encephalitis)
  • A condition in which the muscles become weak and tire easily (myasthenic syndrome)
  • Inflammation of the nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning pain (autoimmune neuropathy)
  • A temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities (Guillain Barre syndrome)
  • Dizziness
  • Excessive accumulation of fluid on the brain,
  • Difficulty in speaking
  • Damage to the nerves (causing pain, weakness and cramps)
  • Difficulty in coordinating movements (ataxia), shaking, twitching, brief involuntary muscle contraction
  • Inflammation of the nerves, foot drop (peroneal nerve palsy)
  • Triad of symptoms (meningism): neck stiffness, intolerance of bright light and headache
  • Inflammation of the spinal cord (myelitis) causing back and neck pain, weakness in the arms or legs, loss of bladder or bowel control
Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT):
  • Complications of stem cell transplant that uses donor cells (allogeneic) may occur after treatment with YERVOY.
  • These complications can be severe and can lead to death. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant.
Problems in other organs:
  • Inflammation of the heart (myocarditis). Symptoms may include shortness of breath, fatigue, palpitations or chest pain.
  • Changes in the rhythm or rate of the heart, abnormal heart rhythm
  • Disease of blood vessels, low blood pressure, feeling intense heat with sweating and rapid heartbeat, weakness of the heart muscle, fluid around the heart
  • Inflammation of muscles (myositis). Symptoms may include muscle pain, stiffness, weakness, chest pain or severe fatigue
  • Muscle breakdown/injury (rhabdomyolysis). Symptoms may include muscle pain, weakness, nausea or vomiting
  • Eye inflammation and vision changes. Symptoms may include redness in the eye, pain in the eye, flashes of lights or tiny specs in your vision, blurry vision and short-term vision loss.
  • Solid organ transplant rejection
  • A condition where the immune system mistakenly destroys red blood cells (oxygen carrying cells) and results in decreased number of red blood cells (autoimmune haemolytic anaemia)
Infusion reactions:
  • Allergic reaction, reaction related to the infusion of the medicine
  • Life threatening allergic reaction
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Other side effects

Other side effectsWhat to do
The following side effects have been reported in clinical trials when YERVOY has been given alone:
Very Common side effects
  • Loss of appetite
  • Diarrhoea
  • Feeling sick (nausea) or being sick (vomiting)
  • Stomach pain
  • Itching, skin rash
  • Feeling tired or weak
  • Cough
  • Headache
  • Fever
  • Insomnia
Common side effects
  • Serious bacterial infection of the blood (sepsis)
  • Tumour pain
  • Dehydration
  • Inflammation of the eye which causes pain and redness, blurred vision
  • Low blood pressure, temporary redness of the face and neck
  • Weight loss
  • Inflammation and redness of the skin, skin colour change in patches (vitiligo)
  • Hair loss or thinning
  • Excessive sweating at night
  • Pain in the muscles and joints
  • Fever, shivering, lack of energy
  • Swelling, pain, reaction at site of injection
  • Confusion
  • Influenza like illness
Speak to your doctor if you have any of these side effects and they worry you.
The following side effects have been reported in clinical trials when YERVOY has been given in combination with nivolumab:
Very Common side effects
  • Decreased appetite
  • Headache
  • Shortness of breath (dyspnoea)
  • Pain in the joints, muscles and bones
  • Feeling tired or weak
  • Fever
Common side effects
  • Serious lung infection (pneumonia), infections of the upper respiratory tract
  • Dehydration
  • Inflammation of the eye, which causes pain and redness, blurred vision
  • Fast heart rate
  • High blood pressure (hypertension)
  • Mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation, dry mouth
  • Pain in the muscles and bones
  • Inflammation of the joints (arthritis)
  • Oedema
Speak to your doctor if you have any of these side effects and they worry you.
The following side effects have been reported in clinical trials when YERVOY has been given in combination with nivolumab and chemotherapy
Very Common side effects
  • Decreased appetite
  • Diarrhoea (watery, loose or soft stools), vomiting, nausea
  • Skin rash sometimes with blisters, itching
  • Feeling tired or weak
Common side effects
  • Conjunctivitis
  • Serious lung infection (pneumonia), infections of the upper respiratory tract
  • Dry eyes
  • Headache
  • Shortness of breath (dyspnoea)
  • Mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation, dry mouth
  • Dry skin, redness of the skin, unusual hair loss or thinning
  • Pain in the joints, muscles and bones, inflammation of the joints
  • Fever
  • Oedema (swelling)
Speak to your doctor if you have any of these side effects and they worry you.

Tell your doctor, nurse or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What YERVOY contains

Active ingredient
(main ingredient)		ipilimumab
Other ingredients
(inactive ingredients)
  • trometamol hydrochloride
  • sodium chloride
  • mannitol (E421)
  • pentetic acid
  • polysorbate 80
  • sodium hydroxide
  • hydrochloric acid
  • water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What YERVOY looks like

YERVOY concentrate for solution for infusion is a clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) particulates and is supplied in a glass vial with a rubber stopper sealed with aluminium.

It is available in packs containing either 1 vial of 10 mL or 1 vial of 40 mL.

YERVOY is available in the following presentations:

  • YERVOY (ipilimumab) concentrate solution for infusion 50mg in 10mL (5mg/mL) AUST R 174319.
  • YERVOY (ipilimumab) concentrate solution for infusion 200mg in 40mL (5mg/mL) AUST R 174322.

Who distributes YERVOY

Bristol-Myers Squibb Australia Pty Ltd
Level 2, 4 Nexus Court
Mulgrave VIC 3170 Australia.
Toll free number: 1800 067 567
Email: [email protected]

YERVOY® (ipilimumab) is a registered trademark of Bristol-Myers Squibb Company

This leaflet was prepared in October 2023.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Yervoy

Active ingredient

Ipilimumab

Schedule

S4

 

1 Name of Medicine

Ipilimumab.

2 Qualitative and Quantitative Composition

5 mg/mL concentrate solution for infusion.
Each 1 mL of concentrate contains 5 mg ipilimumab.
One 10 mL vial contains 50 mg of ipilimumab.
One 40 mL vial contains 200 mg of ipilimumab.
Yervoy (ipilimumab (rch)) is a recombinant, fully human monoclonal antibody that binds to the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.

Excipient with known effect.

Each 1 mL contains 5 mg of ipilimumab and 0.1 mmol sodium (or 2.30 mg sodium).
Full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Concentrate solution for infusion.
Yervoy is a sterile, preservative free liquid for intravenous (IV) administration, which may contain a small amount of visible translucent-to-white, amorphous ipilimumab particulates. Yervoy has a pH of 7.0 and an osmolarity of 260-300 mOsm/kg.

4 Clinical Particulars

4.1 Therapeutic Indications

Melanoma.

Yervoy, as monotherapy, is indicated for the treatment of patients with unresectable or metastatic melanoma.
Yervoy, in combination with nivolumab, is indicated for the treatment of patients with unresectable or metastatic melanoma. The approval of this indication is based on a pre-specified comparison to ipilimumab monotherapy. All analyses comparing nivolumab monotherapy with the nivolumab/ipilimumab combination are descriptive.

Renal cell carcinoma (RCC).

Yervoy, in combination with nivolumab, is indicated for the treatment of patients with intermediate/poor-risk, previously untreated advanced renal cell carcinoma.

Non-small cell lung cancer (NSCLC).

Yervoy, in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of patients with metastatic or recurrent non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumour aberrations.

Malignant pleural mesothelioma (MPM).

Yervoy, in combination with nivolumab, is indicated for the first-line treatment of patients with unresectable malignant pleural mesothelioma.

Oesophageal squamous cell carcinoma (OSCC).

Yervoy in combination with nivolumab is indicated for the first-line treatment of patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1% as determined by a validated test.

4.2 Dose and Method of Administration

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer.
If specified in the indication, patient selection for treatment with Yervoy based on the tumour expression of PD-L1 should be confirmed by a validated test (see Section 4.1; Section 4.4; Section 5.1).
Liver function tests (LFTs) and thyroid function tests should be evaluated at baseline and before each dose of Yervoy. In addition, any signs or symptoms of immune-related adverse reactions, including diarrhoea and colitis, should be assessed during treatment with Yervoy (see Section 4.4 Special Warnings and Precautions for Use).

Yervoy monotherapy.

Unresectable or metastatic melanoma. The recommended dose of Yervoy is 3 mg/kg administered intravenously over 30 minutes every 3 weeks for a total of 4 doses (induction therapy). Where there is any withholding of a dose, Yervoy should be resumed at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from the first administration, whichever occurs earlier.
Assessments of tumour response to Yervoy should be conducted only after completion of induction therapy. The planned induction course should not be discontinued because of the appearance of new lesions or growth of existing lesions.
Additional treatment with Yervoy (re-induction with 4 doses) may be considered for patients who develop PD after prior CR or PR or after SD lasting longer than 3 months from the first tumour assessment. The recommended re-induction regimen of Yervoy is 3 mg/kg administered IV over a 30-minute period every 3 weeks for a total of 4 doses as tolerated, regardless of the appearance of new lesions or growth of existing lesions.

Yervoy in combination with nivolumab.

Yervoy and nivolumab should be administered and monitored under the supervision of physicians experienced with the use of immunotherapy.
Please review the full prescribing information for nivolumab prior to initiation of Yervoy in combination with nivolumab.
In the initial combination phase, administer Yervoy and nivolumab on the same day. Use separate infusion bags and filters for each infusion. Administer nivolumab first followed by Yervoy (ipilimumab), after completion of the nivolumab infusion.
Unresectable or metastatic melanoma.

Combination phase.

The recommended dose of nivolumab in the combination phase is 1 mg/kg administered intravenously over 30 minutes every 3 weeks for the first 4 doses in combination with Yervoy 3 mg/kg administered intravenously over 30 minutes. This should be followed by nivolumab monotherapy therapy in the single-agent phase (see below).

Single-agent phase.

The recommended dose of nivolumab in the single-agent phase administered intravenously over 30 minutes is 3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks. Following the last dose of the combination of nivolumab and ipilimumab, the first dose of nivolumab monotherapy should be administered after 3 weeks when using 3 mg/kg or 240 mg or 6 weeks when using 480 mg.
Treatment with nivolumab in the single-agent phase should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient.
RCC.

Combination phase.

The recommended dose is 3 mg/kg nivolumab administered as an intravenous infusion over 30 minutes every 3 weeks for the first 4 doses in combination with 1 mg/kg Yervoy administered intravenously over 30 minutes. This should be followed by nivolumab monotherapy therapy in the single-agent phase (see below).

Single-agent phase.

The recommended dose of nivolumab in the single agent phase administered intravenously over 30 minutes is 3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks. Following the last dose of the combination of nivolumab and ipilimumab, the first dose of nivolumab monotherapy should be administered after 3 weeks when using 3 mg/kg or 240 mg or 6 weeks when using 480 mg.
Treatment with nivolumab in the single-agent phase should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient.
NSCLC. The recommended dose is 360 mg nivolumab administered as an intravenous infusion over 30 minutes every 3 weeks in combination with 1 mg/kg Yervoy administered as an intravenous infusion over 30 minutes every 6 weeks, and platinum chemotherapy administered every 3 weeks. After completion of 2 cycles of chemotherapy, treatment is continued with 360 mg nivolumab administered as an intravenous infusion every 3 weeks in combination with 1 mg/kg Yervoy every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
MPM. The recommended dose of nivolumab administered as an intravenous infusion over 30 minutes is 3 mg/kg every 2 weeks or 360 mg every 3 weeks in combination with 1 mg/kg Yervoy administered as an intravenous infusion over 30 minutes every 6 weeks. Treatment should be continued until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.
OSCC. The recommended dose is 1 mg/kg Yervoy administered intravenously over 30 minutes every 6 weeks in combination with either 3 mg/kg nivolumab every 2 weeks or 360 mg nivolumab every 3 weeks administered intravenously over 30 minutes. Treatment is recommended until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.

Recommended treatment modifications.

Ipilimumab monotherapy. Management of immune-related adverse reactions may require withholding of a dose or permanent discontinuation of Yervoy therapy and institution of systemic high-dose corticosteroid. In some cases, addition of other immunosuppressive therapy may be considered (see Section 4.4 Special Warnings and Precautions for Use). Dose reduction is not recommended.
Yervoy should be permanently discontinued in patients who:
experience severe or life-threatening adverse reactions (see Table 1);
experience adverse events (Grade 2 protracted, Grade 3 or Grade 4) that are not responsive to corticosteroids and/or require additional immunosuppressive therapy such as TNF-alpha inhibitors.
Yervoy should be discontinued in patients who are unable to complete a full course of Yervoy (4 doses) within 16 weeks from administration of first dose. Any future re-induction in such patients should not be undertaken if they experienced an adverse event fulfilling the criteria for permanent discontinuation described above.
Guidelines for permanent discontinuation or withholding of Yervoy as monotherapy doses are described in Table 1 and Table 2. Detailed guidelines for the management of immune-related adverse reactions are described (see Section 4.4 Special Warnings and Precautions for Use). Not adhering to the dose withholding and discontinuation guidelines may increase the risk of severe adverse events.

Permanent discontinuation of Yervoy as monotherapy.


Withholding Yervoy monotherapy dose.

Withhold Yervoy monotherapy dose in patients with the following immune-related adverse reactions described in Table 2.
Yervoy monotherapy should be administered 3-weekly either for all 4 doses or be completed within 16 weeks from the first dose, whichever occurs earlier. Detailed guidelines for the management of immune related adverse reactions are described in Special Warnings and Precautions for Use. Not adhering to the dose withholding guidelines may increase the risk of severe adverse events.
Ipilimumab in combination with nivolumab. When Yervoy is administered in combination with nivolumab, if either agent is withheld, the other agent should also be withheld. See Table 3. Detailed guidelines for the management of immune related adverse reactions are described in Special Warnings and Precautions for Use.

Special populations.

Paediatric patients.

The safety and efficacy of Yervoy in children below 18 years have not been established. No data are available. The use of Yervoy in children or adolescents is not recommended until further data become available.

Elderly patients.

No overall differences in safety or efficacy were reported between the 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 Pharmacokinetic Properties).

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 Pharmacokinetic Properties). 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 Pharmacodynamic Properties, Clinical trials).

Method of administration.

Yervoy (ipilimumab) solutions must not be administered as an IV push or bolus injection. A separate infusion line must be used for the infusion, and the line must be flushed with sterile sodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose injection at the end of infusion.
Yervoy should not be infused concomitantly in the same IV line with other medicinal products.
Yervoy may be used for IV administration without dilution after transferring to an infusion container using an appropriate sterile syringe, or after diluting with sterile sodium chloride 9 mg/mL (0.9% solution) or 5% glucose injection solution to a concentration ranging from 4 mg/mL to 1 mg/mL. An in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 micrometer or 1.2 micrometer) must be used for IV administration. Care must be taken to ensure aseptic handling when preparing the infusion.
When Yervoy is administered in combination with nivolumab, or with nivolumab and chemotherapy, nivolumab should be given first followed by Yervoy and then chemotherapy on the same day. Use separate infusion bags and filters for each infusion. Administer nivolumab first followed by Yervoy, no earlier than 30 minutes after completion of the nivolumab infusion.
Determine the number of vials of Yervoy needed.
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 x 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).
Allow the vials to stand at room temperature for approximately 5 minutes. Withdraw the required volume of ipilimumab solution (5 mg/mL) using an appropriate sterile syringe and transfer into a sterile, evacuated glass bottle or IV bag (PVC or non-PVC).
Ipilimumab solution is compatible with: glass, polyvinyl chloride (PVC) and non-PVC bags; PVC IV extension/administration sets; polyethersulfone (0.2 micrometer and 1.2 micrometer) and nylon (0.2 micrometer) in-line filters.
Prior to administration, the ipilimumab should be inspected visually for particulate matter and discolouration. The vial should be discarded if solution is cloudy, there is pronounced discolouration (solution may have pale yellow colour), or there is foreign particulate matter.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.

4.4 Special Warnings and Precautions for Use

When assessing the PD-L1 status of the tumour, it is important that a validated test is used.

Immune-related adverse reactions.

Yervoy can cause severe and fatal immune-related adverse reactions (see Boxed Warnings).
In clinical trials, almost all immune-related adverse reactions have occurred at higher frequencies when Yervoy was administered in combination with nivolumab compared with Yervoy as a monotherapy. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and dose modifications.
Early diagnosis and appropriate management are essential to minimise life-threatening complications. Patients should be monitored continuously, as an immune-related adverse reaction with Yervoy monotherapy or Yervoy in combination with nivolumab may occur at any time during or after discontinuation of therapy. The majority of these initially manifested during treatment; however, a minority occurred weeks to months after discontinuation. Patients should be monitored for signs and symptoms suggestive of immune mediated adverse reactions; appropriate investigations (e.g. electrolytes, creatinine, liver and thyroid functions) should be evaluated at baseline and before each dose.
Clinicians should consider immune-related adverse reactions for all unexplained illnesses. Adequate evaluation should be performed to confirm aetiology or exclude other causes. Unless an alternate aetiology has been identified, diarrhoea, increased stool frequency, bloody stool, liver function test (LFT) elevations, rash, and endocrinopathy must be considered inflammatory and Yervoy-related.
Based on the severity of the adverse reaction, interruption or permanent discontinuation of Yervoy monotherapy or Yervoy in combination with nivolumab and use of systemic corticosteroids (with or without additional immunosuppressive therapy) may be required (see Section 4.2 Dose and Method of Administration).
If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least one month duration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the adverse reaction.
Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use.
Yervoy monotherapy or Yervoy in combination with nivolumab should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy.
Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive therapy.
Immune-related gastrointestinal reactions/colitis.

Ipilimumab monotherapy.

Yervoy is associated with serious immune-related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)).
In patients who received Yervoy 3 mg/kg monotherapy in a Phase 3 study of advanced (unresectable or metastatic) melanoma (MDX010-20, see Section 5.1 Pharmacodynamic Properties, Clinical trials), 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 carefully 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. In clinical trials, immune-related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-related colitis. Stool infections workup (including CMV, other viral aetiology, culture, Clostridium difficile, ova, and parasite) should be performed upon presentation of diarrhoea or colitis to exclude infectious or other alternate aetiologies.
Management recommendations for diarrhoea or colitis are based on severity of symptoms (per National Cancer Institute-Common Terminology Criteria for Adverse Events [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 Yervoy therapy. 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 Yervoy 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, Yervoy may be resumed (see Section 4.2 Dose and Method of Administration).
Yervoy must be permanently discontinued in patients with severe (Grade 3 or 4) diarrhoea or colitis (see Section 4.2 Dose and Method of Administration), and high-dose IV corticosteroid therapy should be initiated immediately (in clinical trials, methylprednisolone 2 mg/kg/day has been used). Once diarrhoea and other symptoms are controlled, corticosteroid taper should occur over a period of at least 1 month. 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. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-related colitis if other causes are excluded (including CMV infection/reactivation evaluated with viral PCR on biopsy, and other viral, bacterial, and parasitic aetiology). 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. Refer to the Product Information for infliximab.

Ipilimumab in combination with nivolumab.

Severe diarrhoea or colitis has been observed with Yervoy in combination with nivolumab. Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucous or blood in stool. Infectious and disease-related aetiologies should be ruled out.
For Grade 4 diarrhoea or colitis, Yervoy in combination with nivolumab must be permanently discontinued and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 3 diarrhoea or colitis observed with Yervoy in combination with nivolumab, permanently discontinue both agents and follow the management guideline for Grade 4 diarrhoea or colitis above.
For Grade 2 diarrhoea or colitis, Yervoy in combination with nivolumab should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Yervoy in combination with nivolumab may be resumed (after corticosteroid taper), if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and Yervoy in combination with nivolumab must be permanently discontinued.
Based on limited data from clinical trials on the management of corticosteroid-refractory diarrhoea or colitis, administration of other systemic immunosuppressants (e.g. anti-TNF-α agents) can be considered.
Immune-related pneumonitis.

Ipilimumab in combination with nivolumab.

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with Yervoy in combination with nivolumab.
Patients should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g. focal ground glass opacities, patchy filtrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.
For Grade 3 or 4 pneumonitis, Yervoy in combination with nivolumab must be permanently discontinued and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents.
For Grade 2 (symptomatic) pneumonitis, Yervoy in combination with nivolumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Yervoy in combination with nivolumab may be resumed (after corticosteroid taper). If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents and Yervoy in combination with nivolumab must be permanently discontinued.
Immune-related hepatitis.

Ipilimumab monotherapy.

Yervoy is associated with serious immune-related hepatitis. Fatal hepatic failure has been reported in clinical trials of Yervoy (see Section 4.8 Adverse Effects (Undesirable Effects)).
In patients who received Yervoy 3 mg/kg monotherapy in MDX010-20, time to onset of moderate to severe or fatal (Grade 2-5) immune-related hepatitis 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 Yervoy as early laboratory changes may be indicative of emerging immune-related hepatitis (see Section 4.2 Dose and Method of Administration). 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 medications and monitored until resolution. Liver biopsies from patients who had immune-related hepatitis showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).
For patients with Grade 2 transaminase or total bilirubin elevation, the scheduled dose of Yervoy should be withheld, and LFTs must be monitored until resolution. Upon improvement, Yervoy therapy may be resumed (see Section 4.2 Dose and Method of Administration).
For patients with Grade 3 or 4 transaminase or bilirubin elevation, treatment must be permanently discontinued (see Section 4.2 Dose and Method of Administration), and systemic high-dose IV corticosteroid therapy (e.g. methylprednisolone 2 mg/kg daily or equivalent) should be initiated immediately. In such patients, LFTs must be monitored until normalisation. Once symptoms have resolved and LFTs show sustained improvement or return to baseline, corticosteroid taper 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. Refer to the Product Information for mycophenolate mofetil.

Ipilimumab in combination with nivolumab.

Severe hepatitis has been observed with Yervoy in combination with nivolumab. Infectious and disease-related aetiologies should be ruled out.
Elevations in liver function tests may develop in the absence of clinical symptoms. Monitor patients for abnormal liver tests prior to and periodically during treatment as indicated based on clinical evaluation.
For Grade 3 or 4 transaminase or total bilirubin elevation, Yervoy in combination with nivolumab must be permanently discontinued and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 transaminase or total bilirubin elevation, Yervoy in combination with nivolumab should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement Yervoy in combination with nivolumab may be resumed (after corticosteroid taper).
If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and Yervoy in combination with nivolumab must be permanently discontinued.
Immune-related skin adverse reactions. Caution should be used when considering the use of Yervoy monotherapy or Yervoy in combination with nivolumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on a prior cancer immune-stimulatory therapy.

Ipilimumab monotherapy.

Yervoy is associated with serious skin adverse reactions that may be immune-related. Stevens Johnson Syndrome (SJS) or fatal toxic epidermal necrolysis (TEN) have been reported in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)).
Yervoy-induced rash and pruritus were predominantly mild or moderate (Grade 1 or 2) and responsive to symptomatic therapy. In patients who received Yervoy 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).
Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) has been very rarely reported with Yervoy in post-marketing use.
Yervoy-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 Yervoy 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 Yervoy should be withheld. If initial symptoms improve to mild (Grade 1) or resolve, Yervoy therapy may be resumed (see Section 4.2 Dose and Method of Administration).
Yervoy must be permanently discontinued in patients with a very severe (Grade 4) rash (including SJS and TEN) or severe (Grade 3) pruritus (see Section 4.2 Dose and Method of Administration), and systemic high-dose IV corticosteroid therapy (e.g. methylprednisolone 2 mg/kg/day) should be initiated immediately. Once rash or pruritus is controlled, corticosteroid taper should occur over a period of at least 1 month.

Ipilimumab in combination with nivolumab.

Patients should be monitored for rash. Severe rash has been observed Yervoy in combination with nivolumab. Yervoy in combination with nivolumab should be withheld for Grade 3 rash and permanently discontinued for Grade 4 rash. Severe rash should be managed with high-dose corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
Rare cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcome, have been observed. If symptoms or signs of SJS or TEN appear, Yervoy in combination with nivolumab should be withheld and the patient referred for specialist assessment and treatment. If the patient has confirmed SJS or TEN, permanent discontinuation of Yervoy in combination with nivolumab is recommended.
Immune-related neurological adverse reactions.

Ipilimumab monotherapy.

Yervoy is associated with serious immune-related neurological adverse reactions. In clinical trials, fatal Guillain-Barré syndrome has been reported. Myasthenia gravis-like symptoms have also been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 medications should be excluded. For patients with moderate (Grade 2) neuropathy (motor with or without sensory) likely related to Yervoy, the scheduled dose should be withheld. If neurologic symptoms resolve to baseline, Yervoy may be resumed (see Section 4.2 Dose and Method of Administration).
Yervoy must be permanently discontinued in patients with severe (Grade 3 or 4) sensory neuropathy suspected to be related to Yervoy (see Section 4.2 Dose and Method of Administration). 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. Yervoy must be permanently discontinued in patients with severe (Grade 3 or 4) motor neuropathy regardless of causality (see Section 4.2 Dose and Method of Administration).

Ipilimumab in combination with nivolumab.

The following adverse events have been observed across clinical trials of Yervoy in combination with nivolumab: demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, myasthenic syndrome/myasthenia gravis, and encephalitis.
While other aetiologies are being ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents for patients with immune-related neurological adverse reactions, followed by corticosteroid taper.
Immune-related nephritis and renal dysfunction.

Ipilimumab in combination with nivolumab.

Severe nephritis and renal dysfunction have been observed with Yervoy in combination with nivolumab. Disease-related aetiologies should be ruled out.
Creatinine elevations may develop in the absence of clinical symptoms. Monitor patients for elevated serum creatinine prior to and periodically during treatment as indicated based on clinical evaluation.
For Grade 4 serum creatinine elevation, Yervoy in combination with nivolumab must be permanently discontinued and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 or 3 serum creatinine elevation, Yervoy in combination with nivolumab should be withheld and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Yervoy in combination with nivolumab may be resumed (after corticosteroid taper). If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and Yervoy in combination with nivolumab must be permanently discontinued.
Immune-related endocrinopathy.

Ipilimumab monotherapy.

Yervoy can cause inflammation of the endocrine system organs which may be irreversible and require long-term hormone replacement therapy. These events may manifest as hypophysitis, hypopituitarism, adrenal insufficiency, and hypothyroidism (see Section 4.8 Adverse Effects (Undesirable Effects)) 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.
In patients who received Yervoy 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 IV 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 Yervoy should be withheld (see Section 4.2 Dose and Method of Administration). 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 Yervoy may be resumed, and corticosteroid taper should occur over a period of at least 1 month.

Ipilimumab in combination with nivolumab.

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus, and diabetic ketoacidosis have been observed with Yervoy in combination with nivolumab.
Patients should be monitored for clinical signs and symptoms of endocrinopathies and for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation).
Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or other nonspecific symptoms which may resemble those associated with other causes such as brain metastasis or underlying disease.
Unless an alternate aetiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related.
For symptomatic hypothyroidism, Yervoy in combination with nivolumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, Yervoy in combination with nivolumab should be withheld and an antithyroid medicine should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, Yervoy in combination with nivolumab may be resumed (after corticosteroid taper). Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Yervoy in combination with nivolumab should be permanently discontinued for life-threatening (Grade 4) hypothyroidism or hyperthyroidism.
For symptomatic Grade 2 adrenal insufficiency, Yervoy in combination with nivolumab should be withheld, and physiologic corticosteroid replacement should be initiated as needed. Yervoy in combination with nivolumab must be permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Monitoring of adrenal function and hormone levels should continue to ensure appropriate corticosteroid replacement is utilised.
For symptomatic Grade 2 or 3 hypophysitis, Yervoy in combination with nivolumab should be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the pituitary gland is suspected. Upon improvement, Yervoy in combination with nivolumab may be resumed (after corticosteroid taper). Yervoy in combination with nivolumab must be permanently discontinued for life-threatening (Grade 4) hypophysitis. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised.
For symptomatic diabetes, Yervoy in combination with nivolumab should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Yervoy in combination with nivolumab should be permanently discontinued for life-threatening (Grade 4) diabetes.
Other immune-related adverse reactions.

Ipilimumab monotherapy.

The following additional adverse reactions suspected to be immune-related have been reported in patients treated with Yervoy in clinical trials: uveitis, eosinophilia, lipase elevation, glomerulonephritis, iritis, haemolytic anaemia, amylase elevations, multi-organ failure and pneumonitis.
In the post-marketing setting, cases of Vogt-Koyanagi-Harada syndrome and serous retinal detachment have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
For Yervoy-related uveitis, iritis, serous retinal detachment or episcleritis, topical corticosteroid eye drops should be considered as medically indicated. Transient vision loss has been reported in patients with ipilimumab-related ocular inflammations.
Fatal or serious graft versus-host disease (GVHD) can occur in patients who receive a CTLA-4 receptor blocking antibody either before or after allogeneic haematopoietic stem cell transplantation (HSCT). Follow patients closely for evidence of GVHD and intervene promptly. Consider the benefit versus risks of treatment with a CTLA-4 receptor blocking antibody after allogeneic HSCT. If severe (Grade 3 or 4), these reactions may require immediate high-dose corticosteroid therapy and discontinuation of Yervoy (see Section 4.2 Dose and Method of Administration). For Yervoy-related uveitis, iritis, or episcleritis, topical corticosteroid eye drops should be considered as medically indicated.
Solid organ transplant rejection has been reported in the post-marketing setting in patients who receive treatment with a CTLA-4 receptor blocking antibody. Treatment with ipilimumab may increase the risk of rejection in solid organ transplant recipients (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).
Histiocytosis haematophagic has been reported in relation to ipilimumab therapy. The adverse reaction mostly responded well to treatment with corticosteroids. In most reported cases prior or concurrent therapy with a PD-1 or PD-L1 inhibitor has occurred (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).

Ipilimumab in combination with nivolumab.

Other clinically significant immune-related adverse reactions, including some with fatal outcome, have been observed across clinical trials of Yervoy in combination with nivolumab investigating various doses across tumour types (see Section 4.8 Adverse Effects (Undesirable Effects)). These include rare cases of myotoxicity.
Cases of Vogt-Koyanagi-Harada syndrome and serous retinal detachment have been reported post-marketing (see Section 4.8 Adverse Effects (Undesirable Effects)). Transient vision loss has been reported in patients with ipilimumab-related ocular inflammations. Refer to the Product Information for nivolumab.
For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, Yervoy in combination with nivolumab, should be withheld and corticosteroids administered. Upon improvement, Yervoy in combination with nivolumab, maybe resumed after corticosteroid taper. Yervoy in combination with nivolumab, must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.
Rare cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis) have been reported with Yervoy in combination with nivolumab. If a patient develops signs and symptoms of myotoxicity, close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, Yervoy in combination with nivolumab should be withheld or discontinued (see Section 4.2 Dose and Method of Administration), and appropriate treatment instituted.
Cases of autoimmune haemolytic anaemia, some with fatal outcome, have been reported with Yervoy in combination with nivolumab. Patients with signs and symptoms of anaemia should undergo a prompt diagnostic workup to evaluate for autoimmune haemolytic anaemia.

Infusion reaction.

Severe infusion reactions have been reported in clinical trials of Yervoy as monotherapy or in combination with nivolumab (see Section 4.8 Adverse Effects (Undesirable Effects)). In case of a severe infusion reaction, the infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may continue the infusion with close monitoring, and with use of premedication according to local treatment guidelines for prophylaxis of infusion reactions.

Yervoy in combination with nivolumab.

Review the full prescribing information for nivolumab prior to initiation of Yervoy in combination with nivolumab. Both agents are associated with immune-related adverse reactions and may require immunosuppression.
In clinical trials, immune-related adverse reactions (see Section 4.4 Special Warnings and Precautions for Use) occurred at higher frequencies when Yervoy was administered in combination with nivolumab compared with Yervoy as a monotherapy. Most immune-related adverse reactions (except for endocrinopathies) improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications.
Patients receiving Yervoy in combination with nivolumab should be monitored for immune-related adverse reactions clinically and with appropriate investigations prior to each dose during the combination phase.

Populations excluded from registrational clinical trials.

Populations excluded from clinical trials of Yervoy or Yervoy in combination with nivolumab by tumour type are listed in Table 4 according to studied indication. In the absence of data, Yervoy should be used with caution in these populations after careful consideration of the potential benefit-risk on an individual basis (also see Section 5.1 Pharmacodynamic Properties, Clinical trials).

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 studies. Ipilimumab is a T-cell potentiator that enables the immune response (see Section 5.1 Pharmacodynamic Properties, Mechanism of action) and may interfere with immunosuppressive therapy, resulting in an exacerbation of the underlying disease or increased risk of graft rejection.
Yervoy 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, Yervoy should be administered with caution after careful consideration of the potential risk-benefit on an individual basis.

Concurrent administration with vemurafenib.

A Phase 1 study was conducted to investigate the safety of the concurrent administration of vemurafenib and Yervoy in patients with BRAFV600-mutated metastatic melanoma not previously treated with CTLA-4 blocking antibodies or with BRAF or MEK inhibitors. Following a 1 month lead-in with monotherapy vemurafenib (960 mg or 720 mg twice daily), patients received combination therapy with Yervoy (3 mg/kg IV every 3 weeks) and vemurafenib administered concurrently. Asymptomatic Grade 3 LFT elevations (ALT/AST with or without total bilirubin) were reported in 6 of 10 patients treated with the combination regimen. All were reversible with either interruption or permanent discontinuation of the drugs, and/or treatment with corticosteroids. Based on these data, the concurrent administration of Yervoy and vemurafenib is not recommended outside of a clinical trial. These results do not impact the currently approved use of Yervoy as monotherapy.

Patient counselling information.

Patients should be advised to report immediately any signs or symptoms suggestive of immune-related events as described in Special Warnings and Precautions for Use. The importance of reporting any worsening of symptoms or severity should be emphasised. Patients should be strongly advised not to treat any of these symptoms with over-the-counter medications without consultation with a health care provider.

Use in hepatic impairment.

The safety and efficacy of Yervoy have not been studied in patients with 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. No specific dose adjustment is necessary in patients with mild hepatic impairment (see Section 5.2 Pharmacokinetic Properties). 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 Pharmacodynamic Properties, Clinical trials).

Use in 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 Pharmacokinetic Properties).

Patients on controlled sodium diet.

Each mL of this medicinal product contains 0.1 mmol (or 2.3 mg) sodium. To be taken into consideration when treating patients on a controlled sodium diet.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

The safety and efficacy of Yervoy in children below 18 years have not been established. The use of Yervoy in children or adolescents is not recommended until further data become available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Ipilimumab is a human monoclonal antibody that is not metabolised by cytochrome P450 enzymes (CYPs) or other drug metabolizing enzymes. In a drug-interaction study, ipilimumab did not have a significant effect on the pharmacokinetics of substrates of CYP1A2, CYP2E1, CYP2C8, and CYP3A4 when coadministered with substrates of these CYP isozymes (dacarbazine or paclitaxel/carboplatin).

Other forms of interaction.

Corticosteroids.

The use of systemic corticosteroids at baseline, before starting Yervoy, should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of Yervoy. However, systemic corticosteroids or other immunosuppressants can be used after starting Yervoy to treat immune-related adverse reactions. The use of systemic corticosteroids after starting Yervoy treatment does not appear to impair the efficacy of Yervoy.

Anticoagulants.

The use of anticoagulants is known to increase the risk of gastrointestinal haemorrhage. Since gastrointestinal haemorrhage is an adverse reaction with Yervoy, patients who require concomitant therapy should be monitored closely.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies to evaluate the effect of ipilimumab on fertility have not been performed. Thus, the effect of Yervoy on male and female fertility is unknown.
(Category C)
Yervoy is not recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the clinical benefit outweighs the potential risk.
There are no data on the use of ipilimumab in pregnant women. It is not known whether ipilimumab can cause foetal harm when administered to a pregnant woman (see Section 5.3 Preclinical Safety Data).
 Ipilimumab has been shown to be present at very low levels in milk from cynomolgus monkeys treated during pregnancy. It is not known whether ipilimumab is secreted in breast milk; however, because human IgG1 is known to be secreted in human breast milk, there is potential for infant exposure to ipilimumab via nursing. A risk to the newborns/infants cannot be excluded. Women who are taking Yervoy should not breast-feed.

4.7 Effects on Ability to Drive and Use Machines

Because of potential adverse reactions such as fatigue (see Section 4.8 Adverse Effects (Undesirable Effects)), patients should be advised to use caution when driving or operating machinery until they are reasonably certain that Yervoy does not adversely affect them.

4.8 Adverse Effects (Undesirable Effects)

Ipilimumab monotherapy.

Yervoy 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 described below reflect exposure to Yervoy monotherapy at 3 mg/kg (n = 131) in previously treated patients with advanced melanoma from a Phase 3 study (MDX010-20, see Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients received a median of 4 doses (range 1-4).
Yervoy is most commonly associated with adverse reactions resulting from increased or excessive immune activity (see Section 4.4 Special Warnings and Precautions for Use). Most of these adverse reactions, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of Yervoy.
The safety profile of Yervoy 3 mg/kg in chemotherapy-naïve patients pooled across Phase 2 and 3 clinical trials (N=75; treated) and in treatment-naïve patients in two retrospective observational studies (N = 273 and N = 157) was similar to that in previously-treated advanced melanoma.
Adverse events reported in study MDX010-20. In patients who received 3 mg/kg Yervoy monotherapy in MDX010-20, the most frequently reported adverse events (≥ 10% of patients) were fatigue, diarrhoea, pruritus, rash, decreased appetite, nausea, vomiting, abdominal pain, cough, headache, pyrexia, and insomnia. The majority of adverse events were mild to moderate (Grade 1 or 2). Yervoy therapy was discontinued for adverse reactions in 10% of patients.
Adverse events, regardless of causality, reported in ≥ 1% of patients treated with either Yervoy-containing regimen in MDX010-20 are presented in Table 5. This table includes adverse events that occurred at a greater incidence in a Yervoy group than in the gp100 group (before rounding).
These adverse events are presented by system organ class and by frequency.
Immune-related adverse reactions in MDX010-20 (Table 6).
Adverse reactions observed in Phase 2 studies in patients receiving 3 mg/kg of Yervoy (n = 111) were consistent with those in MDX010-20. Rates of immune-related adverse reactions in HLA-A2*0201 positive patients who received Yervoy in MDX010-20 were similar to those observed in the overall clinical program.
Other adverse reactions reported in ipilimumab monotherapy clinical trials. In addition, the following adverse reactions were reported in other clinical studies. These additional adverse reactions occurred at a frequency of < 1% unless otherwise noted: large intestinal ulcer, oesophagitis, ileus, myasthenia gravis-like syndrome, erythema multiforme, blepharitis, psoriasis, paraneoplastic syndrome, lymphopenia (1%), leucopenia, thyroiditis, hypoparathyroidism, peripheral sensory neuropathy (2%), dizziness (2%), syncope, myoclonus, vitreous haemorrhage, reduced visual acuity, foreign body sensation in eyes, hot flush (1%), orthostatic hypotension, pulmonary oedema, allergic rhinitis, constipation (4%), gastroesophageal reflux disease (1%), gastrointestinal perforation, diverticulitis, gastric ulcer, proctitis, skin exfoliation, palmar-plantar erythrodysesthesia syndrome, amenorrhoea, asthenia (3%), pain (3%), weight decrease (4%), increased blood thyroid stimulating hormone, decreased blood thyroid stimulating hormone, decreased blood cortisol, decreased blood testosterone, decreased blood gonadotrophin, decreased thyroxine, cytokine release syndrome and hair colour changes.
Serious adverse reactions reported in other ipilimumab monotherapy clinical trials. The following serious adverse reactions were also reported in patients with advanced melanoma treated with Yervoy in clinical studies (regardless of dose or regimen). Adverse reactions presented elsewhere in Adverse Effects (Undesirable Effects) are excluded.

Infections and infestations.

Uncommon: septic shock.
Rare: respiratory tract infection.

Blood and lymphatic system disorders.

Uncommon: anaemia.
Rare: polycythemia.

Immune system disorders.

Uncommon: infusion-related reaction.
Rare: hypersensitivity, sarcoidosis.
Very rare: anaphylactic reaction (shock).

Endocrine disorders.

Rare: secondary adrenocortical insufficiency, hyperpituitarism, autoimmune thyroiditis.

Metabolism and nutrition disorders.

Common: dehydration.
Uncommon: hypophosphatemia.
Rare: alkalosis, tumour lysis syndrome.

Psychiatric disorders.

Rare: confusional state, mental status change.

Nervous system disorders.

Uncommon: ataxia, dysarthria.
Rare: Guillain-Barré syndrome, meningism, autoimmune central neuropathy (encephalitis).

Eye disorders.

Rare: episcleritis, scleritis, iritis, eye oedema, ocular myositis.
Very rare: Vogt-Koyanagi-Harada syndrome.

Ear and labyrinth disorders.

Rare: neurosensory hypoacusis.

Cardiac disorders.

Rare: myocarditis, cardiomyopathy, pericardial effusion (pericarditis).

Vascular disorders.

Rare: angiopathy, peripheral ischemia, vasculitis, temporal arteritis, Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders.

Uncommon: lung infiltration.
Rare: dyspnoea, acute respiratory distress syndrome, respiratory failure.

Gastrointestinal disorders.

Uncommon: enterocolitis, nausea, pancreatitis (autoimmune), peritonitis (infectious), mucosal inflammation, stomatitis.

Hepatobiliary disorders.

Uncommon: autoimmune hepatitis.

Skin and subcutaneous tissue disorders.

Uncommon: toxic epidermal necrolysis (including Stevens Johnson syndrome)a,b,c.

Musculoskeletal and connective tissue disorders.

Uncommon: arthralgia, musculoskeletal paind, arthritis.
Rare: polymyalgia rheumatica, myositis, polymyositis.

Renal and urinary disorders.

Uncommon: haematuria.
Rare: autoimmune nephritis, proteinuria, renal tubular acidosis.

General disorders and administration site conditions.

Common: influenza-like illness (symptoms).
Uncommon: multi-organ failure, oedema.
Rare: systemic inflammatory response syndrome.

Investigations.

Common: increased blood alkaline phosphatase.
Uncommon: increased gamma-glutamyltransferase.
Rare: abnormal blood prolactin.
a Including fatal outcome.
b Additional information about these potentially inflammatory adverse reactions is provided in Special Warnings and Precautions for Use. Data presented in those sections primarily reflect experience from a Phase 3 study, MDX010-20.
c Patient developed Stevens-Johnson syndrome which evolved into toxic epidermal necrolysis.
d Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.

Ipilimumab in combination with other therapeutic agents.

Ipilimumab in combination with nivolumab. The overall safety profile of nivolumab in combination with ipilimumab was assessed from a pooled dataset for 448 patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg for melanoma (studies CA209067 [combination group], CA209069, and CA209004-cohort 8), 547 patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg for RCC (study CA209214) and a total of 622 patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg for MPM (study CA209743) and OSCC (study CA209684).
Adverse reactions reported in the pooled dataset for patients treated with nivolumab in combination with ipilimumab (n=1,617) are presented in Table 7. 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).

Melanoma.

In the pooled dataset of ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma (n=448, CA209067 [combination group], CA209069, and CA209004-cohort 8), the most frequent adverse reactions (≥ 10%) were rash (52%), fatigue (46%), diarrhoea (43%), pruritus (36%), nausea (26%), pyrexia (19%), decreased appetite (16%), hypothyroidism (16%), colitis (15%), vomiting (14%), abdominal pain (13%), arthralgia (13%), headache (11%), and dyspnoea (10%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Among the 313 patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in CA209067, 154/313 (49%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 147 patients in this group who continued treatment in the single-agent phase, 47 (32%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.

RCC.

In the CA209214 dataset of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC (n = 547), with a minimum follow-up of 17.5 months, the most frequent adverse reactions (≥ 10%) were fatigue (48%), rash (34%), pruritus (28%), diarrhoea (27%), nausea (20%), hypothyroidism (16%), musculoskeletal pain (15%), arthralgia (14%), decreased appetite (14%), pyrexia (14%), vomiting (11%) and hyperthyroidism (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Among the patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in CA209214, 169/547 (31%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 382 patients in this group who continued treatment in the single-agent phase, 144 (38%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.
The majority of drug-related adverse reactions observed in patients in CA209214 were generally lower in frequency and severity compared to the pooled nivolumab in combination with ipilimumab data from melanoma studies, which utilised a higher ipilimumab dose and regimen (nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg IV Q3W).

OSCC and malignant pleural mesothelioma.

In the dataset of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in malignant pleural mesothelioma (n=300), the most frequent adverse reactions (≥ 10%) were rash (25%), fatigue (22%), diarrhea (21%), pruritus (16%), hypothyroidism (11%), and nausea (10%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). Median duration of therapy was 5.55 months (range: 0-26.2 months) for nivolumab in combination with ipilimumab.
In the dataset of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in 1 L OSCC (n=322), the most frequent adverse reactions (≥ 10%) were rash (25.2%), pruritus (13.4%), hypothyroidism (13.4%) and fatigue (11.2%). The most frequent all-causality serious adverse events reported in ≥ 2% were pneumonia (7.5%), pyrexia (2.7%), pneumonitis (3.7%), dysphagia (3.4%), aspiration pneumonia (3.1%), hepatic function abnormal (2.8%), decreased appetite (2.2%), adrenal insufficiency (2.2%) and dehydration (2.2%). Fatal treatment-related adverse reactions occurred in 5 (1.6%) patients who received Yervoy in combination with nivolumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome.
Ipilimumab in combination with nivolumab and platinum-based chemotherapy.

NSCLC.

In the dataset of nivolumab 360 mg in combination with ipilimumab 1 mg/kg and platinum-doublet chemotherapy in NSCLC (n = 358), the most frequent adverse reactions (≥ 10%) were fatigue (36%), nausea (26%), rash (25%), diarrhoea (20%), pruritus (18%), decreased appetite (16%), hypothyroidism (15%) and vomiting (13%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). Median duration of therapy was 6.1 months (95% CI 4.93, 7.06) for nivolumab in combination with ipilimumab and 2.4 months (95% CI 2.30, 2.83) for platinum-doublet chemotherapy.
Adverse reactions reported in the dataset for patients treated with nivolumab in combination with ipilimumab and platinum-doublet chemotherapy (n = 358) are presented in Table 8 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).

Laboratory abnormalities with ipilimumab in combination with other therapeutic agents.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 2.8% for anaemia (all Grade 3), 1.2% for thrombocytopaenia, 0.5% for leucopoenia, 6.7% for lymphopaenia, 0.7% for neutropaenia, 4.3% for increased alkaline phosphatase, 12.4% for increased AST, 15.3% for increased ALT, 1.2% for increased total bilirubin, 2.4% for increased creatinine, 5.3% for hyperglycaemia, 8.7% for increased amylase, 19.5% for increased lipase, 1.2% for hypocalcaemia, 0.2% each for hypernatraemia and hypercalcaemia, 0.5% for hyperkalemia, 0.3% for hypermagnesaemia, 4.8% for hypokalaemia, and 9.5% for hyponatraemia.
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.0% for anaemia (all Grade 3), 0.7% for thrombocytopaenia, 0.6% for leucopoenia, 5.1% for lymphopaenia, 1.1% for neutropaenia, 2.0% for increased alkaline phosphatase, 4.8% for increased AST, 6.5% for increased ALT, 1.1% for increased total bilirubin, 2.1% for increased creatinine, 7.2% for hyperglycaemia, 1.8% for hypoglycaemia, 12.2% for increased amylase, 20.1% for increased lipase, 0.4% for hypocalcaemia, 1.3% for hypercalcaemia, 2.4% for hyperkalaemia, 1.1% for hypermagnesaemia, 0.4% for hypomagnesaemia 1.9% for hypokalaemia, and 9.9% for hyponatraemia.
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in OSCC and MPM, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 4.5% for anaemia, 1.0% for thrombocytopaenia, 1.2% for leucopoenia, 10.6% for lymphopaenia, 1.3% for neutropaenia, 3.2% for increased alkaline phosphatase, 6.3% for increased AST, 6.5% for increased ALT, 1.2% for increased total bilirubin, 0.5% for increased creatinine, 3.6% for hyperglycaemia, 0.9% for hypoglycaemia, 5.4% for increased amylase, 12.8% for increased lipase, 0.7% for hypernatraemia, 10.0% for hyponatraemia, 2.8% for hyperkalaemia, 3.7% for hypokalaemia, 1.0% for hypercalcaemia, and 0.2% for hypocalcaemia, and 0.3% for hypermagnesaemia.
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.

Description of selected immune-related adverse reactions.

Both Yervoy monotherapy and Yervoy in combination with nivolumab are associated with immune-related adverse reactions. With appropriate medical therapy these resolved in most cases.

Note.

Time to resolution may include censored observations.

Immune-related pneumonitis.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the incidence of pneumonitis including interstitial lung disease, was 7.8% (35/448). Grade 2, Grade 3, and Grade 4 cases were reported in 4.7% (21/448), 1.1% (5/448), and 0.2% (1/448) of patients, respectively. One of the Grade 3 pneumonitis cases worsened over 11 days with a fatal outcome. Median time to onset was 2.6 months (range: 0.7-12.6). Nine patients (2.0%) required permanent discontinuation of ipilimumab in combination with nivolumab. Twenty-one patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 29 patients (87.9%) with a median time to resolution of 6.1 weeks (range: 0.3-46.9).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the incidence of pneumonitis including interstitial lung disease was 6.2% (34/547). Grade 2 and Grade 3 cases were reported in 3.1% (17/547) and 1.1% (6/547), of patients, respectively. No Grade 4 or 5 cases were reported in this study. Median time to onset was 2.6 months (range: 0.25-20.6). Twelve patients (2.2%) required permanent discontinuation of ipilimumab in combination with nivolumab. Fifty-nine patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 31 patients (91.2%) with a median time to resolution of 6.1 weeks (range: 4.3-11.4).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in OSCC and malignant pleural mesothelioma, the incidence of pneumonitis including interstitial lung disease was 7.4% (46/622). Grade 2, Grade 3 and Grade 4 cases were reported in 3.7% (23/622), 1.1% (7/622) and 0.6% (4/622) of patients, respectively. Median time to onset was 2.7 months (range: 0.3-20.8). Seven patients (2.3%) required permanent discontinuation of nivolumab in combination with ipilimumab. Eighteen patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 33 patients (71.7%) with a median time to resolution of 7.1 weeks (range: 0.1+-119.3+).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 360 mg 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), 0.6% (2/358) and of patients, respectively. No Grade 5 cases were reported. 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 colitis.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the incidence of diarrhoea or colitis was 46.7% (209/448). Grade 2, Grade 3, and Grade 4 cases were reported in 13.6% (61/448), 15.8% (71/448), and 0.4% (2/448) of patients, respectively. No deaths due to diarrhoea or colitis were reported. Median time to onset was 1.2 months (range: 0.0-22.61). Seventy-one patients (15.8%) required permanent discontinuation of ipilimumab in combination with nivolumab. Ninety-six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 184 patients (90.6%) with a median time to resolution of 3.0 weeks (range: 0.1-78.7).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the incidence of diarrhoea or colitis was 28.2% (154/547). Grade 2 and Grade 3 cases were reported in 10.4% (57/547) and 4.9% (27/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 1.2 months (range: 0.0-24.7). Twenty-two patients (4.0%) required permanent discontinuation of ipilimumab in combination with nivolumab. Twenty-six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 140 patients (91.5%) with a median time to resolution of 2.4 weeks (range: 01-103.1).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in OSCC and malignant pleural mesothelioma, the incidence of diarrhoea or colitis was 16.7% (104/622). Grade 2 and Grade 3 cases were reported in 5.5% (34/622) and 3.4% (21/622) of patients, respectively. Median time to onset was 3.3 months (range: 0.0-21.7). Nineteen patients (3.1%) required permanent discontinuation of nivolumab in combination with ipilimumab. Twenty-six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 98 patients (94.2%) with a median time to resolution of 3.1 weeks (range: 0.1-100.0+).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 360 mg 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 hepatitis.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the incidence of liver function test abnormalities was 29.5% (132/448). Grade 2, Grade 3, and Grade 4 cases were reported in 6.7% (30/448), 15.4% (69/448), and 1.8% (8/448) of patients, respectively. No deaths due to liver function abnormalities were reported. Median time to onset was 1.5 months (range: 0.0-30.1). Forty-one patients (9.2%) required permanent discontinuation of ipilimumab in combination with nivolumab. Fifty-eight patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 116 patients (92.8%) with a median time to resolution of 5.0 weeks (range: 0.1-53.1).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the incidence of liver function test abnormalities was 18.5% (101/547). Grade 2, Grade 3, and Grade 4 cases were reported in 4.8% (26/547), 6.6% (36/547), and 1.6% (9/547) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.0 months (range: 0.4-26.8). Twenty-four patients (4.4%) required permanent discontinuation of ipilimumab in combination with nivolumab. Thirty-five patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 86 patients (85.1%) with a median time to resolution of 6.1 weeks (range: 0.1-82.9).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in OSCC and malignant pleural mesothelioma, the incidence of liver function test abnormalities was 12.5% (78/622). Grade 2, Grade 3, and Grade 4 cases were reported in 2.3% (14/622), 4.3% (27/622), and 0.5% (3/622) of patients, respectively. Median time to onset was 1.4 months (range: 0.2-20.3). Twenty patients (3.2%) required permanent discontinuation of nivolumab in combination with ipilimumab. Twenty-four patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 68 patients (87.2%) with a median time to resolution of 4.1 weeks (range: 1.0-78.3+).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 360 mg 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. No Grade 5 cases were reported. 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 nephritis and renal dysfunction.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the incidence of nephritis or renal dysfunction was 5.1% (23/448). Grade 2, Grade 3, and Grade 4 cases were reported in 1.6% (7/448), 0.9% (4/448), and 0.7% (3/448) of patients, respectively. No deaths due to nephritis or renal dysfunction were reported. Median time to onset was 2.6 months (range: 0.5-21.8). Four patients (0.9%) required permanent discontinuation of ipilimumab in combination with nivolumab. Four patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 17 patients (89.5%) with a median time to resolution of 1.9 weeks (range: 0.4-42.6).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the incidence of nephritis or renal dysfunction was 8.8% (48/547). Grade 2, Grade 3, and Grade 4 cases were reported in 4.4% (24/547), 0.7% (4/547), and 0.5% (3/547) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.1 months (range: 0.0-16.1). Seven patients (1.3%) required permanent discontinuation of ipilimumab in combination with nivolumab. Twenty-seven patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 37 patients (77.1%) with a median time to resolution of 13.2 weeks (range: 4.1-21.1).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in OSCC and malignant pleural mesothelioma, the incidence of renal dysfunction was 3.7% (23/622). Grade 2 and Grade 3 cases were reported in 1.4% (9/622) and 1.0% (6/622) of patients, respectively. Median time to onset was 2.6 months (range: 0.3-14.4). Six patients (1.0%) required permanent discontinuation of nivolumab in combination with ipilimumab. Nine patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 17 patients (73.9%) with a median time to resolution of 9.6 weeks (range: 0.7-142.3+).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 360 mg 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. No Grade 5 cases were reported. 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 endocrinopathies.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the incidence of thyroid disorders was 25.2% (113/448). Grade 2 and Grade 3 thyroid disorders were reported in 14.5% (65/448) and 1.3% (6/448) of patients, respectively. Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 5.8% (26/448) and 2.0% (9/448) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.4% (2/448) and 0.7% (3/448) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 1.6% (7/448), 1.3% (6/448) and 0.2% (1/448) of patients respectively. Grade 1, Grade 2, Grade 3 and Grade 4 diabetes mellitus and Grade 4 diabetic ketoacidosis were each reported in 0.2% (1/448) of patients. No deaths due to endocrinopathy were reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-28.1). Eleven patients (2.5%) required permanent discontinuation of ipilimumab in combination with nivolumab. Thirty-six patients received high dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 59 patients (45.0%). Time to resolution ranged from 0.4 to 74.4 weeks.
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the incidence of thyroid disorders was 27.2% (149/547). Grade 2 and Grade 3 thyroid disorders were reported in 15.7% (86/547) and 1.3% (7/547) of patients, respectively. Hypophysitis occurred in 4.0% (22/547) of patients. Grade 2, Grade 3, and Grade 4 cases were reported in 0.5% (3/547), 2.4% (13/547), and 0.4% (2/547) of patients, respectively. Grade 2 hypopituitarism occurred in 0.4% (2/547) of patients. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 2.9% (16/547), 2.2% (12/547) and 0.4% (2/547) of patients, respectively. Diabetes mellitus including Type 1 diabetes mellitus (3 Grade 2, 2 Grade 3, and 3 Grade 4), and diabetic ketoacidosis (1 Grade 4) were reported. No Grade 5 endocrinopathy was reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-22.3). Three patients (2.9%) required permanent discontinuation of ipilimumab in combination with nivolumab. Twenty-five patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 71 patients (42.7%) with a median time to resolution of 0.4 to 130.3 weeks.
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in OSCC and malignant pleural mesothelioma, the incidence of thyroid disorders was 18.2% (113/622). Grade 2 and Grade 3 thyroid disorders were reported in 7.9% (49/622) and 0.5% (3/622) of patients, respectively. Hypophysitis occurred in 2.4% (15/622) of patients. Grade 2 cases were reported in 1.3% (8/622) of patients. Grade 2 and Grade 3 hypopituitarism occurred in 1.3% (8/622) and 1.3% (8/622) of patients, respectively. Grade 2, Grade 3 and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 2.3% (14/622), 1.3% (8/622) and 0.2% (1/622) of patients, respectively. Diabetes mellitus including Type 1 diabetes mellitus and fulminant Type 1 diabetes mellitus (3 Grade 2 and 2 Grade 3) were reported. Median time to onset of these endocrinopathies was 2.4 months (range: 0.4-20.8). Twelve patient (1.9%) required permanent discontinuation of nivolumab in combination with ipilimumab. Fifty-eight patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 42 patients (30%). Time to resolution ranged from 0.3 to 154.0+ weeks.
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 360 mg 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. No Grade 5 endocrinopathy was 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.

Immune-related skin adverse reactions.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the incidence of rash was 65% (291/448). Grade 2 and Grade 3 cases were reported in 20.3% (91/448) and 7.6% (34/448) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 0.5 months (range: 0.0-19.4). Three patients (0.7%) required permanent discontinuation of ipilimumab in combination with nivolumab. Twenty patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 192 patients (67.6%) with a median time to resolution of 10.4 weeks (range: 0.1-74.0).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the incidence of rash was 48.8% (267/547). Grade 2 and Grade 3 cases were reported in 13.7% (75/547) and 3.7% (20/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 0.9 months (range: 0.0-17.9). Eight patients (1.5%) required permanent discontinuation of ipilimumab in combination with nivolumab. Seven patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 192 patients (72.2%) with a median time to resolution of 11.6 weeks (range: 8.7-17.1).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in OSCC and malignant pleural mesothelioma, the incidence of rash was 35.0% (218/622). Grade 2, Grade 3 and Grade 4 cases were reported in 11.3% (70/622), 3.4% (21/622) and 0.2% (1/622) of patients, respectively. Median time to onset was 1.1 months (range: 0.0-22.3). Five patients (0.8%) required permanent discontinuation of nivolumab in combination with ipilimumab. Seventeen patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Resolution occurred in 148 patients (68.2%) with a median time to resolution of 11.9 weeks (range: 0.3-146.6+).
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 360 mg 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. No Grade 5 cases were reported. 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+).

Infusion reactions.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the incidence of hypersensitivity/infusion reactions was 3.8% (17/448); all were Grade 1 or 2 in severity. Grade 2 cases were reported in 2.2% (10/448) of patients. No Grade 3-5 cases were reported.
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the incidence of hypersensitivity/infusion reactions was 4.0% (22/547); all were Grade 1 or 2 in severity. Grade 2 cases were reported in 2.4% (13/547) of patients. No Grade 3-5 cases were reported.
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in OSCC and malignant pleural mesothelioma, the incidence of hypersensitivity/infusion reactions was 7.2% (45/622); Grade 1, Grade 2 and Grade 3 cases were reported in 3.4% (21/622), 3.2% (20/622) and 0.6% (4/622) of patients, respectively.
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 360 mg 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. No Grade 5 cases were reported.

Immune-related neurological adverse reactions.

The following adverse events observed across clinical trials of ipilimumab in combination with nivolumab were reported in less than 1% of patients: demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, myasthenic syndrome/myasthenia gravis, and encephalitis.

Other immune-related adverse reactions.

Other clinically significant immune-related adverse reactions have been observed. Some of these have had fatal outcome. Across clinical trials of ipilimumab in combination with nivolumab investigating various doses and tumour types, the following immune-related adverse reactions were reported in less than 1% of patients: pancreatitis, uveitis, gastritis, sarcoidosis, duodenitis, aseptic meningitis, myositis, myocarditis, and rhabdomyolysis.

Postmarketing experience.

The following events have been identified during postapproval use of ipilimumab. Because reports are voluntary from a population of unknown size, an estimate of frequency cannot be made.

Blood and lymphatic system disorders.

Histiocytosis haematophagic.

Immune system disorders.

Graft-versus-host disease, solid organ transplant rejection.

Eye disorders.

Serous retinal detachment.

Nervous system disorders.

Myelitis (including transverse myelitis).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

The maximum tolerated dose of Yervoy has not been determined. In clinical trials, patients received up to 20 mg/kg without apparent toxic effects.
In case of overdosage, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

CTLA-4 is a key regulator of T-cell activity. Ipilimumab is a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the number of tumor reactive T effector cells which mobilize to mount a direct T-cell immune attack against tumor cells. CTLA-4 blockade can also reduce T regulatory cell function, which may lead to an increase in anti-tumor immune response.
In patients with melanoma who received Yervoy, the mean peripheral blood absolute lymphocyte counts (ALC) increased throughout the induction dosing period. In Phase 2 studies, this increase occurred in a dose-dependent fashion. In MDX010-20 (see Section 5.1 Pharmacodynamic Properties, Clinical trials), Yervoy given at 3 mg/kg with or without gp100 increased ALC throughout the induction dosing period, but no meaningful change in ALC was observed in the control group of patients who received an investigational gp100 peptide vaccine alone.
In peripheral blood of patients with melanoma, a mean increase in the percent of activated HLA-DR+ CD4+ and CD8+ T-cells and a mean decrease in the percent of naive (CCR7+ CD45RA+) CD4+ and CD8+ T-cells were observed after treatment with Yervoy, consistent with its mechanism of action. A mean increase in the percent of central memory (CCR7+ CD45RA-) CD4+ and CD8+ T-cells and a smaller, but significant, mean increase in the percent of effector memory (CCR7- CD45RA-) CD8+ T-cells were also observed after treatment with Yervoy.

Clinical trials.

Melanoma.

Previously untreated unresectable or metastatic melanoma - Yervoy monotherapy.

Observational data pooled from multiple studies.

Clinical data to support the use of ipilimumab 3 mg/kg monotherapy in a first line clinical setting in patients with advanced (unresectable or metastatic) melanoma is derived from observational clinical data and pooled data sourced from multiple studies. A prospective, randomised, Phase 3 study of ipilimumab 3 mg/kg monotherapy has not been performed in this setting.
Overall survival of Yervoy 3 mg/kg monotherapy in chemotherapy-naïve patients pooled across Phase 2 and 3 clinical trials (N=78; randomised) and in treatment-naïve 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 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 pooled chemotherapy-naïve patients 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.
Previously untreated unresectable or metastatic melanoma - Yervoy in combination with nivolumab.

Randomised phase 3 study of ipilimumab in combination with nivolumab or nivolumab as monotherapy vs. ipilimumab as monotherapy (CA209067).

The safety and efficacy of nivolumab in combination with ipilimumab and nivolumab monotherapy for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). The study included adult patients (18 years or older) with confirmed unresectable Stage III or Stage IV melanoma, regardless of PD-L1 expression. Patients were to have ECOG performance status score of 0 or 1. Patients who had not received prior systemic anticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant or neoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patients with active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastases were excluded from the study.
A total of 945 patients were randomised to receive nivolumab in combination with ipilimumab (n = 314), nivolumab as monotherapy (n = 316), or ipilimumab as monotherapy (n = 315). Patients in the combination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm received nivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every 2 weeks. Randomisation was stratified by PD-L1 expression (≥ 5% vs. < 5% tumour cell membrane expression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging system. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments were conducted 12 weeks after randomisation then every 6 weeks for the first year, and every 12 weeks thereafter. The co-primary outcome measures were PFS and OS. ORR and the duration of response were also assessed. This study evaluated whether PD-L1 expression was a predictive biomarker for the co-primary endpoints. The efficacy of nivolumab in combination with ipilimumab and nivolumab monotherapy was each compared with that of ipilimumab. In addition, the differences between the two nivolumab-containing groups were evaluated descriptively, but not included in formal hypothesis testing.
Baseline characteristics were balanced across the three treatment groups. The median age was 61 years (range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance status score was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58% had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy. Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1 ≥ 5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and 36% of patients had a baseline LDH level greater than ULN at study entry.
Baseline tumour tissue specimens were systematically collected prior to randomisation in order to conduct planned analyses of efficacy according to PD-L1 expression. Quantifiable tumour PD-L1 expression was measured in 89% (278/314) of patients randomised to nivolumab in combination with ipilimumab, 91% (288/316) of patients randomised to nivolumab monotherapy, and 88% (277/315) of patients randomised to ipilimumab alone. Among patients with quantifiable PD-L1 expression, the distribution of patients was balanced across the three treatment groups at the predefined tumour PD-L1 expression level of ≥ 5% (24% in the nivolumab in combination with ipilimumab arm, 28% in the nivolumab monotherapy arm, and 27% in the ipilimumab arm). Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.
Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORR compared with ipilimumab monotherapy. Efficacy results for all randomised patients are shown in Table 9, Figure 1 (PFS), and Figure 2 (OS).
Among 128 patients who discontinued nivolumab in combination with ipilimumab due to adverse reaction after 18 months of follow-up, median PFS was 16.7 months (95% CI: 10.2, NA). Among 131 patients who discontinued the combination due to adverse reaction after 28 months of follow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median OS was not reached.
The improvements in PFS, OS, ORR and DOR that were seen in both nivolumab-containing arms compared to ipilimumab monotherapy were consistent across patient subgroups including baseline ECOG performance status, BRAF status, M stage (7th Edition of AJCC melanoma of the skin staging classification system), age, history of brain metastases, baseline LDH level and tumour PD-L1 expression levels.
Greater objective response rates were demonstrated for nivolumab in combination with ipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels, with a best overall response of complete response correlating to an improved survival rate.
Analyses comparing nivolumab monotherapy to nivolumab in combination with ipilimumab were all descriptive. Kaplan-Meier plots for exploratory subgroup analyses comparing PFS and OS in patients with tumour PD-L1 expression of < 1% versus ≥ 1% are included as Figure 3 and Figure 4.
No clear cut-off for PD-L1 expression can reliably be established when considering the relevant endpoints of tumour response, PFS and OS.

Randomised phase 2 study of Yervoy in combination with nivolumab vs Yervoy monotherapy (CA209069).

Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination of nivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable or metastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis in patients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was 61% (95% CI: 48.9, 72.4) in the combination arm (n=72) versus 11% (95% CI: 3.0, 25.4) for the ipilimumab arm (n=37). The estimated 12 and 18 month OS rates were 79% (95% CI: 67, 87) and 73% (95% CI: 61, 82) respectively for the combination and 62% (95% CI: 44, 75) and 56% (95% CI: 39, 70) respectively for ipilimumab.
Previously treated unresectable or metastatic melanoma - Yervoy monotherapy.

Randomised phase 3 study of Yervoy monotherapy vs gp100 in combination with Yervoy and gp100 monotherapy (MDX010-20).

Overall survival advantage of Yervoy at the recommended dose of 3 mg/kg in patients with previously-treated advanced (unresectable or metastatic) melanoma was demonstrated in a Phase 3 study (MDX010-20). Yervoy has not been investigated in patients with active or a history of serious chronic viral infections, including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). Clinical studies excluded patients without liver metastasis who had a baseline AST > 2.5 x ULN or patients with liver metastasis who had a baseline AST > 5 x ULN. Patients with a baseline total bilirubin ≥ 3 x ULN were also excluded.
A Phase 3, double-blind study enrolled patients with 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 Yervoy 3 mg/kg in combination with an investigational gp100 peptide vaccine (gp100), Yervoy 3 mg/kg monotherapy, or gp100 alone. All patients in this study were HLA-A2*0201 type; this HLA type supports the immune presentation of gp100. BRAF status was not collected at study entry. Patients received Yervoy 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 Yervoy was conducted at approximately Week 12 after completion of induction therapy.
Additional treatment with Yervoy (re-induction therapy) was offered to patients who developed progressive disease (PD) after initial clinical response (partial response [PR] or complete response [CR]) or after stable disease (SD, per the modified WHO criteria) lasting longer than 3 months from the first tumour assessment. The primary endpoint was overall survival (OS) in the Yervoy + gp100 group vs. the gp100 group. Key secondary endpoints were OS in the Yervoy + gp100 group vs. the Yervoy monotherapy group and in the Yervoy 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 randomised: 137 to the Yervoy monotherapy group, 403 to the Yervoy + gp100 group, and 136 to the gp100 alone group. The majority of patients had received all 4 doses during induction. Thirty-two evaluable patients received a re-induction dose: 8 in the Yervoy monotherapy group, 23 in the Yervoy + gp100 group, and 1 in the gp100 group. Duration of follow-up ranged up to 55 months. Baseline characteristics were well balanced across treatment 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 LDH at baseline. A total of 77 patients had a history of previously treated brain metastases.
The Yervoy-containing regimens demonstrated a statistically significant advantage over the gp100 group in OS. The hazard ratio (HR) for comparison of OS between the Yervoy monotherapy and gp100 groups was 0.66 (95% CI: 0.51, 0.87; p = 0.0026). This result was consistent with the HR for comparison between the Yervoy + gp100 group and the gp100 group (HR 0.68 [95% CI: 0.55, 0.85]; p = 0.0004).
The observed OS benefit was consistently demonstrated across subgroups of patients (M [metastases]-stage, prior interleukin-2, baseline LDH, age, gender, and the type and number of prior therapies).
Overall survival results are shown in Figure 5. Median and estimated rates of OS at 1 year and 2 years are presented in Table 10.
In the Yervoy 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.
Efficacy was demonstrated across the primary and secondary endpoints. Additional efficacy results are presented in Table 11.
Tumour responses were observed as late as 5.5 months from the start of Yervoy therapy.
For patients who required re-induction therapy, the BORR was 38% (3/8 patients) in the Yervoy monotherapy group, 13% (3/23 patients) in the Yervoy + gp100 group, and 0% in the gp100 group. The disease control rate (DCR, defined as CR+PR+SD) was 75% (6/8 patients), 65% (15/23 patients), and 0%, respectively.
The development or maintenance of clinical activity following Yervoy treatment was similar with or without the use of systemic corticosteroids.

Randomised phase 2 study of three different Yervoy doses (CA184022).

The activity of three doses of Yervoy was investigated in a blinded, randomised Phase 2 study in patients with advanced melanoma. Patients who progressed after or were intolerant to prior therapy were enrolled in the study. A total of 217 patients were randomized to three groups: 0.3 mg/kg (n = 73), 3 mg/kg (n = 72), and 10 mg/kg (n = 72). In this study, some objective responses were observed after initial evidence of tumour burden increase, including new lesions. Clinical response, disease control, and survival were similar regardless of the HLA subtype.

Renal cell carcinoma (RCC).

Previously untreated advanced or metastatic RCC - Yervoy in combination with nivolumab.

Randomised phase 3 study of ipilimumab in combination with nivolumab vs. sunitinib (CA209214).

The safety and efficacy of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg for the treatment of advanced RCC was evaluated in a Phase 3, randomised, open-label study (CA209214). The study included patients (18 years or older) with previously untreated, advanced or metastatic renal cell carcinoma and Karnofsky performance status ≥ 70%. Prior adjuvant or neoadjuvant therapy was allowed if such therapy did not include an agent that targets vascular endothelial growth factor (VEGF) or VEGF receptors and recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy. The primary efficacy population includes those intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the International Metastatic RCC Database Consortium (IMDC) criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status < 80%, haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal). This study included patients regardless of their tumour PD-L1 status. Patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients were stratified by (IMDC) prognostic score and region.
A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either ipilimumab 1 mg/kg (n = 425) administered intravenously over 30 minutes in combination with nivolumab 3 mg/kg administered intravenously over 60 minutes every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) 50 mg daily, administered orally for 4 weeks followed by 2 weeks off, every cycle. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour assessments were conducted 12 weeks after randomisation and continued every 6 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug as determined by the investigator. The primary efficacy outcome measures were OS, ORR and PFS as determined by a Blinded Independent Central Review (BICR) in intermediate/poor risk patients.
Baseline characteristics were generally balanced between the two groups. The median age was 61 years (range: 21-85) with 38% ≥ 65 years of age and 8% ≥ 75 years of age. The majority of patients were male (73%) and white (87%), and 31% and 69% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. The median duration of time from initial diagnosis to randomisation was 0.4 years in both the ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg and sunitinib groups. The median duration of treatment was 7.9 months (range: 1 day-21.4+ months) in ipilimumab with nivolumab-treated patients and was 7.8 months (range: 1 days-20.2+ months) in sunitinib-treated patients. Ipilimumab with nivolumab was continued beyond progression in 29% of patients.
The Kaplan-Meier curves for OS in intermediate/poor risk patients is shown in Figure 6.
The trial demonstrated superior OS and ORR and an improvement in PFS for intermediate/poor risk patients randomised to ipilimumab plus nivolumab as compared with sunitinib (Table 12 and Figure 6). OS benefit was observed regardless of tumour PD-L1 expression level.
Efficacy results for intermediate/poor risk patients are shown in Table 12.
The median time to onset of objective response was 2.8 months (range: 0.9-11.3 months) after the start of ipilimumab with nivolumab treatment. One hundred seventy-seven (41.6%) responders had ongoing responses with a duration ranging from 1.4+-25.5+ months.
Disease related symptoms, cancer symptoms and non-disease specific Quality of Life (QoL) were assessed as an exploratory endpoint using the FKSI-19, FACT-G, and EQ-5D scales. Fewer patients in the nivolumab in combination with ipilimumab arm reported symptom deterioration than in the sunitinib arm, and scores for QoL were greater for nivolumab in combination with ipilimumab patients vs. those in the sunitinib arm at each assessment during the first six months of the study, when completion rates exceeded 80%. As patients were not blinded to treatment, interpretation of these patient-reported outcomes is limited.

Non-small cell lung cancer (NSCLC).

Previously untreated advanced or metastatic NSCLC - Yervoy in combination with nivolumab and chemotherapy.

Randomised phase 3 study vs. platinum-doublet chemotherapy (CA2099LA).

CA2099LA was a randomised, open-label trial in patients with metastatic or recurrent NSCLC. The trial included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification [IASLC]), ECOG performance status 0 or 1, and no prior systemic anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients were enrolled regardless of their tumour PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrollment, and either off corticosteroids, or on a stable or decreasing dose of < 10 mg daily prednisone equivalents.
Patients were randomized 1:1 to receive either nivolumab 360 mg administered intravenously over 30 minutes every 3 weeks in combination with ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. Patients with non-squamous NSCLC in the control arm could receive optional pemetrexed maintenance therapy. Stratification factors for randomisation were tumour PD-L1 expression level (≥ 1% versus < 1% or non-quantifiable), histology (squamous versus non-squamous), and gender (male versus female). Platinum-doublet chemotherapy consisted of either:
carboplatin (AUC 5 or 6) and pemetrexed 500 mg/mg2; or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or
carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC.
Study treatment continued until disease progression, unacceptable toxicity, or for up to 2 years. Treatment continued beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse event attributed to ipilimumab were permitted to continue nivolumab as a single agent. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.
A total of 719 patients were randomized to receive either nivolumab in combination with ipilimumab and platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy (n=358). The median age was 65 years (range: 26 to 86) with 51% of patients ≥ 65 years and 10% of patients ≥ 75 years. The majority of patients were white (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 1 (68%), 57% had tumours with PD-L1 expression ≥ 1% and 37% had tumours with PD-L1 expression < 1%, 31% tumours with squamous histology and 69% with non-squamous histology, 17% had brain metastases, and 86% were former or current smokers.
Efficacy results from the prespecified interim analysis when 351 events were observed (87% of the planned number of events for final analysis) demonstrated a statistically significant benefit in OS, PFS, and ORR, and a clinically meaningful benefit in duration of response (see Table 13). With an additional 4.6 months of follow-up, the hazard ratio for overall survival was 0.66 (95% CI: 0.55, 0.80) and median survival was 15.6 months (95% CI: 13.9, 20.0) and 10.9 months (95% CI: 9.5, 12.5) for patients receiving nivolumab and ipilimumab and platinum-doublet chemotherapy or platinum-doublet chemotherapy, respectively (see Figure 7).

Malignant pleural mesothelioma (MPM).

Previously untreated unresectable malignant pleural mesothelioma - Yervoy in combination with nivolumab.

Randomised phase 3 study vs. chemotherapy (CA209743).

CA209743 was a randomised, open-label trial in patients with unresectable malignant pleural mesothelioma. The trial included patients (18 years of age and older) with histologically confirmed and previously untreated malignant pleural mesothelioma of epithelioid or non-epithelioid histology, ECOG performance status 0 or 1, and no palliative radiotherapy within 14 days of first trial therapy. Patients with primitive peritoneal, pericardial, testis, or tunica vaginalis mesothelioma, interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, and brain metastasis (unless surgically resected or treated with stereotaxic radiotherapy and no evolution within 3 months prior to inclusion in the trial) were excluded from the trial. Patients received nivolumab 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years, or chemotherapy consisting of cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 or carboplatin 5 AUC and pemetrexed 500 mg/m2 for up to 6 cycles (each cycle was 21 days). Stratification factors for randomization were tumor histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and gender (male vs. female). Study treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue nivolumab as a single agent as part of the study. Treatment continued beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Tumour assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, duration of response, and disease control rate (DCR) as assessed by BICR utilizing modified RECIST criteria.
A total of 605 patients were randomised to receive either nivolumab in combination with ipilimumab (n=303) or chemotherapy (n=302). The median age was 69 years (range: 25 to 89) with 72% ≥ 65 and 26% ≥ 75 years, 85% White, and 77% male. Baseline ECOG performance status was 0 (40%) or 1 (60%), and 75% had epithelioid and 25% had non-epithelioid histology.
The trial demonstrated a statistically significant improvement in OS for patients randomized to nivolumab in combination with ipilimumab compared to chemotherapy with a minimum follow-up of 22 months. Efficacy results from the prespecified interim analysis when at least 403 events were observed (85% of the planned number of events for final analysis) are presented in Table 14 and Figure 8.
In a prespecified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology, the hazard ratio (HR) for OS was 0.85 (95% CI: 0.68, 1.06), with median OS of 18.7 months in the Yervoy and nivolumab arm and 16.2 months in the chemotherapy arm. In the subgroup of patients with non-epithelioid histology, the HR for OS was 0.46 (95% CI: 0.31, 0.70), with median OS of 16.9 months in the Yervoy and nivolumab arm and 8.8 months in the chemotherapy arm.

Oesophageal squamous cell carcinoma.

Randomised phase 3 study of ipilimumab in combination with nivolumab vs. chemotherapy as first-line treatment (CA209648). CA209648 was a randomised, active-controlled, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic OSCC. The trial enrolled patients with evaluable tumour cell PD-L1 status, and tumour specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay. Patients were required to have squamous cell carcinoma or adenosquamous cell carcinoma of the oesophagus, not amenable to chemoradiation and/or surgery. Prior adjuvant, neoadjuvant, or definitive, chemotherapy, radiotherapy or chemoradiotherapy was permitted if given as part of curative intent regimen prior to trial enrolment. The trial excluded patients with brain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to apparent invasion of tumour to organs adjacent to the oesophageal tumour.
Patients were randomised to receive one of the following treatments:
ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks;
nivolumab 240 mg on days 1 and 15, 5-FU (fluorouracil) 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle);
fluorouracil 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle).
Patients were treated with nivolumab until disease progression, unacceptable toxicity, or up to 2 years.
Patients who discontinued nivolumab in combination with ipilimumab because of an adverse reaction attributed to ipilimumab were permitted to continue nivolumab as a single agent.
In patients who received nivolumab in combination with chemotherapy and in whom either fluorouracil and/or cisplatin were discontinued, other components of the treatment regimen were allowed to be continued.
Randomisation was stratified by tumour cell PD-L1 status (≥ 1% vs. < 1% or indeterminate), region (East Asia vs. Rest of Asia vs. Rest of World), ECOG performance status (0 vs. 1), and number of organs with metastases (≤ 1 vs. ≥ 2). The primary efficacy endpoints were OS and progression-free survival per blinded independent central review in subjects with tumour cell PD-L1 ≥ 1%.
Secondary efficacy outcome measures tested hierarchically included OS in all randomised patients, PFS assessed by BICR in all randomised patients, and ORR assessed by BICR in tumour cell PD-L1 ≥ 1% and in all randomised patients. The tumour assessments per RECIST v1.1 were conducted every 6 weeks up to and including week 48, then every 12 weeks thereafter.
The trial population characteristics were: median age 64 years (range: 26 to 81), 45.9% were ≥ 65 years of age, 83.8% were male, 70.5% were Asian, 25.1% were White, and 1.5% were Black. Patients had histological confirmation of squamous cell carcinoma (98.6%) or adenosquamous cell carcinoma (1.4%) in the oesophagus. The baseline tumour cell PD-L1 status was positive for 48.5% patients, defined as ≥ 1% of tumour cells expressing PD-L1, negative for 50.7%, or indeterminate for 0.8% of patients. Baseline ECOG performance status was 0 (46.2%) or 1 (53.6%).
CA209648 demonstrated a statistically significant improvement in OS for patients with tumour cell PD-L1 ≥ 1%. The minimum follow-up was 13.1 months. Efficacy results are shown in Table 15 and Figure 9.

Immunogenicity.

Ipilimumab monotherapy.

Less than 2% of patients with advanced melanoma who received Yervoy in Phase 2 and 3 clinical studies developed antibodies against ipilimumab. None had any infusion-related or peri-infusional hypersensitivity or anaphylactic reactions. Neutralising antibodies against ipilimumab were not detected. Overall, no apparent association was observed between antibody development and adverse events, or clearance of ipilimumab (see Section 5.2 Pharmacokinetic Properties).

Ipilimumab in combination with nivolumab.

Of the patients who were treated with nivolumab in combination with ipilimumab and evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26.0% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 24.9% with nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks and 37.8% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks. Of the patients who were treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and platinum-doublet chemotherapy and evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 33.8%. The incidence of neutralising antibodies against nivolumab was 0.5% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 1.5% with nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks, 4.6% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks and 2.6% with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and platinum-doublet chemotherapy. Of the patients who were treated with nivolumab in combination with ipilimumab and evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged for 6.3 to 13.7% and neutralising antibodies against ipilimumab ranged from 0 to 0.4%. There was no evidence of altered toxicity profile associated with anti-product antibody development. Neutralising antibodies were not associated with loss of efficacy.

5.2 Pharmacokinetic Properties

Ipilimumab pharmacokinetics (PK) was assessed using a population PK approach for Yervoy monotherapy and Yervoy in combination with nivolumab.

Ipilimumab monotherapy.

The exposure of ipilimumab increased in a dose proportional manner over the dose range of 0.3 to 10 mg/kg when administered as a 90 minute infusion to advanced melanoma patients every 3 weeks for 4 doses.
Ipilimumab clearance (CL) decreases over time by approximately 5% to a geometric mean value (% coefficient of variation [CV%]) of 12.1 mL/h (42%) in patients with advanced melanoma. This decrease in CL is not considered clinically relevant. The geometric mean (CV%) volume of distribution at steady state (Vss) is 7.2 L (17.3%), and terminal half-life (t1/2) is ~20 days. The systemic accumulation achieved after the 4th dose of ipilimumab 3 mg/kg Q3W was approximately 1.7-fold.
Ipilimumab clearance and volume of distribution were found to increase with increasing body weight, and dosing is therefore administered on a mg/kg basis. Ipilimumab clearance was not affected to a clinically significant extent by age (range 23-88 years), gender, concomitant use of budesonide, performance status, HLA-A2*0201 status, tumour type, mild hepatic impairment, mild to moderate renal impairment, immunogenicity, baseline LDH and previous systemic anticancer therapy. The effect of race was not examined as there was insufficient data in non-Caucasian ethnic groups.
The CL of ipilimumab increased by 5.7% in the presence of anti-ipilimumab antibodies and was not considered clinically relevant.
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, overall survival (OS) was independent of prior systemic anti-cancer therapy.

Ipilimumab in combination with nivolumab.

When ipilimumab 3 mg/kg was administered in combination with nivolumab 1 mg/kg in melanoma, the CL of ipilimumab was increased by 9% and the CL of nivolumab was increased by 29% which were not considered clinically relevant.
When ipilimumab 1 mg/kg was administered in combination with nivolumab 3 mg/kg in RCC, the CL of ipilimumab was decreased by 1.5% and the CL of nivolumab was increased by 1% which were not considered clinically relevant.
When ipilimumab 1 mg/kg every 6 weeks was administered in combination with nivolumab 360 mg every 3 weeks and chemotherapy, the CL of nivolumab decreased approximately 10% compared to nivolumab administered alone and the CL of ipilimumab increased approximately 22% compared to ipilimumab administered alone.
The decrease in ipilimumab CL over time when administered in combination with nivolumab was 22%. These differences in CL relative to monotherapy are not considered clinically relevant when ipilimumab is only administered for four doses.
When administered in combination with nivolumab, the CL of ipilimumab increased by 5.7% in the presence of anti-ipilimumab antibodies and the CL of nivolumab increased by 20% in the presence of presence of anti-nivolumab antibodies. These changes were not considered clinically relevant.

Renal impairment.

The effect of renal impairment on the clearance of ipilimumab was evaluated in patients with mild (GFR < 90 and ≥ 60 mL/min/1.73 m2; n=349), moderate (GFR < 60 and ≥ 30 mL/min/1.73 m2; n=82), or severe (GFR < 30 and ≥ 15 mL/min/1.73 m2; n=4) renal impairment compared to patients with normal renal function (GFR ≥ 90 mL/min/1.73 m2; n=350) in population pharmacokinetic analyses. No clinically important differences in the clearance of ipilimumab were found between patients with mild to moderate renal impairment and patients with normal renal function (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Hepatic impairment.

No clinically important differences in the clearance of ipilimumab were found between patients with mild hepatic impairment (Total Bilirubin 1.0-1.5 x ULN or AST > ULN as defined using the National Cancer Institute criteria for hepatic dysfunction; n=76) and normal hepatic function (N=708). Ipilimumab has not been studied in patients with moderate (Total Bilirubin > 1.5-3 x ULN and any AST) or severe hepatic impairment (Total Bilirubin > 3 x ULN and any AST) (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

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 3 or 7 times 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 birthweight), and infant mortality relative to control animals; these findings were dose-dependent. Additionally, visceral abnormalities were identified in the urogenital system of 2 infants of the 30 mg/kg group. 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 oedema. A no adverse effect level was not identified. Due to the low incidences, the relationship of these malformations to treatment is unclear.
Ipilimumab was detected in the serum of monkey infants at similar levels to their mothers' post-partum, likely through in utero exposure. Very low levels of ipilimumab were detected in milk. Human IgG1 is known to cross the placental barrier; therefore, ipilimumab has the potential to be transmitted from the mother to the developing foetus.

Genotoxicity.

Studies to evaluate the genotoxic potential of ipilimumab have not been performed.

Carcinogenicity.

Studies to evaluate the carcinogenic potential of ipilimumab have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Trometamol hydrochloride (2-amino-2-hydroxymethyl-1,3-propanediol hydrochloride), sodium chloride, mannitol (E421), pentetic acid (diethylenetriaminepentaacetic acid), polysorbate 80, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment), water for injections.
This medicinal product does not contain any preservatives.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C to 8°C).
Do not freeze.
Store in the original package in order to protect from light.
Solution for infusion: the chemical and physical in-use stability of the undiluted or diluted concentrate (between 1 mg/mL and 4 mg/mL) has been demonstrated for 24 hours at 25°C and 2°C to 8°C. However, to reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2°C to 8°C for not more than 24 hours.
This medicinal product does not contain any preservatives.

6.5 Nature and Contents of Container

50 mg of ipilimumab in 10 mL of concentrate solution for infusion is supplied in a vial (Type I glass) with a stopper (coated butyl rubber) and an aluminium light blue "flip off" seal.
200 mg of ipilimumab in 40 mL of concentrate solution for infusion is supplied in a vial (Type I glass) with a stopper (coated butyl rubber) and an aluminium purple "flip off" seal.
Pack of 1 vial containing 10 mL.
Pack of 1 vial containing 40 mL.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

Each vial of Yervoy is for single use in one patient only. Discard any residue.
In Australia, any unused medicinal product or waste material should be discarded in accordance with local requirements.

6.7 Physicochemical Properties

CAS number.

CAS: 477202-00-9.

7 Medicine Schedule (Poisons Standard)

S4. Prescription Only Medicine.

Summary Table of Changes