AdultPediatricDosage Forms & Strengths injectable solution 284mg/1.5mL single-dose prefilled syringe Hereditary Transthyretin Amyloidosis Indicated for polyneuropathy of hereditary transthyretin amyloidosis (hATTR-PN) in adults 284 mg SC once weekly; administer on the same day each week Dosage Modifications Platelets Do not initiate if <100x 10^9/L If signs or symptoms of thrombocytopenia develop, obtain platelet count as soon as possible, and hold dosing until platelet count is confirmed; recheck platelet count as soon as possible if a platelet measurement is uninterpretable Platelet count ≥100x 10^9/L Monitor weekly Continue to dose weekly Platelet count ≥75 to <100 x 10^9/L Monitor weekly Stop treatment; may resume if platelet count >100 Platelet count ≥50 to <75x 10^9/L Monitor twice weekly until 3 successive values >75, then weekly Stop treatment; may resume after 3 successive values >100 and the benefit of inotersen outweighs thrombocytopenia risk Platelet count ≥25 to <50x 10^9/L Monitor twice weekly until 3 successive values >75, then weekly Stop treatment; may resume after 3 successive values >100 and the benefit of inotersen outweighs thrombocytopenia risk Corticosteroids recommended Consider discontinuation of any antiplatelet agents or anticoagulants Platelet count <25x 10^9/L Monitor daily until 2 successive values >25, then twice weekly until 3 successive values >75, then weekly until stable Stop treatment Corticosteroids recommended Consider discontinuation of any antiplatelet agents or anticoagulants UPCR or eGFR Urine protein to creatinine ratio (UPCR) ≥1000 mg/g or eGFR <45 mL/min/1.73 m²: Hold dosing pending further evaluation Once eGFR ≥45 mL/minute/1.73 m², UPCR <1000 mg/g, or the underlying cause of the decline in renal function is corrected, may resume weekly dosing UPCR ≥2000 mg/g: Perform further evaluation for acute glomerulonephritis, as clinically indicated If acute glomerulonephritis confirmed, permanently discontinue Renal impairment Mild-to-moderate (eGFR ≥30 to <90 mL/min/1.73 m²): No dose adjustment required Severe or end-stage renal disease: Not studied Hepatic impairment Mild: No dose adjustment required Moderate-to-severe: Not studied Dosing Considerations Laboratory assessment Also see Black Box Warnings Before initiating: Measure platelet count, serum creatinine, eGFR, UPCR, ALT, AST, and total bilirubin, and perform urinalysis After initiating: Monitor platelet count, serum creatinine, eGFR, urinalysis, UPCR, ALT, AST, and total bilirubin during treatment and for 8 weeks after discontinuing Monitor ALT, AST, and total bilirubin q4months Monitor serum creatinine, eGFR, urinalysis, and UPCR q2weeks Safety and efficacy not establishedInteraction CheckerEnter a drug name and inotersenNo Results No Interactions Found Interactions FoundContraindicatedSerious - Use AlternativeSignificant - Monitor CloselyMinorAll Interactions Sort By: SeverityName Contraindicated (0)Serious - Use Alternative (0)Monitor Closely (2)voclosporinvoclosporin, inotersen. Either increases toxicity of the other by nephrotoxicity and/or ototoxicity. Modify Therapy/Monitor Closely. Coadministration with drugs associated with nephrotoxicity may increase the risk for acute and/or chronic nephrotoxicity.warfarininotersen increases effects of warfarin by anticoagulation. Use Caution/Monitor.Minor (0)voclosporinMonitor Closely (1)voclosporin, inotersen. Either increases toxicity of the other by nephrotoxicity and/or ototoxicity. Modify Therapy/Monitor Closely. Coadministration with drugs associated with nephrotoxicity may increase the risk for acute and/or chronic nephrotoxicity.warfarinMonitor Closely (1)inotersen increases effects of warfarin by anticoagulation. Use Caution/Monitor. >10% Injection site reactions (49%) Nausea (31%) Headache (26%) Fatigue (25%) Thrombocytopenia (24%) Fever (20%) Peripheral edema (19%) Chills (18%) Anemia (17%) Vomiting (15%) Myalgia (15%) Decreased renal function (14%) Arrhythmia (13%) Arthralgia (13%) Presyncope or syncope (13%) 1-10% Decreased appetite (10%) Paresthesia (10%) Dyspnea (9%) Elevated liver function test (9%) Orthostasis (8%) Influenzalike illness (8%) Contusion (7%) Bacterial infection (7%) Eosinophilia (5%) Dry mouth (5%) Black Box Warnings Thrombocytopenia Reductions in platelet count may result in sudden and unpredictable thrombocytopenia, which can be life-threatening One clinical trial patient died from intracranial hemorrhage Contraindicated in patients with a platelet count <100x 10^9/L Obtain a platelet count before initiating drug During treatment, monitor platelet counts weekly if values are ≥75x 10^9/L, and more frequently if values are <75x 10^9/L If signs or symptoms of thrombocytopenia develop, obtain a platelet count as soon as possible; hold dosing until platelet count is determined to be interpretable and acceptable by a medical professional Following discontinuation of treatment for any reason, continue to monitor platelet count for 8 weeks, or longer if platelet counts are <100x 10^9/L, to verify that platelet counts remain >75x 10^9/L Glomerulonephritis Inotersen can 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 In clinical trials, cases of glomerulonephritis were accompanied by nephrotic syndrome, which can have manifestations of edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection Should generally not be initiated in patients with UPCR ≥1000 mg/g Before initiating drug, measure serum creatinine, eGFR, UPCR, and perform urinalysis During treatment, monitor serum creatinine, eGFR, urinalysis, and UPCR q2weeks Do not administer to patients who develop UPCR ≥1000 mg/g or eGFR <45 mL/minute/1.73 m², pending further evaluation of the cause If dose held, may reinitiate weekly dosing once eGFR increases to ≥45 mL/minute/1.73 m², UPCR decreases to <1000 mg/g, or the underlying cause of the decline in renal function is corrected If UPCR ≥2000 mg/g, perform further evaluation for acute glomerulonephritis, as clinically indicated; if confirmed, permanently discontinue inotersen REMS program Owing to risks of serious bleeding caused by severe thrombocytopenia and glomerulonephritis, both of which require frequent monitoring, inotersen is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) Contraindications Platelet count <100x 10^9/L History of acute glomerulonephritis caused by inotersen Hypersensitivity Cautions Causes platelet count reduction that may result in sudden and unpredictable thrombocytopenia that can be life-threatening; monitoring required Uninterpretable platelet counts may occur owing to platelet clumping that occurs between antiplatelet antibodies and EDTA; if EDTA-mediated platelet clumping suspected, repeat platelet count using a different anticoagulant (eg, sodium citrate, heparin) in the blood collection tube Can cause glomerulonephritis that may result in dialysis-dependent renal failure; monitoring required; treatment for glomerulonephritis is immunosuppressive therapy; avoid use in patients for whom immunosuppressive treatment is not advised Prescribers must be certified to prescribe inotersen by enrolling in and completing the REMS training program; patients must enroll in the program and comply with ongoing monitoring requirements May cause stroke and cervicocephalic arterial dissection (rare) within 2 days of the first dose; patients may also have symptoms of cytokine release (eg, nausea, vomiting, muscular pain, weakness) and a high-sensitivity C-reactive protein level >100 mg/L during this time Vitamin A levels may decrease; supplementation with recommended daily allowance advised; refer to ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occurs (eg, night blindness) Inflammatory and immune effects May cause inflammatory and immune changes, including immune thrombocytopenia, glomerulonephritis, or rarely, antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis One patient developed gait changes that progressed over 6 months to paraparesis, in the absence of radiologic evidence of spinal cord compression Another patient developed progressive lumbar pain, weight loss, headache, vomiting, and impaired speech 7 months after starting inotersen; CSF analysis findings included elevated protein, lymphocyte-predominant pleocytosis, and testing that was negative for infection; recovery occurred after empiric therapy (ie, high-dose steroids, antibiotics) and the patient resumed inotersen without recurrence of symptoms The liver accumulates antisense oligonucleotides; monitor ALT, AST, and total bilirubin Cases of liver transplant rejection reported 2-4 months after starting therapy in patients whose liver allografts had previously been clinically stable (for over 10 years) prior to starting therapy; patients clinically improved and transaminase levels normalized after glucocorticoid administration and cessation of therapy; in patients with a history of liver transplant, monitor ALT, AST, and total bilirubin monthly; discontinue therapy in patients who develop signs of liver transplant rejection Hypersensitivity may occur; discontinue treatment and do not reinitiate Drug interaction overview Owing to thrombocytopenia risk, caution if inotersen is coadministered with antiplatelets or anticoagulants Caution if coadministered with other drugs that may impair renal function Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to drug during pregnancy; health care providers are encouraged to register patients and pregnant women are encouraged to register themselves by calling: 1-877-465-7510, emailing: tegsedipregnancy@ubc.com, or visiting online at www.tegsedipregnancystudy.com There are no available data regarding use in pregnant women Inotersen treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking inotersen; vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects Effects on the fetus of maternal serum transthyretin (TTR) reduction caused by inotersen and vitamin A supplementation are unknown Animal studies In animal studies, SC administration of inotersen to pregnant rabbits resulted in premature delivery and reduced fetal body weight Lactation Unknown if distributed in human milk The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child or from the underlying maternal conditionPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Antisense oligonucleotide that causes degradation of mutant and wild-type transthyretin (TTR) mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues In patients with ATTR, TTR builds up as fibrils in tissues (eg, peripheral nerves, heart, GI system, eyes, kidneys, CNS, thyroid, bone marrow); the presence of TTR fibrils interferes with the normal functions of these tissues Absorption Peak plasma time: 2-4 hr Peak plasma concentration: 6.39 mcg/mL Trough plasma concentration: 0.034 mcg/mL AUC: 90 mcg·hr/mL Distribution Protein bound: >94% Vd: 293 L Metabolism Metabolized by nucleases to nucleotides of various lengths Elimination Half-life: 32.3 days Total body clearance: 3.18 L/hr Excretion: Urine <1% (unchanged) SC Preparation Remove from refrigerator at least 30 minutes before administration to reach room temperature; do not use other warming methods (eg, water bath, microwave) Inspect visually for particulate matter and discoloration before administration; solution should appear colorless to pale yellow SC Administration For SC injection only Administer first injection by the patient or caregiver under the guidance of an appropriately qualified healthcare professional; train patients and/or caregivers SC administration Injection SC in abdomen, upper thigh region, or outer area of upper arm; injection in upper arm should be administered by person other than the patient Rotate injection sites Avoid injection at the waistline and other sites where pressure or rubbing from clothing may occur Do not inject into areas of skin disease or injury; also avoid tattoos and scars Use each syringe only once Missed dose Instruct patient to take missed dose as soon as possible, unless next scheduled dose is within 2 days If next dose within 2 days, direct patient to skip the missed dose and take the next scheduled dose on the scheduled day Storage Store refrigerated at 2-8°C (36-46°F) in the original container Do not freeze Can be kept at room temperature (not to exceed 30°C [86°F]) in the original container for up to 6 weeks; if not used within the 6 weeks, discard No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions Tier Description 1 This drug is available at the