Tegsedi

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See Section 4.8 for how to report adverse reactions 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tegsedi 284 mg solution for injection in pre-filled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 284 mg inotersen (as sodium). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection) 
 
Clear, colourless to pale yellow solution (pH 7.5 – 8.8) 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Tegsedi is indicated for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with 
hereditary transthyretin amyloidosis (hATTR). 
 
4.2 Posology and method of administration 
 
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 treatment recommendations for platelet count 
 
Platelet count (x109/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 

< 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 



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frequency should be reduced to 
284 mg every 2 weeks. 

< 50‡† 
 
 

Twice weekly until 3 successive 
values above 75 then weekly 
monitoring.   
Consider more frequent 
monitoring 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. 
Consider corticosteroids if 
additional risk factors for 
bleeding are present.   

< 25† Daily until 2 successive values 
above 25. Then monitor twice 
weekly 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.   
 
Missed doses 
If a dose of inotersen is missed, then the next dose should be administered as soon as possible, unless 
the next scheduled dose is within two days, in which case the missed dose should be skipped and the 
next dose administered as scheduled. 
 
Special populations 
 
Elderly 
No dose adjustment is required in patients aged 65 and over (see section 5.2). 
 
Renal impairment 
No dose adjustment is required for patients with mild or moderate renal impairment (see section 5.2).  
Inotersen should not be used in patients with a urine protein to creatinine ratio (UPCR) ≥ 113 
mg/mmol (1 g/g) or estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73m2 (see section 4.3).   
 
Because of the risk of glomerulonephritis and possible renal function decline, UPCR and eGFR should 
be monitored during treatment with inotersen (see section 4.4). If acute glomerulonephritis is 
confirmed, permanent discontinuation of the treatment should be considered. 
 
Hepatic impairment 
No dose adjustment is required for patients with mild or moderate hepatic impairment (see section 
5.2).  Inotersen must not be used in patients with severe hepatic impairment (see section 4.3). 
 
Patients undergoing liver transplant  
Inotersen has not been evaluated in patients undergoing liver transplant.  It is, therefore, recommended 
that dosing of inotersen should be discontinued in subjects undergoing liver transplantation.   
 
Paediatric population 
The safety and efficacy of inotersen in children and adolescents below 18 years of age have not been 
established. No data are available. 
 
Method of administration  
 
Subcutaneous use only. 



4 

 
The first injection administered by the patient or caregiver should be performed under the guidance of 
an appropriately qualified health care professional. Patients and/or caregivers should be trained in the 
subcutaneous administration of Tegsedi. 
 
Sites for injection include the abdomen, upper thigh region, or outer area of the upper arm. It is 
important to rotate sites for injection. If injected in the upper arm, the injection should be administered 
by another person. Injection should be avoided at the waistline and other sites where pressure or 
rubbing from clothing may occur. Tegsedi should not be injected into areas of skin disease or injury. 
Tattoos and scars should also be avoided. 
 
The pre-filled syringe should be allowed to reach room temperature prior to injection. It should be 
removed from refrigerated storage at least 30 minutes before use. Other warming methods should not 
be used. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

Platelet count < 100 x 109/L prior to treatment. 

Urine protein to creatinine ratio (UPCR) ≥ 113 mg/mmol (1 g/g) prior to treatment. 

Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73m2 . 

Severe hepatic impairment. 

4.4 Special warnings and precautions for use 
 
Thrombocytopenia 
 
Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia (see 
section 4.8). Platelet count should be monitored every 2 weeks during 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), neck stiffness or atypical severe headache. 
 
Special caution should be used in elderly patients, in patients taking anithrombotic 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. 
 



5 

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, incuding: 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 3000 IU per day, due to the lack of data supporting higher doses. Thereafter, 
vitamin A supplementation of 3000 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 3000 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 
 
Hepatic enzymes should be measured 4 months after initiation of treatment with inotersen and 
annually thereafter or more frequently as clinically indicated, in order to detect cases of hepatic 
impairment (see section 4.8).   
 

 
 
 



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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 
should be monitored for signs and symptoms of transplant rejection during treatment with Inotersen. 
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) 
and hepatic enzymes should be measured prior to treatment with Tegsedi.   
 
Transient increases of CRP and platelet levels may occur in some patients after initiation of inotersen.  
This reaction typically resolves spontaneously after a few days of treatment.   
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Caution should be used with anithrombotic medicinal products, antiplatelet medicinal products, and 
medicinal products that may lower platelet count, for example acetylsalicyclic acid, clopidogrel, 
warfarin, heparin, low-molecular weight heparins, Factor Xa inhibitors such as rivaroxaban and 
apixaban, and thrombin inhibitors such as dabigatran (see section 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 opiods (see section 4.4).  Although the population PK analysis did 
not identify clinically relevant effects of some nephrotoxic medicines on the clearance of inotersen or 
on the potential for an effect on renal function, a systematic assessment of co-administration of 
inotersen and potentially nephrotoxic medicinal products has not been conducted. 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 



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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. 
 
4.7 Effects on ability to drive and use machines 
 
Tegsedi has no or negligible influence on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
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%), anaemia (27.7%), headache (23.2%), pyrexia (19.6%), peripheral 
oedema (18.8%), chills (17.9%), vomiting (15.2%), thrombocytopenia (13.4%) and platelet count 
decreased (10.7%).   
 
Tabulated summary of adverse reactions 
 
Table 2 presents the adverse 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). 
 
Table 2. List of adverse reactions in clinical studies 
 

System Organ Class Very Common Common 

Blood and lymphatic system 
disorders 

Thrombocytopenia 
Anaemia 
Platelet count decreased 

Eosinophilia 

Metabolism and nutrition 
disorders 

 Decreased appetite 

Nervous system disorders Headache  

Vascular disorders  Orthostatic hypotension 
Hypotension 
Haematoma 

Gastrointestinal disorders Vomiting 
Nausea 

 

Hepatobiliary disorders  Transaminases increased 
 

Skin and subcutaneous 
disorders 

 Pruritus 
Rash 

Renal and urinary disorders  Glomerulonephritis 
Proteinuria 
Renal failure 



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System Organ Class Very Common Common 

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 events associated with injection site reactions (includes 
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). 
 
Glomerulonephritis / renal function decline 
Patients should be monitored for signs of increased proteinuria and reduction in eGFR during 
treatment with inotersen (see section 4.4).   
 
Immunogenicity 
 
In the pivotal Phase 2/3 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 (Cmax, 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. 
 
4.9 Overdose 
 
In the event of an overdose, supportive medical care should be provided including consulting with a 
healthcare professional and close observation of the clinical status of the patient. 
 
Platelet and renal function tests should be monitored regularly. 



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5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other Nervous System Drugs, ATC code: N07XX15 
 
Mechanism of action 
 
Inotersen is a 2′-O-2-methoxyethyl (2′-MOE) phosphorothioate antisense oligonucleotide (ASO) 
inhibitor of human transthyretin (TTR) production. The selective binding of inotersen to the TTR 
messenger RNA (mRNA) causes the degradation of both mutant and wild type (normal) TTR mRNA. 
This prevents the synthesis of TTR protein in the liver, resulting in significant reductions in the levels 
of mutated and wild type TTR protein secreted by the liver into the circulation.  
 
TTR is a carrier protein for retinol binding protein 4 (RBP4) which is the principal carrier of vitamin 
A (retinol).  Therefore, reduction in plasma TTR is expected to result in reduction of plasma retinol 
levels to below the lower limit of normal.   
 
Pharmacodynamic effects 
 
In the pivotal NEURO-TTR study, in the inotersen treatment group, robust reduction in circulating 
TTR levels was observed throughout the 15-month treatment period, with mean percent changes from 
baseline in serum TTR ranging from 68.41% to 74.03% (median range: 74.64% to 78.98%) from 
Week 13 to Week 65 (Figure 1). In the placebo group, mean serum TTR concentration decreased by 
8.50% at Week 3 and then remained fairly constant throughout the treatment period. 

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0

- 8 0

- 7 0

- 6 0

- 5 0

- 4 0

- 3 0

- 2 0

- 1 0

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S t u d y  W e e k

T
T

R

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I n o t e r s e n

 
Figure 1 Percent Change from Baseline in Serum TTR Over Time 
 
Clinical efficacy and safety 
 
The NEURO-TTR multicentre, double-blind, placebo-controlled trial was comprised of 172 treated 
patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).  The disease 
hATTR-PN is classified into 3 stages such that i) Stage 1 patients do not require assistance with 
ambulation, ii) Stage 2 patients do require assistance with ambulation, and iii) Stage 3 patients are 
bound to wheelchair.  Subjects with Stage 1 and Stage 2 hATTR-PN and an NIS ≥10 and ≤130 were 
recruited in the pivotal NEURO-TTR study. The study evaluated 284 mg inotersen administered as 
one subcutaneous injection once per week, for 65 weeks of treatment. Patients were randomised 2:1 to 
receive either inotersen or placebo. The primary efficacy endpoints were the change from baseline to 
Week 66 in the modified Neuropathy Impairment Score + 7 tests (mNIS+7) composite score and in the 
Norfolk Quality of Life – Diabetic Neuropathy (QoL-DN) questionnaire total score. Patients were 
stratified for stage of disease (Stage 1 versus Stage 2), TTR mutation (V30M versus non-V30M) and 
previous treatment with either tafamidis or diflunisal (yes versus no). Baseline demographic and 
disease characteristics are shown in Table 3. 



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Table 3. Baseline demographics 
 
 Placebo 

(N=60) 
Inotersen 
(N=112) 

Age (years), mean (SD) 59.5 (14.05) 59.0 (12.53) 
Age 65 years and older, n (%)   26 (43.3) 48 (42.9) 
Male, n (%) 41 (68.3) 77 (68.8) 
mNIS+7, mean (SD) 74.75 (39.003) 79.16 (36.958) 
Norfolk QoL-DN, mean (SD) 48.68 (26.746) 48.22 (27.503) 
Disease stage, n (%)    
 Stage 1 42 (70.0) 74 (66.1) 
 Stage 2 18 (30.0) 38 (33.9) 
V30M TTR mutation1, n (%)    
 Yes 33 (55.0) 56 (50.0) 
 No 27 (45.0) 56 (50.0) 
Previous treatment with tafamidis or diflunisal1, n (%)    
 Yes 36 (60.0) 63 (56.3) 
 No 24 (40.0) 49 (43.8) 
hATTR-CM2, n (%) 33 (55.0) 75 (66.4) 
hATTR-PN Disease Duration3 (months)   
 mean (SD) 64.0 (52.34) 63.9 (53.16) 
hATTR-CM Disease Duration3 (months)   
 mean (SD) 34.1 (29.33) 44.7 (58.00) 
1  Based on clinical database 
2  Defined as all patients with a diagnosis of hereditary transthyretin amyloidosis with 

cardiomyopathy (hATTR-CM) at study entry or left ventricular wall thickness >1.3 cm on 
echocardiogram without a known history of persistent hypertension 

3  Duration from symptom onset to informed consent date  
 
 
The changes from baseline in both primary endpoints (mNIS+7 and Norfolk QoL-DN) demonstrated 
statistically significant benefit in favour of inotersen treatment at Week 66 (Table 4).  Results across 
multiple disease characteristics [TTR mutation (V30M, non-V30M)], disease stage (Stage 1, Stage 2), 
previous treatment with tafamidis or diflunisal (yes, no), presence of hATTR-CM (yes, no) at Week 66 
showed statistically significant benefit in all subgroups based on mNIS+7 composite score and all but 
one of these subgroups (CM-Echo Set; p=0.067) based on Norfolk QoL-DN total score (Table 5).  
Furthermore, results across the components of mNIS+7 and domains of Norfolk QoL-DN composite 
scores were consistent with the primary endpoint analysis, showing benefit in motor, sensory and 
autonomic neuropathies (Figure 2). 
 
Table 4. Primary Endpoint Analysis mNIS+7 and Norfolk QoL-DN 
 

 

mNIS+7 Norfolk-QOL-DN 
Placebo 
(N=60) 

Inotersen 
(N=112) 

Placebo 
(N=60) 

Inotersen 
(N=112) 

Baseline 
   n 
   Mean (SD) 
 

 
60 

74.75 (39.003) 
 

 
112 

79.16 (36.958) 

 
59 

48.68 (26.746) 

 
111 

48.22 (27.503) 



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Week 66 Change 
   n 
   LSM (SE) 
   95% CI 
   Difference in LSM 
     (Tegsedi – Placebo) 
        95% CI 
        P-value 

 
60 

25.43 (3.225) 
19.11, 31.75 

 
112 

10.54 (2.397) 
5.85, 15.24 

 
-14.89 

-22.55, -7.22 
<0.001 

 
59 

12.94 (2.840) 
7.38, 18.51 

 
111 

4.38 (2.175) 
0.11, 8.64 

 
-8.56 

-15.42, -1.71 
0.015 

 
 
 
Table 5. Subgroup Analysis of mNIS+7 and Norfolk QoL-DN 
 mNIS+7 Norfolk QoL-DN 
  Change from Baseline 

Inotersen – Placebo  
 Change from Baseline 

Inotersen – Placebo  
Subgroup n 

(Placebo, 
Inotersen) 

LSM 
Difference 

(SE) 

P-value n 
(Placebo, 
Inotersen) 

LSM 
Difference 

(SE) 

P-value 

Week 66 
V30M 32, 58 -13.52 

(3.795) 
p<0.001 32, 58 -8.14 

(3.998) 
p=0.042 

Non-V30 28, 54 
 

-19.06 
(5.334) 

p<0.001 27, 53 -9.87  
(4.666) 

p=0.034 

Stage I 
Disease 

39, 74 
 

-12.13 
(3.838) 

P=0.002 38, 73 -8.44  
(3.706) 

p=0.023 

Stage II 
Disease 

21, 38 
 

-24.79 
(5.601) 

p<0.001 21, 38 -11.23  
(5.271) 

p=0.033 

Previous 
use of 
stabilisers 

33, 61 
 

-18.04 
(4.591) 

p<0.001 32, 60 -9.26  
(4.060) 

p=0.022 

Treatment 
naïve 

27, 51 
 

-14.87 
(4.377) 

p<0.001 27, 51 -10.21  
(4.659) 

p=0.028 

CM-Echo 
Set 

33, 75 
 

-14.94 
(4.083) 

p<0.001 33, 75 
 

-7.47  
(4.075) 

p=0.067 

Non-CM-
Echo Set 

27, 37 
 

-18.79 
(5.197) 

p<0.001 26, 36 -11.67 
(4.213) 

p=0.006 

 
 
 

 



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Figure 2 Difference in Least Squares Mean (LSM) Change from Baseline Between 

Treatment Groups in mNIS+7 and Components 
 
 
A responder analysis of mNIS+7 using thresholds ranging from a 0- to 30-point increase from baseline 
(using the safety set), showed the inotersen group had approximately a 2-fold higher response rate than 
the placebo group at each threshold tested, demonstrating consistency of response. A responder was 
defined as a subject who had a change from baseline that was less than or equal to the threshold value.   
Subjects that terminate the treatment early irrespective of the reason or have missing week 66 data are 
considered as non-responders.  Statistical significance in favour of inotersen was demonstrated at all 
thresholds beyond a 0-point change. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Tegsedi in all subsets of the paediatric population in transthyretin amyloidosis (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Following subcutaneous administration, inotersen is absorbed rapidly into systemic circulation in a 
dose-dependent fashion with the median time to maximum plasma concentrations (Cmax) of inotersen 
typically reached within 2 to 4 hours. 
 
Distribution 
 
Inotersen is highly bound to human plasma protein (> 94%) and the fraction bound is independent of 
drug concentration.  The apparent volume of distribution of inotersen at steady-state is 293 L in 
patients with hATTR.  The high volume of distribution suggests inotersen extensively distributes into 
tissues following SC administration. 
 
Biotransformation 
 
Inotersen is not a substrate for CYP450 metabolism, and is metabolised in tissues by endonucleases to 
form shorter inactive oligonucleotides that are the substrates for additional metabolism by 
exonucleases. Unchanged inotersen is the predominant circulating component. 
 
Elimination 
 
The elimination of inotersen involves both metabolism in tissues and excretion in urine. Both 
inotersen and its shorter oligonucleotide metabolites are excreted in human urine. Urinary recovery of 
the parent medicinal product is limited to less than 1% within the 24 hours post dose. Following 
subcutaneous administration, elimination half-life for inotersen is approximately 1 month. 
 
Special populations 
 
Based on the population pharmacokinetic analysis, age, body weight, sex or race has no clinically 
relevant effect on inotersen exposure.  Definitive assessments were limited in some cases as covariates 
were limited by the overall low numbers.   
 
Elderly population 
No overall differences in pharmacokinetics were observed between other adult and elderly patients.  
 
Renal impairment 



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A population pharmacokinetic analysis suggests that mild and moderate renal impairment has no 
clinically relevant effect on the systemic exposure of inotersen. No data are available in patients with 
severe renal impairment. 
 
Hepatic impairment 
The pharmacokinetics of inotersen in patients with hepatic impairment has not been studied.  Inotersen 
is not primarily cleared by metabolism in the liver, not a substrate for CYP450 oxidation, and 
metabolized broadly by nucleases in all tissues of distribution.  Thus, pharmacokinetics should not be 
altered in mild to moderate hepatic impairment.   
 
5.3 Preclinical safety data 
 
Toxicology 
 
Decreased platelet counts were observed in chronic toxicity studies in mice, rats and monkeys at 1.4 to 
2-fold the human AUC at the recommended therapeutic inotersen dose. Severe platelet declines in 
association with increased bleeding or bruising were observed in individual monkeys.  Platelet counts 
returned to normal when treatment was stopped but dropped to even lower levels when inotersen 
aministration was resumed.  This suggests an immunologically related mechanism.   
 
Extensive and persistent uptake of inotersen was observed by various cell types in multiple organs of 
all tested animal species including monocytes/macrophages, kidney proximal tubular epithelia, 
Kupffer cells of the liver, and histiocytic cell infiltrates in lymph nodes and injection sites. The kidney 
accumulation of inotersen was associated with proteinuria in rats at 13.4-fold the human AUC at the 
recommended therapeutic inotersen dose. In addition, reduced thymus weight due to lymphocyte 
depletion was observed in mice and rats. In monkeys, perivascular cell infiltration by 
lymphohistiocytic cells in multiple organs was noted. These pro-inflammatory organ changes were 
observed at 1.4 to 6.6-fold the human AUC at the recommeded therapeutic dose in all animal species 
tested and were accompanied by increases of various plasma cytokines/chemokines.  
 
Genotoxicity/ carcinogenicity 
 
Inotersen did not exhibit genotoxic potential in in vitro and in vivo and was not carcinogenic in 
transgenic rasH2 mice. 
 
Reproductive toxicology 
 
Inotersen showed no effects on fertility, embryo-foetal, or postnatal development in mice and rabbits 
at approximately 3-fold the maximum recommended human equivalent dose. Milk transfer of 
inotersen was low in mice. However, inotersen is not pharmacologically active in mice and rabbits.  
Consequently, only effects related to the chemistry of inotersen could be captured in these 
investigations.  Still, no effect on embryo-foetal development was noted with a mouse-specific 
analogue of inotersen in mice, which was associated with ~60% inhibition (individual range up to 90% 
reduction) of TTR mRNA expression. 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Water for injections 
Hydrochloric acid (for pH adjustment) 
Sodium hydroxide (for pH adjustment) 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 



14

6.3 Shelf life 

3 years. 

Tegsedi may be stored unrefrigerated for up to 6 weeks below 30 °C. If not used within 6 weeks, it 
should be discarded. 

6.4 Special precautions for storage 

Store in a refrigerator (2 °C – 8 °C).   

Do not freeze.    

Store in the original package in order to protect from light. 

6.5 Nature and contents of container  

1.5 mL solution in a clear Type 1 glass pre-filled syringe.  

Tray with tear-off lid.   

Pack sizes of 1 or 4 pre-filled syringes.  Not all pack sizes may be marketed.  

6.6 Special precautions for disposal and other handling 

Tegsedi should be inspected visually prior to administration. The solution should be clear and 
colourless to pale yellow. If the solution is cloudy or contains visible particulate matter, the contents 
must not be injected. 

Each pre-filled syringe should be used only once and then placed in a sharps disposal container for 
disposal. 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  

7. MARKETING AUTHORISATION HOLDER
Akcea Therapeutics Ireland Ltd 
Regus House, 
Harcourt Centre, Harcourt Road 
Dublin 2, Ireland 

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1296/001 
EU/1/18/1296/002 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 06 July 2018 

10. DATE OF REVISION OF THE TEXT



15 

 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 

A.          MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

B.          CONDITIONS OR RESTRICTIONS REGARDING SUPPLY  
AND USE 

C.         OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 
 

D.         CONDITIONS OR RESTRICTIONS WITH REGARD TO  
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



17 

A.         MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer responsible for batch release 

ABF Pharmaceutical Services GmbH 
Brunnerstraße 63/18-19 
1230 Vienna 
AUSTRIA 
 

B.        CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 

C.         OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING  
AUTHORISATION  

• Periodic safety update reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.  
 

D.         CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result 
of an important (pharmacovigilance or risk minimisation) milestone being reached.  

• Additional risk minimisation measures 
 

Prior to the launch of Tegsedi in each Member State (MS), the Marketing Authorisation Holder 
(MAH) must agree about the content and format of the educational materials, including 
communication media, distribution modalities, and any other aspects of the programme, with the 
National Competent Authority (NCA).  

The MAH shall ensure that in each MS where Tegsedi is marketed, all patients who are expected to 
been administered the products are provided with a patient alert card (wallet size), aiming at 
preventing and/or minimising the important identified risks of thrombocytopenia, glomerulonephritis, 
and the important potential risk of ocular toxicity due to vitamin A deficiency, and reminding patients: 



18 

• To carry the card with them at all times during the treatment and up to 8 weeks following 
treatment discontinuation; 

• The list of signs and symptoms of thrombocytopenia, glomerulonephritis, and ocular toxicity 
due to vitamin A deficiency, highlighting that these might be severe or life-threatening, and 
advising patients to call immediately their doctor or attend the emergency room if such signs 
and symptoms appear; 

• To undergo all blood or urine tests as arranged by their doctor;  

• To have a list of all other medicines they are using for any visit to a Health Care Professionals 
(HCP); 

In addition to a prompt to include the contact details of the patient’s physician and a call for reporting, 
the patient card should also:  

• Alert HCPs that the patient is taking Tegsedi, its indication and the key safety concerns; 

• Advise HCPs that, due to the risks of thrombocytopenia and glomerulonephritis, patients 
should have their platelet count monitored at least every 2 weeks, and urine to protein 
creatinine ratio and estimated glomerular filtration rate monitored at least every 3 months; 

• Advise HCPs that if the platelet count falls below 25 x 109/L, Tegsedi treatment should be 
permanently discontinued and corticosteroid therapy is recommended; 

• Advise HCPs that if glomerulonephritis is confirmed, Tegsedi treatment should be 
permanently discontinued and early initiation of immunosuppressive therapy should be 
considered. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 
 
 
 
 
 
 
 
 



21 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tegsedi 284 mg solution for injection in pre-filled syringe 
inotersen  
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 284 mg inotersen (as sodium). 
 
3. LIST OF EXCIPIENTS 
 
Also contains: hydrochloric acid, sodium hydroxide, water for injections.  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection  
1 pre-filled syringe 
4 pre-filled syringes 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
For single use only 
Lift here and pull to open 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  Do not freeze. 
Following distribution to the patient, can be stored 6 weeks below 30°C.  If not used, should be 
discarded.   
Store in the original package in order to protect from light. 
 



22 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Akcea Therapeutics Ireland Ltd 
Regus House, 
Harcourt Centre, Harcourt Road 
Dublin 2, Ireland 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1296/001 
EU/1/18/1296/002 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Tegsedi 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



23 

 
PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
TRAY TEAR-OFF LID  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tegsedi 284 mg solution for injection in pre-filled syringe 
inotersen  
 
2. NAME OF THE MARKETING AUTHORIZATION HOLDER 
 
Akcea Therapeutics 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. OTHER  
 
Subcutaneous use 

.  
1. Bend and snap  
 

 
2. Pull to open  
 
 
 
 
 



24 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Tegsedi 284 mg injection 
inotersen  
SC 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1.5 mL 
 
6. OTHER 
 
 
 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



26 

Package leaflet: Information for the user 
 

Tegsedi 284 mg solution for injection in pre-filled syringe 
inotersen 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor, pharmacist or or nurse. This includes any 

possible side effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What Tegsedi is and what it is used for  
2. What you need to know before you use Tegsedi   
3. How to use Tegsedi 
4. Possible side effects  
5. How to store Tegsedi   
6. Contents of the pack and other information 
 
 
1. What Tegsedi is and what it is used for 
 
Tegsedi contains the active substance inotersen.  It is used to treat adults with hereditary transthyretin 
amyloidosis.  Hereditary transthyretin amyloidosis is a genetic disease, which causes build-up of small 
fibres of a protein called transthyretin in the organs of your body stopping them from working 
properly. Tegsedi is used when the disease is causing symptoms of polyneuropathy (nerve damage). 
 
The active substance in Tegsedi, inotersen, is a type of medicine called an antisense oligonucleotide 
inhibitor. It works by reducing production of transthyretin by the liver and so lowers the risk of fibres 
of transthyretin being deposited in body organs and causing symptoms. 
 
 
2. What you need to know before you use Tegsedi 
 
Do not use Tegsedi if: 

- you are allergic to inotersen or any of the other ingredients of this medicine (listed in section 
6). 

- tests show you have excessively low numbers of platelets, the cells in your blood which stick 
together helping it clot 

- tests of kidney function or protein in the urine show signs of severe kidney problems 
- you have severe reduction in liver function (hepatic impairment) 

 
Warnings and precautions 

 
Before you begin treatment with Tegsedi, your doctor will measure your blood cells, liver function, 
kidney function, and protein levels in your urine. You will only be treated with Tegsedi if these are all 
at acceptable levels and your doctor will repeat these checks regularly during treatment.   
 



27 

 
Thrombocytopenia 
Tegsedi may reduce cells in the blood responsible for clotting of the blood (platelets), which may 
result in a condition called thrombocytopenia (see section 4).  When you do not have enough platelets, 
like in thrombocytopenia, your blood may not clot quickly enough to stop bleeding. This can lead to 
bruising as well as other more serious problems such as excessive bleeding and internal bleeding. 
Your doctor will check your blood for levels of platelets before treatment and regularly during 
treatment with Tegsedi.  If you stop taking Tegsedi then your blood levels should be checked 8 weeks 
after discontinuation.   
 
If you are taking any medicines that can lower platelet count or stop blood from clotting, for example 
acetylsalicylic acid, clopidogrel, warfarin, heparin, rivoraxaban and dabigatran, you must tell your 
doctor before you use Tegsedi. 
 
You should see your doctor immediately if you have unexplained bruising or a rash of small patches 
of red appearing on the skin (called petechiae), bleeding from skin cuts that does not stop or oozes, 
bleeding from the gums or nose, blood in urine or stools, bleeding in the whites of your eyes.  Call for 
immediate help if you have stiffness of the neck or an unusual and severe headache because these 
symptoms may be caused by bleeding in the brain.   
 
Glomerulonephritis / kidney problems 
Glomerulonephritis is a condition of your kidneys, where they do not work properly due to 
inflammation and kidney damage. Some patients treated with inotersen have developed this condition. 
Symptoms of glomerulonephritis are foaming urine, pink or brown coloured urine, blood in the urine, 
and passing less urine than usual. 
Some patients treated with inotersen have also developed a decline in their kidney function without 
having had glomerulonephritis. 
Your doctor will check your kidney function before treatment and regularly during treatment with 
Tegsedi.  If you stop taking Tegsedi then your kidney function should be checked 8 weeks after 
discontinuation. If you develop glomerulonephritis, your doctor will treat you for this condition.  
 
If you are using any medicines that damage the kidney or affect kidney function, for example 
sulfonamides, aldosterone antagonists, and some types of painkillers, you should tell your doctor.  
 
Vitamin A deficiency 
Tegsedi can lower your body’s levels of vitamin A (also called retinol). You doctor will measure 
these, and if they are already low, this should be corrected and any symptoms resolved before you start 
treatment with Tegsedi. Symptoms of low vitamin A include: 

• dry eyes, poor vision, decrease in night vision, hazy or cloudy vision  
 
If you have problems with your sight or any other eye problems when you are using Tegsedi, you 
should speak to your doctor. Your doctor may refer you to an eye specialist for a check-up if it is 
necessary. 
 
Your doctor will ask you to take a daily vitamin A supplement during treatment with Tegsedi.   
 
Both excess and deficient levels of vitamin A can harm the development of your unborn child. 
Therefore women of child-bearing age should exclude any pregnancy, before treatment initiation with 
Tegsedi and should practise effective contraception (see section “Pregnancy and breast-feeding” 
below). 
 
If you are planning to become pregnant you should stop taking inotersen including vitamin A 
supplementation and ensure that your vitamin A levels have returned to normal before conception is 
attempted.   
 
If you have an unplanned pregnancy you should stop taking inotersen. Due to the prolonged activity of 
Tegsedi, however, your reduced vitamin A levels may persist. It is unknown if continuation of your 



28 

vitamin A supplementation with 3000 IU per day will be harmful to your unborn child in the first 
trimester of your pregnancy, but this dose should not be exceeded. You should resume the vitamin A 
supplementation during your second and third trimesters of your pregnancy if your vitamin A levels 
have not yet returned to normal, because of the increased risk of vitamin A deficiency in the third 
trimester. 
 
Liver Transplant Rejection 
Talk to your doctor before using TEGSEDI if you have previously received a liver transplant. Cases of 
liver transplant rejection have been reported in patients being treated with Tegsedi. Your doctor will 
monitor you regularly for this during treatment with Tegsedi.  
 
Children and adolescents 
Tegsedi should not be used in children and adolescents under 18 years old.  
 
Other medicines and Tegsedi 
Tell your doctor or pharmacist if you are taking, have recently taken or might use any other medicines.  
It is important that you tell your doctor if you are already being treated with any of the following: 
 

- Medicines to prevent blood clots or that lower the platelet numbers in your blood, e.g., 
acetylsalicylic acid, heparin, warfarin, clopidogrel, rivoraxaban and dabigatran. 

- Any medicines that may alter your kidney function or may damage the kidneys, e.g., 
sulfonamides (used as an antibacterial), anilides (used to treat fever, aches and pains),  
aldosterone antagonists (used as a diuretic) and natural opium alkaloids and other opiods (used 
for treatment of pain).   
 

Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask 
your doctor for advice before using this medicine.  
 
Women of child-bearing age 
Tegsedi will reduce the level of vitamin A in your body, which is important for normal foetal 
development during pregnancy. It is unknown if vitamin A supplementation can compensate for the 
risk of vitamin A deficiency that might affect your unborn child (see “Warnings and precautions” 
above). If you are a woman of child-bearing age, you should practise effective contraception and any 
pregnancy should be excluded before starting the treatment with Tegsedi. 
 
Pregnancy 
You should not use Tegsedi if you are pregnant, unless explicitly advised by your doctor. If you are of 
child-bearing age and intend to use Tegsedi, you should practise effective contraception. 
 
Breast-feeding 
Tegsedi may pass into breast milk. You should consult your doctor if you should either stop breast-
feeding or stop the treatment with Tegsedi. 
 
Driving and using machines 
Use of Tegsedi has not been shown to affect ability to drive or use machinery. 
 
 
3. How to use Tegsedi 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure. 
 
The recommended dose of Tegsedi is one dose of 284 mg inotersen.   
 
Doses should be administered once every week. All subsequent doses should be injected once weekly 
on the same day each week.  



29 

 
Route and method of administration  
 
Tegsedi is for injection under the skin (subcutaneous use) only. 
 
Instructions for use 
 
Before using your pre-filled syringe, your doctor should show you or your caregiver how to use it the 
right way. If you or your caregiver have any questions, ask your doctor. 
 
Read the Instructions for Use before you start using your pre-filled syringe and each time you get a 
repeat prescription. There may be new information. 
 
 
Guide to parts 

   
  
 
 

 

 
 
Each pre-filled syringe contains one dose and is for one-time use only. 

Before use 

Plunger 

Finger Grip 

Safety Spring 
(inside body) 

Body 
 

Needle Cap 

Needle 

Inspection 
Area 

After use 

After use, the safety spring 
is automatically activated 
and retracts the needle. 



30 

 
 

WARNINGS 

Do not remove needle cap until you have reached Step 6 of these instructions and are 
ready to inject Tegsedi; 
Do not share your syringe with another person or re-use your syringe; 
Do not use if the pre-filled syringe is dropped onto a hard surface or is damaged; 
Do not freeze the pre-filled syringe; 
If any of the above happens, throw away the pre-filled syringe in a puncture-resistant 
(sharps) container and use a new pre-filled syringe. 

PREPARATION 

1. Gather supplies 

- 1 Pre-filled syringe from the refrigerator 
- 1 Alcohol wipe (not supplied) 
- 1 Gauze pad or cotton ball (not supplied) 
- 1 Puncture-resistant (sharps) container (not supplied) 

 
Do not inject the medicine until you have gathered the supplies listed.  

2. Prepare to use your pre-filled syringe 

• Remove the plastic tray from the carton and check the expiry date.  Do not use if the 
expiry date has passed.   

• Let the pre-filled syringe reach room temperature (20 °C to 25 °C) for 30 minutes 
before injecting it.  Do not warm the pre-filled syringe in any other way. For example, 
do not warm in a microwave or hot water, or near other heat sources. 

• Remove the pre-filled syringe from the tray by holding onto the syringe body. 
 
Do not move the plunger.  

 

3. Check medicine in the pre-filled syringe 

 Look in the inspection area to 
check that the solution is clear 
and colourless or pale yellow. It 
is normal to see air bubbles in 
the solution. You do not need to 
do anything about it.  
Do not use if the solution looks 
cloudy, discoloured, or has 
particles.  
If the solution looks cloudy, 
discoloured or has particles, 
throw the pre-filled syringe 
away in a puncture resistant 
(sharps) container, and use a 
new pre-filled syringe. 

 



31 

 

4. Choose the injection site 

  
Choose an injection site on 
your abdomen (belly) or the 
front of your thigh. 
The injection site may also be 
on the outer area of the upper 
arm if Tegsedi is 
administered by a caregiver.  
Do not inject into the 3cm area 
around the belly-button (navel). 
Do not inject into the same 
site each time. 
Do not inject where skin is 
bruised, tender, red or hard. 
Do not inject into tattoos, 
scars or damaged skin. 
Do not inject through 
clothing. 

 

5. Clean the injection site 

 

 

Wash your hands with soap and 
water. 
Clean the injection site with an 
alcohol wipe in a circular motion. 
Let the skin air dry. 
Do not touch the area again 
before injecting. 

 



32 

 

INJECTION 

6. Remove the needle cap 

 Hold the pre-filled syringe by the 
body, with the needle facing away 
from you.  
Remove needle cap by pulling it 
straight off. Do not twist it off.  
You may see a drop of liquid at 
the end of the needle. This is 
normal.  
Keep your hands away from the 
plunger to avoid pushing the 
plunger before you are ready to 
inject.  
Do not remove the needle cap 
until right before you inject.  
Do not pull the cap off while 
holding the pre-filled syringe by 
the plunger. Always hold by the 
body of the syringe.  
Do not let the needle touch any 
surface.  
Do not remove any air bubbles 
from the pre-filled syringe.  
Do not put the needle cap back 
onto the pre-filled syringe. 

7. Insert the needle 
 

 

Hold the pre-filled syringe in 1 hand. 

Hold the skin around at the injection 
site as your healthcare provider has 
instructed you. You should either 
gently pinch the skin at the injection 
site or give the injection without 
pinching the skin. 

Slowly insert the needle into the 
chosen injection site at a 90° angle 
until it is fully inserted. 

Do not hold the pre-filled syringe 
by the plunger or push against the 
plunger to insert the needle. 
 

 



33 

 

8. Start the injection 
 
 
 

 

Slowly and firmly push the plunger 
all the way down until the medicine 
is injected. Make sure the needle 
stays fully inserted in the injection 
site while you are injecting the 
medicine.  

It is important to push the plunger 
all the way down.  

Your pre-filled syringe may make a 
click sound as you push the plunger 
down. This is normal. This does not 
mean that the injection is finished.  

The plunger can feel stiff towards 
the end of the injection. You may 
need to press a little harder on the 
plunger to make sure you have 
pushed it as far as it will go.  

Do not let go of the plunger.  
9. Push the plunger down 

 
 

 

 
Push firmly on the plunger at the end 
of the injection. Hold the plunger 
fully down and wait for 5 seconds. If 
you let go of the plunger too quickly, 
you may lose some of the medicine.  
The plunger will start to lift 
automatically which means that the 
plunger has been pushed fully down.  
Press down again if the plunger 
does not start to lift 
automatically. 

 
 

Slowly and firmly 
push the plunger 
down 
 

Hold 
the plunger 
fully down 
and wait 
5 seconds 
 Wait 

5 
seconds 

 



34 

 
 

10. Complete the injection 
 
 
 
 

 

Slowly lift up on the plunger and let 
the safety spring push the plunger up 
automatically.  
The needle should now be retracted 
safely inside the pre-filled syringe, 
and the safety mechanism spring 
visible on the outside of the plunger.  
When the plunger comes to a stop, 
your injection is complete.  
If the plunger does not rise up 
automatically when you release the 
pressure, it means the safety spring 
did not activate and you should push 
the plunger again but harder.  
Do not pull the plunger up by hand. 
Lift the whole pre-filled syringe 
straight up.  
Do not try to replace the cap on the 
retracted needle.  
Do not rub the injection site. 

DISPOSAL AND CARE 

Dispose of the used pre-filled syringe 

 

 
 

 
Put the used pre-filled syringe in a 
sharps disposal container right away 
after use. Do not throw away the 
pre-filled syringe in your household 
waste.  

 

 
 
If you use more Tegsedi than you should 
Contact your doctor or pharmacist, or go to a hospital emergency department immediately, even if you 
have no symptoms. 
 
If you forget to use Tegsedi  
If you miss your dose of Tegsedi, then you should have your next dose as soon as possible, unless the 
next scheduled dose is within two days, in which case the missed dose should be skipped and the next 
dose given at the scheduled time. 
 
Do not take a double dose to make up for a forgotten dose. 
 

Lift thumb 
slowly 
back up 
 



35 

If you stop using Tegsedi 
Do not stop using Tegsedi unless your doctor tells you to. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
If you get any of the following side effects, stop using Tegsedi and contact your doctor immediately:  

- Symptoms that could indicate glomerulonephritis, (where your kidneys do not work properly), 
such as foaming urine, pink or brown coloured urine, blood in the urine, or passing less urine 
than usual.   

- Symptoms that could indicate thrombocytopenia (where blood will not clot), such as 
unexplained bruising or a rash of small patches of red appearing on the skin (called petechiae), 
bleeding from skin cuts that does not stop or oozes, bleeding from the gums or nose, blood in 
urine or stools, or bleeding in the whites of your eyes.    

Call for immediate help if you have stiffness of the neck or an unusual and severe headache because 
these symptoms may be caused by bleeding in the brain.   
 
Other side effects 
 
Very common (may affect more than 1 in 10 people) 

- Reduction in red blood cells which can make the skin pale and cause weakness or 
breathlessness (anaemia)  

- Headache 
- Vomiting, or nausea (feeling sick)  
- Increase in body temperature 
- Feeling cold (chills) or shivering 
- Injection site pain, redness, itching or bruising 
- Swelling of the ankles, feet or fingers (peripheral oedema) 

 
Common (may affect up to 1 in 10 people) 

 
- An increase in the number of white blood cells called eosinophils in your blood 

(eosinophilia) 
- Decreased appetite  
- Feeling faint or dizzy, especially on standing up (low blood pressure, 

hypotension) 
- Bruising  
- Collection of blood within the tissues, that may look similar to severe bruising 

(haematoma) 
- Itching   
- Rash  
- Kidney damage leading to poor kidney function or kidney failure 
- Changes to your blood and urine test results (this may indicate infection or liver 

or kidney damage) 
- Flu like symptoms, such as high temperature, aches and chills (influenza-like 

illness) 
- Injection site swelling or skin discolouration 



36 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Tegsedi 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the carton, tray and on the pre-filled 
syringe after “EXP”.  The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C - 8°C).  
Do not freeze. 
Tegsedi may be stored unrefrigerated for up to 6 weeks at a temperature below 30°C.  If unrefrigerated 
and not used within 6 weeks then this medicine should be discarded.   
Store in the original package in order to protect from light. 
 
Do not use this medicine if you notice that the contents are cloudy or contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Tegsedi contains  

- The active substance is inotersen.  
-    Each pre-filled syringe contains 284mg of inotersen.  
- The other ingredients are water for injections, sodium hydroxide, and hydrochloric acid. 

 
What Tegsedi looks like and contents of the pack 
 
Tegsedi is a clear, colourless to pale yellow solution (pH 7.5 – 8.8) for injection 
(injection) in a pre-filled syringe.  
Tegsedi is available in pack sizes of either 1 or 4 pre-filled syringes. 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder  
 
Akcea Therapeutics Ireland Ltd 
Regus House, 
Harcourt Centre, Harcourt Road 
Dublin 2, Ireland 
 
Manufacturer 
 
ABF Pharmaceutical Services GmbH 
Brunnerstraße 63/18-19 
1230 Vienna 
Austria 
 
This leaflet was last revised in  
 



37 

 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET