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.

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 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.

Blood homocysteine increased

Blood homocysteine levels may be increased in patients with AHP, vitamin deficiencies, or chronic kidney disease. During treatment with givosiran, increases in blood homocysteine levels have been observed compared to levels before treatment (see section 4.8). The clinical relevance of the elevations in blood homocysteine during treatment with givosiran is unknown. However, homocysteine elevations have been previously associated with an increased risk of thromboembolic events.

Measurement of blood homocysteine levels prior to initiating treatment and monitoring for changes during treatment with givosiran is recommended. In patients with elevated homocysteine levels, consider supplementation with vitamin B6.

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.

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)

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

Rasha

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

Investigations

Blood homocysteine increasedc

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.

c Includes blood homocysteine abnormal, hyperhomocysteinemia, blood homocysteine increased.

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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.