Ipilimumab is a monoclonal antibody used for the treatment of melanoma, a type of skin cancer. It specifically targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a protein receptor that down-regulates the immune system. By blocking CTLA-4, ipilimumab enhances the immune response against melanoma cells.

Ipilimumab (Yervoy) is a fully-humanized monoclonal antibody that acts by activating T-lymphocytes via inhibiting cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). CTLA-4 is a down-regulator of T-lymphocytes.

Ipilimumab (Yervoy) Uses:

• Colorectal cancer, metastatic (microsatellite instability-high or mismatch repair deficient):
  • Microsatellite treatment (in combination with nivolumab)  instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan in adults and pediatric patients ≥12 years of age
• Unresectable or metastatic melanoma:
  • In adult and pediatric patients ≥12 years of age, treatment of unresectable or metastatic melanoma.
• Melanoma, adjuvant treatment:
  • In patients with pathologic involvement of regional lymph nodes of >1 mm, adjuvant treatment of cutaneous melanoma who have undergone complete resection, including total lymphadenectomy
• Advanced Renal cell carcinoma:
  • Treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma (in combination with nivolumab)
• Off Label Use of Ipilimumab in Adults:
  • Melanoma, metastatic with brain metastases
  • Melanoma, unresectable or metastatic, first-line combination therapy
  • Small cell lung cancer (progressive)

Ipilimumab dose in adults:

Ipilimumab (Yervoy) Dose in the treatment of metastatic (microsatellite instability-high or mismatch repair deficient) Colorectal Cancer:

• When treating a certain type of advanced colorectal cancer, a drug called Ipilimumab is given through an IV (a drip into the vein).
• The dose is 1 mg for every kg of the patient's weight.
• This is given every 3 weeks and is used together with another drug called nivolumab.
• They'll get this combination 4 times.
• After that, only nivolumab is given unless the cancer gets worse or the side effects are too hard to handle.

Ipilimumab (Yervoy) Dose in the treatment of Melanoma, metastatic with brain metastases (off-label):

• For advanced skin cancer (melanoma) that has spread to the brain, there's an off-label treatment using Ipilimumab.
• The patient gets a dose of 3 mg for every kg of their weight through an IV drip.
• This is given every 3 weeks and used together with another drug called nivolumab.
• They'll receive this combo 4 times.
• After that, they get only nivolumab for up to 2 years, or until the cancer gets worse or the side effects become too severe.

Ipilimumab (Yervoy) Dose in the treatment of unresectable or metastatic Melanoma:

• For treating a type of skin cancer called melanoma that can't be removed by surgery or has spread to other parts, the drug Ipilimumab is given.
• The patient receives 3 mg for every kg they weigh, using an IV drip, every 3 weeks.
• They'll get this treatment a maximum of 4 times.
• If there are any bad side effects, the doses can be pushed back, but all doses should be given within 16 weeks from the first dose.

Ipilimumab (Yervoy) Dose in the Adjuvant treatment of Melanoma:

• For melanoma treatment after initial care to prevent the disease from coming back (adjuvant treatment), the patient gets the drug Ipilimumab.
• The dose is 10 mg for each kg they weigh.
• They get this through IV drip every 3 weeks for the first 4 times.
• After that, they get the same dose but every 12 weeks, and this continues for up to 3 years.
• The treatment stops if the cancer grows or if the side effects are too severe.
• If there are bad side effects, the doses are skipped entirely, not just postponed.

Ipilimumab (Yervoy) Dose in the treatment of unresectable or metastatic Melanoma, first-line combination therapy (off-label):

• For a type of advanced skin cancer called melanoma, which can't be removed with surgery or has spread elsewhere, there's a treatment using Ipilimumab combined with another drug, nivolumab.
• Patients get a dose of 3 mg of Ipilimumab for every kg they weigh.
• This is given through IV drip every 3 weeks, for a total of 4 doses.
• Alongside this, they get the drug nivolumab.
• After the 4 combination doses, only nivolumab continues to be given until the cancer worsens or if side effects become too severe.

Ipilimumab (Yervoy) Dose in the treatment of advanced Renal cell cancer, combination therapy:

• For treating advanced kidney cancer (renal cell cancer), Ipilimumab is used with another drug, nivolumab.
• The patient gets a dose of 1 mg of Ipilimumab for every kg they weigh through an IV drip once every 3 weeks.
• This combination is given 4 times.
• After those 4 doses, only nivolumab is given.
• This continues until the cancer grows or if side effects are too tough to handle.

Ipilimumab (Yervoy) Dose in the treatment of progressive small cell lung cancer (off-label):

• For a certain type of lung cancer called small cell lung cancer that is getting worse (progressive), there's a treatment using Ipilimumab along with another drug called nivolumab.
• Patients get a dose of 3 mg of Ipilimumab for every kg they weigh through an IV drip once every 3 weeks.
• This combination is given 4 times.
• After these 4 doses, only nivolumab is given.
• This continues until the cancer worsens or if side effects become too difficult.

Ipilimumab dose in children:

Ipilimumab (Yervoy) Dose in the treatment of metastatic (microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) Colorectal Cancer:

For young people aged 12 and older with a specific type of advanced colorectal cancer that has certain genetic features (MSI-H or dMMR), there's a treatment using Ipilimumab together with nivolumab.

• The patient gets a dose of 1 mg of Ipilimumab for every kg they weigh through an IV drip once every 3 weeks.
• This combination is given up to 4 times.
• It's important to know that this treatment was approved by the FDA in a quicker way, but they'll need more studies to make sure it works well.

Ipilimumab (Yervoy) Dose in the treatment of unresectable or metastatic Melanoma: 

For young people aged 12 and older with advanced skin cancer (melanoma) that can't be removed by surgery or has spread to other parts, they can be treated with the drug Ipilimumab.

• The patient gets 3 mg of the drug for every kg they weigh.
• This is given through an IV drip every 3 weeks, and they'll receive this treatment up to 4 times.
• If there are bad side effects, the treatment can be postponed.
• However, all doses should be given within 16 weeks from the first time they receive the drug.

Ipilimumab (Yervoy) Dosing adjustment for toxicity:

For kids 12 years and older:

If taking Ipilimumab with nivolumab: If one drug is stopped, the other should be too.

Skin Issues (Dermatologic toxicity):

• Mild issues like local rashes: Treat with creams or medicines. If no improvement in a week, give steroids.
• More severe skin problems: Stop giving Ipilimumab.
• Very severe skin issues (like deep ulcers or blisters): Stop the drug permanently and give steroids. Taper down the steroids over a month once the issue gets better.

Brain Inflammation (Encephalitis):

• If there's new and serious brain symptoms, stop the drug, check if it's due to the medicine. If yes, don’t give the drug again and start steroids.

Hormonal Issues (Endocrinopathy):

• If there are symptoms, pause the drug and start steroids and other necessary treatments. Can continue drug if the problem resolves and steroids are at a low dose.
• Stop the drug if issues last more than 6 weeks or can't reduce steroids.

Stomach and Gut Issues (Gastrointestinal toxicity):

• For moderate issues: Pause the drug, give medicines for diarrhea. If it lasts more than a week, give steroids. Can restart drug if the issue resolves and steroids are at a low dose.
• For severe issues: Stop the drug permanently, start with high dose steroids. Reduce the steroids slowly over a month. Other treatments might be needed if steroids don't work.

During the Drug Infusion:

• Mild reaction: Slow down the drip.
• Severe reaction: Stop the infusion.

Nerve Issues (Neuropathy):

• For moderate issues: Pause the drug.
• Severe issues affecting daily life: Stop the drug and consider giving steroids.

Eye Issues (Ophthalmologic toxicity):

• For inflammation in the eyes, give steroid eye drops.
• Stop the drug if the problem doesn't get better in 2 weeks or if more severe treatments are needed.

Pancreas Inflammation (Pancreatitis):

• If the pancreas enzyme levels are very high, stop the drug permanently.

Lung Inflammation (Pneumonitis):

• For moderate to severe lung issues, pause or stop the drug. Also, give steroids.

Other Side Effects:

• For moderate reactions: Pause the drug.
• For severe reactions: Give steroids.
• Stop the drug permanently for long-lasting or very serious side effects or if can't reduce steroids.

Pregnancy Risk Category: C

• Ipilimumab is a drug that can potentially harm a baby if a pregnant woman takes it.
• It's made from a type of human protein called IgG, which can sometimes pass from the mother to the baby while in the womb.
• The amount that passes over might change depending on the stage of pregnancy.
• The highest risk of transfer is later in the pregnancy, while the earliest stages when the baby's organs are forming are the safest.
• Because of these risks, women who could become pregnant should use birth control while on this drug and for 3 months after the last dose.
• There's also a special registry set up to collect information from women who took ipilimumab while pregnant to learn more about the risks.

Use of Ipilimumab while breastfeeding

• We aren't sure if ipilimumab gets into breast milk.
• Because of this uncertainty, the company that makes the drug advises moms to stop breastfeeding while taking it and for 3 months after the last dose.

Ipilimumab (Yervoy) Dose in Kidney Disease:

For those with kidney problems before starting the medicine:

• No need to change the ipilimumab dose.

If kidney issues (like nephritis or dysfunction) happen while on the medicine:

• Mild to moderate increase in serum creatinine (Grade 2 or 3): Pause the drug. Start steroids (like prednisone) at a dose of 0.5 to 1 mg/kg daily. Then, slowly reduce the steroid dose over time. If the kidney issue gets worse or doesn't improve, increase the steroid dose.
• Severe increase in serum creatinine (Grade 4): Stop the drug forever. Give high doses of steroids (like prednisone) at 1 to 2 mg/kg daily. After that, gradually decrease the steroid dose.

Ipilimumab (Yervoy) Dose in Liver disease:

For those with liver problems before starting the medicine:

• Mild issue (measured by certain blood test levels): You can take ipilimumab without changing the dose.
• Moderate or severe issue (based on other blood test results): The manufacturer doesn’t give guidance on dosage because it hasn't been studied in this group.

If liver problems occur while on the medicine:

• Moderate liver issue (Grade 2): Pause the medicine for a while.
• More severe liver issues (Grade 3 or 4): Stop the medicine forever. Start taking steroids (like prednisone) at a dose of 1 to 2 mg/kg daily. Once the liver tests show things are getting better or back to normal, you can slowly reduce the steroid dose over a month.

Common Side Effects of Ipilimumab (Yervoy):

• Central Nervous System:
  • Fatigue
  • Headache
• Dermatologic:
  • Skin Rash
  • Pruritus
  • Dermatitis
• Endocrine & Metabolic:
  • Weight Loss
• Gastrointestinal:
  • Diarrhea
  • Nausea
  • Decreased Appetite
  • Increased Serum Lipase
  • Vomiting
  • Constipation
  • Increased Serum Amylase
  • Colitis
  • Enterocolitis
  • Abdominal Pain
• Hematologic & Oncologic:
  • Decreased Hemoglobin
  • Anemia
• Hepatic:
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Alkaline Phosphatase
  • Increased Serum Bilirubin
  • Hepatitis
• Respiratory:
  • Cough
  • Dyspnea
• Miscellaneous:
  • Fever

Less Common Side Effects of Ipilimumab (Yervoy):

• Central Nervous System:
  • Insomnia
  • Neuropathy
• Dermatologic:
  • Urticaria
  • Vitiligo
• Endocrine & Metabolic:
  • Pituitary Insufficiency
  • Hypophysitis
  • Adrenocortical Insufficiency
  • Hypothyroidism
• Gastrointestinal:
  • Intestinal Perforation
  • Pancreatitis
• Hematologic & Oncologic:
  • Eosinophilia
• Hepatic:
  • Hepatotoxicity
• Immunologic:
  • Antibody Development
• Renal:
  • Increased Serum Creatinine
  • Nephritis

Rare Side effects of Ipilimumab (Yervoy):

• Dermatologic:
  • Bullous dermatitis
  • Dermal ulcer
  • Skin or other tissue necrosis
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis

Contraindications to Ipilimumab (Yervoy):

In the U.S.: The manufacturer doesn't list any conditions or situations where you shouldn't take ipilimumab.

In Canada: You shouldn't take ipilimumab if:

• You're allergic to it or any of its ingredients.
• You have a very serious autoimmune disease (where your body attacks itself) that could become life-threatening.
• You've had an organ transplant and activating your immune system more could be immediately dangerous.

Warnings and precautions

Negative effects that are immune-mediated

• Ipilimumab can cause severe and sometimes deadly side effects due to the body's immune response.
• These side effects can affect any organ, but the most common severe ones include skin issues, hormonal imbalances, stomach inflammation, liver problems, and nerve problems.
• These problems usually happen while on the medication, but can also occur weeks to months after stopping.
• If someone has a severe reaction, the drug should be stopped for good, and strong steroids given.
• Before each dose, doctors should run some tests and look for signs of these problems.
• Other, less common side effects have also been reported.
• When used with another drug called nivolumab, certain problems may still arise even after stopping the treatment.
• If someone shows signs of these side effects, other causes should be ruled out.
• Depending on the side effect's severity, the drug may need to be permanently stopped, paused, or changed, and steroids or hormone treatments given.
• Once side effects improve, steroids can be slowly reduced.
• If the side effects weren't too severe, the doctor might consider starting the medication again after the steroids are stopped.

Dermatologic toxicities:

• Ipilimumab can cause severe or even deadly skin reactions.
• When used alone, skin problems usually start around 11 to 22 days after starting the drug.
• When combined with nivolumab, these problems might start in about 1 to 1.5 months.
• It's essential to watch out for signs of skin issues, like rashes or itching.
• If these issues seem related to the immune system, they should be treated as such.
• For mild skin problems, treatments like creams or steroids might be needed if the problem doesn't get better in a week.
• If the skin problems are more severe, the drug should be paused.
• If the skin issue is very severe or dangerous, like certain types of rashes or ulcers, the drug should be stopped for good, and strong steroids should be given.
• Once the skin problem gets better, the steroids should be reduced slowly over a month.
• Some patients might need steroids for up to about 3.5 months, followed by a gradual reduction.

Encephalitis

• When used with nivolumab, ipilimumab might cause a brain problem called immune-mediated encephalitis.
• This usually happens after about 0.5 to 4 months of treatment.
• If someone shows new and strong brain or nerve symptoms, the drug should be paused.
• Doctors will do tests, including a brain scan (MRI) and a spinal tap (lumbar puncture), to check if it's this type of encephalitis and to rule out other causes.
• If it's confirmed that the problem is due to the drug and no other cause is found, they should be given steroids (like prednisone).
• In some severe cases, another drug, infliximab, might also be needed alongside the steroids.
• If this brain problem happens because of the drug, it should be stopped for good.

Endocrinopathy

• Ipilimumab can cause serious hormone problems in the body, like issues with the pituitary gland, adrenal glands, and thyroid.
• These problems can be severe, even life-threatening, and might need hospital care.
• Less severe hormone issues have also been seen, like problems with the thyroid, adrenal glands, and other glands that make hormones.
• When used alone for skin cancer treatment, these hormone problems usually start around 2.2 to 2.5 months into treatment, and hormone therapy might be needed for a long time.
• When used with nivolumab, these hormone problems might start anywhere from 1.1 to 3.7 months.
• To catch these issues early, doctors should do tests and keep an eye out for signs of problems like fatigue, unusual bowel habits, or mental changes.
• Other causes should be ruled out.
• If there are symptoms, the drug should be paused, and steroids (like prednisone) and hormone replacement should be given.

Gastrointestinal toxicities:

• Ipilimumab can cause severe gut problems known as immune-mediated enterocolitis/colitis, and it can even be fatal in some cases.
• When used alone for skin cancer treatment, these gut issues usually start around 1.1 to 1.7 months into treatment.
• When used with nivolumab, they might start around 1.7 to 2.4 months.
• To catch this early, doctors should look out for signs like belly pain, blood or mucus in stool, or diarrhea (with or without fever), and signs of possible hole in the gut.
• If this problem occurs, they should make sure it's not caused by an infection and consider doing a scope if the symptoms are bad or not going away.
• For moderate cases (less severe), the drug should be paused, and antidiarrheal medicines given.
• If it's severe, the drug should be stopped, strong steroids should be given, and if things get better, the steroids should be reduced slowly over a month.
• Some people might need steroids for up to about 4.7 months.
• In some cases, these gut problems might not improve with steroids alone, and other treatments like anti-tumor necrosis factor drugs or immunosuppressants might be needed.
• If someone gets a gut infection that doesn't improve with steroids, doctors should exclude other causes and consider other treatments.

Graft-versus-host disease:

• People taking ipilimumab before or after getting a type of stem cell transplant from another person can experience a severe and sometimes deadly condition called graft-versus-host disease.
• Doctors should watch these patients very carefully.

Hepatotoxicity

• Ipilimumab can cause severe or even fatal liver problems.
• These liver issues usually start around 2 months after beginning treatment, whether the drug is taken alone or with nivolumab.
• Before each dose, doctors should run tests to check liver health and be on the lookout for signs of liver damage.
• If someone shows signs of liver damage, other causes like infections or cancer should be ruled out and the liver should be monitored more closely.
• For moderate liver problems, the drug should be paused.
• For severe liver issues, the drug should be stopped forever and steroids, like prednisone, should be given.
• Some patients might need steroids for up to about 4.4 months.
• If liver tests don't improve within 2 days of starting steroids, another drug called mycophenolate mofetil might be needed.
• Once liver tests show things are getting better or back to normal, the steroids can be reduced slowly over a month.

Reactions that are related to infusion:

• When combined with nivolumab, ipilimumab can cause reactions during the infusion.
• Some of these reactions can be severe.
• Patients should be watched closely during the infusion.
• If the reaction is very severe or life-threatening, the infusion should be stopped.
• For less severe reactions, the infusion might be slowed down or paused.

Nephrotoxicity

• When ipilimumab and nivolumab are used together, kidney problems can happen.
• This might include immune-mediated nephritis, which means kidney issues caused by the immune system.
• These kidney problems can start around 3 months after treatment begins.
• If there are kidney problems, doctors should watch the creatinine levels in the blood.
• If the creatinine levels get very high (Grade 4), the ipilimumab should be stopped, and strong steroids given.
• For less severe kidney problems (Grade 2 or 3), the drug should be paused, and steroids (like prednisone) should be given.
• If the problem doesn't get better, the steroid dose might need to be increased.
• Most patients who had immune-mediated nephritis got better with high doses of steroids, and many could go back to taking the combination therapy without issues.

Neuropathy

• Ipilimumab can cause nerve problems, some of which can be deadly.
• Rarely, severe tingling, muscle weakness, and a severe condition called Guillain-Barré syndrome have been reported.
• These nerve problems can start anytime from about 1.4 to 27.4 months after starting treatment.
• Patients should be monitored for signs like muscle weakness or changes in sensation.
• If they have moderate nerve problems (doesn't interfere with daily life), the drug should be paused.
• If the nerve problem is severe (makes daily activities hard) or resembles Guillain-Barré syndrome, the drug should be stopped for good, and appropriate treatments, including steroids like prednisone, should be given.

Ocular toxicities:

• Ipilimumab can cause eye problems, which could lead to issues like retinal detachment or even permanent loss of vision.
• Patients should be watched for signs like blurred vision or a decrease in how well they can see.
• If someone develops certain eye issues (like inflammation of the eye), they should be given steroid eye drops.
• If these treatments don't work, the drug should be stopped.
• There's a specific type of eye and systemic inflammation, similar to Vogt-Koyanagi-Harada syndrome, that can happen with ipilimumab.
• If this occurs, patients might need systemic steroids to prevent lasting vision damage.
• For serious eye inflammation, steroids (like prednisone) should be given and then reduced slowly over a month.

Toxicity in the lungs:

• When combined with nivolumab, ipilimumab can cause lung problems, known as immune-mediated pneumonitis.
• This can be serious and even lead to death.
• This lung issue often starts around 1.9 to 2.6 months after starting the drug combo.
• Patients should be checked for lung issues using imaging and by watching for symptoms.
• If someone develops this problem, they might need to stop the treatment, be given steroids, or both.
• Moderate to severe cases need treatment with steroids, like prednisone.
• Most people got better after an average of 19 days of steroid treatment, but it ranged from 4 days to a bit over 3 months.
• Some people needed an additional medicine called infliximab.
• If the lung issues are really severe, ipilimumab should be stopped for good.

Monitoring parameters:

Monitoring for Hepatotoxicity:

• Check liver function and signs of liver problems before each dose.
• Monitor liver function more often if hepatotoxicity develops.
• If liver function tests are very high, monitor frequently until they start to come down.

Monitoring for Endocrinopathy:

• Check serum chemistries and ACTH levels before each dose.
• Watch for signs of hypophysitis, adrenal insufficiency, and thyroid disorders.
• Monitor TSH, free T, and cortisol levels at different times.

Monitoring Kidney Function:

• Keep an eye on serum creatinine levels before and during treatment.

Watching for Digestive Problems:

• Be on the lookout for signs of enterocolitis (abdominal pain, stool changes) and intestinal perforation.

Checking for Skin Issues:

• Look for rash, itching, and other skin problems.

Monitoring Nerve Health:

• Watch for changes like weakness or tingling in the limbs.

Checking for Eye Problems:

• Examine for ocular toxicity and possible vision changes.

Monitoring for Lung Issues and Others:

• Keep an eye out for signs of pneumonitis, encephalitis, and infusion-related reactions.

Remember, regular monitoring is important to catch any potential side effects early and manage them properly.

How to administer Ipilimumab (Yervoy)?

General Instructions:

• Use a non-pyrogenic, low protein-binding in-line filter for the infusion.
• Do not mix with other medications.
• Once the infusion is complete, flush with NS (Normal Saline) or D5W (5% Dextrose in Water).

Specific Infusion Durations:

• Colorectal Cancer (metastatic) or Renal Cell Cancer (advanced): Infuse for 30 minutes.
• Melanoma (either unresectable/metastatic or adjuvant treatment): Infuse for 90 minutes.

Combining with Nivolumab:

• When giving with nivolumab, always give nivolumab first.
  • For Renal Cell Cancer: After nivolumab, administer ipilimumab on the same day.
  • For Colorectal Cancer: Give ipilimumab immediately after nivolumab.
• Use separate bags and filters for each drug.
• If you decide to skip the nivolumab dose, also skip the ipilimumab dose.

Mechanism of action of Ipilimumab (Yervoy):

• Ipilimumab is a specially designed human protein that sticks to and blocks a part of our immune cells called CTLA-4.
• Normally, CTLA-4 acts like a brake, slowing down our immune responses.
• By blocking this "brake" with ipilimumab, our immune cells, particularly T-cells, can be more active and effective.
• When it comes to cancers like melanoma, this means that by using ipilimumab, we can boost the body's own immune system to better recognize and fight cancer cells.
• Moreover, when we use ipilimumab along with another drug called nivolumab, which blocks another immune "brake" called PD-1, the combination gives an even stronger boost to the immune system.
• This powerful combo has shown great results in treating advanced skin cancer (melanoma) and kidney cancer (renal cell carcinoma).

Half-life Elimination of Ipilimumab:

• The time it takes for the amount of ipilimumab in the body to reduce by half (known as its half-life) is approximately 15.4 days.
• This means that after 15.4 days, about half of the ipilimumab originally present in the body will have been eliminated or broken down.

International Brands of Ipilimumab:

• Yervoy

Ipilimumab Brand Names in Pakistan:

Not Available.