Inotersen

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Tegsedi: 284 mg/1.5 mL (1.5 mL)

Pharmacology

Mechanism of Action

Inotersen is an antisense oligonucleotide that causes degradation of mutant and wild type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid

Distribution

V_dss: 293 L

Metabolism

Metabolized by nucleases to nucleotides of various lengths

Excretion

Urine (<1% as unchanged drug)

Time to Peak

2 to 4 hours (median)

Half-Life Elimination

32.3 days (range: 29.4 to 35.5 days)

Protein Binding

>94%

Use: Labeled Indications

Polyneuropathy of hereditary transthyretin mediated amyloidosis: Treatment of the polyneuropathy of hereditary transthyretin mediated amyloidosis in adults

Contraindications

Hypersensitivity to inotersen or any component of the formulation; platelet count <100,000/mm³; history of acute glomerulonephritis caused by inotersen

Canadian labeling: Additional contraindications (not in US labeling): Prior to therapy: urine protein to creatinine ratio ≥113 mg/mmol (1 g/g), eGFR <45 mL/minute/1.73 m², severe liver impairment

Dosage and Administration

Dosing: Adult

Polyneuropathy of hereditary transthyretin mediated amyloidosis: SubQ: 284 mg once weekly

Missed doses: If a dose is missed, take the dose as soon as possible. If the next dose is scheduled within 2 days, skip the missed dose and take the next scheduled dose on the scheduled day.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Thrombocytopenia: Platelet count during therapy:

≥100,000/mm³: Continue 284 mg once weekly; monitor platelet count weekly

≥75,000 to <100,000/mm³: Discontinue treatment; monitor platelet count weekly; do not restart therapy until platelet count is >100,000/mm³ then resume 284 mg once weekly.

≥50,000 to <75,000 mm³: Discontinue treatment; monitor platelet count twice weekly until 3 successive value >75,000/mm³ then monitor weekly; do not restart therapy unless there have been 3 successive values >100,000/mm³ and the benefit of therapy outweighs the risk of thrombocytopenia and potential bleeding. If therapy restarted, resume 284 mg once weekly.

≥25,000 to <50,000/ mm³: Discontinue treatment; monitor platelet count twice weekly until 3 successive values >75,000/mm³ then monitor weekly; consider more frequent monitoring if additional risk factors for bleeding are present (>60 years of age, concomitant use of anticoagulant or antiplatelet agents, prior history of major bleeding); do not restart therapy unless there have been 3 successive values >100,000/mm³ and the benefit of therapy outweighs the risk of thrombocytopenia and potential bleeding. Treatment of thrombocytopenia with corticosteroids is recommended and consider discontinuation of antiplatelet or anticoagulant agents. If therapy restarted, resume 284 mg once weekly.

<25,000/mm³: Permanently discontinue therapy. Monitor platelet count daily until 2 successive values >25,000/mm³, then monitor twice weekly until 3 successive values >75,000/mm³, then monitor weekly until stable for a minimum of 8 weeks after drug discontinuation. Treatment of thrombocytopenia with corticosteroids is recommended and consider discontinuation of antiplatelet or anticoagulant agents.

Administration

SubQ: Administer on the same day every week. Allow prefilled syringe to come to room temperature for ≥30 minutes prior to administration; other warming methods should not be used. May self-administer in the abdomen or upper thigh; administration in the upper arm should only be done by a caregiver. Avoid administration at the waistline or other sites where pressure or rubbing from clothing may occur. Rotate injection sites with each injection. Do not administer into skin with disease or injury; avoid areas with tattoos and scars.

Storage

Store at 2°C to 8°C (36°F to 46°F) in the original container. Protect from direct light. Do not freeze. May be stored at room temperature (up to 30°C [86°F]) in the original container for up to 6 weeks; discard if not used within the 6 weeks.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Inotersen may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Anticoagulants: Inotersen may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (19%), cardiac arrhythmia (13%), presyncope (≤13%), syncope (≤13%)

Central nervous system: Headache (26%), fatigue (25%), chills (18%), paresthesia (10%)

Gastrointestinal: Nausea (31%), vomiting (15%).

Hematologic & oncologic: Thrombocytopenia (24%; severe thrombocytopenia: 3%), anemia (17%)

Immunologic: Antibody development (30%)

Local: Injection site reaction (49%)

Neuromuscular & skeletal: Myalgia (15%), arthralgia (13%)

Renal: Renal insufficiency (14%)

Miscellaneous: Fever (20%)

1% to 10%:

Cardiovascular: Orthostatic hypotension (8%)

Gastrointestinal: Decreased appetite (10%), xerostomia (5%)

Hematologic & oncologic: Bruise (7%), eosinophilia (5%)

Hepatic: Increased liver enzymes (9%)

Infection: Increased serum alanine aminotransferase (≥3 x ULN: 8%; ≥8 x ULN: 3%), bacterial infection (7%)

Renal: Glomerulonephritis (3%)

Respiratory: Dyspnea (9%), flu-like symptoms (8%)

Frequency not defined: Endocrine & metabolic: Vitamin A deficiency

<1%, postmarketing, and/or case reports: Autoimmune hepatitis, cerebrovascular accident, coronary artery dissection, hepatobiliary disease, hypersensitivity reaction, immune thrombocytopenia, lower back pain, paraplegia, speech disturbance, vasculitis (antineutrophil cytoplasmic autoantibody - positive systemic vasculitis), weight loss

Warnings/Precautions

Concerns related to adverse effects:

• Cerebrovascular: Stroke and cervicocephalic arterial dissection may occur usually within 2 days of the first dose. Patients should be instructed to notify their health care provider if symptoms of stroke or arterial dissection occur.
• Glomerulonephritis: [US Boxed Warning]: May cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure. One clinical trial patient who developed glomerulonephritis and did not receive immunosuppressive treatment remained dialysis dependent. Cases of glomerulonephritis were accompanied by nephrotic syndrome (may include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection). Use should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1,000 mg/g or higher. Prior to initiation, measure the serum creatinine, estimated glomerular filtration rate (eGFR), UPCR, and perform a urinalysis. During treatment, monitor serum creatinine, eGFR, urinalysis, and UPCR every 2 weeks. Inotersen should not be given to patients who develop a UPCR of 1,000 mg/g or higher, or eGFR below 45 mL/minute/1.73 m², pending further evaluation of the cause. If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m², UPCR decreases to below 1,000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In patients with UPCR of 2,000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, permanently discontinue therapy. Use caution in patients on concomitant nephrotoxic therapy and other agents that may impair renal function; avoid use in patients whom immunosuppressive therapy is not recommended since immunosuppressive therapy is typically used for treatment of glomerulonephritis.
• Hepatic effects: Abnormal LFTs, including increased ALT ≥3 times ULN, have been reported; liver laboratory abnormalities may resolve with continued use. Immune-mediated biliary disease may also occur. Monitor ALT, AST, and total bilirubin at baseline and every 4 months during therapy. Patients who develop signs or symptoms of hepatic dysfunction should have serum transaminases and total bilirubin measured and treatment should be interrupted or discontinued.
• Hypersensitivity reactions: Hypersensitivity reactions have occurred. Symptoms may include headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreiform movements, arthralgia, myalgia, and flu-like symptoms and typically occur within 2 hours of administration. Anti-inotersen antibodies were present in patients that developed hypersensitivity reactions during clinical trials. If a hypersensitivity reaction occurs, discontinue use; patients who have developed hypersensitivity reactions should not be re-treated.
• Inflammatory and immune effects: Serious inflammatory and immune adverse reactions have been reported, including immune thrombocytopenia, glomerulonephritis, and antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis. Rare but serious neurologic adverse reactions have also occurred, including paraparesis and impaired speech.
• Thrombocytopenia: [US Boxed Warning]: Causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia; may be life-threatening. One clinical trial patient died from intracranial hemorrhage. Prior to initiation of therapy, obtain a platelet count. Use is contraindicated in patients with a platelet count <100,000/mm³. During treatment, monitor platelet counts weekly if values are 75,000/mm³ or greater, and more frequently if values are less than 75,000/mm³. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible; therapy should not be continued unless a platelet count is acceptable based on an interpretable blood sample. After discontinuation of treatment, continue to monitor platelet count for ≥8 weeks to verify that platelet counts remain above 75,000/mm³. Use with caution in patients on antiplatelet or anticoagulation therapy; consider discontinuation of antiplatelet or anticoagulation therapy with platelet count <50,000/mm³. Corticosteroid therapy is recommended in patients with platelet count <50,000/mm³ and in patients with suspected immune-mediated thrombocytopenia; avoid inotersen therapy in patients for whom corticosteroid therapy is not advised. Patients should be instructed to notify their health care provider if symptoms of thrombocytopenia occur.
• Vitamin A levels: A decrease in serum vitamin A has been reported with inotersen treatment. Supplement at the recommended daily allowance (RDA) of vitamin A during treatment. Do not administer doses higher than the RDA; serum vitamin A levels do not reflect the total vitamin A in the body. If ocular symptoms develop, such as night blindness, referral to an ophthalmologist is recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Liver transplant: Liver transplant rejection has been reported in clinically stable patients (>10 years post-transplant), usually 2 to 4 months after starting inotersen. LFTs normalized and clinical improvement occurred following discontinuation of inotersen and administration of corticosteroids. Monitor ALT, AST, and total bilirubin at baseline, monthly during treatment, and for 8 weeks following the discontinuation of treatment in liver transplant patients. Discontinue inotersen in patients who develop signs of liver transplant rejection.

Other warnings/precautions:

• Platelet clumping: Platelet clumping may occur due to a reaction between antiplatelet antibodies and ethylenediaminetetra-acetic acid (EDTA) resulting in uninterpretable platelet counts. If EDTA-mediated platelet clumping is suspected, perform a repeat platelet count using a different anticoagulant (eg, sodium citrate, heparin); recheck platelet count as soon as possible if platelet measurement is uninterpretable; hold inotersen therapy until an acceptable platelet count is confirmed with an interpretable blood sample.
• Risk Evaluation and Mitigation Strategy (REMS): [US Boxed Warning]: Due to risks of glomerulonephritis and serious bleeding caused by severe thrombocytopenia, inotersen is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Tegsedi REMS Program. Prescribers must enroll in the program and complete training to be certified within the program; patients must enroll in the program and comply with monitoring requirements; pharmacies must be certified with the program and dispense only to patients who are authorized to receive inotersen. Information is available at www.TegsediREMS.com or 1-844-483-4736.

Monitoring Parameters

Platelets: Monitor at baseline, as necessary throughout treatment and for 8 weeks (or longer if platelet counts remain <100,000/mm³) following the discontinuation of treatment.

Serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), urinalysis: Monitor at baseline, every 2 weeks during treatment, and for 8 weeks following the discontinuation of treatment.

AST, ALT, total bilirubin: Monitor at baseline, every 4 months during treatment, and for 8 weeks following the discontinuation of treatment. In liver transplant patients, monitor at baseline, monthly during treatment, and for 8 weeks following the discontinuation of treatment.

Pregnancy

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Inotersen decreases serum vitamin A levels; appropriate concentrations of vitamin A are required for fetal development.

Females of reproductive potential and males with female partners of reproductive potential were required to use effective contraception during clinical trials of inotersen (Benson 2018).

Patient Education

What is this drug used for?

• It is used to treat nerve problems in people with amyloidosis.

Frequently reported side effects of this drug

• Lack of appetite
• Injection site irritation
• Nausea
• Vomiting
• Dry mouth

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Severe headache
• Stiff neck
• Abnormal gait
• Muscle pain
• Muscle weakness
• Muscle spasm
• Back pain
• Weight loss
• Swelling of arms or legs
• Severe loss of strength and energy
• Abnormal heartbeat
• Burning or numbness feeling
• Shortness of breath
• Severe dizziness
• Passing out
• Vision changes
• Poor night vision
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.