Onasemnogene Abeparvov Intrathecal

Onasemnogene abeparvovec intrathecal is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of spinal muscular atrophy (SMA) in adult and pediatric patients 2 years of age and older with confirmed mutation in the survival motor neuron 1 (SNM1) gene.

• Onasemnogene abeparvovec intrathecal is available under the following different brand names: Itvisma, onasemnogene abeparvovec-brve

Common side effects of Onasemnogene abeparvovec intrathecal include:

• upper respiratory tract infection
• upper gastrointestinal symptoms 
• fever
• headache

Serious side effects of Onasemnogene abeparvovec intrathecal include:

• hepatotoxicity 
• thrombocytopenia
• peripheral sensory neuropathy 
• thrombotic microangiopathy 
• risk of tumor formation

Rare side effects of Onasemnogene abeparvovec intrathecal include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

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

Adult and pediatric dosage

Suspension for intrathecal administration

• Each single-dose vial contains 1.2 x 10^14 vector genomes (vg) of onasemnogene abeparvovec in 3 mL of suspension
• Vial contains nominal concentration of 4 x 10^13 vg/mL, and each vial contains an extractable volume of at least 3 mL

Spinal Muscular Atrophy

Adult dosage

• Do not administer if previously treated with IV onasemnogene abeparvovec (Zolgensma)
• 1.2 x 10^14 vg by intrathecal injection
• Corticosteroid regimen pre- and post- intrathecal injection
• If at any time patients do not respond adequately to an equivalent of 1 mg/kg/day prednisolone orally, based on the patient’s clinical course, obtain prompt consultation with a gastroenterologist or hepatologist and consider adjustment to the recommended corticosteroid regimen, including increased dose, longer duration, or prolongation of corticosteroid taper
• If oral corticosteroid therapy is not tolerated or not effective, consider IV corticosteroids, as clinically indicated
• 24 hours pre-injection
  • Prednisolone 1 mg/kg/day orally (or equivalent)
  • 30 days post-injection
• Prednisolone 1 mg/kg/day orally (or equivalent)
  • Followed by 28 days (ie, Days 31-58)
  • Normal clinical exam, total bilirubin, and alanine transaminase (ALT) and aspartate transaminase (AST) levels below 2× of upper limit of normal (ULN): Taper corticosteroid gradually
  • Liver function abnormalities: Continue corticosteroids until AST/ALT is less than 2x ULN and all other assessments return to normal, and then, taper corticosteroid dose over next 28 days or longer if needed

Pediatric dosage

• See onasemnogene abeparvovec IV (Zolgensma) for children younger than 2 years
• Children aged 2 years and older: 1.2 x 10^14 vg by intrathecal injection
• Corticosteroid regimen pre- and post- intrathecal injection
• If at any time patients do not respond adequately to an equivalent of 1 mg/kg/day prednisolone oral, based on the patient’s clinical course, obtain prompt consultation with a gastroenterologist or hepatologist and consider adjustment to the recommended corticosteroid regimen, including increased dose, longer duration, or prolongation of corticosteroid taper
• If oral corticosteroid therapy is not tolerated or not effective, consider IV corticosteroids, as clinically indicated
• 24 hours pre-injection
  • Prednisolone 1 mg/kg/day orally (or equivalent)
• 30 days post-injection
  • Prednisolone 1 mg/kg/day orally (or equivalent)
• Followed by 28 days (ie, Days 31-58)
  • Normal clinical exam, total bilirubin, and ALT and AST levels is less than 2× ULN: Taper corticosteroid gradually
  • Liver function abnormalities: Continue corticosteroids until AST/ALT is less than 2x ULN and all other assessments return to normal, and then, taper corticosteroid dose over the next 28 days or longer if needed

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

Drug interaction overview

• Where feasible, adjust vaccination schedule to accommodate concomitant corticosteroid administration prior to and following onasemnogene abeparvovec infusion
• Certain vaccines (.eg, MMR, varicella) are contraindicated for patients on a substantially immunosuppressive steroid dose (ie, 2 weeks or more of prednisone 2 mg/kg/day or 20 mg/day or equivalent)
• Seasonal RSV prophylaxis is not precluded
• Refer to CDC vaccination guidelines for immunosuppressed patients

Contraindications

• None

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Onasemnogene abeparvovec intrathecal?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Onasemnogene abeparvovec intrathecal?”

Cautions

• Hepatotoxicity
  • Hepatotoxicity, with elevated ALT and/or AST levels, reported
  • Patients with preexisting hepatic impairment or acute hepatic viral infection may be at higher risk of liver injury
  • To mitigate potential aminotransferase elevations, administer systemic corticosteroid before and after intrathecal (IT) injection
  • Immune-mediated hepatotoxicity may require corticosteroid dose adjustment, including longer duration, increased dose, or prolonged taper
  • Before IT injection, assess liver function by clinical examination and laboratory testing
  • Continue to monitor liver function for greater than 3 months after IT administration, and at other times as clinically indicated
  • Monitor AST, ALT, and total bilirubin weekly for 1 month after injection and during the corticosteroid taper period
  • If the patient is clinically stable with unremarkable findings at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month
  • Tapering of systemic corticosteroids should not be considered until AST/ALT levels are below 2x ULN
  • Monitor patients with worsening liver function test results and/or signs or symptoms of acute illness (eg, vomiting, deterioration in health)
  • If hepatic injury is suspected, further testing is recommended (eg, albumin, prothrombin time, partial thromboplastin time (PTT), INR)
  • Promptly consult with a gastroenterologist or hepatologist, as necessary
• Thrombocytopenia
  • Transient decreases in platelet counts were observed within the first week after administration
  • Platelet counts are expected to return to baseline 2 weeks following injection
  • Monitor platelet counts before injection and regularly afterwards (at least weekly for the first month and as clinically indicated until platelet counts return to baseline)
• Peripheral sensory neuropathy
  • Peripheral sensory neuropathy has occurred
  • Signs and symptoms may include numbness, tingling, prickling, or pain in the arms, hands, legs, and/or feet, with onset seen at approximately 3 weeks post-injection
  • Consider complete neurologic evaluation and other testing and/or symptom management based on the patient's clinical presentation
  • Inform patients and caregivers about signs and symptoms of peripheral sensory neuropathy, and ask them to notify their physician promptly if symptoms occur
• Thrombotic microangiopathy
  • Thrombotic microangiopathy (TMA) may occur with administration
  • TMA is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury
  • Concurrent immune system activation (eg, infections, vaccinations) may be a contributing factor
  • Prompt attention to signs and symptoms of TMA is advised, as it can result in life-threatening or fatal outcomes
  • Monitor platelet counts regularly following injections, as well as signs and symptoms (eg, hypertension, bruising easily, seizures, or decreased urine output)
  • In case these signs and symptoms occur in the presence of thrombocytopenia, promptly evaluate for hemolytic anemia and renal dysfunction
  • If clinical signs, symptoms, and/or laboratory findings consistent with TMA occur, consult a hematologist and/or nephrologist immediately to manage as clinically indicated
• Elevated cardiac troponin I
  • Increases in cardiac troponin I levels have occurred following administration without clinical sequelae 
  • Cardiac toxicity was observed in animal studies
  • Consider cardiac evaluation after administration and consult a cardiologist as needed
• AAV vector integration and risk of tumorigenicity
  • There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome
  • Onasemnogene abeparvovec is composed of a recombinant, non-replicating AAV9 vector whose DNA persists largely in episomal form
  • Random integration of recombinant AAV-vector DNA into human DNA has been reported with AAV gene therapies
  • Clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumorigenicity
  • If a tumor develops in a patient, health care providers should contact and report the event to Novartis Gene Therapies, Inc. at 1-833-828-3947

Pregnancy and Lactation

• Studies have not been conducted during pregnancy to inform of a product-associated risk
• There are no available data in animal embryo-fetal development studies
• Unknown if it has the potential to be transferred to the fetus
• Verify the pregnancy status of females of reproductive potential before treatment
• Contraception
  • Females of reproductive potential: Use effective contraception (methods that result in below 1% pregnancy rates) and refrain from egg donation for 6 months following administration
  • Men capable of fathering a child: Use the barrier method of contraception and refrain from sperm donation for 3 months following administration
• Infertility
  • There are no data regarding the effects on human fertility
  • In animal fertility studies, onasemnogene abeparvovec did not impact fertility in male and female mice at a dose of 1.1 × 10^14 vg/kg administered IV

Lactation

There is no information available on the presence of the drug in human milk, its effects on breastfed infants, or milk production