Givlaari

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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 
 
Givlaari 189 mg/mL solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of solution contains givosiran sodium equivalent to 189 mg givosiran. 
 
Each vial contains 189 mg givosiran. 
 
Excipients with known effect 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection. 
 
Clear, colourless to yellow solution (pH of approximately 7.0; osmolality: 275 – 295 mOsm/kg). 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Givlaari is indicated for the treatment of acute hepatic porphyria (AHP) in adults and adolescents aged 
12 years and older. 
 
4.2 Posology and method of administration 
 
Therapy should be initiated under the supervision of a healthcare professional experienced in the 
management of porphyria. 
 
Posology 
 
The recommended dose of Givlaari is 2.5 mg/kg once monthly, administered via subcutaneous 
injection. Dosing is based on actual body weight. 
 
The patient dose (in mg) and volume (in mL) should be calculated as follows: 
 
Patient body weight (kg) × dose (2.5 mg/kg) = total amount (mg) of medicinal product to be 
administered. 
Total amount (mg) divided by vial concentration (189 mg/mL) = total volume of medicinal product 
(mL) to be injected. 
 
Missed dose 
If a dose is missed, treatment should be administered as soon as possible. Dosing should be resumed at 
monthly intervals following administration of the missed dose. 
 



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Dose modification for adverse reactions 
In patients with clinically relevant transaminase elevations, who have dose interruption and subsequent 
improvement in transaminase levels, a dose resumption at 1.25 mg/kg once monthly could be 
considered (see sections 4.4 and 4.8). 
 
Special populations 
 
Elderly 
No dose adjustment is required in patients aged > 65 years of age (see section 5.2). 
 
Hepatic impairment 
No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤ 1× the upper 
limit of normal (ULN) and aspartate aminotransferase (AST) > 1×ULN, or bilirubin > 1×ULN to 
1.5×ULN). Givlaari has not been studied in patients with moderate or severe hepatic impairment (see 
section 4.4). 
 
Renal impairment 
No dose adjustment is necessary in patients with mild, moderate or severe renal impairment (estimated 
glomerular filtration rate [eGFR] ≥ 15 to < 90 mL/min/1.73 m²). Givlaari has not been studied in 
patients with end-stage renal disease or patients on dialysis (see section 4.4). 
 
Paediatric population 
No dose adjustment is required for patients aged ≥ 12 to < 18 years of age (see section 5.2). The safety 
and efficacy of Givlaari in children aged < 12 years of age has not been established. No data are 
available. 
 
Method of administration 
 
For subcutaneous use only. 
 
This medicinal product is provided as a ready-to-use solution in a single use vial. 
 
• The required volume of Givlaari should be calculated based on the recommended weight-based 

dose. 
• The maximum acceptable single injection volume is 1.5 mL. If the dose is more than 1 mL, 

more than one vial will be needed. 
• Doses requiring more than 1.5 mL should be administered as multiple injections (the total 

monthly dose divided equally between syringes with each injection containing approximately 
the same volume) to minimise potential injection site discomfort due to injection volume. 

• This medicinal product should be injected subcutaneously into the abdomen; alternative 
injection sites include the thigh or upper arm. 

• For subsequent injections or doses, rotating the injection site is recommended. 
• This medicinal product should not be administered into scar tissue or areas that are reddened, 

inflamed, or swollen. 
 
4.3 Contraindications 
 
Severe hypersensitivity (e.g. anaphylaxis) to the active substance or to any excipients listed in 
section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Patients with AHP subtypes other than acute intermittent porphyria (AIP) 
 
The efficacy and safety data in patients with AHP subtypes other than AIP (hereditary coproporphyria 
(HCP), variegate porphyria (VP) and ALA dehydratase-deficient porphyria (ADP)) are limited (see 



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section 5.1). This should be taken into consideration when assessing the individual benefit-risk in these 
rare AHP subtypes. 
 
Anaphylactic reaction 
 
In clinical studies, anaphylaxis occurred in one patient who had a history of allergic asthma and atopy 
(see section 4.8). Signs and symptoms of anaphylaxis should be monitored. If anaphylaxis occurs, 
administration of this medicinal product should be immediately discontinued and appropriate medical 
treatment should be instituted. 
 
Transaminase elevations 
 
Transaminase elevations have been observed in patients treated with givosiran. Transaminase 
elevations primarily occurred between 3 to 5 months following initiation of treatment (see section 4.8). 
 
Liver function tests should be performed prior to initiating treatment. These tests should be repeated 
monthly during the first 6 months of treatment, and as clinically indicated thereafter. Interrupting or 
discontinuing treatment should be considered for clinically relevant transaminase elevations. In case of 
subsequent improvement in transaminase levels, resumption of treatment at a 1.25 mg/kg dose after 
interruption could be considered (see section 4.2). There are limited data on efficacy and safety of the 
lower dose, particularly in patients who previously experienced transaminase elevations. There are no 
data on sequentially increasing the 1.25 mg/kg dose to the 2.5 mg/kg dose after dose interruption for 
transaminase elevations (see section 4.8). 
 
Effects on renal function 
 
Increases in serum creatinine levels and decreases in eGFR have been reported during treatment with 
givosiran. In the placebo-controlled study, the median increase in creatinine at month 3 was 
6.5 µmol/L (0.07 mg/dL) and resolved or stabilised by month 6 with continued monthly treatment with 
2.5 mg/kg givosiran. 
 
Progression of renal impairment has been observed in some patients with pre-existing renal disease. 
Careful monitoring of renal function during treatment is required in such cases. 
 
Excipients 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a clinical drug-drug interaction study, givosiran resulted in a weak to moderate reduction in activity 
of certain CYP450 enzymes in the liver thereby increasing plasma exposures: 
• CYP1A2: 1.3-fold increase in Cmax and 3.1-fold increase in AUC0–∞ of caffeine 
• CYP2D6: 2.0-fold increase in Cmax and 2.4-fold increase in AUC0–∞ of dextromethorphan 
• CYP2C19: 1.1-fold increase in Cmax and 1.6-fold increase in AUC0–∞ of omeprazole 
• CYP3A4: 1.2-fold increase in Cmax and 1.5-fold increase in AUC0–∞ of midazolam 
• CYP2C9: no effect on the exposure of losartan 
 
Caution is recommended during the use of medicinal products that are substrates of CYP1A2 or 
CYP2D6 while on treatment with Givlaari as this medicinal product may increase or prolong their 
therapeutic effect, or alter their adverse event profiles Consider decreasing the CYP1A2 or CYP2D6 
substrate dosage in accordance with the approved product labelling. 
 



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4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited amount of data from the use of givosiran in pregnant women. Studies in 
animals have shown reproductive toxicity in the presence of maternal toxicity (see section 5.3). The 
use of this medicinal product could be considered during pregnancy taking into account the expected 
health benefit for the woman and potential risks to the foetus. 
 
Breast-feeding 
 
It is unknown whether givosiran is excreted in human milk. A risk to the newborns/infants cannot be 
excluded. Available pharmacodynamic/toxicological data in animals have shown excretion of 
givosiran in milk (see section 5.3). A decision must be made whether to discontinue breast-feeding or 
to discontinue/abstain from Givlaari therapy 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 givosiran 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 
 
Givlaari has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most frequently occurring adverse reactions reported in patients treated with givosiran are 
injection site reactions (ISRs) (36 %), nausea (32.4 %) and fatigue (22.5 %). The adverse reactions 
resulting in discontinuation of treatment were elevated transaminases (0.9 %) and anaphylactic 
reaction (0.9 %). 
 
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 
System organ class Adverse reaction Frequency 

Immune system disorders 
Anaphylactic reaction Uncommon 

Hypersensitivity Common 
Gastrointestinal disorders Nausea Very common 
Hepatobiliary disorders Transaminase elevations Very common 
Skin and subcutaneous tissue 
disorders Rash

a Very common 

Renal and urinary disorders Glomerular filtration rate decreasedb Very common 

General disorders and administration 
site conditions 

Injection site reactions Very common 
Fatigue Very common 

a Includes pruritus, eczema, erythema, rash, rash pruritic, urticaria. 
b Includes blood creatinine increased, glomerular filtration rate decreased, chronic kidney disease (decreased 

eGFR), renal impairment. 
 
Description of selected adverse reactions 
 
Liver function tests 
In the placebo-controlled study, 7 (14.6 %) patients treated with givosiran and one (2.2 %) patient 
treated with placebo had an increased alanine aminotransferase (ALT) more than 3 times the ULN. In 
5 patients treated with givosiran the transaminase elevations resolved with ongoing dosing at 
2.5 mg/kg. Per protocol, one patient (with variegate porphyria) with ALT more than 8 times the ULN 
discontinued treatment and one patient with ALT more than 5 times the ULN interrupted treatment and 
resumed dosing at 1.25 mg/kg. ALT elevations in both patients resolved. 
 
Injection site reactions 
In placebo-controlled and open-label clinical studies, injection site reactions have been reported in 
36 % of patients and generally have been mild or moderate in severity, mostly transient and resolved 
without treatment. The most commonly reported symptoms included erythema, pain, and pruritus. 
Injection-site reactions occurred in 7.8 % of injections and did not result in discontinuation of 
treatment. Three patients (2.7 %) experienced single, transient, recall reactions of erythema at a prior 
injection site with a subsequent dose administration. 
 
Immunogenicity 
In placebo-controlled and open-label clinical studies, 1 of 111 patients with AHP (0.9 %), developed 
treatment emergent anti-drug antibodies (ADA) during treatment with givosiran. ADA titres were low 
and transient with no evidence of an effect on clinical efficacy, safety, pharmacokinetic or 
pharmacodynamic profiles of the medicinal product. 
 
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 
 
No case of overdose has been reported. In case of overdose, it is recommended that the patient be 
monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be 
instituted. 
 
 

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


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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: not yet assigned, ATC code: not yet assigned 
 
Mechanism of action 
 
Givosiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of 
aminolevulinic acid synthase 1 (ALAS1) messenger ribonucleic acid (mRNA) in hepatocytes through 
RNA interference, resulting in a reduction of induced liver ALAS1 mRNA towards normal. This leads 
to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and 
porphobilinogen (PBG), the key causal factors of attacks and other disease manifestations of AHP. 
 
Pharmacodynamic effects 
 
In the placebo-controlled study in patients with AHP receiving givosiran 2.5 mg/kg once monthly 
(ENVISION), median reductions from baseline in urinary ALA and PBG of 83.7 % and 75.1 %, 
respectively, were observed 14 days after the first dose. Maximal reductions in ALA and PBG levels 
were achieved around month 3 with median reductions from baseline of 93.8 % for ALA and 94.5 % 
for PBG, and were sustained with repeated once monthly dosing. 
 
Observed data and modelling demonstrated that once monthly dosing with 2.5 mg/kg givosiran 
resulted in a greater reduction and less fluctuation in ALA levels compared with doses less than 
2.5 mg/kg or dosing once every 3 months. 
 
Clinical efficacy 
 
The efficacy of givosiran was evaluated in a randomised, double-blind, placebo-controlled, 
multinational study (ENVISION). 
 
ENVISION 
A total number of 94 patients with AHP (89 patients with acute intermittent porphyria (AIP), 2 patients 
with variegate porphyria (VP), 1 patient with hereditary coproporphyria (HCP), and 2 patients with no 
identified mutation in a porphyria-related gene) were randomised 1:1 to receive once monthly 
subcutaneous injections of givosiran 2.5 mg/kg or placebo during the 6-month double-blind period. 
Patients randomised to givosiran included 46 patients with AIP, 1 patient with VP, and 1 patient with 
HCP. In this study, inclusion criteria specified a minimum of 2 porphyria attacks requiring 
hospitalisation, urgent healthcare visit, or intravenous (IV) hemin administration at home in the 
6 months prior to study entry. Hemin use during the study was permitted for the treatment of acute 
porphyria attacks. The median age of patients in the ENVISION study was 37.5 years (range 19 to 
65 years); 89.4 % of patients were female, and 77.7 % were white. The treatment arms were balanced 
with respect to historical annualised porphyria attack rate (overall median baseline rate of 8 per year), 
prior hemin prophylaxis, use of opioid medicinal products, and patient-reported measures of chronic 
symptoms between attacks. 
 
The major efficacy measure was the annualised attack rate (AAR) of composite porphyria attacks 
during the 6-month double-blind period and consisted of three components: attacks requiring 
hospitalisation, urgent healthcare visit, or IV hemin administration at home. This composite efficacy 
measure was evaluated as the primary endpoint in patients with AIP, and as a secondary endpoint in 
the overall population of patients with AHP. Treatment with this medicinal product resulted in a 
significant reduction of the AAR of composite porphyria attacks, compared with placebo, of 74 % in 
patients with AIP (Table 2). Comparable results were seen in patients with AHP, with a reduction of 
73 %. Consistent results were observed for each of the 3 components of the composite porphyria attack 
endpoint. 
 



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The results observed over 6 months were maintained through Month 12, with a median AAR (Q1, Q3) 
of 0.0 (0.0, 3.5) observed for patients with continued dosing with the medicinal product during the 
open-label extension period. 
 
Givosiran reduced porphyria attacks compared to placebo in patients with AHP across all pre-specified 
subgroups, including age, sex, race, region, baseline body mass index (BMI), prior hemin prophylaxis 
use, historical attack rate, prior chronic opioid use when not having attacks, and the presence of prior 
chronic symptoms when not having attacks. 
 
Additional clinical efficacy endpoints were studied in AIP patients and are summarised in Table 2. 
 
Table 2: Clinical Efficacy Results in Patients with AIP during the 6-Month Double-Blind Period 
of the ENVISION Study 

Endpoint 
Placebo Givosiran 
(N=43) (N=46) 

Annualised attack rate of composite porphyria attacksa 
Mean AAR (95 % CI)b 12.5 (9.4, 16.8) 3.2 (2.3, 4.6) 
Rate ratio (95 % CI)b (givosiran/placebo) 0.26 (0.16, 0.41) 
P-valueb < 0.001 
Median AAR, (Q1, Q3) 10.7 (2.2, 26.1) 1.0 (0.0, 6.2) 
Number of patients with 0 attacks (%) 7 (16.3) 23 (50.0) 
Annualised days of hemin use 
Mean (95 % CI)b 29.7 (18.4, 47.9) 6.8 (4.2, 10.9) 
Ratio (95 % CI)b (givosiran/placebo) 0.23 (0.11, 0.45) 
P-valueb < 0.001 
Daily worst pain scorec 
Baseline, median (Q1, Q3) 3.3 (1.9, 5.6) 2.2 (1.2, 4.5) 
Median of treatment difference (95 %) 
(givosiran-placebo) −10.1 (−22.8, 0.9) 

P-value < 0.05 
PCS of SF-12d 
Baseline, mean (SD) 38.4 (9.4) 39.4 (9.6) 
Change from baseline at Month 6, LS mean 
(95 % CI) 1.4 (−1.0, 3.9) 5.4 (3.0, 7.7) 

LS mean difference (95 % CI) (givosiran-
placebo) 3.9 (0.6, 7.3) 

Nominal P-value < 0.05 
AAR, Annualised Attack Rate; AIP, Acute Intermittent Porphyria; CI, Confidence Interval; Q1, Quartile 1; Q3, 
Quartile 3; LS, Least Square; PCS, Physical Component Summary; SF-12, the 12-item Short-Form Health 
Survey 
a Composite porphyria attacks includes three components: attacks requiring hospitalisation, urgent healthcare 

visits, or IV hemin administration at home. 
b Based on negative binomial regression model. A rate ratio < 1 represents a favourable outcome for givosiran. 
c Patients provided a daily self-assessment of their worst pain based on a 0 to 10 numerical rating scale (NRS). 

A lower score indicates fewer symptoms. Median of treatment difference and CI were estimated using the 
Hodges-Lehmann method; p-value was based on Wilcoxon rank sum test, which was conducted post-hoc 
after data showed a significant deviation from normal distribution. 



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d A higher score indicates improved health-related quality of life; analysed using the mixed-effect model 
repeated measures (MMRM) method. The endpoint was not formally tested for statistical significance; a 
nominal p-value was reported. 

 
In addition to greater improvement from baseline in the SF-12 PCS score compared to patients treated 
with placebo at Month 6, there was consistent evidence of effect favouring this medicinal product in 
bodily pain, role-physical, and social functioning domains, but not in the general health, physical 
functioning, role-emotional, vitality, and mental health domains (Figure 1). 
 
Figure 1: Change from Baseline to Month 6 in SF-12 Domain Scores in Patients with AIP 

SF-12 Domain Givosiran – Placebo  
Pbo 
(n) 

Givo 
(n) 

LS Mean 
Difference 95 % Cl 

Physical Component 
Summary (PCS) 

 

42 45 3.9 (0.6, 7.3) 

Mental Component 
Summary (MCS) 42 45 2.1 (−1.7, 5.8) 

Physical Functioning 43 46 1.4 (−2.0, 4.7) 

Role Physical 43 46 4.4 (1.3, 7.5) 

Bodily Pain 43 46 7.2 (3.2, 11.2) 

General Health 42 46 3.3 (−0.7, 7.2) 

Vitality 42 45 1.7 (−2.0, 5.5) 

Social Functioning 42 45 5.1 (1.6, 8.7) 

Role Emotional 43 46 1.4 (−2.5, 5.2) 

Mental Health 42 45 2.8 (−0.9, 6.4) 

     

 Favours Placebo Favours Givosiran      
AIP, Acute Intermittent Porphyria; CI, Confidence Interval; Givo, givosiran; Pbo, placebo; LS, Least Square; 
MCS, Mental Component Summary; PCS, Physical Component Summary; SF-12, the 12-item Short-Form health 
survey version 2. 
 
In a patient global assessment (Patient Global Impression of Change – PGIC) a larger proportion of 
patients with AIP treated with givosiran (61.1 %) than with placebo (20 %) rated their overall status as 
“very much improved” or “much improved” since the start of the study. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with this 
medicinal product in all subsets of the paediatric population in the treatment of AHP (see section 4.2 
and section 5.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Following subcutaneous administration, givosiran is rapidly absorbed with a time to maximum plasma 
concentration (tmax) of 0.5 to 2 hours. At the 2.5 mg/kg once monthly dose, the steady-state peak 
plasma concentrations of givosiran (Cmax) and area under the curve from time of dosing up to 24 hours 
after dosing (AUC24) were 321 ± 163 ng/mL and 4130 ± 1780 ng·h/mL, respectively, and 
corresponding values for the active metabolite were 123 ± 79.0 ng/mL and 1930 ± 1210 ng·h/mL, 
respectively. 
 



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Distribution 
 
Givosiran is greater than 90 % bound to plasma proteins over the concentration range observed in 
humans at the 2.5 mg/kg once monthly dose. The population estimate for the steady state apparent 
volume of distribution (Vd/F) for givosiran and for the active metabolite was 10.4 L. Givosiran and its 
active metabolite distribute primarily to the liver after subcutaneous dosing. 
 
Biotransformation 
 
Givosiran is metabolised by nucleases to oligonucleotides of shorter lengths. Active metabolite 
AS(N-1)3’ givosiran (with equal potency as that of givosiran) was a major metabolite in plasma with 
45 % exposure (AUC0–24) relative to givosiran at the 2.5 mg/kg once monthly dose. In vitro studies 
indicate that givosiran does not undergo metabolism by CYP450 enzymes. 
 
Elimination 
 
Givosiran and its active metabolite are eliminated from plasma primarily by metabolism with an 
estimated terminal half-life of approximately 5 hours. The population estimate for apparent plasma 
clearance was 36.6 L/h for givosiran and 23.4 L/h for AS(N-1)3’ givosiran. After subcutaneous 
dosing, up to 14 % and 13 % of the administered givosiran dose was recovered in urine as givosiran 
and its active metabolite, respectively, over 24 hours. The renal clearance ranged from 1.22 to 9.19 L/h 
for givosiran and 1.40 to 12.34 L/h for the active metabolite. 
 
Linearity/non-linearity 
 
Givosiran and its active metabolite exhibited linear pharmacokinetics in plasma over the 0.35 to 
2.5 mg/kg dose range. At doses greater than 2.5 mg/kg, plasma exposure increased slightly greater 
than dose-proportionally. Givosiran exhibited time-independent pharmacokinetics with chronic dosing 
at the recommended dose regimen of 2.5 mg/kg once monthly. There was no accumulation of 
givosiran or the active metabolite in plasma after repeated once monthly dosing. 
 
Pharmacokinetic/pharmacodynamic relationship 
 
Plasma concentrations of givosiran are not reflective of the extent or duration of pharmacodynamic 
activity. Since givosiran is a liver targeted therapy, concentrations in plasma decline rapidly due to 
uptake by the liver. In the liver, givosiran exhibits a long half-life leading to extended duration of 
pharmacodynamic effect maintained over the monthly dosing interval. 
 
Special populations 
 
Elderly 
No studies have been conducted in patients aged > 65 years. Age was not a significant covariate in the 
pharmacokinetics of givosiran. 
 
Gender and race 
In clinical studies there was no difference in the pharmacokinetics or pharmacodynamics of givosiran 
based on gender or race. 
 
Hepatic impairment 
Adult patients with mild hepatic impairment (bilirubin ≤ 1×ULN and AST > 1×ULN, or 
bilirubin > 1×ULN to 1.5×ULN) had comparable plasma exposure of givosiran and its active 
metabolite and similar pharmacodynamics (percent reduction in urinary ALA and PBG) as patients 
with normal hepatic function. No studies have been conducted in patients with moderate or severe 
hepatic impairment (see sections 4.2 and 4.4). 
 



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Renal impairment 
Adult patients with mild renal impairment (eGFR ≥ 60 to < 90 mL/min/1.73 m²), moderate renal 
impairment (eGFR ≥ 30 to < 60 mL/min/1.73 m²) or severe renal impairment (eGFR ≥ 15 to 
< 30 mL/min/1.73 m²) had comparable plasma exposure of givosiran and its active metabolite and 
similar pharmacodynamics (percent reduction in urinary ALA and PBG) as patients with normal renal 
function (eGFR ≥ to 90 mL/min/1.73 m²). No studies have been conducted in patients with end-stage 
renal disease or patients with dialysis (see sections 4.2 and 4.4). 
 
Paediatric population 
Available data suggest that body weight but not age was a significant covariate in the 
pharmacokinetics of givosiran. At the 2.5 mg/kg dose, a similar exposure is expected in adolescents 
aged 12 years or older, as in adults with the same body weight. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development. In the 
repeat-dose toxicity studies conducted in rats and monkeys, the rat was identified as the most sensitive 
species to givosiran-related effects, with the liver being identified as the primary target organ of 
toxicity in both the rat and monkey. No adverse findings were associated with chronic, weekly 
administration of givosiran to rats and monkeys at doses that achieved exposure multiples of 3.5- and 
26.3-fold, respectively when compared to exposures achieved in patients receiving the maximum 
recommended human dose. 
 
Genotoxicity/carcinogenicity 
 
Givosiran did not exhibit a genotoxic potential in vitro and in vivo. 
 
Animal studies have not been conducted to evaluate the carcinogenic potential of givosiran. 
 
Reproductive toxicity 
 
Embryo-foetal development studies have been performed in rats and rabbits during organogenesis. 
Givosiran showed marked maternal toxicity in rabbits (including mean maternal body weight loss) and 
resulted in increased post-implantation loss as a result of increased early resorptions and a low 
incidence of skeletal variations. These findings are considered an indirect effect, secondary to maternal 
toxicity. No adverse developmental effects were observed in rats administered the maternally toxic 
dose of approximately 9 times the normalised maximum recommended human dose. 
 
In a postnatal development study in rats, there was no effect on growth and development of the 
offspring. 
 
No adverse effects were observed in the fertility of male and female rats when administered with 
givosiran. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium hydroxide (pH adjustment) 
Phosphoric acid (pH adjustment) 
Water for injections 
 



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6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
3 years 
 
Once the vial is opened, the medicinal product should be used immediately. 
 
6.4 Special precautions for storage 
 
Do not store above 25 °C. 
Keep vial in the outer carton to protect from light. 
 
6.5 Nature and contents of container 
 
Glass vial with a PTFE-coated chlorobutyl rubber stopper and a flip-off aluminium seal. Each vial 
contains 1 mL solution for injection. 
 
Pack size of one vial. 
 
6.6 Special precautions for disposal and other handling 
 
This medicinal product is for single use only. 
 
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 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/20/1428/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
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. 
  

http://www.ema.europa.eu/


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ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 
  



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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer 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. 

  



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 
  



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 
  



17 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Givlaari 189 mg/mL solution for injection 
givosiran 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains givosiran sodium equivalent to 189 mg givosiran in 1 mL of solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: 
Sodium hydroxide 
Phosphoric acid 
Water for injections 
See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
189 mg/1 mL 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
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. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



18 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25 °C. 
Keep vial in the outer carton to protect from light. 
 
 
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/1/20/1428/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Givlaari 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



19 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Givlaari 189 mg/mL solution for injection 
givosiran 
Subcutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
189 mg/1 mL 
 
 
6. OTHER 
 
 
  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
  



21 

Package leaflet: Information for the user 
 

Givlaari 189 mg/mL solution for injection 
givosiran 

 
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 Givlaari is and what it is used for 
2. What you need to know before you are given Givlaari 
3. How Givlaari is given 
4. Possible side effects 
5. How to store Givlaari 
6. Contents of the pack and other information 
 
 
1. What Givlaari is and what it is used for 
 
What Givlaari is 
Givlaari contains the active substance ‘givosiran’. 
 
What Givlaari is used for 
Givlaari is used to treat acute hepatic porphyria in adults and adolescents aged 12 years and older. 
 
What acute hepatic porphyria is 
Acute hepatic porphyria is a rare illness that runs in families. It is caused by a defect in one of the 
proteins that make a molecule called haem in the liver. Because there is a problem in one of the 
proteins required to make haem, there is a build-up of some of the substances that are used to produce 
haem, namely aminolevulinic acid (ALA) and porphobilinogen (PBG). Having too much ALA and 
PBG can injure nerves and cause serious attacks of pain, nausea, muscle weakness and changes in 
mental functioning. Some people with acute hepatic porphyria may also have symptoms, such as pain 
and nausea, in between attacks. Longer-term complications that can be seen in people with acute 
hepatic porphyria include high blood pressure, chronic kidney disease and liver disease. 
 
How Givlaari works 
This medicine works by lowering the amount of an enzyme, called ALAS1, that controls how much 
ALA and PBG are made by the liver. By lowering ALAS1, the liver makes less ALA and PBG. This 
can help to reduce the effects of this illness. 
 
 
2. What you need to know before you are given Givlaari 
 
You must not be given Givlaari: 
• if you have ever had a severe allergic reaction to givosiran or any of the other ingredients of this 

medicine (listed in section 6). 
 
Warnings and precautions 
Talk to your doctor or nurse before you are given this medicine. 



22 

 
Severe allergic reaction 
• Tell your doctor or nurse straight away if you get any signs of a severe allergic reaction. The 

signs are listed in “Serious side effects” in section 4. 
• If you have a severe allergic reaction, your doctor or nurse will stop using the medicine straight 

away and you may need to take other medicines to control the symptoms. 
 
Liver problems 
Using this medicine can affect your liver. You will have blood tests to check your liver function before 
you start treatment with Givlaari and periodically during treatment. If these tests show abnormal 
results, your doctor or nurse will decide whether to interrupt treatment or stop treatment permanently. 
Abnormal results have been seen in some patients treated with this medicine, mainly between 3 to 
5 months after starting treatment. 
 
Kidney problems 
Using this medicine can affect your kidneys, especially if you have already been diagnosed with 
kidney problems. Your doctor will check how your kidneys are working while you are using this 
medicine, especially if you already have kidney problems. 
 
Children 
This medicine should not be used in children below 12 years of age because there is no experience of 
using the medicine in this age group. 
 
Other medicines and Givlaari 
Tell your doctor or pharmacist if you are using, have recently used or might be using any other 
medicines. 
 
When using certain medicines, this medicine may prolong or increase their effect or change their side 
effects. 
 
Pregnancy 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
nurse for advice before using this medicine. 
 
Breast-feeding 
Studies in animals suggest this medicine may pass into breast milk. If you are breast-feeding ask your 
doctor for advice before taking this medicine. Your doctor will then help you decide whether to stop 
breast-feeding or to stop treatment with Givlaari taking into account the benefit of breast-feeding for 
your child and benefit of therapy for you. 
 
Driving and using machines 
This medicine is unlikely to have any effect on your ability to drive or use machines. 
 
Givlaari contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially ‘sodium-
free’. 
 
 
3. How Givlaari is given 
 
How much Givlaari is given 
Your doctor will work out how much medicine to give you. The amount will depend on your body 
weight. 
• The recommended dose is 2.5 milligrams for every kilogram you weigh 
• You will be given the medicine once a month (every 4 weeks) 
• If blood tests show problems with your liver, your doctor may interrupt Givlaari treatment or 

stop treatment permanently. Your doctor may consider starting again at a lower dose. 



23 

 
How Givlaari is given 
This medicine will be given to you once every month by a doctor or nurse. It is given as an injection 
under the skin (subcutaneously) into your stomach area (abdomen), or in some cases, your upper arm 
or thigh. The site of the injection will be rotated. If the dose is more than 1 mL, more than one vial will 
need to be used and more than one subcutaneous injection may need to be given. 
 
If you are given too much Givlaari 
In the unlikely event that your doctor or nurse gives you too much (an overdose) they will check you 
for side effects. 
 
If you miss your dose of Givlaari 
If you have missed an appointment for your injection, talk to your doctor or nurse as soon as possible. 
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. 
 
Serious side effects 
Severe allergic reactions (uncommon: may affect up to 1 in 100 people) 
Tell your doctor or nurse straight away if you get any of the following signs of a severe allergic 
reaction (anaphylactic reaction) – the injection will need to be stopped and you may need to take other 
medicines to manage the reaction: 
• swelling – mainly of the lips, tongue or throat which makes it difficult to swallow or breathe 
• breathing problems or wheezing 
• feeling dizzy or fainting 
• rash, hives 
• itching 
 
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 
• Nausea 
• Redness, pain, itching or swelling at the site of the injection (injection site reaction) 
• Skin rashes including red, itchy or dry skin, eczema or hives 
• Feeling tired 
• Blood tests showing an increase in transaminases, which are liver enzymes (a sign of possible 

liver inflammation) 
• Blood tests showing an increase in creatinine, a substance removed from your body by your 

kidneys, or decrease in glomerular filtration rate (signs of possible kidney problems) 
 
Common: may affect up to 1 in 10 people 
• A type of allergic reaction (hypersensitivity) – with symptoms such as hives, rash, swelling of 

eyes, mouth or face, difficulty breathing, itching. 
 
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. 
 
 

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


24 

5. How to store Givlaari 
 
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 and vial after EXP. The 
expiry date refers to the last day of that month. 
 
This medicine is for single use only. Once the product is opened, use immediately. 
 
Do not store above 25 °C. 
 
Keep vial in the outer carton to protect from light. 
 
Do not throw away any medicines via wastewater or household waste. Your doctor or nurse 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 Givlaari contains 
• The active substance is givosiran. 
• Each mL contains givosiran sodium equivalent to 189 mg givosiran. 
• The other ingredients are sodium hydroxide, phosphoric acid and water for injections. 
 
What Givlaari looks like and contents of the pack 
This medicine is a clear, colourless to yellow solution for injection. 
 
Each pack contains one vial of 1 mL solution for injection. 
 
Marketing Authorisation Holder and Manufacturer 
Alnylam Netherlands B.V. 
Strawinskylaan 3051 
1077 ZX Amsterdam 
The 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 
 

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 
 



25 

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

http://www.ema.europa.eu/


26 

<------------------------------------------------------------------------------------------------------------------------> 
 
The following information is intended for healthcare professionals only: 
 
Instructions for use 
 
For subcutaneous use only. 
 
• Collect materials not included in the pack that are needed for administration which will include 

a sterile syringe (1 mL or 3 mL), 21-gauge (G) or a larger needle, 25 G or 27 G needle and a 
sharps container. 

• Calculate the required volume of Givlaari based on the recommended weight-based dose. If the 
dose is more than 1 mL, more than one vial will need to be used and more than one 
subcutaneous injection may need to be given. The maximum acceptable single injection volume 
to be administered is 1.5 mL. 

• To withdraw Givlaari, hold the vial upright or tilt at a slight angle and ensure the flat edge of the 
needle is pointed downwards. 

• Draw up the indicated injection volume with the 21 G or larger needle. 
• Divide doses requiring volumes greater than 1.5 mL equally into multiple syringes, with each 

injection containing approximately the same volume. 
• Point the needle and syringe straight up and tap the syringe to move any bubbles to the top. 

Once the bubbles are at the top, gently push the plunger to force the bubbles out of the syringe. 
Check to make sure you still have the correct amount of medicine in the syringe. 

• Once the dose is prepared and in the administration syringe, replace the 21 G or larger needle 
with either a 25 G or 27 G needle. 

• Note: Do not push this medicine into the 25 G or 27 G needle. 
• Injection can be into the abdomen, or if required, the back or side of the upper arms, or the 

thighs. Consider rotating injection sites. Do not administer into scar tissue or areas that are 
reddened, inflamed, or swollen. 

• Note: When administering subcutaneous injections into the abdomen, a 5.0 cm diameter circle 
around the navel should be avoided. 

• Clean the area you intend to inject with an alcohol swab and wait for the area to dry completely. 
• Ensure proper injection technique. Do not inject into a vein or muscle. 
• Pinch and elevate the skin at the selected injection site. Insert the needle at a right angle (90 

degrees) to deliver the injection just below the skin. In patients with little subcutaneous tissue or 
if the needle size is longer than 2.5 cm, the needle should be inserted at a 45-degree angle. 

• Do not press down on the plunger while piercing the skin. Once the needle is inserted through 
the skin, release the pinched skin and administer the dose in a slow and steady manner. Once 
this medicine has been administered count for at least 5 seconds before withdrawing the needle 
from the skin. Lightly press gauze or cotton ball on the injection site as needed. Do not put the 
needle cap back on. 

• Note: Don’t aspirate after inserting the needle to prevent tissue damage, haematoma and 
bruising. 

• If more than one injection is needed for a single dose of Givlaari, the injection sites should be at 
least 2 cm apart from previous injection locations. 

• Only use the vial once. After you inject the dose, dispose of any unused medicine in the vial 
according to local regulations. 

• Use the syringes, transfer needles and injection needles only once. Dispose of any used syringes 
and needles in accordance with local requirements. 


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

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