iobenguane I 131 injection

Iobenguane I 131 is a therapeutic radiopharmaceutical agent used to treat iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma in adult and pediatric patients 12 years or older who require systemic anticancer therapy. Iobenguane is used with iodine-123 for diagnosing these cancers, and with iodine-131 for destroying the tumor cells.

Pheochromocytomas are tumors that grow in the chromaffin cells found in the adrenal glands, and paragangliomas are rare tumors that grow along nerve pathways in the neck and head, near the carotid artery. Both are neuroendocrine tumors that secrete extra quantities of hormones (catecholamines) epinephrine and norepinephrine, chemical messengers (neurotransmitters) that nerve cells use to transmit signals.

Epinephrine and norepinephrine are neurotransmitters in the sympathetic nervous system that drive the fight-or-flight response, increasing the heart rate, blood pressure, blood sugar and metabolism to deal with stress. Excessive secretions of catecholamines by the tumors keep these parameters high increasing the risk for associated cardiovascular and other diseases. A small percentage of the tumors may turn malignant and spread to other organs.

Iobenguane has a structure similar to norepinephrine and undergoes uptake and accumulation in the same tissues such as adrenal medulla, heart, liver, lungs, salivary glands, and spleen, as well as the norepinephrine-secreting tumors. Following intravenous administration, iobenguane I 131 accumulates within the pheochromocytoma and paraganglioma cells, and the radiation resulting from radioactive decay of iodine-131 causes cell death and destruction of the tumors.

• Iobenguane I 131 contributes to a patient’s long-term cumulative radiation exposure and increases the risk for cancer. The risk is higher in pediatric patients than in adults.
• Iobenguane I 131 must be handled with appropriate safety measures to minimize radiation exposure to patients, medical personnel and household contacts during and after treatment.
• Treatment with iobenguane I 131 can cause severe and prolonged bone marrow suppression (myelosuppression). Monitor complete blood count every week for up to 12 weeks or until counts return to normal. Reduce dosage or withhold treatment depending on the severity of myelosuppression.
• Iobenguane I 131 therapy can cause secondary malignancies such as myelodysplastic syndrome, leukemia and other cancers.
• Underactivity of thyroid gland (hypothyroidism) was reported in some patients. Initiate thyroid-blocking medications starting at least one day before and continuing for 10 days after each dose of iobenguane I 131 to reduce the risk of hypothyroidism and thyroid tumor. Evaluate patient’s hypothyroidism status and thyroid stimulating hormone (TSH) levels before starting iobenguane I 131 and annually thereafter.
• Iobenguane I 131 can worsen pre-existing high blood pressure (hypertension), usually within the first 24 hours after infusion. Monitor the patient’s blood pressure for the first 24 hours after administration of each therapeutic dose.
• Iobenguane I 131 can cause acute kidney injury and renal failure, and the risk is higher in patients with already impaired renal function. Assess kidney function frequently in patients with mild or moderate impairment of renal function.
• There was one record of fatal lung inflammation (pneumonitis). Monitor patients for signs and symptoms of pneumonitis and treat appropriately.
• Iobenguane I 131 can cause temporary or permanent infertility in both men and women.
• Iobenguane I 131 can cause fetal harm.
  • Verify pregnancy status in women before initiating iobenguane I 131.
  • Advise women of pregnancy potential and men of reproductive potential with women partners to practice effective contraception for periods as recommended.
• The risk of radiation associated with iobenguane I 131 is greater in children compared to adults because of the larger absorption of radiation doses and longer life expectancy. Consider benefits and risks before administration.

Common side effects of iobenguane I 131 include:

• Blood disorders including:
  • Low count of lymphocyte immune cells (lymphopenia)
  • Low red blood cell count (anemia)
  • Low platelet count (thrombocytopenia)
  • Low count of neutrophil immune cells (neutropenia)
• Increased international normalized ratio (INR)
• Increase in blood alkaline phosphatase
• Increase in liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
• Nausea
• Retching
• Vomiting
• Dry mouth (xerostomia)
• Salivary gland inflammation (sialadenitis)
• Salivary gland pain and enlargement
• Diarrhea
• Abdominal pain
• Constipation
• Mouth and throat pain (oropharyngeal pain)
• Indigestion (dyspepsia)
• Taste disorder (dysgeusia)
• Decreased appetite
• Dehydration
• Decrease in weight
• Fatigue
• Weakness (asthenia)
• Fever (pyrexia)
• Dizziness
• Postural dizziness
• Headache
• Back pain
• Pain in extremity
• High blood pressure (hypertension)
• Low blood pressure (hypotension)
• Rapid heart rate (tachycardia)
• Shortness of breath (dyspnea)
• Cough
• Upper respiratory tract infection
• Sinus inflammation (sinusitis)
• Runny nose (rhinorrhea)
• Nose and throat inflammation (nasopharyngitis)
• Urinary tract infection
• Excessive sweating (hyperhidrosis)
• Hair loss (alopecia)
• Injection site pain

Less common side effects of iobenguane I 131 include:

• Palpitations
• Feeling faint (presyncope)
• Fainting (syncope)
• Drop in blood pressure when getting up from sitting or lying down (orthostatic hypotension)
• Prolonged prothrombin time
• Nasal bleeding (epistaxis)
• Nasal congestion
• Blood clot in lungs (pulmonary embolism)
• Protein excretion in urine (proteinuria)
• Kidney failure
• Insomnia
• Chills
• Chest pain
• Joint pain (arthralgia)
• Neck pain
• Jaw pain
• Muscle spasms
• Rash
• Dry skin (xeroderma)
• Red/purple spots from bleeding into the skin (petechiae)
• Swallowing difficulties (dysphagia)
• Gastroesophageal reflux disease (GERD)
• Abdominal distension
• Oral inflammation (stomatitis)
• Candida infection
• Decreased thyroid-stimulating hormone (TSH) levels
• Underactive thyroid (hypothyroidism)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Solution for injection

• 555 MBq/mL (15 mCi/mL)

Adult and pediatric:

Pheochromocytoma or Paraganglioma

• Indicated in adults and children 12 years or older for iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma in patients who require systemic anticancer therapy
• Administer thyroid blockade and other pre- and concomitant medications as recommended

Dosimetric dose

• The recommended dosimetric dose administered as an intravenous (IV) injection is
  • Patients weighing more than 50 kg: 185-222 MBq (5 or 6 mCi)
  • Patients weighing 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg)

Dosimetry and biodistribution assessment

• Following the dosimetric dose
  • Acquire anterior/posterior whole body gamma camera images within 1 hour of the dosimetric dose and prior to patient voiding (Day 0; Scan 1)
  • Acquire additional images on Day 1 or 2 following patient voiding (Scan 2)
  • Acquire additional images between Days 2-5 following patient voiding (Scan 3)
  • For each individual patient, calculate the radiation dose estimates to normal organs and tissues per unit activity (D [organ]) of administered dose using data extracted from the 3 images scanned
  • Calculate in accordance with the Medical Internal Radiation Dose (MIRD) schema or related methodology
  • Whenever possible, use patient-specific organ masses (e.g., estimated from imaging)

Therapeutic dose

• Recommended therapeutic dose is based on body weight and reduced, if necessary, based on the dosimetry data
• Administer a total of 2 therapeutic doses IV a minimum of 90 days apart
• Weight-based dose per therapeutic cycle
  • Patients weighing more than 62.5 kg: 18,500 MBq (500 mCi)
  • Patients weighing 62.5 kg or less: 296 MBq/kg (8 mCi/kg)
• Determine if dose reduction needed based on critical organ limits
  • Calculate the estimated critical organ absorbed-dose by multiplying the dosimetry-derived radiation absorbed-dose per unit activity (D [organ]) by weight-based therapeutic total activity (Aw)
  • See full prescribing information for details regarding adsorbed dose threshold values for radiation toxicity in critical organs and determine if vital dose adjustments are needed

Thyroid blockade and other pre- and concomitant medication

• Thyroid blockade
  • Administer inorganic iodine starting at least 24 hours before and continuing for 10 days after each iobenguane I 131 dose
• Hydration
  • Instruct patients to increase fluid intake to at least 2 liters a day starting at least 1 day before and continuing for 1 week after each dose to minimize irradiation to the bladder
• Drugs that reduce catecholamine uptake or deplete stores
  • Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry dose or a therapeutic dose of iobenguane I 131
  • Do not administer these drugs until at least 7 days after each dose
• Antiemetics
  • Administer antiemetics 30 minutes before administering each iobenguane I 131 dose

Dosage Modifications

Myelosuppression

• Do not administer the first therapeutic dose for platelet counts below 80,000/mcL or ANC counts below 1,200/mcL
• Do not administer the second therapeutic dose until platelets and neutrophils return to baseline or to the normal range
• Reduce the second therapeutic dose for the following
  • Platelet count below 25,000/mcL, ANC below 500/mcL, or life-threatening anemia for longer than 7 days
  • Febrile neutropenia
  • Platelet count below 50,000/mcL with active bleeding

Myelosuppression, recommended dose reduction for second dose

• Weight more than 62.5 kg
  • If first therapeutic dose was weight based: Reduce the second therapeutic dose to 425 mCi
  • If first therapeutic dose was reduced based on critical organ limits: Reduce second therapeutic dose to 85% of the first dose
• Weight 62.5 kg or less
  • If first therapeutic dose was weight based: Reduce the second therapeutic dose to 7 mCi/kg
  • If first therapeutic dose was reduced based on critical organ limits: Reduce second therapeutic dose to 85% of the first dose

Pneumonitis

• Do not administer the second therapeutic dose if pneumonitis is diagnosed after the first therapeutic dose

Renal impairment

• The radiation dose to patients with renal impairment may be increased owing to the delayed elimination of the drug
• Adjust the therapeutic dose based on radiation exposure estimates from the dosimetry assessment
• Severe renal impairment (creatinine clearance [CrCl] below 30 mL/minute) or end-stage renal disease: Not studied

Overdose

Iobenguane I 131 overdose can increase the adverse effects of radiation exposure. Iobenguane I 131 can affect the thyroid, cause kidney injury, bone marrow depression, lung inflammation, and increase long-term risk for secondary malignancies. Radiation exposure is managed with symptomatic and supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Iobenguane I 131 has no known severe interactions with other drugs.
• Iobenguane I 131 has serious interactions with at least 65 different drugs.
• Moderate interactions of iobenguane I 131 include:
  • siponimod
• Iobenguane I 131 has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no animal or human studies on the use of iobenguane I 131 during pregnancy. All radiopharmaceuticals, including iobenguane I 131, have the potential to harm the fetus, based on their mechanism.
• Women of pregnancy potential must use effective contraception during treatment and for 7 months after the final dose. Males of reproductive potential with women partners must use effective contraception during treatment and for 4 months after the final dose.
• Radiation exposure may cause temporary or permanent infertility in men and women.
• There are no data on the presence of iobenguane I 131 in breastmilk or on its effects on milk production or the breastfed infant. Nursing mothers should not breastfeed during treatment and for 80 days after the final dose, because of the potential for serious adverse reactions in the breastfed infant.

• Drink at least 2 liters of water on the day before and for a week after a dose of iobenguane I 131 to minimize irradiation to the bladder.
• Follow instructions on radiation safety practices to minimize radiation exposure to others in the household.
• Notify your healthcare provider immediately if you experience:
  • Symptoms of any blood disorders such as easy bleeding and bruising, fatigue, dizziness or persistent infections.
  • Increase in blood pressure
  • Signs of pneumonitis such as shortness of breath, cough or other respiratory symptoms
• Do not miss taking your thyroid-blocking medications as prescribed. You will need lifelong monitoring for hypothyroidism.