Onpattro

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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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 
 
Onpattro 2 mg/mL concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL contains patisiran sodium equivalent to 2 mg patisiran. 
 
Each vial contains patisiran sodium equivalent to 10 mg patisiran formulated as lipid nanoparticles. 
 
Excipients with known effect 
 
Each mL of concentrate contains 3.99 mg sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
White to off-white, opalescent, homogeneous solution (pH: 6.3 – 7.5). 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Onpattro is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR 
amyloidosis) in adult patients with stage 1 or stage 2 polyneuropathy. 
 
4.2 Posology and method of administration 
 
Therapy should be initiated under the supervision of a physician knowledgeable in the management of 
amyloidosis. 
 
Posology 
 
The recommended dose of Onpattro is 300 micrograms per kg body weight administered via 
intravenous (IV) infusion once every 3 weeks. 
 
Dosing is based on actual body weight. For patients weighing ≥ 100 kg, the maximum recommended 
dose is 30 mg. 
 
Vitamin A supplementation at approximately 2500 IU vitamin A per day is advised for patients treated 
with Onpattro (see section 4.4). 
 



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Required premedication 
All patients should receive premedication prior to Onpattro administration to reduce the risk of 
infusion-related reactions (IRRs) (see section 4.4). Each of the following medicinal products should be 
given on the day of Onpattro infusion at least 60 minutes prior to the start of infusion: 
• Intravenous corticosteroid (dexamethasone 10 mg, or equivalent) 
• Oral paracetamol (500 mg) 
• Intravenous H1 blocker (diphenhydramine 50 mg, or equivalent) 
• Intravenous H2 blocker (ranitidine 50 mg, or equivalent) 
 
For premedications not available or not tolerated intravenously, equivalents may be administered 
orally. 
 
If clinically indicated, the corticosteroid may be tapered in decrements no greater than 2.5 mg to a 
minimum dose of 5 mg of dexamethasone (IV), or equivalent. The patient should receive at least 3 
consecutive IV infusions of Onpattro without experiencing IRRs before each reduction in 
corticosteroid premedication. 
 
Additional or higher doses of one or more of the premedications may be administered to reduce the 
risk of IRRs, if needed (see sections 4.4 and 4.8). 
 
Missed dose 
If a dose is missed, Onpattro should be administered as soon as possible. 
• If Onpattro is administered within 3 days of the missed dose, dosing should be continued 

according to the patient’s original schedule. 
• If Onpattro is administered more than 3 days after the missed dose, dosing should be continued 

every 3 weeks thereafter. 
 
Special populations 
 
Elderly patients 
No dose adjustment is required in patients ≥ 65 years of age (see section 5.2). 
 
Hepatic impairment 
No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤ 1 x ULN and 
AST > 1 x ULN, or bilirubin > 1.0 to 1.5 x ULN and any AST). Onpattro has not been studied in 
patients with moderate or severe hepatic impairment and should not be used in these patients unless 
the anticipated clinical benefit outweighs the potential risk (see section 5.2). 
 
Liver transplant 
Onpattro has not been studied in patients with prior liver transplant; however, no dose adjustments are 
considered necessary. 
 
Renal impairment 
No dose adjustment is necessary in patients with mild or moderate renal impairment (estimated 
glomerular filtration rate [eGFR] ≥ 30 to < 90 mL/min/1.73m2). Onpattro has not been studied in 
patients with severe renal impairment or end-stage renal disease and should not be used in these 
patients unless the anticipated clinical benefit outweighs the potential risk (see section 5.2). 
 
Paediatric population 
The safety and efficacy of Onpattro in children or adolescents < 18 years of age have not been 
established. No data are available. 
 
Method of administration 
 
Onpattro is for intravenous use. 
• Onpattro must be diluted prior to intravenous infusion (see instructions in section 6.6). 



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• A dedicated line with an infusion set containing a 1.2 micron polyethersulfone (PES) in-line 
infusion filter must be used. The infusion sets and lines must be free of di(2-
ethylhexyl)phthalate (DEHP). 

• The diluted solution of Onpattro should be infused intravenously over approximately 80 minutes 
at an initial infusion rate of approximately 1 mL/min for the first 15 minutes, followed by an 
increase to approximately 3 mL/min for the remainder of the infusion. The duration of infusion 
may be extended in the event of an IRR (see section 4.4). 

• Onpattro must be administered through a free-flowing venous access line. The infusion site 
should be monitored for possible infiltration during administration. Suspected extravasation 
should be managed according to local standard practice for non-vesicants. 

• The patient should be observed during the infusion and, if clinically indicated, following the 
infusion (see section 4.4). 

• After completion of the infusion, the intravenous administration set should be flushed with 
sodium chloride 9 mg/mL (0.9%) solution to ensure that all medicinal product has been 
administered. 

 
Infusion of Onpattro at home may be considered for patients who have tolerated at least 3 infusions 
well in the clinic. The decision for a patient to receive home infusions should be made after evaluation 
and recommendation by the treating physician. Home infusions should be performed by a healthcare 
professional. 
 
4.3 Contraindications 
 
Severe hypersensitivity (e.g., anaphylaxis) to the active substance or any of the excipients listed in 
section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Infusion-related reactions 
 
IRRs have been observed in patients treated with Onpattro. In patients experiencing an IRR, the 
majority experienced the first IRR within the first 2 infusions (see section 4.8). Across clinical studies, 
the most common symptoms (reported in ≥ 2% of patients) of IRRs were flushing, back pain, nausea, 
abdominal pain, dyspnoea, and headache. IRRs may also include hypotension and syncope. 
 
 
To reduce the risk of IRRs, patients should receive premedications on the day of Onpattro infusion, at 
least 60 minutes prior to the start of infusion (see section 4.2). If an IRR occurs, slowing or 
interrupting the infusion and institution of medical management (e.g., corticosteroids or other 
symptomatic treatment) should be considered, as clinically indicated. If the infusion is interrupted, 
resumption of the infusion at a slower infusion rate may be considered after symptoms have resolved. 
The Onpattro infusion should be discontinued in the case of a serious or life-threatening IRR. 
 
Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher 
doses of one or more of the premedications with subsequent infusions to reduce the risk of IRRs. 
 
Vitamin A deficiency 
 
By reducing serum TTR protein, Onpattro treatment leads to a decrease in serum vitamin A (retinol) 
levels (see section 5.1). Serum vitamin A levels below the lower limit of normal should be corrected 
and any ocular symptoms or signs due to vitamin A deficiency should be evaluated prior to initiation 
of treatment with Onpattro. 
 
Patients receiving Onpattro should take oral supplementation of approximately 2500 IU vitamin A per 
day to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral for 
ophthalmological assessment is recommended if patients develop ocular symptoms suggestive of 



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vitamin A deficiency, including reduced night vision or night blindness, persistent dry eyes, eye 
inflammation, corneal inflammation or ulceration, corneal thickening or corneal perforation. 
 
Serum vitamin A levels should not be used to guide vitamin A supplementation during treatment with 
Onpattro (see section 4.5). 
 
During the first 60 days of pregnancy, both too high or too low vitamin A levels may be associated 
with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before 
initiating Onpattro and women of childbearing potential should practise effective contraception. If a 
woman intends to become pregnant, Onpattro and vitamin A supplementation should be discontinued 
and serum vitamin A levels should be monitored and have returned to normal before conception is 
attempted. 
 
In the event of an unplanned pregnancy, Onpattro should be discontinued (see section 4.6). Vitamin A 
supplementation should be discontinued during the first trimester, unless the pregnant woman has 
clinical signs of vitamin A deficiency. If such signs are present, vitamin A supplementation should not 
exceed 2500 IU per day. Thereafter, vitamin A supplementation of 2500 IU per day should be resumed 
in the second and third trimesters if serum vitamin A levels have not returned to normal, because of 
the increased risk of vitamin A deficiency in the third trimester. 
 
Excipients 
 
This medicinal product contains 3.99 mg sodium per mL, equivalent to 0.2% of the WHO 
recommended maximum daily intake of 2 g sodium for an adult. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No formal clinical drug interaction studies have been performed. Onpattro is not expected to be 
affected by inhibitors or inducers of cytochrome P450 enzymes or to cause drug-drug interactions, 
except for induction and time-dependent inhibition of CYP2B6 in vitro. The net effect on CYP2B6 
substrates (e.g., bupropion and efavirenz) in vivo is unknown. 
 
Vitamin A testing 
 
Serum TTR is a carrier of retinol binding protein, which facilitates transport of vitamin A in the blood. 
Treatment with Onpattro reduces serum TTR levels, which results in reduced levels of retinol binding 
protein and vitamin A in the serum. However, transport and tissue uptake of vitamin A can occur 
through alternative mechanisms in the absence of retinol binding protein. As a result, during treatment 
with Onpattro, laboratory tests for serum vitamin A do not reflect the total amount of vitamin A in the 
body and should not be used to guide vitamin A supplementation (see sections 4.4 and 5.1). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Treatment with Onpattro reduces serum levels of vitamin A. Both too high or too low vitamin A levels 
may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be 
excluded before initiation of treatment and women of childbearing potential should use effective 
contraception. If a woman intends to become pregnant, Onpattro and vitamin A supplementation 
should be discontinued and serum vitamin A levels should be monitored and have returned to normal 
before conception is attempted. 
 
Pregnancy 
 
There are no data on the use of Onpattro 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, Onpattro should not be used during pregnancy, unless the clinical 



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condition of the woman requires treatment. As a precautionary measure, vitamin A and thyroid 
stimulating hormone (TSH) levels should be obtained early in pregnancy (see section 5.3). Close 
monitoring of the foetus should be carried out in the event of an unplanned pregnancy, especially 
during the first trimester (see section 4.4). Women of childbearing potential have to use effective 
contraception during treatment with Onpattro. 
 
Breast-feeding 
 
It is unknown whether Onpattro is excreted in human milk. Available toxicological data in animals 
have shown excretion of small amounts of the lipid components DLin-MC3-DMA and 
PEG2000-C-DMG in milk (see section 5.3). 
 
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from 
Onpattro, taking into account the benefit of breast-feeding for the child and the benefit of therapy for 
the woman. 
 
Fertility 
 
There are no data on the effects of Onpattro on human fertility. No impact on male or female fertility 
was detected in animal studies (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
On the basis of the pharmacodynamic and pharmacokinetic profiles, Onpattro is considered to have no 
or negligible influence on the ability to drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most frequently occurring adverse reactions reported in Onpattro-treated patients were peripheral 
oedema (29.7%) and infusion-related reactions (18.9%). The only adverse reaction resulting in the 
discontinuation of Onpattro was an infusion-related reaction (0.7%). 
 
Tabulated list of adverse reactions 
 
The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ 
Class (SOC) by frequency. Within each frequency grouping, adverse reactions are presented in order 
of decreasing seriousness. The frequency of the adverse reactions is expressed according to the 
following categories: 
• Very common (≥ 1/10) 
• Common (≥ 1/100 to < 1/10) 
• Uncommon (≥ 1/1,000 to < 1/100) 
 



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Table 1: Adverse reactions reported for Onpattro 300 micrograms per kg 
System Organ Class Adverse Reaction Frequency 

Infections and infestations Bronchitis Common 
Sinusitis Common 
Rhinitis Common 

Immune system disorders Infusion-related reaction Very common 
Ear and labyrinth disorders Vertigo Common 
Respiratory, thoracic and mediastinal 
disorders Dyspnoea Common 

Gastrointestinal disorders  Dyspepsia Common 
Skin and subcutaneous tissue disorders Erythema Common 
Musculoskeletal and connective tissue 
disorders 

Arthralgia Common 
Muscle spasms Common 

General disorders and administration site 
conditions 

Peripheral oedema Very common 
Extravasation Uncommon 

 
Description of selected adverse reactions 
 
Infusion-related reactions 
Symptoms of IRRs include, but are not limited to: arthralgia or pain (including back, neck, or 
musculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal pain, 
dyspnoea or cough, chest discomfort or chest pain, headache, rash, chills, dizziness, fatigue, increased 
heart rate or palpitations, hypotension which may include syncope, hypertension, facial oedema. 

 
In clinical studies, all patients received premedication with a corticosteroid, paracetamol, and H1 and 
H2 blockers to reduce the risk of IRRs. In the double-blind placebo-controlled study, 18.9% of 
Onpattro-treated patients experienced IRRs, compared to 9.1% of placebo-treated patients. In 
Onpattro-treated patients, all IRRs were either mild (95.2%) or moderate (4.8%) in severity. Among 
Onpattro-treated patients who experienced an IRR, 78.6% experienced the first IRR within the first 
2 infusions. The frequency of IRRs decreased over time. Few IRRs led to infusion interruption. IRRs 
resulted in permanent discontinuation of Onpattro in < 1% of patients in clinical studies. For clinical 
management of IRRs, see section 4.4. 
 
Peripheral oedema 
In the placebo-controlled study, peripheral oedema was reported in 29.7% of Onpattro-treated patients 
and 22.1% of placebo-treated patients. All events were mild or moderate in severity and did not lead to 
treatment discontinuation. In Onpattro-treated patients, the events decreased in frequency over time. 
 
Extravasation 
Extravasation was observed in < 0.5% of infusions in clinical studies. Signs and symptoms included 
phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneous 
inflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain. 
 
Immunogenicity 
 
Anti-drug antibodies to Onpattro were evaluated by measuring antibodies specific to PEG2000-C-DMG, 
a lipid component exposed on the surface of Onpattro. In the placebo-controlled and open-label 
clinical studies, 7 of 194 (3.6%) patients with hATTR amyloidosis developed anti-drug antibodies 
during treatment with Onpattro. One additional patient had pre-existing anti-drug antibodies. Anti-
drug antibody titres were low and transient with no evidence of an effect on clinical efficacy, the 
safety profile, or the pharmacokinetic or pharmacodynamic profiles of Onpattro. 
 



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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 case of overdose, it is recommended that the patient be monitored for any signs or symptoms of 
adverse reactions and given symptomatic treatment, as appropriate. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other nervous System Drugs; ATC code: N07XX12. 
 
Mechanism of action 
 
Onpattro contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA) that 
specifically targets a genetically conserved sequence in the 3’ untranslated region of all mutant and 
wild-type TTR mRNA. Patisiran is formulated as lipid nanoparticles to deliver the siRNA to 
hepatocytes, the primary source of TTR protein in the circulation. Through a natural process called 
RNA interference (RNAi), patisiran causes the catalytic degradation of TTR mRNA in the liver, 
resulting in a reduction of serum TTR protein. 
 
Pharmacodynamic effects 
 
Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose with 
300 micrograms per kg Onpattro. With repeat dosing every 3 weeks, mean reductions of serum TTR 
after 9 and 18 months of treatment were 83% and 84%, respectively. Serum TTR reduction was 
maintained with continued dosing. 
 
Serum TTR is a carrier of retinol binding protein, which facilitates transport of vitamin A in the blood. 
Mean reductions in serum retinol binding protein of 45% and serum vitamin A of 62% were observed 
over 18 months (see sections 4.4 and 4.5). 
 
Clinical efficacy 
 
The efficacy of Onpattro was studied in a randomised, double-blind, placebo-controlled study in 225 
hATTR amyloidosis patients with a TTR mutation and symptomatic polyneuropathy. Patients were 
randomised 2:1 to receive 300 micrograms per kg Onpattro or placebo via intravenous infusion once 
every 3 weeks for 18 months. All patients received premedication with a corticosteroid, paracetamol, 
and H1 and H2 blockers. 
 
In the study, 148 patients received Onpattro and 77 patients received placebo. The median patient age 
at baseline was 62 (range, 24 to 83) years and 74% of patients were male, 26% were female. Thirty-
nine (39) different TTR mutations were represented; the most common (≥ 5%) were V30M (43%), 
A97S (9%), T60A (7%), E89Q (6%), and S50R (5%). Approximately 10% of patients had the V30M 
mutation and early onset of symptoms (< 50 years of age). At baseline, 46% of patients had stage 1 
disease (unimpaired ambulation; mostly mild sensory, motor and autonomic neuropathy in the lower 
limbs), and 53% had stage 2 disease (assistance with ambulation required; mostly moderate 
impairment progression to the lower limbs, upper limbs, and trunk). Approximately half (53%) of 
patients had prior treatment with tafamidis meglumine or diflunisal. Forty-nine percent (49%) and 
50% of patients had a New York Heart Association (NYHA) Class of I or II, respectively. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Approximately half of patients (56%) met pre-defined criteria for cardiac involvement (defined as 
baseline LV wall thickness ≥ 13 mm with no history of hypertension or aortic valve disease). Patient 
demographics and baseline characteristics were balanced between treatment groups, except that a 
higher proportion of patients in the Onpattro group had a non-V30M mutation (62% vs. 48%). Ninety-
three percent (93%) of Onpattro-treated and 62% of placebo-treated patients completed 18 months of 
the assigned treatment. 
 
The primary efficacy endpoint was the change from baseline to 18 months in modified Neuropathy 
Impairment Score +7 (mNIS+7). This endpoint is a composite measure of motor, sensory, and 
autonomic polyneuropathy including assessments of motor strength and reflexes, quantitative sensory 
testing, nerve conduction studies, and postural blood pressure, with the score ranging from 0 to 
304 points, where an increasing score indicates worsening impairment. 
 
A statistically significant benefit in mNIS+7 with Onpattro relative to placebo was observed at 18 
months (Table 2). Benefits relative to placebo were also observed across all mNIS+7 components. 
Changes were also seen at 9 months, the first post-baseline assessment in the study, where treatment 
with Onpattro led to a 16.0-point treatment difference, with a mean change from baseline 
of -2.0 points, compared to an increase of 14.0 points with placebo. In a threshold analysis of mNIS+7 
(change from baseline of < 0 points), 56.1% of Onpattro-treated patients versus 3.9% of placebo-
treated patients experienced improvement in mNIS+7 (p <0.001). 
 
Patients treated with Onpattro experienced statistically significant benefits in all secondary endpoints 
compared to patients who received placebo (all p <0.001) (Table 2). 
 
The key secondary endpoint was the change from baseline to 18 months in Norfolk Quality of Life-
Diabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN questionnaire (patient-reported) 
includes domains relating to small fibre, large fibre, and autonomic nerve function, symptoms, and 
activities of daily living, with the total score ranging from -4 to 136, where an increasing score 
indicates worsening quality of life. At 18 months, a benefit with Onpattro to placebo was observed 
across all domains of Norfolk QoL-DN, and 51.4% of Onpattro-treated patients experienced an 
improvement in quality of life (Norfolk QoL-DN change from baseline of < 0 points) compared to 
10.4% of placebo-treated patients. Improvement was observed at 9 months, the first post-baseline 
assessment in the study. 
 



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Table 2: Clinical Efficacy Results from the Placebo-Controlled Study  

Endpointa 

Baseline, Mean (SD) 
Change from Baseline at 

18 months, LS Mean 
(SEM) 

(Onpattro – 
Placebo) 

Treatment 
Difference, 
LS Mean 
(95% CI)  

p-value 
Onpattro 

N=148 
Placebo 

N=77 
Onpattro Placebo 

Primary 

mNIS+7b 80.9 (41.5) 74.6 (37.0) −6.0 (1.7) 28.0 (2.6) 
−34.0 

(−39.9, −28.1) 
p < 0.001 

Secondary 
Norfolk  
QoL-DNb 59.6 (28.2) 55.5 (24.3) −6.7 (1.8) 14.4 (2.7) 

−21.1 
(−27.2, −15.0) 

p < 0.001 

NIS-Wb 32.7 (25.2) 29.0 (23.0) 0.05 (1.3) 17.9 (2.0) 
−17.9 

(−22.3, −13.4) 
p < 0.001 

R-ODSc 29.7 (11.5) 29.8 (10.8) 0.0 (0.6) −8.9 (0.9) 
9.0 

(7.0, 10.9) 
p < 0.001 

10-metre walk 
test (m/sec)c 0.80 (0.40) 0.79 (0.32) 0.08 (0.02) −0.24 (0.04) 

0.31 
(0.23, 0.39) 

p < 0.001 

mBMId 970 (210) 990 (214) −3.7 (9.6) −119 (14.5) 
116 

(82, 149) 
p < 0.001 

COMPASS 
31b 30.6 (17.6) 30.3 (16.4) −5.3 (1.3) 2.2 (1.9) 

−7.5 
(−11.9, −3.2) 

p < 0.001 

SD, standard deviation; LS mean, least squares mean; SEM, standard error of the mean; CI, confidence interval, 
NIS-W, NIS-weakness (motor strength); R-ODS, Rasch-Built Overall Disability (patient reported ability to 
perform activities of daily living); 10-metre walk test (gait speed); mBMI, modified body mass index (nutritional 
status); COMPASS 31, Composite Autonomic Symptom Score 31 (patient reported symptom score) 
 
aAll endpoints analysed using the mixed-effect model repeated measures (MMRM) method. 
bA lower number indicates less impairment/fewer symptoms. 
cA higher number indicates less disability/less impairment.  
dmBMI: body mass index (BMI; kg/m2) multiplied by serum albumin (g/L); a higher number indicates better 
nutritional status; nutritional status favoured Onpattro as early as 3 months. 

 
Patients receiving Onpattro experienced similar benefits relative to placebo in mNIS+7 and Norfolk 
QoL-DN score across all subgroups including age, sex, race, region, NIS score, V30M mutation status, 
prior tafamidis meglumine or diflunisal use, disease stage, and patients with pre-defined cardiac 
involvement. Patients experienced benefit across all TTR mutations and the full range of disease 
severity studied. 
 
In patients with pre-defined cardiac involvement, centrally-assessed echocardiograms showed 
decreases in LV wall thickness (LS mean difference: −0.9 mm [95% CI −1.7, −0.2]) and longitudinal 
strain (LS mean difference: −1.37% [95% CI -2.48, -0.27]) with Onpattro treatment relative to 
placebo. N-terminal pro-B type natriuretic peptide (NT-proBNP) was 727 ng/L and 711 ng/L at 
baseline (geometric mean) in Onpattro-treated and placebo-treated patients, respectively. At 18 
months, the adjusted geometric mean ratio to baseline was 0.89 with Onpattro and 1.97 with placebo 
(ratio, 0.45; p < 0.001), representing a 55% difference in favour of Onpattro. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Onpattro in all subsets of the paediatric population in hATTR amyloidosis (see section 4.2 for 
information on paediatric use). 
 



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5.2 Pharmacokinetic properties 
 
The pharmacokinetic properties of Onpattro were characterised by measuring the plasma 
concentrations of patisiran and the lipid components DLin-MC3-DMA and PEG2000-C-DMG. 
 
Absorption 
 
Greater than 95% of patisiran in the circulation is associated with lipid nanoparticles. At the dose 
regimen of 300 micrograms per kg every 3 weeks, steady state was reached by 24 weeks of treatment. 
The estimated patisiran mean ± SD steady-state peak concentration (Cmax), trough concentration 
(Ctrough), and area under the curve (AUCτ) were 7.15 ± 2.14 µg/mL, 0.021 ± 0.044 µg/mL, and 
184 ± 159 µg·h/mL, respectively. The accumulation of AUCτ was 3.2-fold at steady-state compared to 
the first dose. 
 
The estimated DLin-MC3-DMA mean ± SD steady-state Cmax, Ctrough and AUCτ were 
40.2 ± 11.5 µg/mL, 1.75 ± 0.698 µg/mL, and 1403 ± 105 µg·h/mL, respectively. The accumulation of 
AUCτ was 1.76-fold at steady-state compared to the first dose. 
 
The estimated PEG2000-C-DMG mean ± SD steady-state Cmax, Ctrough and AUCτ were 
4.22 ± 1.22 µg/mL, 0.0236 ± 0.0093 µg/mL, and 145 ± 64.7 µg·h/mL, respectively. There was no 
accumulation of AUCτ at steady-state compared to the first dose. 
 
Distribution 
 
Plasma protein binding of Onpattro is low, with ≤ 2.1% binding observed in vitro with human serum 
albumin and human α1-acid glycoprotein. At the dose regimen of 300 micrograms per kg every 
3 weeks, the mean ± SD steady-state volume of distribution (Vss) of patisiran, DLin-MC3-DMA and 
PEG2000-C-DMG was 0.26 ± 0.20 L/kg, 0.47 ± 0.24 L/kg and 0.13 ± 0.05 L/kg, respectively. 
 
Biotransformation 
 
Patisiran is metabolized by nucleases to nucleotides of various lengths. DLin-MC3-DMA is primarily 
metabolised to 4-dimethylaminobutyric acid (DMBA) by hydrolysis. There is little to no metabolism 
of PEG2000-C-DMG. 
 
Elimination 
 
At the dose regimen of 300 micrograms per kg every 3 weeks, mean ± SD steady state plasma 
clearance (CLss) of patisiran was 3.0 ± 2.5 mL/h/kg. The mean ± SD terminal elimination half-life 
(t1/2β) of patisiran was 3.2 ± 1.8 days. Less than 1% of patisiran in the administered dose was recovered 
intact in urine. 
 
The estimated DLin-MC3-DMA mean ± SD steady-state CLss was 2.1 ± 0.8 mL/h/kg. Approximately 
5.5% of DLin-MC3-DMA was recovered after 96 hours as its metabolite (DMBA) in urine. 
 
The estimated PEG2000-C-DMG mean ± SD steady-state CLss was 2.1 ± 0.6 mL/h/kg. In rats and 
monkeys, PEG2000-C-DMG is eliminated unchanged in the bile. PEG2000-C-DMG excretion in humans 
was not measured. 
 
Linearity/non-linearity 
 
Exposure to patisiran and the lipid components (DLin-MC3-DMA and PEG2000-C-DMG) increased 
proportionally with increase in dose over the range evaluated in clinical studies (10 to 500 micrograms 
per kg). Patisiran and the lipid components exhibit linear and time-independent pharmacokinetics with 
chronic dosing at the dose regimen of 300 micrograms per kg every 3 weeks. 
 



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Pharmacokinetic/pharmacodynamic relationship(s) 
 
Increasing the dose of patisiran resulted in greater TTR reduction, with maximal reductions plateauing 
at patisiran exposures obtained with 300 micrograms per kg every 3 weeks dosing. 
 
Interactions 
 
The components of Onpattro are not inhibitors or inducers of cytochrome P450 enzymes or 
transporters, except for CYP2B6 (see Section 4.5). Patisiran is not a substrate of cytochrome P450 
enzymes. 
 
Special populations 
 
Gender and race 
Clinical studies did not identify significant differences in steady state pharmacokinetic parameters or 
TTR reduction according to gender or race (non-Caucasian vs. Caucasian). 
 
Weight 
No data are available for patients weighing ≥ 110 kg. 
 
Elderly patients 
In the placebo-controlled study, 62 (41.9%) patients treated with Onpattro were ≥ 65 years of age and 
9 (6.1%) patients were ≥ 75 years of age. There were no significant differences in steady state 
pharmacokinetic parameters or TTR reduction between patients < 65 years of age and ≥ 65 years of 
age. 
 
Hepatic impairment 
Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild hepatic 
impairment (bilirubin ≤ 1 x ULN and AST > 1 x ULN, or bilirubin > 1.0 to 1.5 x ULN and any AST) 
on patisiran exposure or TTR reduction compared to patients with normal hepatic function. Onpattro 
has not been studied in patients with moderate or severe hepatic impairment. 
 
Renal impairment 
Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate 
renal impairment (eGFR ≥ 30 to < 90 mL/min/1.73m2) on patisiran exposure or TTR reduction 
compared to subjects with normal renal function. Onpattro has not been studied in patients with severe 
renal impairment or end-stage renal disease. 
 
5.3 Preclinical safety data 
 
General toxicology 
 
Liver and spleen were the primary target organs of toxicity in both rats and monkeys. Intravenous 
administration of Onpattro led to increases in serum liver markers (ALT, AST, ALP, and/or total 
bilirubin) and histopathology findings in the liver (hepatocellular/single cell necrosis, inflammation, 
pigment deposition, and/or monocytic infiltration) at doses > 100 micrograms per kg every 4 weeks 
and > 1.0 mg/kg every 3 weeks in rats and monkeys, respectively. In spleen, lymphoid 
atrophy/necrosis and histiocytosis in the white pulp was observed in rats and hypocellularity of the red 
pulp was observed in monkeys. 
 
In general, all findings observed at the end of dosing in the rat and monkey toxicity studies had either 
a full recovery or were observed with reduced severity at the end of the 60-90 day recovery period, 
indicating at least partial reversibility. 
 



13 

Genotoxicity/Carcinogenicity 
 
Onpattro did not exhibit a genotoxic potential in vitro and in vivo and was not carcinogenic in 
transgenic rasH2 mice. 
 
Reproductive toxicity 
 
In rats, while there were parental decreases in serum TTR (≥ 90%), thyroxine (≥ 66%) and vitamin A 
(≥ 75%) levels using a rat specific surrogate to patisiran, no effects were found on male or female 
fertility, embryo-foetal development, or pre-/post-natal development. 
 
In rabbits, Onpattro generated spontaneous abortions, reduced embryo-foetal survival, and reduced 
foetal body weights at maternally toxic doses ≥ 1 mg/kg (HED 3.2 times the RHD). As patisiran is not 
pharmacologically active in rabbits, these effects are not due to reductions in TTR, thyroxine or 
vitamin A. 
 
Intravenous administration of Onpattro had no effect on male reproductive assessments in sexually 
mature cynomolgus monkeys. 
 
In lactating rats, patisiran was not present in milk, although small amounts of the lipid components 
DLin-MC3-DMA and PEG2000-C-DMG were present in milk (up to 7% of concomitant maternal 
plasma concentrations). There were no adverse effects on the pups. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
DLin-MC3-DMA 
((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino) butanoate) 
PEG2000-C-DMG (α-(3’-{[1,2-di(myristyloxy)propanoxy]carbonylamino}propyl)-ω-methoxy, 
polyoxyethylene) 
DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) 
Cholesterol 
Disodium hydrogen phosphate, heptahydrate 
Potassium dihydrogen phosphate, anhydrous 
Sodium chloride 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vials 
 
30 months. 
 
After dilution 
 
Chemical and physical in-use stability has been demonstrated for 16 hours at room temperature (up to 
30°C). From a microbiological point of view, it is recommended that the product should be used 
immediately. If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user and should not be longer than 16 hours at either 2°C to 8°C or room 
temperature (up to 30°C), including infusion time. 



14 

 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C to 8°C). 
Do not freeze. 
 
If refrigeration is not available, Onpattro can be stored at room temperature up to 25°C for up to 
14 days. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
5 mL concentrate in a Type I glass vial with a chlorobutyl stopper and an aluminium flip-off cap. Pack 
size of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
This medicinal product is for single-use only. 
 
Onpattro must be diluted with sodium chloride 9 mg/mL (0.9%) solution prior to intravenous infusion. 
The diluted solution for infusion should be prepared by a healthcare professional using aseptic 
technique as follows: 
• Remove Onpattro from the refrigerator. Do not shake or vortex. 
• Discard vial if it has been frozen. 
• Inspect visually for particulate matter and discolouration. Do not use if discolouration or foreign 

particles are present. Onpattro is a white to off-white, opalescent, homogeneous solution. A 
white to off-white coating may be observed on the inner surface of the vial, typically at the 
liquid-headspace interface. Product quality is not impacted by presence of the white to off-white 
coating. 

• Calculate the required volume of Onpattro based on the recommended weight-based dosage (see 
section 4.2). 

• Withdraw the entire contents of one or more vials into a single sterile syringe. 
• Filter Onpattro through a sterile 0.45 micron polyethersulfone (PES) syringe filter into a sterile 

container. 
• Withdraw the required volume of filtered Onpattro from the sterile container using a sterile 

syringe. 
• Dilute the required volume of filtered Onpattro into an infusion bag containing sodium chloride 

9 mg/mL (0.9%) solution for a total volume of 200 mL. Use infusion bags that are free of 
di(2-ethylhexyl)phthalate (DEHP). 

• Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other 
medicinal products. 

• Discard any unused portion of Onpattro. Any unused medicinal product or waste material 
should be disposed of in accordance with local requirements. 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Alnylam Netherlands B.V. 
Strawinskylaan 3051 
1077 ZX Amsterdam 
Netherlands 
 
 



15 

8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1320/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 August 2018 
 
10. DATE OF REVISION OF THE TEXT 
 
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(S) 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(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Alnylam Netherlands B.V. 
Strawinskylaan 3051 
1077 ZX Amsterdam 
Netherlands 
 
 

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 (PSURs) 
 
The requirements for submission of PSURs 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 (MAH) shall submit the first PSUR 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 marketing authorisation holder (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 Onpattro 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). 



18 

The MAH shall ensure that in each MS where Onpattro is marketed, all health care professionals 
(HCPs) and patients are provided with educational materials in order to ensure the safe and sustainable 
administration of the product in the home setting, aiming at preventing and/or minimising the important 
identified risk of Infusion Related Reactions (IRRs). 

 
The educational material for HCPs should include information about: 
• Suitability of the patient for home infusion; 
• Requirements for home infusion, including availability and timely administration of the 

appropriate premedication; 
• The appropriate infusion rate; 
• Signs and symptoms of IRRs; 
• Action to take in the event of an IRRs and in case of emergency; 
• Steps to consider to prevent further IRRs; 
• Reasons triggering HCPs to consider whether the patient should stop home infusions and return 

to the clinic to receive the infusions. 
 
The educational material for patients (a home infusion guide detailing the steps to undertake during 
home infusion) should include information about: 
• How the infusion is given; 
• The potential for IRRs to occur; 
• Signs and symptoms of IRRs; 
• Patients to inform immediately the HCP if they experience any of the signs and symptoms of 

IRRs. 
  



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 
 
Onpattro 2 mg/mL concentrate for solution for infusion 
patisiran 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL contains 2 mg patisiran. 
 
Each vial contains patisiran sodium equivalent to 10 mg patisiran formulated as lipid nanoparticles. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients 
 
DLin-MC3-DMA 
PEG2000-C-DMG 
DSPC 
Cholesterol 
Disodium hydrogen phosphate, heptahydrate 
Potassium dihydrogen phosphate, anhydrous 
Sodium chloride 
Water for injections 
 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
10 mg/5 mL 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use after dilution. 
Do not shake or vortex. 
For single use only. 
 
 
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. 
 
 



22 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
 
 
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 
 
Alnylam Netherlands B.V. 
Strawinskylaan 3051 
1077 ZX Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1320/001 
 
 
13. BATCH NUMBER 
 
Lot 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Onpattro 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



23 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Onpattro 2 mg/mL sterile concentrate 
patisiran 
IV use after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
Do not shake or vortex. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 mg/5 mL 
 
 
6. OTHER 
 
 
  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



25 

Package leaflet: Information for the patient 
 

Onpattro 2 mg/mL concentrate for solution for infusion 
patisiran 

 
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 are given 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 or nurse. 
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
 
1. What Onpattro is and what it is used for 
2. What you need to know before you are given Onpattro 
3. How Onpattro is given 
4. Possible side effects 
5. How to store Onpattro 
6. Contents of the pack and other information 
 
 
1. What Onpattro is and what it is used for 
 
The active substance in Onpattro is patisiran. 
 
Onpattro is a medicine that treats an illness which runs in families called hereditary ATTR (hATTR) 
amyloidosis. 
 
hATTR amyloidosis is caused by problems with a protein in the body called ‘transthyretin’ (TTR). 
• This protein is made mostly in the liver and carries vitamin A and other substances around the 

body. 
• In people with this illness, abnormally shaped TTR proteins clump together to make deposits 

called ‘amyloid’. 
• Amyloid can build up around the nerves, heart, and other places in the body, preventing them 

from working normally. This causes the symptoms of the illness. 
 
Onpattro works by lowering the amount of TTR protein that the liver makes. 
• This means there is less TTR protein in the blood that can form amyloid. 
• This can help to reduce the effects of this illness. 
 
Onpattro is used in adults only. 
 
 
2. What you need to know before you are given Onpattro 
 
You must not be given Onpattro 
• if you have ever had a severe allergic reaction to patisiran, or any of the other ingredients of this 

medicine (listed in section 6). If you are not sure, talk to your doctor or nurse before you are given 
Onpattro. 

 



26 

Warnings and precautions 
 
Infusion-related reactions 
 
Onpattro is given as a drip into a vein (called an ‘intravenous infusion’). Reactions to this infusion 
may happen during treatment with Onpattro. Before each infusion you will be given medicines that 
help to lower the chance of infusion-related reactions (see “Medicines given during treatment with 
Onpattro” in section 3). 
 
Tell your doctor or nurse straight away if you get any signs of an infusion-related reaction. These signs 
are listed at the beginning of section 4. 
 
If you have an infusion-related reaction, your doctor or nurse may slow down or stop your infusion, 
and you may need to take other medicines to control the symptoms. When these reactions stop, or get 
better, your doctor or nurse may decide to start the infusion again. 

 
Vitamin A deficiency 
 
Treatment with Onpattro lowers the amount of vitamin A in your blood. Your doctor will measure 
your vitamin A levels, and if they are too low they should have returned to normal and any symptoms 
due to vitamin A deficiency should have resolved before you start treatment with Onpattro. Symptoms 
of vitamin A deficiency may include: 
• Decrease in night vision, dry eyes, poor vision, hazy or cloudy vision 

 
If you have problems with your vision or any other eye problems whilst using Onpattro, you should 
talk 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 Onpattro. 
 
Both too high and too low levels of vitamin A can harm the development of your unborn child. 
Therefore, women of child-bearing age should not be pregnant when starting treatment with Onpattro 
and should practice effective contraception (see section “Pregnancy, breast-feeding and contraception” 
below). 
 
Tell your doctor if you are planning to become pregnant. Your doctor may tell you to stop taking 
Onpattro. Your doctor will ensure that your vitamin A levels have returned to normal before you try to 
become pregnant. 
 
Tell your doctor if you have an unplanned pregnancy. Your doctor may tell you to stop taking 
Onpattro. During the first 3 months of your pregnancy, your doctor may tell you to stop your vitamin 
A supplement. During the last 6 months of your pregnancy you should resume vitamin A 
supplementation if the vitamin A levels in your blood have not yet returned to normal, because of an 
increased risk of vitamin A deficiency during the last 3 months of your pregnancy. 
 
Children and adolescents 
Onpattro is not recommended in children and adolescents under 18 years of age. 
 
Other medicines and Onpattro 
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines. It is 
important to tell your doctor or nurse if you are taking any of the following medicines as your doctor 
may need to change the dose: 
• Bupropion, a medicine used to treat depression or to help you to stop smoking 
• Efavirenz, a medicine used to treat HIV infection and AIDS 
 
Pregnancy, breast-feeding and contraception 
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 starting this medicine. 



27 

 
Women of child-bearing age 
 
Onpattro will reduce the level of vitamin A in your blood, which is important for normal development 
of your unborn child. If you are a woman of child-bearing age, you should practice effective 
contraception during treatment with Onpattro. Talk to your doctor or nurse about suitable methods of 
contraception. Pregnancy should be excluded before starting treatment with Onpattro. 
 
Pregnancy 
 
You should not use Onpattro if you are pregnant, unless advised by your doctor. If you are of child-
bearing age and intend to use Onpattro, you should practise effective contraception. 
 
Breast-feeding 
 
Ingredients of Onpattro may pass into breast milk. Talk to your doctor about stopping breast-feeding 
or treatment with Onpattro. 
 
Driving and using machines 
Onpattro is believed to have no or negligible influence on the ability to drive or use machines. Your 
doctor will tell you whether your condition allows you to drive vehicles and use machines safely. 
 
Onpattro contains sodium 
This medicine contains 3.99 milligrams (mg) of sodium (main component of cooking/table salt) per 
millilitre (mL). This is 0.2% of the recommended maximum daily dietary intake of sodium for an 
adult. 
 
 
3. How Onpattro is given 
 
How much Onpattro is given 
• Your doctor will work out how much Onpattro to give you – this will depend on your body weight. 
• The usual dose of Onpattro is 300 micrograms per kilogram (kg) of body weight given once every 

3 weeks. 
 
How Onpattro is given 
• Onpattro will be given to you by a doctor or nurse. 
• It is given as a drip into a vein (‘intravenous infusion’) usually over about 80 minutes. 
 
If you do not have problems with your infusions in the clinic, your doctor may talk with you about a 
healthcare professional giving you your infusions at home. 
 
Medicines given during treatment with Onpattro 
Before each infusion of Onpattro, you will be given medicines that help to lower the risk of infusion-
related reactions. These include anti-histamines, a corticosteroid (a medicine that suppresses 
inflammation), and a pain reliever. 
 
How long to use Onpattro 
Your doctor will tell you how long you need to receive Onpattro. Do not stop treatment with Onpattro 
unless your doctor tells you to. 
 
If you are given more Onpattro than you should receive 
This medicine will be given to you by your doctor or nurse. In the unlikely event that you are given 
too much (an overdose) your doctor or nurse will check you for side effects. 
 



28 

If you miss your dose of Onpattro 
If you miss an appointment to have Onpattro, ask your doctor or nurse when to book your next 
treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Infusion-related reactions 
Infusion-related reactions are very common (may affect more than 1 in 10 people). 
 
Tell your doctor or nurse straight away if you get any of the following signs of an infusion-related 
reaction during treatment. The infusion may need to be slowed down or stopped, and you may need to 
take other medicines to manage the reaction. 
• Stomach pain 
• Feeling sick (nausea) 
• Body aches or pain, including pain in the back, neck, or joints 
• Headache 
• Feeling tired (fatigue) 
• Chills 
• Dizziness 
• Cough, feeling short of breath, or other breathing problems 
• Reddening of the face or body (flushing), warm skin, or rash 
• Chest discomfort or chest pain 
• Rapid heart rate 
• Low or high blood pressure; some patients have fainted during the infusion due to low blood 

pressure 
• Pain, redness, burning sensation, or swelling at or near the infusion site 
• Swelling of the face 
 
 
Other side effects 
Tell your doctor or nurse if you notice any of the following side effects: 
 
Very common: may affect more than 1 in 10 people 
• Swelling of the arms or legs (peripheral oedema) 
 
Common: may affect up to 1 in 10 people 
• Pain in the joints (arthralgia) 
• Muscle spasms 
• Indigestion (dyspepsia) 
• Shortness of breath (dyspnoea) 
• Redness of the skin (erythema) 
• Feeling dizzy or faint (vertigo) 
• Stuffy or runny nose (rhinitis) 
• Irritation or infection of the airways (sinusitis, bronchitis) 
 
Uncommon: may occur in up to 1 in 100 infusions 
• Leakage of the drug into the surrounding tissue at the site of infusion, which may cause swelling 

or redness 
 
Tell your doctor or nurse if you notice any of the side effects listed above. 
 



29 

Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. 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 Onpattro 
 
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 after ‘EXP’. The expiry 
date refers to the last day of that month. 
 
Store in a refrigerator (2°C to 8°C). Do not freeze. 
 
If refrigeration is not available, Onpattro can be stored at room temperature (up to 25°C) for up to 
14 days. 
 
Medicines should not be disposed of via wastewater or household waste. Your healthcare professional 
will throw away any medicines that are no longer being used. These measures will help protect the 
environment. 
 
 
6. Contents of the pack and other information 
 
What Onpattro contains 
• The active substance is patisiran. 
• Each mL contains patisiran sodium equivalent to 2 mg patisiran. 
• Each 5 mL vial contains patisiran sodium equivalent to 10 mg patisiran. 
• The other ingredients are DLin-MC3-DMA 

((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4- (dimethylamino) butanoate), 
PEG2000-C-DMG (α- (3’-{[1,2-di(myristyloxy)propanoxy]carbonylamino}propyl)-ω-methoxy, 
polyoxyethylene), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), cholesterol, disodium 
hydrogen phosphate, heptahydrate, potassium dihydrogen phosphate, anhydrous, sodium 
chloride, and water for injections (see “Onpattro contains sodium” in section 2). 

 
What Onpattro looks like and contents of the pack 
• Onpattro is a white to off-white, opalescent, homogeneous concentrate for solution for infusion. 
• Onpattro is supplied in cartons containing one vial each. 
 
Marketing Authorisation Holder and Manufacturer 
Alnylam Netherlands B.V. 
Strawinskylaan 3051 
1077 ZX Amsterdam 
Netherlands 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Alnylam Netherlands B.V. 
Tél/Tel: 0800 81 443 (+32 234 208 71) 
medinfo@alnylam.com 
 

Malta 
Genesis Pharma (Cyprus) Ltd 
Tel: +357 22769946 
medinfo@genesispharmagroup.com 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


30 

България 
Genesis Pharma Bulgaria EOOD 
Teл.: +359 2 969 3227 
medinfo@genesispharmagroup.com 
 

Nederland 
Alnylam Netherlands B.V. 
Tel: 08002820025 (+31 203697861) 
medinfo@alnylam.com 
 

Česká republika 
Alnylam Czech s.r.o. 
Tel: 800 050 450 (+420 234 092 195) 
medinfo@alnylam.com 
 

Norge 
Alnylam Sweden AB 
Tlf: 800 544 00 (+472 1405 657) 
medinfo@alnylam.com 
 

Danmark 
Alnylam Sweden AB 
Tlf: 433 105 15 (+45 787 453 01) 
medinfo@alnylam.com 
 

Österreich 
Alnylam Austria GmbH 
Tel: 0800070339 (+43 720 778 072) 
medinfo@alnylam.com 
 

Deutschland 
Alnylam Germany GmbH 
Tel: 08002569526 (+49 8920190112) 
medinfo@alnylam.com 
 

Portugal 
Alnylam Portugal 
Tel: 707201512 (+351 707502642) 
medinfo@alnylam.com 
 

Ελλάδα 
ΓΕΝΕΣΙΣ ΦΑΡΜΑ Α.Ε 
Τηλ: +30 210 87 71 500 
medinfo@genesispharmagroup.com 
 

România 
Genesis Biopharma Romania SRL 
Tel: +40 21 403 4074 
medinfo@genesispharmagroup.com 
 

España 
Alnylam Pharmaceuticals Spain SL 
Tel: 900810212 (+34 910603753) 
medinfo@alnylam.com 
 

Slovenija 
Genesis Pharma Adriatic d.o.o 
Tel: +385 1 5813 652 
medinfo@genesispharmagroup.com 
 

France 
Alnylam France SAS 
Tél: 0805542656 (+33 187650921) 
medinfo@alnylam.com 
 

Suomi/Finland 
Alnylam Sweden AB 
Puh/Tel: 0800 417 452 (+358 942 727 020) 
medinfo@alnylam.com 
 

Hrvatska 
Genesis Pharma Adriatic d.o.o 
Tel: +385 1 5813 652 
medinfo@genesispharmagroup.com 
 

Sverige 
Alnylam Sweden AB 
Tel: 020109162 (+46 842002641) 
medinfo@alnylam.com 
 

Italia 
Alnylam Italy S.r.l. 
Tel: 800 90 25 37 (+39 02 89 73 22 91) 
medinfo@alnylam.com 
 

United Kingdom 
Alnylam UK Ltd. 
Tel: 08001412569 (+44 1628 878592) 
medinfo@alnylam.com 
 

Κύπρος 
Genesis Pharma (Cyprus) Ltd 
Τηλ: +357 22769946 
medinfo@genesispharmagroup.com 
 

Eesti, Ireland, Ísland, Latvija, Lietuva, 
Magyarország, Polska, Slovenská republika 
Alnylam Netherlands B.V. 
Tel/Sími: +31 20 369 7861 
medinfo@alnylam.com 

Luxembourg/Luxemburg 
Alnylam Netherlands B.V. 
Tél/Tel: 80085235 (+352 203 014 48) 
medinfo@alnylam.com 
 

 

  
This leaflet was last revised in MM/YYYY. 



31 

 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
Required premedication 
 
All patients should receive premedication prior to Onpattro administration to reduce the risk of 
infusion-related reactions (IRRs). Each of the following medicinal products should be given on the 
day of Onpattro infusion at least 60 minutes prior to the start of infusion: 
• Intravenous corticosteroid (dexamethasone 10 mg, or equivalent) 
• Oral paracetamol (500 mg) 
• Intravenous H1 blocker (diphenhydramine 50 mg, or equivalent) 
• Intravenous H2 blocker (ranitidine 50 mg, or equivalent) 
 
For premedications not available or not tolerated intravenously, equivalents may be administered 
orally. 
 
If clinically indicated, the corticosteroid may be tapered in decrements no greater than 2.5 mg to a 
minimum dose of 5 mg of dexamethasone (intravenous, IV), or equivalent. The patient should receive 
at least 3 consecutive infusions of Onpattro without experiencing IRRs before each reduction in 
corticosteroid premedication. 
 
Additional or higher doses of one or more of the premedications may be administered to reduce the 
risk of IRRs, if needed. 
 
Preparation of the solution for infusion 
 
This medicinal product is for single-use only. 
 
Onpattro must be diluted with sodium chloride 9 mg/mL (0.9%) solution prior to intravenous infusion. 
The diluted solution for infusion should be prepared by a healthcare professional using aseptic 
technique as follows: 
• Remove Onpattro from the refrigerator. Do not shake or vortex. 
• Discard vial if it has been frozen. 
• Inspect visually for particulate matter and discolouration. Do not use if discolouration or foreign 

particles are present. Onpattro is a white to off-white, opalescent, homogeneous solution. A 
white to off-white coating may be observed on the inner surface of the vial, typically at the 
liquid-headspace interface. Product quality is not impacted by presence of the white to off-white 
coating. 

• Calculate the required volume of Onpattro based on the recommended weight-based dosage. 
• Withdraw the entire contents of one or more vials into a single sterile syringe. 
• Filter Onpattro through a sterile 0.45 micron polyethersulfone (PES) syringe filter into a sterile 

container. 
• Withdraw the required volume of filtered Onpattro from the sterile container using a sterile 

syringe. 
• Dilute the required volume of filtered Onpattro into an infusion bag containing sodium chloride 

9 mg/mL (0.9%) solution for a total volume of 200 mL. Use infusion bags that are free of di(2-
ethylhexyl)phthalate (DEHP). 



32 

• Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other 
medicinal products. 

• Discard any unused portion of Onpattro. Any unused medicinal product or waste material 
should be disposed of in accordance with local requirements. 

• Onpattro does not contain preservatives. The diluted solution should be administered 
immediately after preparation. If not used immediately, store the diluted solution in the infusion 
bag at room temperature (up to 30°C) or at 2°C to 8°C for up to 16 hours (including infusion 
time). Do not freeze. 

 
Administration 
 
Onpattro is for intravenous use. 
• Onpattro must be diluted prior to intravenous infusion. 
• A dedicated line with an infusion set containing a 1.2 micron PES in-line infusion filter must be 

used. The infusion sets must be free of di(2-ethylhexyl)phthalate (DEHP). 
• The diluted solution of Onpattro should be infused intravenously over approximately 

80 minutes at an initial infusion rate of approximately 1 mL/min for the first 15 minutes, 
followed by an increase to approximately 3 mL/min for the remainder of the infusion. The 
duration of infusion may be extended in the event of an IRR. 

• Onpattro must be administered through a secure and free-flowing venous access line. The 
infusion site should be monitored for possible infiltration during administration. Suspected 
extravasation should be managed according to local standard practice for non-vesicants. 

• The patient should be observed during the infusion and, if clinically indicated, following the 
infusion. 

• After completion of the infusion, the intravenous administration set should be flushed with 
sodium chloride 9 mg/mL (0.9%) solution to ensure that all medicinal product has been 
administered. 

  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) 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