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. Women of child-bearing potential have to use effective contraception during treatment with inotersen.
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. 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 inotersen therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
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.
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.
Inotersen has no or negligible influence on the ability to drive and use machines.
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%).
The following table 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).
List of adverse reactions in clinical studies and post-marketing sources:
| 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 |
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.
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.
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 (Cmax), 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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.