TEGSEDI Solution for injection Ref.[116635] Active ingredients: Inotersen

Thrombocytopenia

Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia at any time during treatment (see section 4.8). Platelet count should be monitored every 2 weeks during the entire course of treatment with inotersen and for 8 weeks following discontinuation of treatment. Recommendations for adjustments to monitoring frequency and inotersen dosing are specified in Table 1 (see section 4.2).

Patients should be instructed to report to their physician immediately if they experience any signs of unusual or prolonged bleeding (e.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.

Special caution should be used in elderly patients, in patients taking antithrombotic medicinal products, antiplatelet medicinal products, or medicinal products that may lower platelet count (see section 4.5), and in patients with prior history of major bleeding events.

Glomerulonephritis/renal function decline

Glomerulonephritis has occurred in patients treated with inotersen (see section 4.8). Renal function decline has also been observed in a number of subjects without signs of glomerulonephritis (see section 4.8).

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. If glomerulonephritis is excluded, dosing may be resumed if clinically indicated and following improvement of renal function (see section 4.3).

Early initiation of immunosuppressive therapy should be considered if a diagnosis of glomerulonephritis is confirmed.

Caution should be used with nephrotoxic medicinal products and other medicinal products that may impair renal function (see section 4.5).

Vitamin A deficiency

Based on the mechanism of action, inotersen is expected to reduce plasma vitamin A (retinol) below normal levels (see section 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. During the first 60 days of pregnancy, both too high and too low vitamin A levels may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before treatment initiation and women of childbearing potential should practise effective contraception (see section 4.6). If a woman intends to become pregnant, inotersen and vitamin A supplementation should be discontinued and plasma vitamin A levels should be monitored and have returned to normal before conception is attempted.

In the event of an unplanned pregnancy, inotersen should be discontinued. Due to the long half-life of inotersen (see section 5.2), a vitamin A deficit may even develop after cessation of treatment. No recommendation can be given whether to continue or discontinue vitamin A supplementation during the first trimester of an unplanned pregnancy. If vitamin A supplementation is continued, the daily dose should not exceed 3 000 IU per day, due to the lack of data supporting higher doses. Thereafter, vitamin A supplementation of 3 000 IU per day should be resumed in the second and third trimester if plasma retinol levels have not yet returned to normal, because of the increased risk of vitamin A deficiency in the third trimester.

It is not known whether vitamin A supplementation in pregnancy will be sufficient to prevent vitamin A deficiency if the pregnant female continues to receive inotersen. However, increasing vitamin A supplementation to above 3 000 IU per day during pregnancy is unlikely to correct plasma retinol levels due to the mechanism of action of inotersen and may be harmful to the mother and foetus.

Liver monitoring and drug-induced liver injury

Elevated transaminases occur commonly in patients treated with inotersen. Serious cases of drug induced liver injury (DILI) have also been reported, including cases with a long time to onset (up to 1 year). Liver function should be assessed before initiating treatment with inotersen. Hepatic enzymes should be measured 4 months after initiation of treatment with inotersen and annually thereafter or more frequently as clinically indicated. Prompt clinical evaluation and measurement of liver function tests should be performed preferably within 72 hours in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Dose interruption should be considered until clinical and liver function evaluation is performed. If a patient is suspected to have developed liver injury induced by inotersen, inotersen should be permanently discontinued.

Inotersen must not be used in patients with severe hepatic impairment (see sections 4.2 and 4.3).

Liver transplant rejection

Inotersen was not evaluated in patients undergoing liver transplantation in clinical trials (section 4.2). Cases of liver transplant rejection have been reported in patients treated with inotersen. Patients with a prior liver transplant should be monitored for signs and symptoms of transplant rejection during treatment with inotersen. In these patients liver function tests should be performed monthly. Discontinuation of inotersen should be considered in patients who develop liver transplant rejection during treatment.

Precautions prior to initiation of inotersen

Platelet count, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), hepatic enzymes, pregnancy and vitamin A levels should be measured prior to treatment with Tegsedi.

Transient increases of C-reactive protein (CRP) and platelet levels may occur in some patients after initiation of inotersen. This reaction typically resolves spontaneously after a few days of treatment.

Sodium Content

This medicinal product contains less than 1 mmol sodium (23 mg) per 1.5 mL, that is to say essentially "sodium free".

Caution should be used with antithrombotic medicinal products, antiplatelet medicinal products, and medicinal products that may lower platelet count, for example acetylsalicylic acid, clopidogrel, warfarin, heparin, low-molecular weight heparins, Factor Xa inhibitors such as rivaroxaban and apixaban, and thrombin inhibitors such as dabigatran (see sections 4.2 and 4.4).

Caution should be exercised with concomitant use of nephrotoxic medicinal products and other medicines that may impair renal function, such as sulfonamides, aldosterone antagonists, anilides, natural opium alkaloids and other opioids (see section 4.4). A systematic assessment of co-administration of inotersen and potentially nephrotoxic medicinal products has not been conducted.

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 (see section 4.4). 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 (see section 5.3). 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. Women of child-bearing potential have to use effective contraception during treatment with inotersen.

Breast-feeding

It is unknown whether inotersen/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of inotersen metabolites in milk (see section 5.3). 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.

Fertility

There is no information available on the effects of inotersen on human fertility. Animal studies did not indicate any impact of inotersen on male or female fertility.

Tegsedi has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequently observed adverse reactions during treatment with inotersen were events associated with injection site reactions (50.9%). Other most commonly reported adverse reactions with inotersen were nausea (31.3%), headache (23.2%), pyrexia (19.6%), peripheral oedema (18.8%), chills (17.9%), vomiting (15.2%), anaemia (13.4%), thrombocytopenia (13.4%) and platelet count decreased (10.7%).

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:

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. In the Phase 3, NEURO-TTR trial, platelet count reductions to below normal (140 x 10⁹/L) were observed in 54% of patients treated with inotersen and 13% of placebo patients; reductions to below 100 x 10⁹/L were observed in 23% of patients treated with inotersen and 2% of the patients receiving placebo; confirmed platelet counts of <75 x 10⁹/L were observed in 10.7% of inotersen-treated patients. Three (3%) patients developed platelet counts <25 x 10⁹/L; one of these patients experienced a fatal intracranial haemorrhage. Patients should be monitored for thrombocytopenia during treatment with inotersen (see section 4.4).

Immunogenicity

In the pivotal Phase ⅔ study, 30.4% of patients treated with inotersen tested positive for anti-drug antibodies following 15 months of treatment. Development of anti-drug antibodies to inotersen was characterised by late onset (median onset >200 days) and low titer (median peak titer of 284 in the pivotal study). No effect on the pharmacokinetic properties (maximum plasma concentration (C_max), area under the curve (AUC) or half-life) and efficacy of inotersen was observed in the presence of anti-drug antibodies, but patients with anti-drug antibodies had more reactions at the injection site.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.