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Inotersen

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
Brands: Tegsedi

Medically reviewed by Drugs.com. Last updated on March 2, 2020.

Warning

    Thrombocytopenia
  • Sudden, unpredictable, and potentially life-threatening reductions in platelet count may occur.1 (See Thrombocytopenia under Cautions.)

  • Do not initiate therapy in patients with platelet counts <100,000/mm3.1 (See Contraindications under Cautions.)

  • Monitor platelet counts at baseline and throughout treatment.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

  • If any signs or symptoms of thrombocytopenia develop, check platelet counts immediately and withhold therapy until platelet count is determined to be acceptable.1

    Glomerulonephritis
  • Glomerulonephritis, sometimes requiring immunosuppressive treatment and resulting in dialysis-dependent renal failure, may occur.1 (See Glomerulonephritis under Cautions.)

  • May be accompanied by nephrotic syndrome.1

  • Generally not recommended in patients with urinary protein-to-creatinine ratio of ≥1000 mg/g.1

  • Monitor renal function at baseline and throughout treatment.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

    Restricted Distribution Program
  • Available only through the Tegsedi REMS program.1 (See Restricted Distribution Program under Dosage and Administration.)

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for inotersen to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of inotersen and consists of the following: elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/. Also see Restricted Distribution Program under Dosage and Administration.

Introduction

Antisense oligonucleotide that targets transthyretin messenger RNA (mRNA).1 11 14

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).1 2 14

Inotersen Dosage and Administration

General

  • Monitor platelet counts prior to initiation of therapy, at recommended intervals during therapy (weekly if platelet count ≥75,000/mm3 or more frequently if platelet count <75,000/mm3), and for ≥8 weeks following discontinuance of therapy.1 (See Thrombocytopenia under Cautions.)

  • Monitor Scr, eGFR, and urinary protein-to-creatinine ratio and perform urinalysis prior to initiation of therapy, every 2 weeks during therapy, and for 8 weeks following discontinuance of therapy.1 (See Glomerulonephritis under Cautions.)

  • Monitor ALT, AST, and total bilirubin concentrations prior to initiation of therapy, every 4 months during therapy, and for 8 weeks following discontinuance of therapy.1

Restricted Distribution Program

  • Available only through a restricted distribution program (Tegsedi REMS program) because of the risks of severe thrombocytopenia and glomerulonephritis.1 12

  • Additional information available at 844-483-4736 or at [Web].1 12

Administration

Administer by sub-Q injection only.1

Sub-Q Administration

Administer once weekly (preferably on the same day each week).1

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.1

Available as single-use prefilled syringes.1 Prior to administration, allow prefilled syringe to reach room temperature for ≥30 minutes (see Storage under Stability);1 do not use other warming methods (e.g., microwave, hot water, placement near other heat sources).1 13 Do not remove needle cap from syringe until immediately prior to injection.13

Administer sub-Q injections into abdomen (except within 2 inches of the navel), upper thigh, or outer area of upper arm (by a caregiver).1 Rotate injection sites.1 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.1 13

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.1

Dosage

Dosage of inotersen sodium expressed in terms of inotersen.1

Adults

Hereditary Transthyretin-mediated Amyloidosis
Polyneuropathy
Sub-Q

284 mg once weekly.1

Dosage Modification for Toxicity
Thrombocytopenia
Sub-Q

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

Table 1: Dosage Adjustments and Monitoring Recommendations Based on Platelet Count1

Platelet Count

Monitoring Frequency

Recommendation

≥75,000 to <100,000/mm3

Weekly

Withhold therapy; do not resume until platelet counts >100,000/mm3

≥50,000 to <75,000/mm3

Twice weekly until 3 successive platelet counts >75,000/mm3, then monitor weekly

Withhold therapy; do not resume until 3 successive platelet counts >100,000/mm3 and the benefit of inotersen outweighs risk of thrombocytopenia and potential bleeding

≥25,000 to <50,000/mm3

Twice weekly until 3 successive platelet counts >75,000/mm3, then monitor weekly.

Consider more frequent monitoring if patient has additional risk factors for bleeding (e.g., age >60 years, concomitant anticoagulant or antiplatelet therapy, history of major bleeding events)

Withhold therapy; do not resume until 3 successive platelet counts >100,000/mm3 and the benefit of inotersen outweighs risk of thrombocytopenia and potential bleeding

<25,000/mm3

Daily until 2 successive platelet counts >25,000/mm3, then monitor twice weekly until 3 successive values >75,000/mm3, then monitor weekly until stable

Permanently discontinue therapy

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/mm3.1

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.1 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.1

If urinary protein-to-creatinine ratio ≥2000 mg/g, further evaluate for acute glomerulonephritis, as clinically indicated.1 If confirmed, permanently discontinue inotersen therapy.1

Special Populations

Hepatic Impairment

Mild hepatic impairment: No dosage adjustment necessary.1 (See Hepatic Impairment under Cautions.)

Not studied in patients with moderate or severe hepatic impairment or in patients who have received a prior liver transplant.1

Renal Impairment

Mild to moderate renal impairment (eGFR 30 to <90 mL/minute per 1.73 m2): No dosage adjustment necessary.1 (See Renal Impairment under Cautions.)

Not studied in patients with severe renal impairment or end-stage renal disease.1

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Inotersen

Contraindications

  • Platelet counts <100,000/mm3.1

  • History of acute glomerulonephritis attributed to inotersen.1

  • History of hypersensitivity to inotersen or any ingredient in formulation.1

Warnings/Precautions

Warnings

Thrombocytopenia

Risk of sudden and potentially life-threatening thrombocytopenia.1 (See Boxed Warning.) Reduction in platelet counts to <100,000/mm3 reported in about 25% of inotersen-treated patients in clinical studies.1

Sudden severe thrombocytopenia (platelet counts <25,000/mm3) reported in a few patients; one fatality occurred as a result of intracranial hemorrhage.1 14 15 IgG antiplatelet antibodies were detected in these patients.1 14

Monitor platelet counts prior to initiating inotersen and at least weekly during therapy.1 Follow manufacturer's platelet monitoring guidelines and treatment recommendations.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

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.1 If any such symptoms develop, obtain a platelet count as soon as possible and withhold inotersen therapy until an acceptable platelet count is confirmed.1

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.1 (See Interference with Platelet Measurements under Cautions.)

Risk of bleeding from thrombocytopenia is increased if inotersen is used concomitantly with antiplatelet or anticoagulant drugs.1 (See Antiplatelet or Anticoagulant Agents under Interactions.)

Contraindicated in patients with a baseline platelet count <100,000/mm3.1 Do not use in patients who are unable to adhere to recommended platelet monitoring guidelines.1 Also not recommended in patients in whom corticosteroid therapy not advised.1

Glomerulonephritis

Risk of glomerulonephritis.1 (See Boxed Warning.) Discontinuance of drug alone may be insufficient to resolve the condition and treatment with immunosuppressive therapy may be required.1

Preclinical studies indicate that antisense oligonucleotides can accumulate in proximal tubule cells of the kidney, sometimes leading to proteinemia.1

Other evidence of renal toxicity such as increased urinary protein-to-creatinine ratio and increased Scr also reported.1

Monitor Scr, urinary protein-to-creatinine ratio, and eGFR and perform urinalysis prior to initiation of therapy and every 2 weeks during treatment.1 Follow manufacturer's renal monitoring guidelines and treatment recommendations.1 (See Dosage Modification for Toxicity under Dosage and Administration.) If glomerulonephritis is suspected, promptly diagnose and initiate immunosuppressive therapy.1 If acute glomerulonephritis is confirmed, permanently discontinue inotersen therapy; monitor for nephrotic syndrome and treat patients accordingly.1

Use with caution in patients receiving other nephrotoxic drugs.1 (See Nephrotoxic Drugs under Interactions.)

Contraindicated in patients with a history of acute glomerulonephritis caused by the drug.1 Use generally not recommended in patients with urinary protein-to-creatinine ratio ≥1000 mg/g.1 Also not recommended in patients in whom immunosuppressive therapy not advised.1

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.1 Such reactions generally occurred within 2 hours of administration and were associated with presence of anti-drug antibodies.1 (See Immunogenicity under Cautions.)

If a hypersensitivity reaction occurs, discontinue inotersen and initiate appropriate therapy.1 Contraindicated in patients with previous hypersensitivity to the drug.1

Other Warnings and Precautions

Stroke and Cervicocephalic Arterial Dissection

Inotersen may cause stroke and cervicocephalic arterial dissection.1 In clinical trials, such events were reported within 2 days of the first dose.1 14

Monitor patients for symptoms of stroke and CNS arterial dissection.1 (See Advice to Patients.)

Inflammatory and Immune Effects

Antisense oligonucleotides are known to cause inflammatory and immune effects.1 15

In clinical trials, serious inflammatory and immune-mediated adverse effects (e.g., immune thrombocytopenia, glomerulonephritis, antineutrophil cytoplasmic autoantibody [ANCA]-positive systemic vasculitis) reported.1 15 Serious adverse neurologic effects consistent with inflammatory and immune effects (e.g., encephalitis, myelitis) also occurred.1 15

Hepatic Effects

Antisense oligonucleotides can accumulate in the liver; increased ALT concentrations reported.1 Confirmed or possible cases of immune-mediated biliary disease also reported.1

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.1 If patients develop clinical signs and symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine), monitor liver function tests promptly and withhold or discontinue therapy, as appropriate.1

Interference with Platelet Measurements

Platelet clumping may interfere with the diagnosis and treatment of thrombocytopenia.1 (See Thrombocytopenia under Cautions.) In some patients who developed severe thrombocytopenia from inotersen, platelet clumping caused uninterpretable platelet measurements that delayed diagnosis and treatment.1 Platelet clumping can have a variety of causes, including a reaction between antiplatelet antibodies and EDTA (an anticoagulant used in blood collection tubes).1

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.1 If an EDTA-mediated etiology is suspected, repeat platelet count using an alternative anticoagulant (e.g., sodium citrate, heparin).1

Reduced Vitamin A Concentrations

Inotersen may reduce serum vitamin A concentrations by up to 63%.1

Patients should receive supplementation with the recommended daily allowance (RDA) of vitamin A.1 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.1

Refer patients who develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness) to an ophthalmologist.1

Immunogenicity

Anti-inotersen antibodies detected (by an assay that measured only IgG isotypes); the presence of other isotypes cannot be excluded.1 While adverse reactions occurred in many patients with antibodies, data insufficient to establish a causal relationship.1

Specific Populations

Pregnancy

No data regarding use of inotersen in pregnant women.1

In animal reproductive studies, premature births and reduced fetal body weights observed with doses associated with maternal toxicity.1

Lactation

Distributed into milk in mice; not known whether inotersen distributes into human milk, affects the breast-fed infant, or affects milk production.1 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.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

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).1

Hepatic Impairment

Not studied in patients with moderate or severe hepatic impairment or in patients who have received a prior liver transplant.1 Mild hepatic impairment not expected to affect inotersen exposure.1

Renal Impairment

Not studied in patients with severe renal impairment or end-stage renal disease.1 Mild or moderate renal impairment (eGFR 30 to <90 mL/min per 1.73 m2) not expected to affect inotersen exposure.1

Common Adverse Effects

Injection site reactions,1 nausea,1 14 headache,1 fatigue,1 thrombocytopenia,1 14 fever,1 14 peripheral edema,1 chills,1 14 anemia,1 14 vomiting,1 14 myalgia,1 decreased renal function,1 arrhythmia,1 arthralgia,1 presyncope or syncope,1 decreased appetite,1 paresthesia,1 dyspnea,1 elevated liver function test values,1 orthostasis,1 influenza-like illness,1 contusion,1 bacterial infection,1 eosinophilia,1 dry mouth.1

Interactions for Inotersen

No formal drug interaction studies to date.1 Not a substrate, inhibitor, or inducer of major CYP isoenzymes.1 Not a substrate or inhibitor of major transporters.1

Drugs Affecting Hepatic Microsomal Enzymes

Not expected to be affected by inhibitors or inducers of CYP isoenzymes.1

Antiplatelet or Anticoagulant Agents

Possible increased risk of bleeding.1 Use concomitantly with caution; consider discontinuance of antiplatelet and anticoagulant drugs in patients with platelet counts <50,000/mm3.1

Nephrotoxic Drugs

Use nephrotoxic drugs and other drugs that may impair renal function concomitantly with caution.1

Specific Drugs

Drug

Interaction

Comments

Analgesics

No effect on inotersen pharmacokinetics expected1

Anticoagulants (e.g., heparin, warfarin)

Possible increased risk of bleeding1

Use concomitantly with caution; consider discontinuance of the anticoagulant in patients with a platelet count <50,000/mm31

Antiplatelet agents (e.g., aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine)

Possible increased risk of bleeding1

Use concomitantly with caution; consider discontinuance of the antiplatelet agent in patients with a platelet count <50,000/mm31

Diuretics

No effect on inotersen pharmacokinetics1

NSAIAs

Possible increased risk of bleeding1

Use concomitantly with caution; consider discontinuance of the NSAIA in patients with a platelet count <50,000/mm31

Inotersen Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma concentration is 2–4 hours.1

Steady-state concentrations attained after approximately 3 months.1

Accumulation does not occur with repeated dosing.1

Plasma Concentrations

Following sub-Q administration, systemic exposure increases in a dose-proportional manner over the dose range of 142–379 mg.1

Special Populations

Geriatric patients: Pharmacokinetics similar in patients ≥65 years of age and younger adults.1

Mild hepatic impairment (bilirubin concentration ≤1.5 times ULN and/or AST <1.9 times ULN): No effect on systemic exposure.1

Mild or moderate renal impairment (eGFR 30 to <90 mL/min per 1.73 m2): No effect on systemic exposure.1

Distribution

Extent

Does not cross the blood-brain barrier.1

Not known whether distributed into human milk.1

Plasma Protein Binding

>94%; protein binding is independent of concentration.1

Elimination

Metabolism

Metabolized by nucleases to nucleotides of various lengths.1

Elimination Route

Clearance principally through metabolism.1

<1% excreted unchanged in urine.1

Half-life

Mean terminal half-life is 32.3 days.1

Stability

Storage

Parenteral

Injection

2–8°C.1 Store in original carton until time of use; protect from light.1 Do not freeze.1

If refrigeration is not available, may store prefilled syringes at room temperature (up to 30°C) in the original carton for ≤6 weeks.1 Discard drug if not used within 6 weeks.1 Avoid exposure to temperatures >30°C.1

Actions

  • Phosphorothioate-modified antisense oligonucleotide that targets and prevents translation of transthyretin mRNA; causes degradation of both mutant and wild type transthyretin mRNA.1 11 14

  • Reduces transthyretin (disease-causing protein) in patients with hereditary transthyretin-mediated amyloidosis.1 3 4 5 7 8 14 15

  • Reduces serum transthyretin concentrations by approximately 68–74% from baseline.1

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.1 13

  • Risk of thrombocytopenia.1 Importance of monitoring platelet counts during inotersen therapy.1 Advise patients to notify their clinician immediately if symptoms of thrombocytopenia (e.g., unusual or prolonged bleeding, neck stiffness, atypical severe headache) occur.1

  • Risk of glomerulonephritis.1 Importance of monitoring urinary protein-to-creatinine ratio during inotersen therapy.1 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.1

  • Importance of advising patients that inotersen can only be obtained through the Tegsedi REMS program.1 12 (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

  • Risk of stroke and CNS arterial dissection.1 Importance of educating patients on possible symptoms, and advising them to seek immediate assistance if such symptoms occur.1

  • Advise patients to notify clinician if symptoms suggestive of hepatic dysfunction or hypersensitivity occur.1

  • Importance of advising patients to take the RDA of vitamin A.1 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.1

  • Importance of instructing patients and/or their caregivers on use of the prefilled syringes and proper sub-Q administration technique.1

  • Risk of fetal harm.1 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • 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.1

  • Importance of informing patients of other important precautionary information.1 (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.1 12 (See Restricted Distribution Program under Dosage and Administration.)

Inotersen Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

284 mg (of inotersen)/1.5 mL

Tegsedi (available as single-dose prefilled syringes)

Ionis

AHFS DI Essentials™. © Copyright 2021, Selected Revisions March 2, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Ionis Pharmaceuticals, Inc. Tegsedi (inotersen) injection prescribing information. Carlsbad, CA; 2018 Oct.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2019 Feb 12. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

3. Adams D, Suhr OB, Dyck PJ et al. Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017; 17:181. http://www.ncbi.nlm.nih.gov/pubmed/28893208?dopt=AbstractPlus

4. Adams D, Gonzalez-Duarte A, O'Riordan WD et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018; 379:11-21. http://www.ncbi.nlm.nih.gov/pubmed/29972753?dopt=AbstractPlus

5. Coelho T, Adams D, Silva A et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013; 369:819-29. http://www.ncbi.nlm.nih.gov/pubmed/23984729?dopt=AbstractPlus

6. Suhr OB, Coelho T, Buades J et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015; 10:109. http://www.ncbi.nlm.nih.gov/pubmed/26338094?dopt=AbstractPlus

7. Hawkins PN, Ando Y, Dispenzeri A et al. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015; 47:625-38. http://www.ncbi.nlm.nih.gov/pubmed/26611723?dopt=AbstractPlus

8. Titze-de-Almeida R, David C, Titze-de-Almeida SS. The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. Pharm Res. 2017; 34:1339-1363. http://www.ncbi.nlm.nih.gov/pubmed/28389707?dopt=AbstractPlus

9. Kerschen P, Planté-Bordeneuve V. Current and Future Treatment Approaches in Transthyretin Familial Amyloid Polyneuropathy. Curr Treat Options Neurol. 2016; 18:53. http://www.ncbi.nlm.nih.gov/pubmed/27873215?dopt=AbstractPlus

10. Kristen AV. [What gnaws at the heart and gets on the nerves]. Internist (Berl). 2018; 59:1208-1213. http://www.ncbi.nlm.nih.gov/pubmed/30039176?dopt=AbstractPlus

11. Gertz MA, Scheinberg M, Waddington-Cruz M et al. Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis. Expert Rev Clin Pharmacol. 2019; 12:701-711. http://www.ncbi.nlm.nih.gov/pubmed/31268366?dopt=AbstractPlus

12. Tegsedi (inotersen) risk evaluation and mitigation strategy (REMS). From FDA website. Accessed 2019 Feb 13.

13. Ionis Pharmaceuticals, Inc. Tegsedi (inotersen) injection instructions for use. Carlsbad, CA; 2018 Oct.

14. Benson MD, Waddington-Cruz M, Berk JL et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018; 379:22-31. http://www.ncbi.nlm.nih.gov/pubmed/29972757?dopt=AbstractPlus

15. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 211172Orig1s000: Summary review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211172Orig1s000SumR.pdf

16. Waddington-Cruz M, Ackermann EJ, Polydefkis M et al. Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial. Amyloid. 2018; 25:180-188. http://www.ncbi.nlm.nih.gov/pubmed/30169969?dopt=AbstractPlus

17. Crooke ST, Baker BF, Witztum JL et al. The Effects of 2'-O-Methoxyethyl Containing Antisense Oligonucleotides on Platelets in Human Clinical Trials. Nucleic Acid Ther. 2017; 27:121-129. http://www.ncbi.nlm.nih.gov/pubmed/28145801?dopt=AbstractPlus

Frequently asked questions