Ipilimumab

Ipilimumab (Yervoy) is an immunotherapy that treats certain types of cancer, including melanoma, non-small cell lung cancer (NSCLC), pleural mesothelioma, esophageal cancer, kidney cancer (RCC), liver cancer, or colorectal cancer. It is given as an infusion into a vein over 30 minutes.

Ipilimumab is a monoclonal antibody that works by blocking a protein called CTLA-4, which normally acts as a brake on your immune system. With that brake released, your immune system is better able to find and attack cancer cells. Because of how it works, ipilimumab belongs to a group of medicines called immune checkpoint inhibitors, and more specifically CTLA-4 inhibitors.

Ipilimumab is used on its own only for melanoma. For every other cancer it treats, it is given together with nivolumab (Opdivo), and for one lung cancer regimen it is given with nivolumab plus chemotherapy.

Ipilimumab works by releasing a natural brake on immune cells so they can attack cancer. T-cells are white blood cells that find and destroy abnormal cells, including cancer cells.

A protein on the surface of T-cells called cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) acts as a negative regulator, dialing down T-cell activity. Ipilimumab binds to CTLA-4 and blocks it from connecting with its partner proteins (CD80 and CD86). This increases the activation and multiplication of T-cells, including the T-effector cells that move into tumors. Blocking CTLA-4 signaling can also reduce the activity of regulatory T-cells, which may further increase the overall immune response against the cancer.

Ipilimumab treats seven cancers, and the exact circumstances differ for each one. Whether you can receive it depends on the cancer type, whether it has spread, whether you have had other treatments, and for some cancers, the results of a tumor test.

Melanoma (skin cancer)

• Melanoma that cannot be removed by surgery (unresectable) or that has spread (metastatic), in adults and children 12 years and older. It can be used alone or with nivolumab.
• Melanoma of the skin (cutaneous melanoma) in adults, after surgery, to help stop it coming back. This is called adjuvant treatment. It applies when the cancer had spread to nearby lymph nodes measuring more than 1 mm, and all of it has been removed by surgery, including a full lymph node clearance (total lymphadenectomy).

Kidney cancer (renal cell carcinoma)

• Advanced kidney cancer in adults classed as intermediate or poor risk, as the first treatment, in combination with nivolumab.

Colon or rectal cancer (colorectal cancer)

• Colorectal cancer that cannot be removed by surgery or has spread, in adults and children 12 years and older, in combination with nivolumab. Your tumor must test positive for microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) using an FDA-authorized test.

Liver cancer (hepatocellular carcinoma)

• Liver cancer that cannot be removed by surgery or has spread, in adults, as the first treatment, in combination with nivolumab.
• Liver cancer that cannot be removed by surgery or has spread, in adults who have already been treated with sorafenib, in combination with nivolumab.

Non-small cell lung cancer (NSCLC)

• Lung cancer that has spread, in adults, as the first treatment, in combination with nivolumab. Your tumor must express PD-L1 at 1% or higher on an FDA-authorized test, and must not have EGFR or ALK gene changes.
• Lung cancer that has spread or come back, in adults, as the first treatment, in combination with nivolumab and 2 cycles of platinum-based combination chemotherapy. Your tumor must not have EGFR or ALK gene changes. There is no PD-L1 requirement for this regimen.

Cancer of the lining of the lungs and chest wall (malignant pleural mesothelioma)

• Mesothelioma that cannot be removed by surgery, in adults, as the first treatment, in combination with nivolumab.

Esophageal cancer

• Squamous cell cancer of the esophagus that is advanced and cannot be removed by surgery, or that has spread, in adults, as the first treatment, in combination with nivolumab. Your tumor must express PD-L1 at 1 or higher.

Ipilimumab is given as an infusion into a vein over 30 minutes by a doctor or nurse. You do not take it at home, and it is not available as a tablet or an injection you give yourself.

When ipilimumab is given with nivolumab, the nivolumab infusion goes first, followed by ipilimumab on the same day. When chemotherapy is also part of your treatment, the order is nivolumab, then ipilimumab, then chemotherapy. Each infusion uses its own bag and filter, and the line is flushed after each dose.

Your treatment team will give you blood tests before you start and before each dose. These check your liver enzymes, kidney function (creatinine), and hormone levels, including thyroid function and adrenocorticotropic hormone (ACTH). Your treatment may be delayed or stopped depending on the results.

The most important warning for ipilimumab is that it can cause your immune system to attack normal organs and tissues in any area of your body and affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death.

You may have more than one of these problems at the same time. They can happen at any point during treatment, or even after your treatment has ended. Some of them happen more often when ipilimumab is used in combination with nivolumab.

Call or see your doctor right away if you develop any new or worse signs or symptoms, including any of the following.

Intestinal problems

• diarrhea (loose stools) or more frequent bowel movements than usual
• stools that are black, tarry, sticky, or have blood or mucus in them
• severe stomach-area (abdominal) pain or tenderness

Liver problems

• yellowing of your skin or the whites of your eyes
• severe nausea or vomiting
• pain on the right side of your stomach area (abdomen)
• dark urine (tea colored)
• bleeding or bruising more easily than normal

Skin problems

• rash
• itching
• skin blistering or peeling
• painful sores in your mouth or nose, throat, or genital area

Hormone gland problems

• a headache that will not go away, or unusual headaches
• eye sensitivity to light
• eye problems
• rapid heartbeat
• increased sweating
• extreme tiredness
• weight gain or weight loss
• feeling more hungry or thirsty than usual
• urinating more often than usual
• hair loss
• feeling cold
• constipation
• your voice gets deeper
• dizziness or fainting
• changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness

Lung problems

• new or worsening cough
• shortness of breath
• chest pain

Kidney problems

• a decrease in the amount of urine you pass
• blood in your urine
• swelling of your ankles
• loss of appetite

Eye problems

• blurry vision, double vision, or other vision problems
• eye pain or redness

Problems in other organs and tissues

Problems can also happen in other organs and tissues. The signs and symptoms listed above are not all of the immune system problems that can happen with ipilimumab. Call or see your doctor right away for any new or worsening signs or symptoms, including:

• chest pain, irregular heartbeat, shortness of breath, or swelling of your ankles
• confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, or tingling or numbness of your arms or legs
• double vision, blurry vision, sensitivity to light, eye pain, or changes in your eyesight
• persistent or severe muscle pain or weakness, or muscle cramps
• low red blood cells, or bruising

Getting medical treatment right away may help keep these problems from becoming more serious. Your doctor will check you for these problems during your treatment with ipilimumab, and may treat you with corticosteroid or hormone replacement medicines. Your doctor may also need to delay or completely stop your treatment if you have severe side effects.

The prescribing information for ipilimumab lists no contraindications, which means there is no group of people for whom the medicine is formally ruled out. Your doctor will still weigh up your medical history carefully before starting treatment, particularly if you have an autoimmune condition or have had a stem cell transplant.

Tell your doctor about all your medical conditions before you receive ipilimumab, especially if you:

• have an immune system problem such as ulcerative colitis, Crohn's disease, or lupus
• have received an organ transplant
• have received or plan to receive a donor stem cell transplant (allogeneic)
• have a condition affecting your nervous system, such as myasthenia gravis or Guillain-Barre syndrome
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Also tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

What are the common side effects of ipilimumab?

The most common side effects of ipilimumab are tiredness, diarrhea, rash, itching, and nausea. The full list differs depending on whether you receive ipilimumab on its own, with nivolumab, or with nivolumab and chemotherapy.

Common side effects when ipilimumab is used on its own

• feeling tired
• diarrhea
• nausea and vomiting
• itching
• rash
• headache
• fever
• decreased appetite
• weight loss
• difficulty falling or staying asleep

Common side effects when ipilimumab is used with nivolumab

• feeling tired
• diarrhea
• rash
• itching
• nausea and vomiting
• pain in your muscles, bones, or joints
• fever
• cough
• shortness of breath
• decreased appetite
• stomach-area pain
• upper respiratory tract infection
• headache and dizziness
• low thyroid hormone levels (hypothyroidism)
• constipation
• weight loss

Common side effects when ipilimumab is used with nivolumab and chemotherapy

• feeling tired
• pain in your muscles, bones, or joints
• nausea
• diarrhea
• rash
• decreased appetite
• constipation
• itching

This is not a complete list of side effects, and others may occur. Call your doctor for medical advice about side effects. You may report side effects to Bristol-Myers Squibb at 1-800-721-5072 or to the FDA at 1-800-FDA-1088.

Serious side effects

The most serious side effects of ipilimumab happen when your immune system attacks your own healthy organs and tissues. These are called immune-mediated adverse reactions, and the symptoms to watch for are covered in the warnings and precautions section below.

Get emergency medical help if you have signs of a severe allergic reaction, such as hives, difficulty breathing, or swelling in your face or throat, or a severe skin reaction with fever, sore throat, burning eyes, skin pain, and a red or purple rash with blistering and peeling.

Infusion-related reactions

Some reactions happen during the infusion itself. Tell your nurse straight away if you feel chilled or shaky, itchy, flushed, dizzy, faint, short of breath or wheezy, feverish, or if you develop a rash or back or neck pain. Mild or moderate reactions are managed by pausing or slowing the infusion. Severe reactions mean ipilimumab is stopped permanently.

Stem cell transplant complications

Serious and sometimes fatal graft-versus-host disease (GVHD) can occur in people who have a donor stem cell transplant (allogeneic hematopoietic stem cell transplant) either before or after ipilimumab treatment. This can happen even if you receive other treatments in between. Tell your doctor if you have had, or plan to have, this type of transplant.

The ipilimumab dose is either 1 mg/kg or 3 mg/kg of body weight, given every 3 weeks, every 6 weeks, or every 12 weeks depending on which cancer is being treated. There is no dose reduction for ipilimumab. If you have a serious side effect, your treatment is paused or stopped rather than given at a lower dose.

Ipilimumab can harm an unborn baby and is not recommended during pregnancy. In animal studies, ipilimumab given during pregnancy led to higher rates of miscarriage, stillbirth, premature delivery with lower birth weight, and infant death. The risk appears to be greatest during the second and third trimesters.

If you are able to become pregnant, your doctor will give you a pregnancy test before you start treatment. You should use effective birth control during treatment and for 3 months after your last dose. Tell your doctor straight away if you become pregnant or think you may be pregnant. You or your doctor can report a pregnancy to Bristol-Myers Squibb on 1-844-593-7869.

Do not breastfeed while receiving ipilimumab or for 3 months after your last dose. There is no information on whether ipilimumab passes into human breast milk, but it was found in the milk of monkeys given the medicine, and there is a risk of serious side effects in a breastfed child.

Ipilimumab has no established drug interactions listed in its prescribing information. Even so, tell your doctor about every medicine you take, and let them know if you start or stop any medicine during your cancer treatment. This includes over-the-counter medicines, vitamins, minerals, and herbal products.

The safety and effectiveness of ipilimumab combined with vemurafenib have not been established. In an early-stage trial, 6 of 10 people who received both medicines developed significant increases in liver enzymes.

Ipilimumab is stored by your treatment team, refrigerated at 2°C to 8°C (36°F to 46°F). It is protected from light by being kept in its original carton until it is used, and it must not be frozen or shaken.

Yervoy is manufactured by Bristol-Myers Squibb Company, Princeton, NJ 08543, USA. U.S. License No. 1713.

Active ingredient: ipilimumab. Each milliliter contains 5 mg of ipilimumab.

Inactive ingredients in the Yervoy brand: diethylene triamine pentaacetic acid (DTPA), mannitol, polysorbate 80 (vegetable origin), sodium chloride, tris hydrochloride, and Water for Injection.

Ipilimumab is a recombinant IgG1 kappa antibody with a molecular weight of about 148 kDa, produced in Chinese hamster ovary cells. The solution is clear to slightly opalescent and colorless to pale yellow, and may contain a small amount of visible white or translucent particles.