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Antisense oligonucleotide (TTR) Pregnancy: Section 4.6: 'Women of child-bearing potential - Inotersen will reduce the plasma levels of vitamin A, which is crucial for normal foetal development. It is not known whether vitamin A supplementation will be sufficient to reduce the risk to the foetus. For this reason, pregnancy should be excluded before initiation of inotersen therapy and women of child-bearing potential should practise effective contraception. Pregnancy - There are no or limited amount of data from the use of inotersen in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Due to the potential teratogenic risk arising from unbalanced vitamin A levels, inotersen should not be used during pregnancy, unless the clinical condition of the woman requires treatment with inotersen. Breast-feeding - It is unknown whether inotersen/metabolites are excreted in human milk. A risk to the breastfed newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Tegsedi therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.'

Inotersen

Brand names: Tegsedi

Inotersen is an antisense oligonucleotide given by subcutaneous injection for the treatment of polyneuropathy in hereditary transthyretin amyloidosis in adults.

Adult dose

Dose: Stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR): 284 mg inotersen by subcutaneous injection once every week, on the same day each week.
Route: Subcutaneous
Frequency: Once every week (same day each week)
Strength (SPC section 2): each pre-filled syringe contains 284 mg inotersen (as inotersen sodium) in 1.5 mL of solution (189 mg/mL); one syringe = one dose; each syringe is for one-time use only. Treatment should be initiated by and remain under the supervision of a physician experienced in hATTR (section 4.2). PLATELET-BASED DOSE ADJUSTMENT (SPC Table 1, section 4.2): platelets > 100 x10^9/L - continue weekly dosing, monitor every 2 weeks; >= 75 to < 100 - reduce dosing frequency to 284 mg every 2 weeks, monitor every week; < 75 - pause dosing until 3 successive values > 100, then reinitiate at 284 mg every 2 weeks, monitor twice weekly until 3 successive values above 75 then weekly; < 50 - as for < 75 and consider corticosteroids if additional bleeding risk factors; < 25 - treatment should be discontinued, corticosteroids recommended, monitor daily until 2 successive values above 25, then twice weekly until 3 successive values above 75, then weekly until stable. Patients who discontinue because of platelets below 25 x10^9/L should not reinitiate. Footnote to Table 1 (marked on the >= 75 to < 100, < 75 and < 50 bands): if the subsequent test confirms the initial test result, then monitoring frequency and dosing should be adjusted as recommended in the table. Missed dose (section 4.2): give as soon as possible, unless the next scheduled dose is within two days, in which case skip it and give the next dose as scheduled. Vitamin A (section 4.4): patients should take oral supplementation of approximately 3 000 IU vitamin A per day; plasma retinol below the lower limit of normal should be corrected before initiation. Patients undergoing liver transplant: discontinuation recommended (section 4.2). Administration (section 4.2): subcutaneous use only; sites are abdomen, upper thigh or outer upper arm (arm injection given by another person); rotate sites; allow the syringe to reach room temperature, removing it from refrigerated storage at least 30 minutes before use. The retrieved text of sections 4.4 and 4.8 is cut off by the fetch limit; nothing beyond it is used.

Dose adjustments

Renal

SPC 4.2: no dose adjustment for mild or moderate renal impairment. Inotersen should not be used in patients with a urine protein to creatinine ratio (UPCR) >= 113 mg/mmol (1 g/g) or estimated GFR < 45 ml/min/1.73 m2 (contraindicated, section 4.3). Monitor UPCR and eGFR during treatment; if acute glomerulonephritis is confirmed, permanent discontinuation should be considered (section 4.2; section 4.4 says it should permanently be discontinued).

Hepatic

SPC 4.2: no dose adjustment is required for mild or moderate hepatic impairment. Inotersen must not be used in patients with severe hepatic impairment (section 4.3). Not evaluated in liver transplant patients - discontinue in subjects undergoing liver transplantation.

Dose independently re-sourced from UK Summary of Product Characteristics (SPC) via MHRA Products — clinician-reviewed. Always confirm against the product SmPC and your local formulary before prescribing.

Contraindications

  • Hypersensitivity to the active substance or to any of the excipients (section 4.3)
  • Platelet count < 100 x 10^9/L prior to treatment (section 4.3)
  • Urine protein to creatinine ratio (UPCR) >= 113 mg/mmol (1 g/g) prior to treatment (section 4.3)
  • Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2 (section 4.3)
  • Severe hepatic impairment (section 4.3)

Side effects

  • Injection site reactions (50.9%): pain, erythema, pruritus, swelling, rash, induration, bruising, haemorrhage (section 4.8)
  • Nausea (31.3%), headache (23.2%), pyrexia (19.6%), peripheral oedema (18.8%), chills (17.9%), vomiting (15.2%) (section 4.8)
  • Anaemia (13.4%), thrombocytopenia (13.4%), platelet count decreased (10.7%) (section 4.8)
  • Thrombocytopenia - platelet count below 100 x 10^9/L in 23% of inotersen-treated patients vs 2% placebo in the NEURO-TTR trial; confirmed counts < 75 x 10^9/L in 10.7% (section 4.8)
  • Glomerulonephritis and renal function decline (sections 4.4, 4.8)
  • Reduced plasma vitamin A (retinol) with risk of ocular toxicity (section 4.4)
  • Elevated transaminases (common); serious drug-induced liver injury, including cases with onset up to 1 year (sections 4.4, 4.8)

Interactions

  • Antithrombotic medicinal products, antiplatelet medicinal products and medicinal products that may lower platelet count (e.g. acetylsalicylic acid, clopidogrel, warfarin, heparin, low-molecular weight heparins, rivaroxaban, apixaban, dabigatran) - use with caution (section 4.5)
  • Nephrotoxic medicinal products and other medicines that may impair renal function (e.g. sulfonamides, aldosterone antagonists, anilides, natural opium alkaloids and other opioids) - use with caution; no systematic assessment has been conducted (section 4.5)

Monitoring

  • Platelet count every 2 weeks during the entire course of treatment and for 8 weeks after discontinuation; more frequently according to SPC Table 1 (sections 4.2, 4.4)
  • UPCR and eGFR every 3 months or more frequently as clinically indicated, and for 8 weeks after discontinuation; every 4 weeks if UPCR >= twice the upper limit of normal or eGFR < 60 ml/min confirmed on repeat testing (section 4.4)
  • Consider pausing dosing for an eGFR decrease > 30% without alternative explanation; pause dosing if UPCR >= 2 g/g (226 mg/mmol) is confirmed on repeat testing while evaluating for acute glomerulonephritis (section 4.4)
  • Plasma vitamin A (retinol) before initiation; ophthalmological assessment if ocular symptoms of vitamin A deficiency (reduced night vision, persistent dry eyes, corneal changes) (section 4.4)
  • Liver function before initiation; hepatic enzymes 4 months after initiation and annually thereafter or more frequently as clinically indicated; prompt evaluation, preferably within 72 hours, if symptoms of liver injury (section 4.4)
  • Signs of unusual or prolonged bleeding, neck stiffness or atypical severe headache - report immediately (section 4.4)

Clinical monograph

How it works

It is an antisense oligonucleotide that binds transthyretin messenger RNA and promotes its degradation, lowering production of both mutant and wild-type transthyretin protein.

Prescribing in practice

  • It can cause severe thrombocytopenia and glomerulonephritis, so platelet count and renal function must be monitored regularly and the drug withheld for significant abnormalities.
  • It is contraindicated where platelet counts are below the recommended threshold, and bleeding precautions apply.
  • Vitamin A supplementation is generally recommended because transthyretin lowering reduces serum vitamin A.

Monitoring

Monitor platelet count and renal function (including urine protein) regularly throughout treatment to detect thrombocytopenia and glomerulonephritis early.

Counselling the patient

  • Report any unusual bruising, bleeding, neck stiffness or rash promptly.
  • Attend all scheduled blood and urine tests, which are essential for safety.
  • Take any recommended vitamin A supplement as advised.

Evidence & guidelines

Inotersen efficacy in hereditary transthyretin amyloid polyneuropathy was demonstrated in the NEURO-TTR randomised controlled trial.

Reference: NICE HST10; SmPC; Drug verified in RxNorm (NLM); confirm dosing against the manufacturer SPC (eMC). Verify against your local formulary and current prescribing references before prescribing. The structured dose values shown have been reviewed by a clinician. Monograph status: clinician-reviewed (2026-07-04).

Related

Curated clinical cross-links plus same-class fallbacks.

Pathways