Dinutuximab (Unituxin) is a chemotherapeutic antineoplastic drug that is used to treat children with high-risk neuroblastoma.

Indications of Dinutuximab (Unituxin):

• Neuroblastoma:
  • It is useful for the treatment of high-risk neuroblastoma (in combination with granulocyte-macrophage colony-stimulating factor [GM-CSF; sargramostim], interleukin-2 [IL-2; aldesleukin] and 13-cis-retinoic acid [RA; isotretinoin]) in pediatric patients who achieve at least a partial response to prior first-line multiagent, multimodality therapy.

Dinutuximab dose in Adults:

Not indicated

Dinutuximab dose in children:

Note:

Before giving dinutuximab (a medicine for a kind of cancer in kids), some important steps are needed:

• The patient gets fluids directly into their veins.
• They also receive medicines to prevent pain, allergies, and fever.
• Doctors check to make sure the patient's blood, breathing, liver, and kidneys are working okay before each treatment round.

Dinutuximab (Unituxin) Dose in the treatment of high-risk Neuroblastoma:

For Kids (Including Babies as young as 11 months):

• Dinutuximab: Given directly into the veins:
  • Dose: 17.5 mg for each square meter of body surface area, once a day for 4 days in a row.
  • Given in a total of 5 cycles:
    • On days 4-7 for the 1st, 3rd, and 5th cycle (these cycles last 24 days).
    • On days 8-11 for the 2nd and 4th cycle (these cycles last 32 days).

Before Giving Dinutuximab:

Hydration: Fluid is given directly into the veins (10 mL for each kg of body weight) over an hour.

Antihistamine: Diphenhydramine (like Benadryl) is given:

• Dose: 0.5 to 1 mg for each kg of body weight (but not more than 50 mg).
• Given over 10-15 minutes, starting 20 minutes before the dinutuximab, and then every 4-6 hours as needed during the medicine infusion.

Antiemetics: Other medicines are given to prevent feeling sick or throwing up because dinutuximab can make some kids nauseous.

Fever & Pain Reducers:

• Acetaminophen (like Tylenol): 10 to 15 mg for each kg of body weight, given 20 minutes before and then every 4-6 hours as needed. The maximum is 650 mg each time.
• Ibuprofen: 5 to 10 mg for each kg of body weight, given every 6 hours if needed. The maximum is 400 mg each time.

Painkillers:

• Morphine is given directly into the veins to manage pain.
• Dose: 50 micrograms for each kg of body weight right before dinutuximab, and then kept going during and 2 hours after the medicine. More can be given if needed.
• If morphine isn't suitable, other pain medicines like fentanyl, hydromorphone, gabapentin, or lidocaine might be used.

Dinutuximab (Unituxin) Dosing adjustment for toxicity:

Dosing of dinutuximab in children and adolescents based on different side effects or toxicities:

• Anaphylaxis (serious allergic reaction):
  • If it's very severe (grade 3 or 4): Stop the medicine forever.
• Capillary leak syndrome (fluid leaks from blood vessels):
  • If it's moderate to severe but not life-threatening: Pause the infusion. Once better, continue at half the previous speed.
  • If it's life-threatening: Stop for this treatment cycle. For the next cycles, give at half speed. If it happens again, stop the medicine forever.
• Hemolytic uremic syndrome (blood and kidney disorder): Stop the medicine forever.
• Severe low salt in blood (despite good fluid management): Stop the medicine forever.
• Low blood pressure: Pause the infusion until the blood pressure gets better. Then, continue at half the previous speed. If stable for 2+ hours, you can slowly increase the speed up to a certain limit.
• Severe infection or sepsis: Stop the medicine until the infection is gone. You can start again in the next treatment cycles.
• Infusion-related reactions (reactions during the medicine infusion):
  • Mild to moderate: Reduce speed by half. If it gets better, you can slowly increase the speed.
  • Severe but not life-threatening: Pause the infusion. If it gets better quickly, continue at half speed. If it happens again, stop for the day and give at a very slow rate in an ICU the next time.
  • Life-threatening: Stop the medicine forever.
• Neuropathy (nerve problems):
  • Very severe sensory issues or moderate sensory issues that last: Stop the medicine forever.
  • Motor nerve issues: Stop the medicine forever.
• Eye and vision problems: Pause the infusion. If it gets better, continue at half speed. If it happens again or affects vision, stop the medicine forever.
• Severe pain: Reduce the speed of the infusion. If the pain doesn't improve even with other treatments, stop the medicine forever.
• Reversible posterior leukoencephalopathy syndrome (brain issue): Stop the medicine forever.
• Serum sickness: If it's very severe (grade 3 or 4): Stop the medicine forever.
• Transverse myelitis (spinal cord inflammation): Stop the medicine forever.
• Urinary retention (can't pee even after stopping pain meds): Stop the medicine forever.

Dinutuximab  dose in pregnancy: X

• Dinutuximab hasn't been studied to see how it affects pregnancies.
• Since this type of medicine (monoclonal antibodies) can pass to the baby during pregnancy, especially in the last 3 months, it might harm the baby due to how it works.
• If you can get pregnant, use reliable birth control while taking this medicine and for 2 months after your last dose.

Use of Dinutuximab while breastfeeding

• We don't know if dinutuximab gets into breast milk.
• However, similar types of molecules do appear in breast milk.
• Because of the risk of serious side effects in a baby who is breastfed, the company that makes the medicine recommends not breastfeeding while using it.

Dinutuximab (Unituxin) Dose adjustment in renal disease:

• Infants, Children, and Adolescents:
  • There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dinutuximab (Unituxin) Dose adjustment in liver disease:

• Infants, Children, and Adolescents:
  • There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Common Side Effects of Dinutuximab (Unituxin):

• Cardiovascular:
  • Hypotension
  • Capillary Leak Syndrome
  • Tachycardia
  • Edema
  • Hypertension
• Central Nervous System:
  • Pain
  • Peripheral Neuropathy
• Dermatologic:
  • Urticaria
• Endocrine & Metabolic:
  • Hyponatremia
  • Hypokalemia
  • Hypoalbuminemia
  • Hypocalcemia
  • Hypophosphatemia
  • Hyperglycemia
  • Hypertriglyceridemia
  • Hypomagnesemia
• Gastrointestinal:
  • Increased Serum ALT
  • Vomiting
  • Diarrhea
  • Increased Serum AST
  • Decreased Appetite
• Genitourinary:
  • Proteinuria
• Hematologic & Oncologic:
  • Thrombocytopenia
  • Lymphocytopenia
  • Anemia
  • Neutropenia
  • Hemorrhage
• Hypersensitivity:
  • Severe Infusion-Related Reaction
• Infection:
  • Sepsis
  • Infection
  • Bacteremia
• Renal:
  • Increased Serum Creatinine
• Respiratory:
  • Hypoxia
• Miscellaneous:
  • Fever
  • Infusion-Related Reaction

Rare Side Effects Of Dinutuximab:

• Central Nervous System:
  • Peripheral Sensory Neuropathy
  • Peripheral Motor Neuropathy
• Dermatologic:
  • Anaphylaxis
• Endocrine & Metabolic:
  • Weight Gain
• Gastrointestinal:
  • Nausea
• Hematologic & Oncologic:
  • Febrile Neutropenia
  • Hemolytic-Uremic Syndrome
• Ophthalmic:
  • Blurred Vision

Dinutuximab (Unituxin) Side effect (Frequency not known):

• Ophthalmic:
  • Blepharoptosis
  • Optic Nerve Damage
  • Papilledema
  • Photophobia

Contraindications to Dinutuximab (Unituxin):

• Dinutuximab can cause strong side effects on the bone marrow, which makes blood cells.
• Patients taking this medicine have experienced severe decreases in red blood cells (anemia), white blood cells (neutropenia), platelets (thrombocytopenia), and even had fevers due to very low white blood cells (neutropenic fever).

Warnings and precautions

Suppression of bone marrow

• Capillary leak syndrome is a serious side effect that happens to roughly 1 in 4 patients taking dinutuximab.
• This condition causes fluids to leak out of tiny blood vessels called capillaries.
• If it happens, the dinutuximab drip needs to be paused right away.
• Depending on how bad it is, the speed of the drip might need to be lowered or stopped altogether.
• If someone shows symptoms or if the condition becomes severe, they should receive the right treatment immediately.

Capillary leak syndrome

• Dinutuximab can cause problems with the levels of minerals in the blood.
• Around 1 in 4 patients taking it had issues like low sodium (hyponatremia), low potassium (hypokalemia), and low calcium (hypocalcemia).
• Some of these cases were pretty severe.
• In another study on a similar drug, there was an issue where the body made too much of a hormone, leading to very low sodium levels.
• It's essential to keep a close eye on these mineral levels when someone is on this treatment.

An abnormality in the electrolyte:

• Dinutuximab can cause problems with the levels of minerals in the blood.
• Around 1 in 4 patients taking it had issues like low sodium (hyponatremia), low potassium (hypokalemia), and low calcium (hypocalcemia).
• Some of these cases were pretty severe.
• In another study on a similar drug, there was an issue where the body made too much of a hormone, leading to very low sodium levels.
• It's essential to keep a close eye on these mineral levels when someone is on this treatment.

Gastrointestinal toxicities:

• Dinutuximab can make some people feel nauseous or even cause them to vomit.
• It's a good idea to give medicines (antiemetics) that help prevent this feeling when someone is on dinutuximab.

Hemolytic uremic Syndrome:

• Dinutuximab can sometimes cause a condition called hemolytic uremic syndrome.
• This can lead to kidney problems, imbalances in blood minerals, low red blood cells, and high blood pressure in a few patients.
• One person even had this problem come back when they were given the drug again.
• If this condition happens, stop dinutuximab for good and provide care to help manage the symptoms.

Hypotension

• Dinutuximab can cause a significant drop in blood pressure in some people.
• Before giving the drug, patients need fluids given directly into their veins.
• It's important to watch their blood pressure closely while they get the medicine.
• If their blood pressure drops too much or goes below the usual range for their age, you might need to pause or even stop the treatment.
• Give the right medical care if this happens.

Infection

• Dinutuximab can increase the risk of serious bacterial infections in the blood.
• Some patients even developed sepsis, which is a severe response to infection.
• It's crucial to watch patients closely for any signs of a spreading infection.
• If they show signs, the treatment might need to be paused until the infection is under control.
• These infections often need strong IV antibiotics or other urgent treatments.

Infusion reaction: [US Boxed Warning]

• There's a very serious warning about dinutuximab: About one in four patients can have severe and even life-threatening reactions when getting this medicine through their veins.
• To help prevent this, patients are given fluids before and medicines like antihistamines before the dinutuximab.
• While they get the medicine and for at least 4 hours after, they need to be watched closely for any signs of a reaction.
• If a severe reaction happens, the medicine should be immediately stopped, and if there's a life-threatening allergic reaction (anaphylaxis), dinutuximab should be stopped forever.
• These reactions usually happen during or within a day of getting the medicine.
• The reactions can include things like swelling of the face and airways, difficulty breathing, tightness in the chest, hives, and low blood pressure.
• If a reaction occurs, patients might need blood pressure support, medicines for the airways, steroids, stopping or slowing down the medicine infusion, or even stopping the treatment forever.
• The medicine should be given in a place where there's equipment and medicines to handle heart and lung issues.

Neurotoxicity: [US Boxed Warn]

• Dinutuximab can cause serious problems with the nerves in the body, called neurotoxicity.
• Most patients feel severe nerve pain.
• To help manage this, they're given strong pain medicines through their veins before, during, and for 2 hours after the dinutuximab.
• In studies, about 2% to 9% of patients had grade 3 sensory neuropathy, which is when they lose sensation in parts of their body.
• In other cases, severe motor neuropathy occurred, which affects the ability to move muscles.
• Not all motor neuropathy gets better, and even if it does, it might not happen in every case.
• If the pain is very severe and doesn't respond well to treatment, if the sensory neuropathy is severe, or if there's moderate to severe motor neuropathy, dinutuximab should be stopped.
• For grade 2 or higher motor neuropathy, severe sensory neuropathy, or grade 4 sensory neuropathy, dinutuximab should be stopped forever.
• In patients who had sensory neuropathy, it usually lasted around 9 days, but it can range from 3 to 163 days.

Ocular toxicities:

• Dinutuximab can cause eye problems.
• Some patients in studies experienced symptoms like blurry vision, sensitivity to light, dilated pupils, pupils that don't react or are different sizes, issues with the optic nerve, droopy eyelids, and swelling of the optic disc (papilledema).
• For those whose eye issues went away, the problems typically lasted about 4 days, but it could range from no time to 221 days.
• Depending on how severe these eye issues are, the dinutuximab treatment might need to be paused, given at a lower dose, or stopped altogether.

Pain:

• Pain is a common side effect of dinutuximab.
• More than half of the patients treated with it experienced severe pain, even if they were given pain medicines or opioids.
• This pain often happens while getting the medicine and can feel like it's in the stomach, all over the body, in the arms or legs, back, nerves, chest muscles, or joints.
• Patients need to be given pain relievers, including strong ones like opioids, before, during, and for 2 hours after getting dinutuximab.
• If the pain is very severe, the speed of giving the medicine might need to be slowed down or the treatment might have to be stopped.

Reversible posterior Leukoencephalopathy Syndrome:

• Dinutuximab can sometimes cause a condition called reversible posterior leukoencephalopathy syndrome (RPLS).
• Symptoms of RPLS are strong headaches, high blood pressure, changes in vision, seizures, or feeling very tired and unresponsive.
• If someone shows these signs or symptoms, they should get the right treatment and stop taking dinutuximab.

Transverse myelitis

• Dinutuximab can sometimes cause a condition called transverse myelitis.
• This can lead to symptoms like weakness, a tingling feeling, loss of sensation, or loss of bladder/bowel control.
• If someone shows these signs, they need to be checked out quickly.
• If they have transverse myelitis, they should stop taking dinutuximab forever.

Urinary retention

• Dinutuximab can sometimes cause problems with urination, making it hard for patients to pee.
• This can continue for weeks or even months after they stop taking strong painkillers like opioids.
• If someone still can't pee properly after they stop taking the painkillers, they should stop taking dinutuximab forever.

Dinutuximab: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

Blood Tests:

• CBC (Complete Blood Count) with details about different blood cells.
• Serum electrolytes to check minerals in the blood.
• Renal function to see how the kidneys are working.

Physical Checks:

• Blood pressure.

Watch Out For:

• Infusion Reactions:
  • Check during the infusion and for at least 4 hours after.
• Pain.
• Nerve Issues (Peripheral Neuropathy).
• Capillary Leak Syndrome: Where fluids leak from tiny blood vessels.
• Infections or Sepsis: Serious body response to infection.
• Hemolytic Uremic Syndrome: Blood and kidney problem.
• Eye Problems (Ocular Toxicity).
• Urinary Retention: Trouble urinating.
• Transverse Myelitis: Spinal cord inflammation.
• Reversible Posterior Leukoencephalopathy Syndrome: A brain issue with symptoms like headache and high blood pressure.

Patients receiving dinutuximab should be closely monitored for these signs and symptoms. If any are noticed, medical attention should be sought immediately.

How to administer Dinutuximab (Unituxin)?

Nausea and Vomiting:

• Dinutuximab can make people feel nauseous.
• Medicines (antiemetics) are given to prevent this feeling.

Preparation for Infusion:

• Dilute dinutuximab before giving it.
• Do not give it quickly as an IV push or bolus.

Before the Infusion:

• Give a fluid (NS) at 10 mL/kg IV over 1 hour.
• Give pain relievers, allergy medicine (antihistamine), and fever reducer (antipyretic) before the dinutuximab.

During the Infusion:

• Start at a slow rate: 0.875 mg for each square meter of body surface area per hour for the first 30 minutes.
• If the patient is doing well, slowly increase the speed. The max speed is 1.75 mg/m^2/hour. It should take 10-20 hours to give the whole dose each day.
• Watch closely for any signs of a reaction while giving the medicine and for at least 4 hours afterward.
• Give in a place ready to handle any infusion reactions.
• If there's a bad reaction, pause the infusion (see guidelines for adjusting dose based on side effects).

Mechanism of action of Dinutuximab (Unituxin):

Dinutuximab attaches to a molecule called GD2 found on the surface of certain cancer cells like neuroblastoma and melanoma, as well as on normal tissues like nerves and skin cells. When dinutuximab binds to GD2 on cancer cells, it triggers a process where immune cells attack and destroy these cancer cells. This happens through two ways:

• Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): Immune cells are guided by dinutuximab to target and kill the cancer cells.
• Complement-Dependent Cytotoxicity (CDC): Dinutuximab activates a part of the immune system that helps destroy the cancer cells.

So, dinutuximab works by attaching to GD2 on cells and helping the immune system to eliminate those cells, both cancerous and normal ones.

Distribution:

• The medicine spreads through about 5.4 liters in the body.

Half-life:

• It takes about 10 days for half of the medicine to be removed from the body.

Removal (Excretion):

• The body clears about 0.21 liters of the drug each day.
• As the child's body size increases, it can remove the drug faster.

International Brand Names of Dinutuximab:

• Unituxin

Dinutuximab Brand Names in Pakistan:

Not available.