ONPATTRO 2mg / ml perfusive solution concentrate medication leaflet

Onpattro 2 mg/mL concentrate for solution for infusion

Each mL contains patisiran sodium equivalent to 2 mg patisiran.

Each vial contains patisiran sodium equivalent to 10 mg patisiran formulated as lipid nanoparticles.

Each mL of concentrate contains 3.99 mg sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

White to off-white, opalescent, homogeneous solution (pH approximately 7).

Onpattro is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (hATTRamyloidosis) in adult patients with stage 1 or stage 2 polyneuropathy.

Therapy should be initiated under the supervision of a physician knowledgeable in the management ofamyloidosis.

The recommended dose of Onpattro is 300 micrograms per kg body weight administered viaintravenous (IV) infusion once every 3 weeks.

Dosing is based on actual body weight. For patients weighing ≥ 100 kg, the maximum recommendeddose is 30 mg.

Treatment should be initiated as early as possible after symptom onset (see section 5.1). The decisionto continue treatment in those patients whose disease progresses to stage 3 polyneuropathy should betaken at the discretion of the physician based on the overall benefit and risk assessment(see section 5.1).

Vitamin A supplementation at approximately 2 500 IU vitamin A per day is advised for patientstreated with Onpattro (see section 4.4).

Required premedication

All patients should receive premedication prior to Onpattro administration to reduce the risk ofinfusion-related reactions (IRRs) (see section 4.4). Each of the following medicinal products should begiven 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 (famotidine 20 mg, or equivalent)

For premedications not available or not tolerated intravenously, equivalents may be administeredorally.

If clinically indicated, the corticosteroid may be tapered in decrements no greater than 2.5 mg to aminimum dose of 5 mg of dexamethasone (IV), or equivalent. The patient should receive at least3 consecutive IV infusions of Onpattro without experiencing IRRs before each reduction incorticosteroid premedication.

Additional or higher doses of one or more of the premedications may be administered to reduce therisk of IRRs, if needed (see sections 4.4 and 4.8).

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 continuedaccording to the patient’s original schedule.

* If Onpattro is administered more than 3 days after the missed dose, dosing should be continuedevery 3 weeks thereafter.

No dose adjustment is required in patients ≥ 65 years of age (see section 5.2).

No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤ 1 x upper limitof normal [ULN] and aspartate aminotransferase [AST] > 1 x ULN, or bilirubin > 1.0 to 1.5 x ULNand any AST). Onpattro has not been studied in patients with moderate or severe hepatic impairmentand should not be used in these patients unless the anticipated clinical benefit outweighs the potentialrisk (see section 5.2).

No dose adjustment is necessary in patients with mild or moderate renal impairment (estimatedglomerular filtration rate [eGFR] ≥ 30 to < 90 mL/min/1.73m2). Onpattro has not been studied inpatients with severe renal impairment or end-stage renal disease and should not be used in thesepatients unless the anticipated clinical benefit outweighs the potential risk (see section 5.2).

The safety and efficacy of Onpattro in children or adolescents < 18 years of age have not beenestablished. No data are available.

Onpattro is for intravenous use.

* Onpattro must be diluted prior to intravenous infusion (see section 6.6).

* A dedicated line with an infusion set containing a 1.2 micron polyethersulfone (PES) in-lineinfusion 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 minutesat an initial infusion rate of approximately 1 mL/min for the first 15 minutes, followed by anincrease to approximately 3 mL/min for the remainder of the infusion. The duration of infusionmay 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 siteshould be monitored for possible infiltration during administration. Suspected extravasationshould be managed according to local standard practice for non-vesicants.

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

* After completion of the infusion, the intravenous administration set should be flushed withsodium chloride 9 mg/mL (0.9%) solution to ensure that all medicinal product has beenadministered.

Infusion of Onpattro at home may be considered for patients who have tolerated at least 3 infusionswell in the clinic. The decision for a patient to receive home infusions should be made after evaluationand recommendation by the treating physician. Home infusions should be performed by a healthcareprofessional.

Severe hypersensitivity (e.g., anaphylaxis) to the active substance or any of the excipients listed insection 6.1.

IRRs have been observed in patients treated with Onpattro. In patients experiencing an IRR, themajority 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, atleast 60 minutes prior to the start of infusion (see section 4.2). If an IRR occurs, slowing orinterrupting the infusion and institution of medical management (e.g., corticosteroids or othersymptomatic 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 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 higherdoses 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 correctedand any ocular symptoms or signs due to vitamin A deficiency should be evaluated prior to initiationof treatment.

Patients receiving Onpattro should take oral supplementation of approximately 2 500 IU vitamin A perday to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral forophthalmological assessment is recommended if patients develop ocular symptoms suggestive ofvitamin A deficiency, including reduced night vision or night blindness, persistent dry eyes, eyeinflammation, 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 associatedwith an increased risk of foetal malformation. Therefore, pregnancy should be excluded beforeinitiating Onpattro and women of childbearing potential should practise effective contraception. If awoman 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 isattempted.

In the event of an unplanned pregnancy, Onpattro should be discontinued (see section 4.6). Vitamin Asupplementation should be discontinued during the first trimester, unless the pregnant woman hasclinical signs of vitamin A deficiency. If such signs are present, vitamin A supplementation should notexceed 2 500 IU per day. Thereafter, vitamin A supplementation of 2 500 IU per day should beresumed 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.

This medicinal product contains 3.99 mg sodium per mL, equivalent to 0.2% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No formal clinical drug interaction studies have been performed. At doses higher than the clinicallyrelevant dose, induction and time-dependent inhibition of CYP2B6 was observed in vitro. The neteffect on CYP2B6 substrates (e.g., bupropion and efavirenz) in vivo is unknown.

Onpattro is not expected to cause interactions or be affected by inhibitors or inducers of cytochrome

P450 enzymes.

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 bindingprotein and vitamin A in the serum. However, transport and tissue uptake of vitamin A can occurthrough alternative mechanisms in the absence of retinol binding protein. As a result, during treatmentwith Onpattro, laboratory tests for serum vitamin A do not reflect the total amount of vitamin A in thebody and should not be used to guide vitamin A supplementation (see sections 4.4 and 5.1).

Treatment with Onpattro reduces serum levels of vitamin A. Both too high or too low vitamin A levelsmay be associated with an increased risk of foetal malformation. Therefore, pregnancy should beexcluded before initiation of treatment and women of childbearing potential should use effectivecontraception. If a woman intends to become pregnant, Onpattro and vitamin A supplementationshould be discontinued and serum vitamin A levels should be monitored and have returned to normalbefore conception is attempted.

There are no data on the use of Onpattro in pregnant women. Animal studies are insufficient withrespect to reproductive toxicity (see section 5.3). Due to the potential teratogenic risk arising fromunbalanced vitamin A levels, Onpattro should not be used during pregnancy, unless the clinicalcondition of the woman requires treatment. As a precautionary measure, vitamin A and thyroidstimulating hormone (TSH) levels should be obtained early in pregnancy (see section 5.3). Closemonitoring of the foetus should be carried out in the event of an unplanned pregnancy, especiallyduring the first trimester (see section 4.4). Women of childbearing potential have to use effectivecontraception during treatment with Onpattro.

It is unknown whether Onpattro is excreted in human milk. A risk to the breastfed newborn/infantcannot be excluded. Available toxicological data in animals have shown excretion of small amounts ofthe 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 forthe woman.

There are no data on the effects of Onpattro on human fertility. No impact on male or female fertilitywas detected in animal studies (see section 5.3).

On the basis of the pharmacodynamic and pharmacokinetic profiles, Onpattro is considered to have noor negligible influence on the ability to drive or use machines.

The most frequently occurring adverse reactions reported in Onpattro-treated patients were peripheraloedema (29.7%) and infusion-related reactions (18.9%). One patient (0.7%) discontinued treatmentduring clinical studies due to an infusion-related reaction.

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 orderof decreasing seriousness. The frequency of the adverse reactions is expressed according to thefollowing categories:

* Very common (≥ 1/10)

* Common (≥ 1/100 to < 1/10)

* Uncommon ( 1/1 000 to < 1/100)

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

Dyspnoea Commondisorders

Gastrointestinal disorders Dyspepsia Common

Skin and subcutaneous tissue disorders Erythema Common

Musculoskeletal and connective tissue Arthralgia Commondisorders Muscle spasms Common

General disorders and administration site Peripheral oedema Very commonconditions Extravasation Uncommon

Symptoms of IRRs include, but are not limited to: arthralgia or pain (including back, neck, ormusculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal pain,dyspnoea or cough, dysphonia, chest discomfort or chest pain, headache, rash, pruritus, 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 first2 infusions. The frequency of IRRs decreased over time. Some patients still experienced IRRs after18 months of treatment, and in a few patients IRRs continued to be frequent. Few IRRs led to infusioninterruption. IRRs resulted in permanent discontinuation of Onpattro in < 1% of patients in clinicalstudies. 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 patientsand 22.1% of placebo-treated patients. All events were mild or moderate in severity and did not lead totreatment discontinuation. In Onpattro-treated patients, the events decreased in frequency over time.

Extravasation was observed in < 0.5% of infusions in clinical studies. Signs and symptoms includedphlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneousinflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain.

Other special population(s)

In an open-label study in 23 hATTR amyloidosis patients with polyneuropathy progression post livertransplant, the safety profile of patisiran was consistent with previous clinical studies (see section 5.1).

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-labelclinical studies, 7 of 194 (3.6%) patients with hATTR amyloidosis developed anti-drug antibodiesduring 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, thesafety profile, or the pharmacokinetic or pharmacodynamic profiles of Onpattro.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, it is recommended that the patient be monitored for any signs or symptoms ofadverse reactions and given symptomatic treatment, as appropriate.

Pharmacotherapeutic group: Other nervous System Drugs; ATC code: N07XX12.

Onpattro contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA) thatspecifically targets a genetically conserved sequence in the 3’ untranslated region of all variant andwild-type TTR mRNA. Patisiran is formulated as lipid nanoparticles to deliver the siRNA tohepatocytes, 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.

Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose with300 micrograms per kg Onpattro. With repeat dosing every 3 weeks, mean reductions of serum TTRafter 9 and 18 months of treatment were 83% and 84%, respectively. Serum TTR reduction wasmaintained 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 observedover 18 months (see sections 4.4 and 4.5).

The efficacy of Onpattro was studied in a randomised, double-blind, placebo-controlled study in225 hATTR amyloidosis patients with a TTR mutation and symptomatic polyneuropathy. Patientswere randomised 2:1 to receive 300 micrograms per kg Onpattro or placebo via intravenous infusiononce 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 ageat 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 hadstage 1 disease (unimpaired ambulation; mostly mild sensory, motor and autonomic neuropathy in thelower limbs), and 53% had stage 2 disease (assistance with ambulation required; mostly moderateimpairment progression to the lower limbs, upper limbs, and trunk). Approximately half (53%) ofpatients had prior treatment with tafamidis meglumine or diflunisal. Forty-nine percent (49%) and50% of patients had a New York Heart Association (NYHA) Class of I or II, respectively.

Approximately half of patients (56%) met pre-defined criteria for cardiac involvement (defined asbaseline left ventricular [LV] wall thickness ≥ 13 mm with no history of hypertension or aortic valvedisease). 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 completed18 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, andautonomic polyneuropathy including assessments of motor strength and reflexes, quantitative sensorytesting, nerve conduction studies, and postural blood pressure, with the score ranging from 0 to304 points, where an increasing score indicates worsening impairment.

A statistically significant benefit in mNIS+7 with Onpattro relative to placebo was observed at18 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 treatmentwith Onpattro led to a 16.0-point treatment difference, with a mean change from baselineof -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 endpointscompared 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, andactivities of daily living, with the total score ranging from -4 to 136, where an increasing scoreindicates worsening quality of life. At 18 months, a benefit with Onpattro to placebo was observedacross all domains of Norfolk QoL-DN, and 51.4% of Onpattro-treated patients experienced animprovement in quality of life (Norfolk QoL-DN change from baseline of < 0 points) compared to10.4% of placebo-treated patients. Improvement was observed at 9 months, the first post-baselineassessment in the study.

Table 2: Clinical efficacy results from the placebo-controlled study

Change from baseline at (Onpattro -

Baseline, Mean (SD) 18 months, LS mean Placebo)(SEM) treatment

Endpointa p-valuedifference,

Onpattro Placebo

Onpattro Placebo LS mean

N=148 N=77 (95% CI)

Primary−34.0mNIS+7b 80.9 (41.5) 74.6 (37.0) −6.0 (1.7) 28.0 (2.6) p < 0.001(−39.9, −28.1)

Secondary

Norfolk −21.1b 59.6 (28.2) 55.5 (24.3) −6.7 (1.8) 14.4 (2.7) p < 0.001

QoL-DN (−27.2, −15.0)−17.9

NIS-Wb 32.7 (25.2) 29.0 (23.0) 0.05 (1.3) 17.9 (2.0) p < 0.001(−22.3, −13.4)9.0

R-ODSc 29.7 (11.5) 29.8 (10.8) 0.0 (0.6) −8.9 (0.9) p < 0.001(7.0, 10.9)10-metre walk 0.31c 0.80 (0.40) 0.79 (0.32) 0.08 (0.02) −0.24 (0.04) p < 0.001test (m/sec) (0.23, 0.39)mBMId 970 (210) 990 (214) −3.7 (9.6) −119 (14.5) p < 0.001(82, 149)

COMPASS −7.5b 30.6 (17.6) 30.3 (16.4) −5.3 (1.3) 2.2 (1.9) p < 0.00131 (−11.9, −3.2)

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 Score31 (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 indicatesbetter 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 cardiacinvolvement. Patients experienced benefit across all TTR mutations and the full range of diseaseseverity studied.

In patients with pre-defined cardiac involvement, centrally-assessed echocardiograms showeddecreases in LV wall thickness (LS mean difference: −0.9 mm [95% CI −1.7, −0.2]) and longitudinalstrain (LS mean difference: −1.37% [95% CI -2.48, -0.27]) with Onpattro treatment relative toplacebo. N-terminal pro-B type natriuretic peptide (NT-proBNP) was 727 ng/L and 711 ng/L atbaseline (geometric mean) in Onpattro-treated and placebo-treated patients, respectively. At18 months, the adjusted geometric mean ratio to baseline was 0.89 with Onpattro and 1.97 withplacebo (ratio, 0.45; p < 0.001), representing a 55% difference in favour of Onpattro.

Global open-label extension study

Of 218 patients who completed one of the two parent studies with patisiran (18-monthplacebo-controlled study [Study 004] or 2-year open-label study [Study 003]), 211 patients (25 priorpatisiran from Study 003, 49 prior placebo and 137 prior patisiran from Study 004) enrolled in a globalopen-label extension study (Study 006). All patients in Study 006 received 300 micrograms per kg ofpatisiran via IV infusion once every 3 weeks. At Study 006 baseline, for the prior (Study 004)patisiran and placebo groups, 42.3% and 28.6% had stage 1 disease, 51.8% and 55.1% had stage 2disease and 5.8% and 16.3% had stage 3 disease, respectively.

After initiation of patisiran in Study 006, clinical benefit was observed in patients who previouslyreceived placebo as demonstrated by stable measures of disease manifestations. Although thesepatients achieved stabilisation of their disease, measures of disease manifestations remained worsecompared to the prior patisiran group, supporting the early initiation of patisiran treatment after theonset of symptoms. Continued treatment with patisiran through Year 3, across a range of diseasestages, resulted in continued benefit.

In an open-label study, 23 patients with hATTR amyloidosis and polyneuropathy progression afterreceiving a liver transplant were treated with patisiran at a dose of 300 micrograms per kg via IVinfusion once every 3 weeks. Median time from transplant to first patisiran dose was 9.4 years andmedian duration of patisiran treatment was 13.1 months. All patients received concomitantimmunosuppressants. The study demonstrated a statistically significant median reduction in serum

TTR levels from baseline of 91% (p < 0.001). Patients also showed stable or improved efficacyendpoints at Month 12 compared to baseline. This was consistent with the findings in theplacebo-controlled patisiran study.

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 forinformation on paediatric use).

The pharmacokinetic properties of Onpattro were characterised by measuring the plasmaconcentrations of patisiran and the lipid components DLin-MC3-DMA and PEG2000-C-DMG.

Greater than 95% of patisiran in the circulation is associated with lipid nanoparticles. At the doseregimen 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 (AUC) were 7.15 ± 2.14 µg/mL, 0.021 ± 0.044 µg/mL, and184 ± 159 µg·h/mL, respectively. The accumulation of AUC was 3.2-fold at steady-state compared tothe first dose.

The estimated DLin-MC3-DMA mean ± SD steady-state Cmax, Ctrough and AUC were40.2 ± 11.5 µg/mL, 1.75 ± 0.698 µg/mL, and 1403 ± 105 µg·h/mL, respectively. The accumulation of

AUC was 1.76-fold at steady-state compared to the first dose.

The estimated PEG2000-C-DMG mean ± SD steady-state Cmax, Ctrough and AUC were4.22 ± 1.22 µg/mL, 0.0236 ± 0.0093 µg/mL, and 145 ± 64.7 µg·h/mL, respectively. There was noaccumulation of AUC at steady-state compared to the first dose.

Plasma protein binding of Onpattro is low, with ≤ 2.1% binding observed in vitro with human serumalbumin and human α1-acid glycoprotein. At the dose regimen of 300 micrograms per kg every3 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.

Patisiran is metabolized by nucleases to nucleotides of various lengths. DLin-MC3-DMA is primarilymetabolised to 4-dimethylaminobutyric acid (DMBA) by hydrolysis. There is little to no metabolismof PEG2000-C-DMG.

At the dose regimen of 300 micrograms per kg every 3 weeks, mean ± SD steady state plasmaclearance (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 recoveredintact in urine.

The estimated DLin-MC3-DMA mean ± SD steady-state CLss was 2.1 ± 0.8 mL/h/kg. Approximately5.5% 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 andmonkeys, PEG2000-C-DMG is eliminated unchanged in the bile. PEG2000-C-DMG excretion in humanswas not measured.

Exposure to patisiran and the lipid components (DLin-MC3-DMA and PEG2000-C-DMG) increasedproportionally with increase in dose over the range evaluated in clinical studies (10 to 500 microgramsper kg). Patisiran and the lipid components exhibit linear and time-independent pharmacokinetics withchronic dosing at the dose regimen of 300 micrograms per kg every 3 weeks.

Increasing the dose of patisiran resulted in greater TTR reduction, with maximal reductions plateauingat patisiran exposures obtained with 300 micrograms per kg every 3 weeks dosing.

The components of Onpattro are not inhibitors or inducers of cytochrome P450 enzymes ortransporters, except for CYP2B6 (see section 4.5). Patisiran is not a substrate of cytochrome P450enzymes.

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.

In the placebo-controlled study, 62 (41.9%) patients treated with Onpattro were ≥ 65 years of age and9 (6.1%) patients were ≥ 75 years of age. There were no significant differences in steady statepharmacokinetic parameters or TTR reduction between patients < 65 years of age and ≥ 65 years ofage.

Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild hepaticimpairment (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. Onpattrohas not been studied in patients with moderate or severe hepatic impairment.

Liver transplant

In a clinical study in hATTR amyloidosis patients who had undergone prior liver transplant, steadystate pharmacokinetic parameters and TTR reduction were comparable to those observed in patientswithout a liver transplant.

Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderaterenal impairment (eGFR ≥ 30 to < 90 mL/min/1.73m2) on patisiran exposure or TTR reductioncompared to subjects with normal renal function. Onpattro has not been studied in patients with severerenal impairment or end-stage renal disease.

General toxicology

Liver and spleen were the primary target organs of toxicity in both rats and monkeys. Intravenousadministration of Onpattro led to increases in serum liver markers (alanine aminotransferase [ALT],

AST, alkaline phosphatase [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 inrats 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 eithera full recovery or were observed with reduced severity at the end of the 60-90 day recovery period,indicating at least partial reversibility.

Onpattro did not exhibit a genotoxic potential in vitro and in vivo and was not carcinogenic intransgenic rasH2 mice.

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 femalefertility, embryo-foetal development, or pre-/post-natal development.

In rabbits, Onpattro generated spontaneous abortions, reduced embryo-foetal survival, and reducedfoetal body weights at maternally toxic doses ≥ 1 mg/kg (human equivalent dose [HED] 3.2 times therecommended human dose [RHD]). As patisiran is not pharmacologically active in rabbits, theseeffects are not due to reductions in TTR, thyroxine or vitamin A.

Intravenous administration of Onpattro had no effect on male reproductive assessments in sexuallymature 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 maternalplasma concentrations). There were no adverse effects on the pups.

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

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vials3 years.

Chemical and physical in-use stability has been demonstrated for 16 hours at room temperature (up to30°C). From a microbiological point of view, it is recommended that the product should be usedimmediately. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user and should not be longer than 16 hours at either 2°C to 8°C or roomtemperature (up to 30°C), including infusion time.

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 to14 days.

For storage conditions after dilution of the medicinal product, see section 6.3.

Type I glass vial with a chlorobutyl stopper and an aluminium flip-off cap.

Pack size of 1 vial containing 5 mL concentrate.

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

* Calculate the required volume of Onpattro based on the recommended weight-based dosage (seesection 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 sterilecontainer.

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

* Dilute the required volume of filtered Onpattro into an infusion bag containing sodium chloride9 mg/mL (0.9%) solution for a total volume of 200 mL. Use infusion bags that are free ofdi(2-ethylhexyl)phthalate (DEHP).

* Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with othermedicinal products.

* Discard any unused portion of Onpattro. Any unused medicinal product or waste materialshould be disposed of in accordance with local requirements.

Alnylam Netherlands B.V.

Antonio Vivaldistraat 1501083 HP Amsterdam

Netherlands

EU/1/18/1320/001

Date of first authorisation: 27 August 2018

Date of latest renewal: 04 April 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu