Inotersen (Monograph)

Brand name: Tegsedi
Drug class: Antisense Oligonucleotides
Chemical name: DNA, d(P-thio)([2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2- methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2- methoxyethyl)]rG-G-T-T-A-m5C-A-T-G-A-A-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2- methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2- methoxyethyl)]m5rC)
Molecular formula: C₂₃₀H₂₉₉N₆₉Na₁₉O₁₂₁P₁₉S₁₉
CAS number: 1432726-13-0

Medically reviewed by Drugs.com on Jul 27, 2022. Written by ASHP.

Introduction

Antisense oligonucleotide that targets transthyretin messenger RNA (mRNA); a transthyretin (TTR) silencer.

Uses for Inotersen

Hereditary Transthyretin-mediated Amyloidosis

Treatment of polyneuropathy in patients with hereditary transthyretin-mediated amyloidosis (designated an orphan drug by FDA for use in this condition).

Transthyretin-mediated amyloidosis (ATTR) can be inherited as an autosomal dominant trait caused by pathogenic variants/mutations in the TTR gene (ATTRv) or by deposition of wild-type TTR protein (ATTRwt). Selection of an appropriate disease-modifying therapy in patients with ATTR is based on the presence of cardiomyopathy and polyneuropathy and the distinction between ATTRv and ATTRwt amyloidosis.

The American Heart Association (AHA) states that TTR silencing therapy with patisiran or inotersen may be considered in patients with ATTRv and polyneuropathy; these drugs are currently not indicated for ATTRv-cardiomyopathy without polyneuropathy or in patients with ATTRwt-cardiomyopathy. In patients with ATTRv-cardiomyopathy with polyneuropathy, the choice between inotersen and patisiran is based on availability and adverse effect profiles.

Inotersen Dosage and Administration

General

Pretreatment Screening

• Monitor platelet counts prior to initiating inotersen therapy. Do not initiate the drug in patients with a platelet count <100,000/mm³.

• Monitor S_cr, eGFR, and urinary protein-to-creatinine ratio prior to initiating inotersen therapy. Do not initiate the drug in patients with a urinary protein-to-creatinine ratio ≥1000 mg/g.

• Perform urinalysis prior to initiating therapy.

• Monitor ALT, AST, and total bilirubin concentrations prior to initiating therapy.

Patient Monitoring

• Monitor platelet counts at recommended intervals during therapy (weekly if platelet count ≥75,000/mm³ or more frequently if platelet count <75,000/mm³), and for at least 8 weeks following discontinuance of therapy.

• Monitor serum creatinine concentration, eGFR, and urinary protein-to-creatinine ratio every 2 weeks during therapy, and for 8 weeks following discontinuance of therapy.

• Perform urinalysis every 2 weeks during therapy, and for 8 weeks following discontinuance of therapy.

• Monitor ALT, AST, and total bilirubin concentrations every 4 months during therapy, and for 8 weeks following discontinuance of therapy. In patients with a history of liver transplant, monitor ALT, AST, and bilirubin concentrations monthly during inotersen treatment.

REMS

• Because of the risk of serious bleeding from thrombocytopenia and the risk of glomerulonephritis, inotersen is available only through a restricted distribution program called the Tegsedi REMS program. Information about the Tegsedi REMS program is available at 844-483-4736 or at [Web].

Administration

Administer by sub-Q injection only.

Sub-Q Administration

Administer once weekly (preferably on the same day each week).

Patients and/or caregivers may self-administer drug after receiving appropriate training; self-administer first injection under the guidance of an appropriately qualified healthcare professional.

Available as single-use prefilled syringes. Prior to administration, allow prefilled syringe to reach room temperature for ≥30 minutes; do not use other warming methods (e.g., microwave, hot water, placement near other heat sources). Do not remove needle cap from syringe until immediately prior to injection.

Administer sub-Q injections into abdomen (except within 2 inches of the navel), upper thigh, or outer area of upper arm (by a caregiver). Rotate injection sites. Do not inject into the waistline or other areas where pressure or rubbing from clothing may occur; also avoid injection into areas where the skin is tender, bruised, red, damaged, tattooed, or scarred.

If a dose is missed, administer as soon as possible unless next scheduled dose is within 2 days; in this case, skip missed dose and resume regular dosing schedule.

Dosage

Dosage of inotersen sodium expressed in terms of inotersen.

Adults

Hereditary Transthyretin-mediated Amyloidosis

Polyneuropathy

Sub-Q

284 mg once weekly.

Dosage Modification for Toxicity

Thrombocytopenia

Sub-Q

Withhold therapy if platelet count decreases to <100,000/mm³. See Table 1 for recommendations for subsequent platelet monitoring and for when therapy may be resumed. In patients with platelet counts <50,000/mm³, it is strongly recommended that corticosteroid therapy be administered (unless contraindicated). Also consider discontinuing any concomitant antiplatelet or anticoagulant agents.

If inotersen therapy is discontinued for any reason, continue platelet count monitoring for 8 weeks (or longer if platelet count <100,000/mm³) to verify that platelet count >75,000/mm³.

Renal Toxicity

Sub-Q

If urinary protein-to-creatinine ratio ≥1000 mg/g or eGFR <45 mL/minute per 1.73 m², withhold therapy until the cause can be further evaluated. May resume weekly dosing once eGFR recovers to ≥45 mL/minute per 1.73 m², urinary protein-to-creatinine ratio decreases to <1000 mg/g, or underlying cause of renal abnormality is identified and corrected.

If urinary protein-to-creatinine ratio ≥2000 mg/g, further evaluate for acute glomerulonephritis, as clinically indicated. If confirmed, permanently discontinue inotersen therapy.

Special Populations

Hepatic Impairment

Mild hepatic impairment: No dosage adjustment necessary.

Not studied in patients with moderate or severe hepatic impairment or in patients who have received a prior liver transplant.

Renal Impairment

Mild to moderate renal impairment (eGFR 30 to <90 mL/minute per 1.73 m²): No dosage adjustment necessary.

Not studied in patients with severe renal impairment or end-stage renal disease.

Geriatric Patients

No specific dosage recommendations at this time.

Related/similar drugs

Vyndamax, Amvuttra, Vyndaqel, Onpattro, Tegsedi, Wainua, tafamidis

Cautions for Inotersen

Contraindications

• Platelet counts <100,000/mm³.

• History of acute glomerulonephritis attributed to inotersen.

• History of hypersensitivity to inotersen or any ingredient in formulation.

Warnings/Precautions

Warnings

Thrombocytopenia

Risk of sudden and potentially life-threatening thrombocytopenia. (See Boxed Warning.) Reduction in platelet counts to <100,000/mm³ reported.

Sudden severe thrombocytopenia (platelet counts <25,000/mm³) reported in a few patients; one fatality occurred as a result of intracranial hemorrhage. IgG antiplatelet antibodies were detected in these patients.

Monitor platelet counts prior to initiating inotersen and at least weekly during therapy. Follow manufacturer's platelet monitoring guidelines and treatment recommendations.

Monitor patients for symptoms of thrombocytopenia, including unusual or prolonged bleeding (e.g., petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier-than-normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache. If any such symptoms develop, obtain a platelet count as soon as possible and withhold inotersen therapy until an acceptable platelet count is confirmed.

If platelet measurement is uninterpretable (e.g., due to clumping of the sample), recheck platelet count as soon as possible and withhold inotersen therapy until an acceptable platelet count is confirmed.

Risk of bleeding from thrombocytopenia is increased if inotersen is used concomitantly with antiplatelet or anticoagulant drugs.

Contraindicated in patients with a baseline platelet count <100,000/mm³. Do not use in patients who are unable to adhere to recommended platelet monitoring guidelines. Also not recommended in patients in whom corticosteroid therapy not advised.

Glomerulonephritis

Risk of glomerulonephritis. (See Boxed Warning.) Discontinuance of drug alone may be insufficient to resolve the condition and treatment with immunosuppressive therapy may be required.

Preclinical studies indicate that antisense oligonucleotides can accumulate in proximal tubule cells of the kidney, sometimes leading to proteinemia.

Other evidence of renal toxicity such as increased urinary protein-to-creatinine ratio and increased S_cr also reported.

Monitor S_cr, urinary protein-to-creatinine ratio, and eGFR and perform urinalysis prior to initiation of therapy and every 2 weeks during treatment. Follow manufacturer's renal monitoring guidelines and treatment recommendations. If glomerulonephritis is suspected, promptly diagnose and initiate immunosuppressive therapy. If acute glomerulonephritis is confirmed, permanently discontinue inotersen therapy; monitor for nephrotic syndrome and treat patients accordingly.

Use with caution in patients receiving other nephrotoxic drugs.

Contraindicated in patients with a history of acute glomerulonephritis caused by the drug. Use generally not recommended in patients with urinary protein-to-creatinine ratio ≥1000 mg/g. Also not recommended in patients in whom immunosuppressive therapy not advised.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreiform movements, arthralgia, myalgia, flu-like symptoms) reported. Such reactions generally occurred within 2 hours of administration and were associated with presence of anti-drug antibodies.

If a hypersensitivity reaction occurs, discontinue inotersen and initiate appropriate therapy. Contraindicated in patients with previous hypersensitivity to the drug.

Other Warnings and Precautions

Stroke and Cervicocephalic Arterial Dissection

Inotersen may cause stroke and cervicocephalic arterial dissection. In clinical trials, such events were reported within 2 days of the first dose.

Monitor patients for symptoms of stroke and CNS arterial dissection.

Inflammatory and Immune Effects

Antisense oligonucleotides are known to cause inflammatory and immune effects.

In clinical trials, serious inflammatory and immune-mediated adverse effects (e.g., immune thrombocytopenia, glomerulonephritis, antineutrophil cytoplasmic autoantibody [ANCA]-positive systemic vasculitis) reported. Serious adverse neurologic effects consistent with inflammatory and immune effects (e.g., encephalitis, myelitis) also occurred.

Liver Injury

Antisense oligonucleotides can accumulate in the liver; increased ALT concentrations reported. Confirmed or possible cases of immune-mediated biliary disease also reported.

Liver transplant rejection reported 2–4 months after starting inotersen in patients with previously stable liver allografts. Patients improved and transaminase levels normalized after glucocorticoids were administered and the drug was discontinued.

Monitor ALT, AST, and total bilirubin concentrations prior to initiation of inotersen, every 4 months during therapy, and for 8 weeks following discontinuance of therapy. In patients with a history of liver transplant, monitor ALT, AST, and total bilirubin concentrations monthly; discontinue inotersen in patients who develop signs of liver transplant rejection.

If clinical signs and symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine) develop, monitor liver function tests promptly and withhold or discontinue therapy, as appropriate.

Interference with Platelet Measurements

Platelet clumping may interfere with the diagnosis and treatment of thrombocytopenia. In some patients who developed severe thrombocytopenia from inotersen, platelet clumping caused uninterpretable platelet measurements that delayed diagnosis and treatment. Platelet clumping can have a variety of causes, including a reaction between antiplatelet antibodies and EDTA (an anticoagulant used in blood collection tubes).

If a platelet count is deemed uninterpretable, repeat test as soon as possible; withhold inotersen therapy until an acceptable platelet count (from an interpretable sample) is confirmed. If an EDTA-mediated etiology is suspected, repeat platelet count using an alternative anticoagulant (e.g., sodium citrate, heparin).

Reduced Vitamin A Concentrations

Inotersen may reduce serum vitamin A concentrations by up to 63%.

Patients should receive supplementation with the recommended daily allowance (RDA) of vitamin A. Manufacturer states that dosages exceeding the RDA should not be administered in an attempt to achieve normal serum vitamin A concentrations since serum concentrations are not reflective of total vitamin A concentrations in the body.

Refer patients who develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness) to an ophthalmologist.

Immunogenicity

Anti-inotersen antibodies detected (by an assay that measured only IgG isotypes); the presence of other isotypes cannot be excluded. While adverse reactions occurred in many patients with antibodies, data insufficient to establish a causal relationship.

Specific Populations

Pregnancy

No data regarding use of inotersen in pregnant women.

In animal reproductive studies, premature births and reduced fetal body weights observed with doses associated with maternal toxicity.

A pregnancy registry has been established; encourage patients to enroll by calling 1-877-465-7510, emailing tegsedipregnancy@ubc.com or visiting www.tegsedipregnancystudy.com.

Lactation

Distributed into milk in mice; not known whether inotersen distributes into human milk, affects the breast-fed infant, or affects milk production. Consider benefits of breast-feeding and importance of drug to the woman; also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in efficacy relative to younger adults; however, patients ≥65 years of age may be at increased risk of certain adverse reactions (e.g., heart failure, chills, myalgia, extremity pain).

Hepatic Impairment

Not studied in patients with moderate or severe hepatic impairment or in patients who have received a prior liver transplant. Mild hepatic impairment not expected to affect inotersen exposure.

Renal Impairment

Not studied in patients with severe renal impairment or end-stage renal disease. Mild or moderate renal impairment (eGFR 30 to <90 mL/min per 1.73 m²) not expected to affect inotersen exposure.

Common Adverse Effects

Adverse effects (≥20%) include injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever.

Drug Interactions

No formal drug interaction studies to date. Not a substrate, inhibitor, or inducer of major CYP isoenzymes. Not a substrate or inhibitor of major transporters.

Drugs Affecting Hepatic Microsomal Enzymes

Not expected to be affected by inhibitors or inducers of CYP isoenzymes.

Antiplatelet or Anticoagulant Agents

Possible increased risk of bleeding. Use concomitantly with caution; consider discontinuance of antiplatelet and anticoagulant drugs in patients with platelet counts <50,000/mm³.

Nephrotoxic Drugs

Use nephrotoxic drugs and other drugs that may impair renal function concomitantly with caution.

Specific Drugs

Inotersen Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma concentration is 2–4 hours.

Steady-state concentrations attained after approximately 3 months.

Accumulation does not occur with repeated dosing.

Plasma Concentrations

Following sub-Q administration, systemic exposure increases in a dose-proportional manner over the dose range of 142–379 mg.

Special Populations

Geriatric patients: Pharmacokinetics similar in patients ≥65 years of age and younger adults.

Mild hepatic impairment (bilirubin concentration ≤1.5 times ULN and/or AST <1.9 times ULN): No effect on systemic exposure.

Mild or moderate renal impairment (eGFR 30 to <90 mL/min per 1.73 m²): No effect on systemic exposure.

Distribution

Extent

Does not cross the blood-brain barrier.

Not known whether distributed into human milk.

Plasma Protein Binding

>94%; protein binding is independent of concentration.

Elimination

Metabolism

Metabolized by nucleases to nucleotides of various lengths.

Elimination Route

Clearance principally through metabolism.

<1% excreted unchanged in urine.

Half-life

Mean terminal half-life is 32.3 days.

Stability

Storage

Parenteral

Injection

2–8°C. Store in original carton until time of use; protect from light. Do not freeze.

If refrigeration is not available, may store prefilled syringes at room temperature (up to 30°C) in the original carton for ≤6 weeks. Discard drug if not used within 6 weeks. Avoid exposure to temperatures >30°C.

Actions

• Phosphorothioate-modified antisense oligonucleotide that targets and prevents translation of transthyretin mRNA; causes degradation of both mutant and wild type transthyretin mRNA.

• Reduces transthyretin (disease-causing protein) in patients with hereditary transthyretin-mediated amyloidosis.

• Reduces serum transthyretin concentrations by approximately 68–74% from baseline.

Advice to Patients

• Importance of advising patients and caregivers to read the manufacturer's medication guide and instructions for use prior to initiation of therapy and each time the prescription is refilled.

• Risk of thrombocytopenia. Importance of monitoring platelet counts during inotersen therapy. Advise patients to notify their clinician immediately if symptoms of thrombocytopenia (e.g., unusual or prolonged bleeding, neck stiffness, atypical severe headache) occur.

• Risk of glomerulonephritis. Importance of monitoring urinary protein-to-creatinine ratio during inotersen therapy. Advise patients to notify their clinician immediately if symptoms of renal toxicity (e.g., facial or extremity edema, new onset or worsening dyspnea or cough, hematuria, proteinuria, oliguria) occur.

• Importance of advising patients that inotersen can only be obtained through the Tegsedi REMS program.

• Risk of stroke and CNS arterial dissection. Importance of educating patients on possible symptoms, and advising them to seek immediate assistance if such symptoms occur.

• Advise patients to notify clinician if symptoms suggestive of hepatic dysfunction or hypersensitivity occur.

• Importance of advising patients to take the RDA of vitamin A. Advise patients to notify clinician if they experience ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness), and refer patients who develop such symptoms to an ophthalmologist.

• Importance of instructing patients and/or their caregivers on use of the prefilled syringes and proper sub-Q administration technique.

• Risk of fetal harm. Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., anticoagulants, antiplatelet agents) and OTC drugs (e.g., aspirin, NSAIAs) and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of inotersen is restricted.

Inotersen is available only through the Tegsedi REMS program. Additional information available at 844-483-4736 or at [Web].

Reload page with references included

Frequently asked questions

• Onpattro vs Tegsedi - how do they compare?
• What is the Tegsedi REMS Program?

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