Leaflet GIVLAARI 189mg / ml solution for injection
Indicated for: acute hepatic porphyria
Route of administration: injectable
Substance: givosiran (RNA interference therapeutic)
ATC: A16AX16 (Alimentary tract and metabolism | Other alimentary tract and metabolism products | Various alimentary tract and metabolism products)
Givosiran is a medication used for the treatment of acute hepatic porphyria, a rare genetic condition affecting heme metabolism. It reduces the frequency of acute attacks and the severity of symptoms.
This medication works by inhibiting the synthesis of an enzyme involved in heme production, thereby reducing the accumulation of toxic substances in the body. It is administered via subcutaneous injection, usually once a month.
Common side effects include nausea, fatigue, injection site reactions, and elevated liver enzyme levels. In rare cases, severe allergic reactions may occur.
It is important to follow your doctor's instructions and undergo regular tests to monitor the treatment's effects and prevent complications.
General data about GIVLAARI 189mg / ml
- Substance: givosiran
- Date of latest medicines list: 01-06-2026
- Product code: W66769001
- Concentration: 189mg / ml
- Pharmaceutical form: solution for injection
- Quantity: 1
- Product type: Original
- Price: 199081.94 RON
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Leaflet GIVLAARI 189mg/ml
Compensation lists for GIVLAARI 189mg / ml Alnylam Netherlands
Contents of the package leaflet for the medicine GIVLAARI 189mg / ml solution for injection
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.
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 aged12 years and older.
4.2 Posology and method of administration
Therapy should be initiated under the supervision of a healthcare professional experienced in themanagement of porphyria.
PosologyThe recommended dose of Givlaari is 2.5 mg/kg once monthly, administered via subcutaneousinjection. 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 beadministered.
Total amount (mg) divided by vial concentration (189 mg/mL) = total volume of medicinal product(mL) to be injected.
Missed doseIf a dose is missed, treatment should be administered as soon as possible. Dosing should be resumed atmonthly intervals following administration of the missed dose.
Dose modification for adverse reactionsIn patients with clinically relevant transaminase elevations, who have dose interruption and subsequentimprovement in transaminase levels, a dose resumption at 1.25 mg/kg once monthly could beconsidered (see sections 4.4 and 4.8).
Special populationsElderly
No dose adjustment is required in patients aged > 65 years of age (see section 5.2).
Hepatic impairmentNo dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤ 1× the upperlimit of normal (ULN) and aspartate aminotransferase (AST) > 1×ULN, or bilirubin > 1×ULN to1.5×ULN). Givlaari has not been studied in patients with moderate or severe hepatic impairment (seesection 4.4).
Renal impairmentNo 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 beenstudied in patients with end-stage renal disease or patients on dialysis (see section 4.4).
Paediatric populationNo dose adjustment is required for patients aged ≥ 12 to < 18 years of age (see section 5.2). The safetyand efficacy of Givlaari in children aged < 12 years of age has not been established. No data areavailable.
Method of administrationFor 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-baseddose.
* 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 totalmonthly dose divided equally between syringes with each injection containing approximatelythe same volume) to minimise potential injection site discomfort due to injection volume.
* This medicinal product should be injected subcutaneously into the abdomen; alternativeinjection 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.
For detailed instructions, please refer to the instructions for use intended for healthcare professionalsonly, provided with the package leaflet.
4.3 Contraindications
Severe hypersensitivity (e.g. anaphylaxis) to the active substance or to any excipients listed insection 6.1.
4.4 Special warnings and precautions for use
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 (seesection 5.1). This should be taken into consideration when assessing the individual benefit-risk inthese rare AHP subtypes.
Anaphylactic reactionIn 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 medicaltreatment should be instituted.
Transaminase elevationsTransaminase elevations have been observed in patients treated with givosiran. Transaminaseelevations 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 repeatedmonthly during the first 6 months of treatment, and as clinically indicated thereafter. Interrupting ordiscontinuing treatment should be considered for clinically relevant transaminase elevations. In case ofsubsequent improvement in transaminase levels, resumption of treatment at a 1.25 mg/kg dose afterinterruption could be considered (see section 4.2). There are limited data on efficacy and safety of thelower dose, particularly in patients who previously experienced transaminase elevations. There are nodata on sequentially increasing the 1.25 mg/kg dose to the 2.5 mg/kg dose after dose interruption fortransaminase elevations (see section 4.8).
Blood homocysteine increasedBlood homocysteine levels may be increased in patients with AHP, vitamin deficiencies, or chronickidney disease. During treatment with givosiran, increases in blood homocysteine levels have beenobserved compared to levels before treatment (see section 4.8). The clinical relevance of the elevationsin blood homocysteine during treatment with givosiran is unknown. However, homocysteineelevations have been previously associated with an increased risk of thromboembolic events.
Measurement of blood homocysteine levels prior to initiating treatment and monitoring for changesduring treatment with givosiran is recommended. In patients with elevated homocysteine levels,homocysteine-lowering therapy can be considered.
Effects on renal function
Increases in serum creatinine levels and decreases in eGFR have been reported during treatment withgivosiran (see section 4.8). In the placebo-controlled study, the median increase in creatinine atmonth 3 was 6.5 µmol/L (0.07 mg/dL) and resolved or stabilised by month 6 with continued monthlytreatment 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.
ExcipientsThis 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 activityof 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 theirtherapeutic effect or alter their adverse event profiles. Consider decreasing the CYP1A2 or CYP2D6substrate dose in accordance with the approved product information.
4.6 Fertility, pregnancy and lactation
There are no or limited amount of data from the use of givosiran in pregnant women. Studies inanimals have shown reproductive toxicity in the presence of maternal toxicity (see section 5.3). Theuse of this medicinal product could be considered during pregnancy taking into account the expectedhealth benefit for the woman and potential risks to the foetus.
Breast-feedingIt is unknown whether givosiran/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. Available pharmacodynamic/toxicological data in animals haveshown excretion of givosiran/metabolites in milk (for details see section 5.3). A decision must bemade whether to discontinue breast-feeding or to discontinue/abstain from Givlaari therapy taking intoaccount the benefit of breast-feeding for the child and the benefit of therapy for the woman.
FertilityThere are no data on the effects of givosiran on human fertility. No impact on male or female fertilitywas 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
The most frequently occurring adverse reactions reported in patients treated with givosiran areinjection site reactions (ISRs) (36%), nausea (32.4%) and fatigue (22.5%). The adverse reactionsresulting in discontinuation of treatment were elevated transaminases (0.9%) and anaphylactic reaction(0.9%).
Tabulated list of adverse reactionsThe adverse reactions are presented as MedDRA preferred terms under the MedDRA system organclass (SOC) by frequency. Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness. The frequency of the adverse reactions is expressed according to the followingcategories:
* Very common (≥ 1/10)
* Common (≥ 1/100 to < 1/10)
* Uncommon (≥ 1/1 000 to < 1/100)
Table 1: Adverse reactions
System organ class Adverse reaction Frequency
Hypersensitivity Common
Immune system disordersAnaphylactic reaction Uncommon
Nausea Very common
Gastrointestinal disordersPancreatitis Common
Hepatobiliary disorders Transaminase elevations Very common
Skin and subcutaneous tissue
Rasha Very commondisorders
Glomerular filtration rate (GFR)
Renal and urinary disorders b Very commondecreased
General disorders and administration Injection site reactions Very commonsite conditions Fatigue Very common
Investigations Blood homocysteine increasedc Commona Includes pruritus, eczema, erythema, rash, rash pruritic, urticaria.b Includes blood creatinine increased, GFR decreased, chronic kidney disease (estimated GFR (eGFR)decreased), renal impairment.c Includes blood homocysteine abnormal, hyperhomocysteinemia, blood homocysteine increased.
Description of selected adverse reactionsLiver function tests
In the placebo-controlled study, 7 (14.6%) patients treated with givosiran and one (2.2%) patienttreated with placebo had an increased alanine aminotransferase (ALT) more than 3 times the ULN. In5 patients treated with givosiran the transaminase elevations resolved with ongoing dosing at2.5 mg/kg. Per protocol, one patient (with variegate porphyria) with ALT more than 8 times the ULNdiscontinued treatment and one patient with ALT more than 5 times the ULN interrupted treatmentand resumed dosing at 1.25 mg/kg. ALT elevations in both patients resolved.
Injection site reactionsIn placebo-controlled and open-label clinical studies, injection site reactions have been reported in36% of patients and generally have been mild or moderate in severity, mostly transient and resolvedwithout 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 oftreatment. Three patients (2.7%) experienced single, transient, recall reactions of erythema at a priorinjection site with a subsequent dose administration.
Reporting of suspected adverse reactionsReporting 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.
4.9 Overdose
No case of overdose has been reported. In case of overdose, it is recommended that the patient bemonitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment beinstituted.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Various alimentary tract and metabolism products, ATC code: A16AX16
Mechanism of actionGivosiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation ofaminolevulinic 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 leadsto reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) andporphobilinogen (PBG), the key causal factors of attacks and other disease manifestations of AHP.
Pharmacodynamic effectsIn 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 levelswere 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 givosiranresulted in a greater reduction and less fluctuation in ALA levels compared with doses less than2.5 mg/kg or dosing once every 3 months.
ImmunogenicityIn placebo-controlled and open-label clinical studies, 1 of 111 patients with AHP (0.9%), developedtreatment emergent anti-drug antibodies (ADA) during treatment with givosiran. ADA titres were lowand transient with no evidence of an effect on clinical efficacy, safety, pharmacokinetic orpharmacodynamic profiles of the medicinal product.
Clinical efficacyThe efficacy of givosiran was evaluated in a randomised, double-blind, placebo-controlled,multinational study (ENVISION).
ENVISIONA 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), and2 patients with no identified mutation in a porphyria-related gene) were randomised 1:1 to receiveonce 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, and1 patient with HCP. In this study, inclusion criteria specified a minimum of 2 porphyria attacksrequiring hospitalisation, urgent healthcare visit, or intravenous hemin administration at home in the6 months prior to study entry. Hemin use during the study was permitted for the treatment of acuteporphyria attacks. The median age of patients in the ENVISION study was 37.5 years (range 19 to65 years); 89.4% of patients were female, and 77.7% were white. The treatment arms were balancedwith 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 chronicsymptoms between attacks.
The major efficacy measure was the annualised attack rate (AAR) of composite porphyria attacksduring the 6-month double-blind period and consisted of three components: attacks requiringhospitalisation, urgent healthcare visit, or intravenous hemin administration at home. This compositeefficacy measure was evaluated as the primary endpoint in patients with AIP, and as a secondaryendpoint in the overall population of patients with AHP. Treatment with this medicinal productresulted 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 areduction of 73%. Consistent results were observed for each of the 3 components of the compositeporphyria attack endpoint.
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 theopen-label extension period.
Givosiran reduced porphyria attacks compared to placebo in patients with AHP across all pre-specifiedsubgroups, including age, sex, race, region, baseline body mass index (BMI), prior hemin prophylaxisuse, historical attack rate, prior chronic opioid use when not having attacks, and the presence of priorchronic 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 ofthe ENVISION study
Placebo Givosiran
Endpoint(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, pct. 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%)−10.1 (−22.8, 0.9)(givosiran-placebo)
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 mean1.4 (−1.0, 3.9) 5.4 (3.0, 7.7)(95% CI)
LS mean difference (95% CI) (givosiran-3.9 (0.6, 7.3)placebo)
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
Surveya Composite porphyria attacks include three components: attacks requiring hospitalisation, urgent healthcarevisits, or intravenous 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-hocafter data showed a significant deviation from normal distribution.d A higher score indicates improved health-related quality of life; analysed using the mixed-effect modelrepeated measures (MMRM) method. The endpoint was not formally tested for statistical significance; anominal p-value was reported.
In addition to greater improvement from baseline in the SF-12 PCS score compared to patients treatedwith placebo at Month 6, there was consistent evidence of effect favouring this medicinal product inbodily pain, role-physical, and social functioning domains, but not in the general health, physicalfunctioning, 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
Pbo Givo LS Mean
SF-12 Domain Givosiran - Placebo (n) (n) Difference 95% Cl
Physical Component42 45 3.9 (0.6, 7.3)
Summary (PCS)
Mental Component42 45 2.1 (−1.7, 5.8)
Summary (MCS)
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, pct. 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-Formhealth survey version 2.
In a patient global assessment (Patient Global Impression of Change - PGIC) a larger proportion ofpatients 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 populationThe European Medicines Agency has waived the obligation to submit the results of studies with thismedicinal product in all subsets of the paediatric population in the treatment of AHP (see section 4.2and section 5.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Following subcutaneous administration, givosiran is rapidly absorbed with a time to maximum plasmaconcentration (tmax) of 0.5 to 2 hours. At the 2.5 mg/kg once monthly dose, the steady-state peakplasma concentrations of givosiran (Cmax) and area under the curve from time of dosing up to 24 hoursafter dosing (AUC24) were 321 ± 163 ng/mL and 4130 ± 1780 ng·h/mL, respectively, andcorresponding values for the active metabolite were 123 ± 79.0 ng/mL and 1930 ± 1210 ng·h/mL,respectively.
DistributionGivosiran is greater than 90% bound to plasma proteins over the concentration range observed inhumans at the 2.5 mg/kg once monthly dose. The population estimate for the steady state apparentvolume of distribution (Vd/F) for givosiran and for the active metabolite was 10.4 L. Givosiran and itsactive metabolite distribute primarily to the liver after subcutaneous dosing.
BiotransformationGivosiran 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 with45% exposure (AUC0-24) relative to givosiran at the 2.5 mg/kg once monthly dose. In vitro studiesindicate that givosiran does not undergo metabolism by CYP450 enzymes.
EliminationGivosiran and its active metabolite are eliminated from plasma primarily by metabolism with anestimated terminal half-life of approximately 5 hours. The population estimate for apparent plasmaclearance was 36.6 L/h for givosiran and 23.4 L/h for AS(N-1)3’ givosiran. After subcutaneousdosing, up to 14% and 13% of the administered givosiran dose was recovered in urine as givosiran andits active metabolite, respectively, over 24 hours. The renal clearance ranged from 1.22 to 9.19 L/h forgivosiran and 1.40 to 12.34 L/h for the active metabolite.
Linearity/non-linearityGivosiran and its active metabolite exhibited linear pharmacokinetics in plasma over the 0.35 to2.5 mg/kg dose range. At doses greater than 2.5 mg/kg, plasma exposure increased slightly greaterthan dose-proportionally. Givosiran exhibited time-independent pharmacokinetics with chronic dosingat the recommended dose regimen of 2.5 mg/kg once monthly. There was no accumulation ofgivosiran or the active metabolite in plasma after repeated once monthly dosing.
Pharmacokinetic/pharmacodynamic relationshipPlasma concentrations of givosiran are not reflective of the extent or duration of pharmacodynamicactivity. Since givosiran is a liver targeted therapy, concentrations in plasma decline rapidly due touptake by the liver. In the liver, givosiran exhibits a long half-life leading to extended duration ofpharmacodynamic effect maintained over the monthly dosing interval.
Special populationsElderly
No studies have been conducted in patients aged > 65 years. Age was not a significant covariate in thepharmacokinetics of givosiran.
Gender and raceIn clinical studies there was no difference in the pharmacokinetics or pharmacodynamics of givosiranbased on gender or race.
Hepatic impairmentAdult patients with mild hepatic impairment (bilirubin ≤ 1×ULN and AST > 1×ULN, orbilirubin > 1×ULN to 1.5×ULN) had comparable plasma exposure of givosiran and its activemetabolite and similar pharmacodynamics (percent reduction in urinary ALA and PBG) as patientswith normal hepatic function. No studies have been conducted in patients with moderate or severehepatic impairment (see sections 4.2 and 4.4).
Renal impairmentAdult patients with mild renal impairment (eGFR ≥ 60 to < 90 mL/min/1.73 m²), moderate renalimpairment (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 andsimilar pharmacodynamics (percent reduction in urinary ALA and PBG) as patients with normal renalfunction (eGFR ≥ to 90 mL/min/1.73 m²). No studies have been conducted in patients with end-stagerenal disease or patients with dialysis (see sections 4.2 and 4.4).
Paediatric populationAvailable data suggest that body weight but not age was a significant covariate in thepharmacokinetics of givosiran. At the 2.5 mg/kg dose, a similar exposure is expected in adolescentsaged 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 safetypharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development. In therepeat-dose toxicity studies conducted in rats and monkeys, the rat was identified as the most sensitivespecies to givosiran-related effects, with the liver being identified as the primary target organ oftoxicity in both the rat and monkey. No adverse findings were associated with chronic, weeklyadministration of givosiran to rats and monkeys at doses that achieved exposure multiples of 3.5- and26.3-fold, respectively when compared to exposures achieved in patients receiving the maximumrecommended human dose.
Genotoxicity/carcinogenicityGivosiran did not exhibit a genotoxic potential in vitro and in vivo.
Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats. Evaluation ofgivosiran in a 26-week carcinogenicity study in Tg-rasH2 mice showed no evidence of carcinogenicityat dose levels up to 1500 mg/kg/month. The 2-year rat carcinogenicity study resulted in neoplasticeffects limited to an increased incidence of hepatocellular adenomas in males at the dose of100 mg/kg/month (42 times the plasma exposure levels achieved at the maximum recommendedhuman dose (MRHD), based on AUC). In addition, proliferative preneoplastic lesions in the liver wereobserved in females at doses of 50 mg/kg/month (15 times the plasma exposure levels achieved on
MRHD, based on AUC). The relevance of this finding for the intended target population is unknown.
Reproductive toxicityEmbryo-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) andresulted in increased post-implantation loss as a result of increased early resorptions and a lowincidence of skeletal variations. These findings are considered an indirect effect, secondary to maternaltoxicity. No adverse developmental effects were observed in rats administered the maternally toxicdose 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 theoffspring.
No adverse effects were observed in the fertility of male and female rats when administered withgivosiran.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium hydroxide (pH adjustment)
Phosphoric acid (pH adjustment)
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.
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 the vial in the outer carton in order to protect from light.
6.5 Nature and contents of container
Glass vial with a fluoropolymer-coated rubber stopper and a flip-off aluminium seal. Each vialcontains 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 localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.