Tegsedi

Treatment should be initiated by and remain under the supervision of a physician experienced in the treatment of patients with hereditary transthyretin amyloidosis. Posology The recommended dose is 284 mg inotersen by subcutaneous injection.

Doses should be administered once every week. For consistency of dosing, patients should be instructed to receive the injection on the same day every week. Dose adjustment in case of reduction in platelet count Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia.

Dosing should be adjusted according to laboratory values as follows:

Table 1 . Inotersen monitoring and dosing recommendations according to platelet count Platelet count (x 109/L) Monitoring frequency Dosing > 100 Every 2 weeks Weekly dosing should be continued. ≥ 75 to < 100* Every week Dosing frequency should be reduced to 284 mg every 2 weeks.

3 < 75* Twice weekly until 3 successive values above 75 then weekly monitoring. Dosing should be paused until 3 successive values > 100. On reinitiation of treatment dose frequency should be reduced to 284 mg every 2 weeks. < 50‡† Twice weekly until 3 successive values above 75 then weekly monitoring.

More frequent monitoring should be considered if additional risk factors for bleeding are present. Dosing should be paused until 3 successive values > 100. On reinitiation of treatment dose frequency should be reduced to 284 mg every 2 weeks.

Corticosteroids should be considered if additional risk factors for bleeding are present. < 25† Daily until 2 successive values above 25. Then twice weekly monitoring until 3 successive values above 75. Then weekly monitoring until stable.

Treatment should be discontinued. Corticosteroids recommended. * If the subsequent test confirms the initial test result, then monitoring frequency and dosing should be adjusted as recommended in the table. ‡ Additional risk factors for bleeding include age > 60 years, receiving anticoagulant or antiplatelet medicinal products, and /or prior history of major bleeding events.

† It is strongly recommended that, unless corticosteroids are contraindicated, the patient receives glucocorticoid therapy to reverse the platelet decline. Patients who discontinue therapy with inotersen due to platelet counts below 25 x 109/L should not reinitiate therapy.

9%). 7%). Tabulated summary of adverse reactions Table 2 presents the adverse drug reactions (ADRs) listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first.

Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each ADR is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known (cannot be estimated from the available data).

Table 2. List of adverse reactions in clinical studies and post-marketing sources 8 System Organ Class Very Common Common Uncommon Not known Blood and lymphatic system disorders Thrombocytopenia Anaemia Platelet count Decreased Eosinophilia Immune system disorders Hypersensitivity Metabolism and nutrition disorders Decreased appetite Nervous system disorders Headache Vascular disorders Orthostatic hypotension Hypotension Haematoma Gastrointestinal disorders Vomiting Nausea Hepatobiliary disorders Transaminases increased Drug-induced liver injury Skin and subcutaneous disorders Pruritus Rash Renal and urinary disorders Glomerulonephritis Proteinuria Renal failure Acute kidney injury Renal impairment General disorders and administration site conditions Pyrexia Chills Injection site reactions Peripheral oedema Influenza like illness Peripheral swelling Injection site discolouration Injury, poisoning and procedural complications Contusion Description of selected adverse reactions Injection site reactions The most frequently observed events included those associated with injection site reactions (injection site pain, erythema, pruritus, swelling, rash, induration, bruising and haemorrhage).

These events are usually either self-limiting or can be managed using symptomatic treatment. Thrombocytopenia Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia. 7% of inotersen-treated patients.

8). Platelet count should be monitored every 2 weeks during the entire course of treatment with inotersen and for 8 weeks following discontinuation of treatment. 2). g. petechia, spontaneous bruising, subconjunctival bleeding, nosebleeds, bleeding from the gums, blood in urine or stools, bleeding in the whites of eyes), neck stiffness or atypical severe headache because these symptoms may be caused by bleeding in the brain.

5), and in patients with prior history of major bleeding events. 8). 8). 5 UPCR and eGFR should be monitored every 3 months or more frequently, as clinically indicated, based on history of chronic kidney disease and/or renal amyloidosis.

UPCR and eGFR should be monitored for 8 weeks following discontinuation of treatment. Patients with UPCR more than or equal to twice the upper limit of normal, or eGFR < 60 ml/min, which is confirmed on repeat testing and in the absence of an alternative explanation, should be monitored every 4 weeks.

In the case of a decrease in eGFR > 30%, in the absence of an alternative explanation, pausing of inotersen dosing should be considered pending further evaluation of the cause. In the case of UPCR ≥ 2 g/g (226 mg/mmol), which is confirmed on repeat testing, dosing of inotersen should be paused while further evaluation for acute glomerulonephritis is performed.

Inotersen should permanently be discontinued if acute glomerulonephritis is confirmed. 3). Early initiation of immunosuppressive therapy should be considered if a diagnosis of glomerulonephritis is confirmed. 5). 1). Plasma vitamin A (retinol) levels below lower limit of normal should be corrected and any ocular symptoms or signs of vitamin A deficiency should have resolved prior to initiation of inotersen.

Patients receiving inotersen should take oral supplementation of approximately 3 000 IU vitamin A per day in order to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms consistent with vitamin A deficiency, including: reduced night vision or night blindness, persistent dry eyes, eye inflammation, corneal inflammation or ulceration, corneal thickening, corneal perforation.

1. Platelet count < 100 x 109/L prior to treatment. Urine protein to creatinine ratio (UPCR) ≥ 113 mg/mmol (1 g/g) prior to treatment. 73 m2 . Severe hepatic impairment.