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Treatment Name: Nivolumab (Opdivo®) + Ipilimumab (Yervoy®)

Nivolumab (Opdivo®) + Ipilimumab (Yervoy®) is an Immunotherapy Regimen for Melanoma

How does Nivolumab + Ipilimumab work?
Each of the medications are designed to stimulate the immune sytem to kill or slow growth of melanoma cancer cells.

  • Ipilimumab binds to T-lymphocytes (a type of white blood cell of the immune system) and activates them to destroy cancer cells
  • Nivolumab prevents melanoma cells from inactivating T-lymphocytes by binding to the receptor first, causing activation rather than inactivation
  • Combining Nivolumab and Ipilimumab leads to greater immune system activation than either drug alone

Goals of therapy:
The combination of Nivolumab and Ipilimumab is given to shrink tumors and decrease symptoms from melanoma. This treatment can be given when melanoma has spread beyond the original location and cannot be removed by surgery, or it can be given after surgery to remove melanoma from affected lymph nodes and prevent it from coming back. For most patients, the goal of therapy is longer survival and cure.


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  • Nivolumab intravenous (I.V.) infusion given over 30 minutes on Day 1
  • Ipilimumab I.V. infusion given over 90 minutes on Day 1, starting thirty minutes after the completion of the Nivolumab infusion (30 minutes after, per the clinical trial)

Maintenance therapy, after four doses of Ipilimumab therapy is complete:

  • Nivolumab I.V. infusion is given over 30 minutes every two weeks until it no longer works or causes intolerable side effects, or
  • Nivolumab I.V. infusion over 30 minutes every four weeks

Estimated total infusion time for this treatment:

  • Up to five hours for Cycle 1, Day 1; as short as four hours for the next cycles, if well tolerated
  • Infusion times are based on clinical studies, but may vary depending on doctor preference or patient tolerability
  • Pre-medications and I.V. fluids, such as hydration, may add more time. If a reaction to Nivolumab occurs during the infusion, acetaminophen (Tylenol®) and diphenhydramine (Benadryl®) may be given 30 – 60 minutes before future Nivolumab doses. On occasion, the infusion will need to be stopped temporarily until symptoms go away before the infusion can be restarted

Nivolumab + Ipilimumab are usually given in an outpatient infusion center, allowing the person to go home afterwards.

During the initial phase of treatment, Nivolumab + Ipilimumab are repeated every three weeks (21 days). This is known as one Cycle. Each cycle may be repeated up to four times, depending upon side effects experienced and how well the treatment is tolerated. The initial duration of therapy may last up to four months for the first 4 doses, then Nivolumab can continue indefinitely (non-stop) as long as side effects are acceptable and melanoma has not worsened or come back.

Click here for nivolumab + ipilimumab starting doses for melanoma.


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Side Effects

In a multi-drug regimen, each medication has unique side effects. When these medicines are given together, drug-related side effects reported in clinical studies give the best estimate of what to expect. In clinical studies, the most commonly reported side effects with Nivolumab + Ipilimumab combination are shown here:

Early recognition of immune-related side effects is extremely important for managing them successfully.

  • Diarrhea; (44 - 45%), (moderate - severe 9 - 11%)
  • Rash; (40 - 41%), (moderate - severe 5%)
  • Fatigue; (35 - 39%), (moderate - severe 5%)
  • Itching; (33 - 35%), (moderate - severe 2%)
  • Nausea; (22 - 26%), (moderate - severe 2%)
  • Fever; (19 - 20%)
  • Decreased appetite; (15 - 18%)
  • Liver enzymes increased; (18 - 22%), (moderate - severe 8 - 11%)
  • Low thyroid hormone levels; (15 - 16%)
  • Vomiting; (15%), (moderate - severe 1 - 3%)
  • Inflammation of the colon [colitis]; (12 - 23%), (moderate - severe 8 - 17%)
  • Joint pain; (11%), (moderate - severe less than 1%)
  • Headache; (10 - 14%), (moderate - severe less 1 - 2%)
  • Chills; (11%)
  • Loss of skin pigment [vitiligo]; (11%)
  • Abdominal pain; (11%)
  • Muscle pain; (10%)
  • Constipation; (10%), (moderate - severe 1%)
  • Shortness of breath; (10%), (moderate - severe less than 1%)

*Roughly 5% of patients receiving Ipilimumab require hospitalization for diarrhea or colitis management.

*Roughly 36 - 45% of patients stopped treatment with Nivolumab + Ipilimumab due to intolerable side effects. This is higher than with Nivolumab alone.

*Only half of all patients receive more than 4 doses of Nivolumab alone during maintenance treatment.

Side effect videos Side Effect Videos
DiarrheaDiarrheaFatigue Fatigue Nausea and VomitingNausea and VomitingPainPainBleedingBleedingConstipationConstipation


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How often is monitoring needed?
Labs (blood tests) are often checked before every treatment, and periodically if side effects are experienced. Labs often include: Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), calcium, magnesium, amylase, lipase, bilirubin, alkaline phosphatase, AdrenoCorticoTropic Hormone (ACTH), serum cortisol, thyroid function using the TSH and/or free-T4 tests, hepatitis screening, pregnancy test (when applicable), plus any others your doctor may order.

How often is imaging needed?
Imaging may be checked before treatment, after 12 weeks of treatment, up to every 6 weeks for the first year, then up to every 12 weeks until treatment discontinuation. Imaging may include: X-ray, computerized tomography (CT scan), positron emission tomography (PET scan), magnetic resonance imaging (MRI), plus any others your doctor may order.

How might blood test results/imaging affect treatment? 
Depending upon the results, your doctor may advise to continue Nivolumab + Ipilimumab, or Nivolumab without Ipilimumab as planned, or delay or switch therapy. 

  • If liver enzymes, such as AST or ALT as noted in the CMP above, increase to more than 5 times the upper limit of normal, or bilirubin increases to more than 3 times the upper limit of normal, Ipilimumab should be permanently discontinued
  • If certain changes in the lungs are found after chest X-ray or CT scan, anti-inflammatory steroids (example: prednisone or methylprednisolone) may be started

Treatment may need to be delayed or discontinued if patients experience severe fatigue, severe headaches, altered thinking, low blood pressure, uncontrolled bowel movements, or abdominal pain.


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ChemoExperts Tips

  • Patients with immune reactions from Ipilimumab that cause inflammation and damage to tissue or organs are often given corticosteroids, such as prednisone or methylprednisolone, and advised to take them daily for weeks or months. If these corticosteroid doses are decreased (tapered) too quickly, symptoms may return
  • If a reaction occurs during an infusion, pre-medications such as acetaminophen (Tylenol®) or diphenhydramine (Benadryl®) may be given prior to future doses to help prevent another reaction
  • Side effects from this drug combination may appear more quickly than if using either drug alone
  • If symptoms from immune reactions do not go away or get significantly better with steroids after 3 to 5 days, an additional I.V. medication known as Infliximab (Remicade®) may be given to help reduce symptoms
  • If you experience fevers, they may be managed by taking anti-inflammatory medications (examples: ibuprofen or naproxen). If fevers still do not go away, Nivolumab + Ipilumumab treatment may be stopped temporarily and restarted at a later time
  • If you have a pre-existing autoimmune disease (such as Lupus, Crohn's disease, or Rheumatoid Arthritis) and exerience a flare-up requiring steroid treatment (example: prednisone, methylprednisolone, or Medrol dosepak), then treatment with Nivolumab + Ipilimumab may held until the flare is gone
  • A pharmacist should ALWAYS review your medication list to ensure that drug interactions are prevented or managed appropriately
  • Clinical trials may exist for melanoma. Ask your doctor if any studies are currently enrolling in your area. If not, go to to search for other centers offering study medications

Patient Assistance & Co-payment Coverage

Patients under the age of 65 years, or those with private insurance plans:
If you have insurance and are looking for patient assistance or copay assistance for Nivolumab (Opdivo®) + Ipilimumab (Yervoy®), we have provided links that may help.

Visit our Patient Assistance page and click the links to various patient assistance programs for help paying for Nivolumab (Opdivo®) + Ipilimumab (Yervoy®). Depending upon your income, they may be able to help cover the cost of:

  • Nivolumab
  • Ipilimumab

For Branded medications (may be available for generic medications too), check with the manufacturer to determine if a co-pay card is offered and if it could reduce your monthly copay.

  • If you are uninsured, check with the manufacturer to determine if you are eligible to receive medication at no cost.

Medicare and Medicaid patients (Patients 65 years or older):
The clinic providing treatment will likely pre-authorize medications and immune therapies such as Nivolumab (Opdivo®) + Ipilimumab (Yervoy®) and are the best source to help you understand drug cost.

  • Ask to speak with a patient assistance technician or financial counselor at the clinic or hospital administering this therapy.

Emotional Wellness

What is Emotional Wellness?
Emotional wellness is having a positive outlook balanced with a realistic understanding of current life events. This requires both an awareness and acceptance of your emotions. It is with this knowledge that you can develop a plan to take the necessary actions to positively impact your life.

Emotional wellness uses an ongoing process to continually reflect on the stressors of life in a constructive manner to move forward and create happiness.

Because emotional wellness is deeply connected with physical, social, and spiritual wellness, pursuing it often becomes particularly difficult in times of major illness. Despite this difficulty, working toward emotional wellness has been connected to improved treatment outcomes and a higher likelihood of achieving goals of therapy.

Learn more about pursuing emotional wellness while receiving treatment with Nivolumab (Opdivo®) + Ipilimumab (Yervoy®)

Individual Drug Label Information

Nivolumab (Opdivo®)

  • Nivolumab is an intravenous (I.V.) infusion commonly infused over one hour
  • Doses may need to be delayed due to lung, gastrointestinal (stomach & intestines), or other treatment related problems
  • Dose adjustments may need to be made due to kidney or liver problems
General Nivolumab (Opdivo) side effects
  • Fatigue is the most commonly reported side effect. This may be due to low red blood cells
  • May cause skin problems such as itching, blotching, or rash
  • Diarrhea or constipation may occur
  • Although uncommon, it can cause nausea
  • May cause muscles to feel weak and joints to feel achy
  • May decrease your appetite. Talk to a dietitian about meal options that may work for you
  • Click on the nivolumab (Opdivo) package insert link below for reported side effects and possible drug interactions

Side Effect Videos
DiarrheaDiarrheaFatigue Fatigue ConstipationConstipationPainPainAnemiaAnemia

See DailyMed package insert.

Ipilimumab (Yervoy®)

  • Ipilimumab is an intravenous infusion 
  • Severe or life-threatening reactions have occurred and may affect the large intestine, liver, skin, nerves, or certain glands such as the thyroid or pituitary gland. If severe immune-mediated side effects are experienced, ipilimumab therapy should be stopped and high-dose steroids should be started 
  • A severe reaction in the intestine (colon), may present as diarrhea, abdominal cramping, mucus or red blood in the stool, and may cause a fever. Seek a doctor immediately if any of these symptoms occur. The doctor will evaluate whether it could be infection, whether it is severe enough to advise hospitalization, or whether it can be managed at home with either loperamide (Imodium®) or corticosteroids 
  • Inflammation in the liver can occur. This is known as hepatitis. Treatment with ipilimumab may have to be permanently discontinued if hepatitis is severe. If mild or moderate, high-dose corticosteroids (such as prednisone 1 to 2 mg/kg or equivalent) are recommended until liver enzymes return to normal, at which time the steroid dose may be slowly decreased over time as tolerated 
  • Nerve pain, known as neuropathy, may occur and can be severe. Signs or symptoms of neuropathy include one-sided weakness or weakness in both arms or feet. Ipilimumab may also affect the sensation in the hands or feet 
  • Fatigue, headache, difficulty thinking, uncontrolled bowel movements, low blood pressure, may suggest ipilimumab-induced inflammation with the adrenal, thyroid, or pituitary gland 
  • If blurry vision or trouble seeing, corticosteroid eye drops are recommended. If eye drops do improve vision back to baseline, ipilimumab treatment should be discontinued 
  • May cause fetal harm, avoid this drug during pregnancy. Effective contraception should be used during treatment and for 3 months after the last dose 
General Ipilimumab (Yervoy) Side Effects 
  • Fatigue 
  • Diarrhea (severe, life-threatening diarrhea is usually considered 7 or more stools per day). Diarrhea can begin as early as 2 days into treatment 
  • Itching 
  • Rash 
  • Nausea or vomiting 
  • Headache 
  • Weight loss 
  • Fever 
  • Decreased appetite 
  • Numbness or tingling in hands or feet 
  • Weakness in arms or legs 
  • Trouble sleeping 
  • Click on the ipilimumab (Yervoy) package insert below for reported side effects and possible drug interactions

Side Effect Videos
Nausea and VomitingNausea and VomitingDiarrheaDiarrheaFatigue Fatigue BleedingBleedingPainPain

See DailyMed package insert.

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1) Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.  

2) Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006-2017.

Created: April 2, 2016 Updated: October 3, 2018

What is Melanoma?

A disease of the melanocytes found in the skin. Melanoma is a rare diagnosed condition. The risk of melanoma may increase with increased exposure to UV light. Melanoma may be hereditary. Melanoma may occur in areas that do not receive much sun light, such as the bottom of a foot. It may also occur in places other than skin, such as the eye. The stage of melanoma can vary at diagnosis and throughout treatment. Stages of melanoma include Stage I, II, III, and IV. The effectiveness of the treatment may depend upon the stage at diagnosis.

NOTE: Treatment Options listed below are not all-inclusive. Other treatments may be available. ChemoExperts provides drug information and does not recommend any one treatment over another. Only your Doctor can choose which therapy is appropriate for you.

What does "Cure" mean?

The word “cure” means there are no cancer cells left in the body and cancer will never come back. Depending on the cancer type and stage, this may be the true goal of therapy. However, it is very difficult to prove all cancer cells are gone. Even though images, like X-rays and MRI’s, and blood tests may not show any signs of cancer, there can be a small amount of cancer cells still left in the body. Because of this, doctors use the word “remission” is used more often. This means there are no signs or symptoms of cancer. Patients in remission are followed closely for any signs of cancer returning. Sometimes, more chemotherapy may be given while in remission to prevent the cancer from coming back.

Doctors usually do not consider a patient “cured” until the chance of cancer returning is extremely low. If cancer does return, it usually happens within 5 years of having a remission. Because of this, doctors do not consider a patient cured unless the cancer has not come back within 5 years of remission. The five-year cutoff does not apply to all cancers.

Common nivolumab + ipilimumab starting doses

  • Nivolumab 1 mg/kg intravenous (I.V.) infusion given over 30 minutes on Day 1
  • Ipilimumab 3 mg/kg I.V. infusion over 90 minutes on Day 1, thirty minutes after the completion of Nivolumab infusion (30 minutes after, per the clinical trial)

Cycle is every 3 weeks and each cycle is repeated four times over the course of roughly 12 weeks.

Maintenance therapy, after four doses of Ipilimumab therapy have been given:

  • Nivolumab (as single-agent, without ipilimumab) 240 mg I.V. infusion given over 30 minutes every two weeks until it no longer works or causes intolerable side effects, or
  • Nivolumab 480 mg I.V. infusion over 30 minutes every four weeks

If the melanoma disappears, or has not shown any growth during maintenance treatment, some experts may discuss stopping maintenance therapy after 1 - 2 years, and recommend close monitoring.


What is "Colitis"?

  • Inflammation of the intestine is referred to as “colitis”
  • Roughly 1 out of every 13 patients will require hospitalization for colitis
  • Blood may be seen in the stool, and stools may be dark, tarry, or sticky
  • Abdominal pain or cramping, with or without constipation, may also be a sign of colitis
  • Colitis may also cause a fever
  • Prednisone, or other corticosteroid, is used to treat severe colitis
  • High-dose corticosteroid treatment may be required for weeks to months
  • If improvement is NOT seen within 3 – 5 days, an additional medicine known as infliximab (Remicade®) may be given to reduce inflammation sooner and reduce the chance of the intestine developing a hole, known as an “intestinal perforation.”

What is a "CBC"?

A Complete Blood Count (CBC) is a frequently ordered blood test that tells clinicians the status of your: 1) White blood cell count, 2) Hemoglobin, and 3) Platelet count at the time the test was taken.

Common uses:
1) White blood cell count (WBC): is used to determine infection risk, or response to chemotherapy. Certain chemotherapy agents may harm our good infection-fighting cells. Sometimes chemotherapy may need to be delayed to allow these cells to recover.

2) Hemoglobin: is used to determine if someone is anemic. Anytime the hemoglobin is below 12 g/dL, the person is said to be anemic. Red blood cell transfusions, and sometimes iron can be given to restore the hemoglobin level, but anemia treatment should always aim at treating the underlying cause or condition.

3) Platelet count: is used to determine if the risk of bleeding is increased or if a platelet transfusion is required to prevent bleeding. Certain medications that increase bleeding risk, such as: aspirin, certain chemotherapy agents, and blood thinners, may need to be stopped temporarily until the platelet count is within a safe range.

What is a "CMP"?

A Comprehensive Metabolic Panel (CMP) is a frequently ordered blood test that tells clinicians the status of your: 1) Electrolytes & Acid/Base status2) Kidney function, 3) Liver function, 4) Blood sugar, and 5) Calcium at the time the test was taken. It is commonly used to monitor liver and kidney function when beginning new medications such as chemotherapy. A total of 14 tests are run simultaneously and are shown below.

Electrolytes & Acid/Base status:
1) Sodium, 2) Potassium, 3) Carbon dioxide, 4) Chloride

Kidney Function:
5) BUN (blood urea nitrogen), 6) Serum creatinine (Scr)

Liver Function:
7) AST, 8) ALT, 9) Total bilirubin, 10) Alk Phos, 11) Albumin, 12) Total protein

Blood sugar:
13) Serum glucose

14) Serum calcium