4.1. Therapeutic indications

Glecaprevir/Pibrentasvir coated granules is indicated for the treatment of chronic hepatitis C virus (HCV) infection in children 3 years and older (see sections 4.2, 4.4. and 5.1).

4.2. Posology and method of administration

Glecaprevir/Pibrentasvir treatment should be initiated and monitored by a physician experienced in the management of patients with HCV infection.

Posology

Children aged 3 years to less than 12 years and weighing 12 kg to less than 45 kg

The recommended Glecaprevir/Pibrentasvir treatment durations for HCV genotype 1, 2, 3, 4, 5, or 6 infected patients with compensated liver disease (with or without cirrhosis) are provided in Table 1 and Table 2. The number of sachets and dose based on body weight for children are shown in Table 3. The sachets should be taken together, with food once daily.

Table 1: Recommended Glecaprevir/Pibrentasvir treatment duration for patients without prior HCV therapy

Genotype

Recommended treatment duration

No cirrhosis

Cirrhosis

GT 1, 2, 3, 4, 5, 6

8 weeks

8 weeks

Table 2: Recommended Glecaprevir/Pibrentasvir treatment duration for patients who failed prior therapy with peg-IFN + ribavirin +/- sofosbuvir, or sofosbuvir + ribavirin

Genotype

Recommended treatment duration

No cirrhosis

Cirrhosis

GT 1, 2, 4-6

8 weeks

12 weeks

GT 3

16 weeks

16 weeks

For patients who failed prior therapy with an NS3/4A- and/or an NS5A inhibitor, see section 4.4.

Table 3: Recommended dose for children 3 to less than 12 years of age

Weight of child (kg)

Number of sachets once daily

(glecaprevir + pibrentasvir)

≥ 12 to < 20 kg

3 sachets (150 mg + 60 mg)

≥ 20 to < 30 kg

4 sachets (200 mg + 80 mg)

≥ 30 to < 45 kg

5 sachets (250 mg + 100 mg)

The adult dose of Glecaprevir/Pibrentasvir tablets should be used in children weighing 45 kg or greater. Refer to the Summary of Product Characteristics for Glecaprevir/Pibrentasvir film-coated tablets for dosing instructions.

Missed dose

In case a dose of Glecaprevir/Pibrentasvir is missed, the prescribed dose can be taken within 18 hours after the time it was supposed to be taken. If more than 18 hours have passed since Glecaprevir/Pibrentasvir is usually taken, the missed dose should not be taken and the patient should take the next dose per the usual dosing schedule. Patients should be instructed not to take a double dose.

If vomiting occurs within 3 hours of dosing, an additional dose of Glecaprevir/Pibrentasvir should be taken. If vomiting occurs more than 3 hours after dosing, an additional dose of Glecaprevir/Pibrentasvir is not needed.

Renal impairment

No dose adjustment of Glecaprevir/Pibrentasvir is required in patients with any degree of renal impairment including patients on dialysis (see sections 5.1 and 5.2).

Hepatic impairment

No dose adjustment of Glecaprevir/Pibrentasvir is required in patients with mild hepatic impairment (Child-Pugh A). Glecaprevir/Pibrentasvir is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.3, 4.4, and 5.2).

Liver or kidney transplant patients

A 12-week treatment duration has been evaluated and is recommended in liver or kidney transplant recipients with or without cirrhosis (see section 5.1). A 16-week treatment duration should be considered in genotype 3-infected patients who are treatment-experienced with peg-IFN + ribavirin +/- sofosbuvir, or sofosbuvir + ribavirin.

Patients with HIV-1 co-infection

Follow the dosing recommendations in Tables 1 and 2. For dosing recommendations with HIV antiviral agents, refer to section 4.5.

Paediatric population

The safety and efficacy of Glecaprevir/Pibrentasvir in children aged less than 3 years or weighing under 12 kg have not been established. No data are available. Children weighing 45 kg or more should use the tablet formulation. Because the formulations have different pharmacokinetic profiles, the tablets and the coated granules are not interchangeable. A full course of treatment with the same formulation is therefore required (see section 5.2).

Method of administration

Oral use

• Patients should be instructed to take the recommended dose of Glecaprevir/Pibrentasvir with food once daily.

• The granules for the total daily dose (the whole content of the required number of sachets, pink and yellow granules) should be sprinkled on a small amount of soft food with a low water content that will stick to a spoon and can be swallowed without chewing (e.g., peanut butter, chocolate hazelnut spread, soft/cream cheese, thick jam, or Greek yogurt).

• Liquids or foods that would drip or slide off the spoon should not be used as the medicine may dissolve quickly and become less effective.

• The mixture of food and granules should be swallowed immediately; the granules should not be crushed or chewed.

• Glecaprevir/Pibrentasvir granules should not be administered via enteral feeding tubes.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, 4.4, and 5.2).

Concomitant use with atazanavir containing products, atorvastatin, simvastatin, dabigatran etexilate, ethinyl oestradiol-containing products, strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St. John's wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) (see section 4.5).

4.4. Special warnings and precautions for use

Hepatitis B virus reactivation

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should, therefore, be monitored and managed according to current clinical guidelines.

Hepatic impairment

Glecaprevir/Pibrentasvir is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, 4.3, and 5.2).

Patients who failed a prior regimen containing an NS5A- and/or an NS3/4A-inhibitor

Genotype 1-infected (and a very limited number of genotype 4-infected) patients with prior failure on regimens that may confer resistance to glecaprevir/pibrentasvir were studied in studies MAGELLAN-1 and B16-439 (section 5.1). The risk of failure was, as expected, highest for those exposed to both classes. A resistance algorithm predictive of the risk for failure by baseline resistance has not been established. Accumulating double class resistance was a general finding for patients who failed re-treatment with glecaprevir/pibrentasvir in MAGELLAN-1. No re-treatment data is available for patients infected with genotypes 2, 3, 5 or 6. Glecaprevir/Pibrentasvir is not recommended for the re-treatment of patients with prior exposure to NS3/4A- and/or NS5A inhibitors.

Drug-drug interactions

Co-administration is not recommended with several medicinal products as detailed in section 4.5.

Use in diabetic patients

Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabetic patients initiating direct acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medicine modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct acting antiviral therapy is initiated.

Lactose

Glecaprevir/Pibrentasvir granules contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Propylene glycol

This medicinal product contains 4 mg propylene glycol in each sachet.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Potential for Glecaprevir/Pibrentasvir to affect other medicinal products

Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Co-administration with Glecaprevir/Pibrentasvir may increase plasma concentrations of medicinal products that are substrates of P-gp (e.g. dabigatran etexilate, digoxin), BCRP (e.g. rosuvastatin), or OATP1B1/3 (e.g. atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin). See Table 4 for specific recommendations on interactions with sensitive substrates of P-gp, BCRP, and OATP1B1/3. For other P-gp, BCRP, or OATP1B1/3 substrates, dose adjustment may be needed.

Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A and uridine glucuronosyltransferase (UGT) 1A1 in vivo. Clinically significant increases in exposure were not observed for sensitive substrates of CYP3A (midazolam, felodipine) or UGT1A1 (raltegravir) when administered with Glecaprevir/Pibrentasvir.

Both glecaprevir and pibrentasvir inhibit the bile salt export pump (BSEP) in vitro.

Significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A6, UGT1A9, UGT1A4, UGT2B7, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K are not expected.

Patients treated with vitamin K antagonists

As liver function may change during treatment with Glecaprevir/Pibrentasvir, a close monitoring of International Normalised Ratio (INR) values is recommended.

Potential for other medicinal products to affect Glecaprevir/Pibrentasvir

Use with strong P-gp/CYP3A inducers

Medicinal products that are strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St. John's wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) could significantly decrease glecaprevir or pibrentasvir plasma concentrations and may lead to reduced therapeutic effect of Glecaprevir/Pibrentasvir or loss of virologic response. Co-administration of such medicinal products with Glecaprevir/Pibrentasvir is contraindicated (see section 4.3).

Co-administration of Glecaprevir/Pibrentasvir with medicinal products that are moderate inducers P-gp/CYP3A may decrease glecaprevir and pibrentasvir plasma concentrations (e.g. oxcarbazepine, eslicarbazepine, lumacaftor, crizotinib). Co-administration of moderate inducers is not recommended (see section 4.4).

Glecaprevir and pibrentasvir are substrates of the efflux transporters P-gp and/or BCRP. Glecaprevir is also a substrate of the hepatic uptake transporters OATP1B1/3. Co-administration of Glecaprevir/Pibrentasvir with medicinal products that inhibit P-gp and BCRP (e.g. ciclosporin, cobicistat, dronedarone, itraconazole, ketoconazole, ritonavir) may slow elimination of glecaprevir and pibrentasvir and thereby increase plasma exposure of the antivirals. Medicinal products that inhibit OATP1B1/3 (e.g. elvitegravir, ciclosporin, darunavir, lopinavir) increase systemic concentrations of glecaprevir.

Established and other potential medicinal product interactions

Table 4 provides the least-squares mean Ratio (90% Confidence Interval) effect on concentration of Glecaprevir/Pibrentasvir and some common concomitant medicinal products. The direction of the arrow indicates the direction of the change in exposures (Cmax, AUC, and Cmin) in glecaprevir, pibrentasvir, and the co-administered medicinal product (↑ = increase (more than 25%), ↓ = decrease (more than 20%)), ↔ = no change (equal to or less than 20% decrease or 25% increase). This is not an exclusive list. All interaction studies were performed in adults.

Table 4: Interactions between Glecaprevir/Pibrentasvir and other medicinal products

Medicinal product by therapeutic areas/possible mechanism of interaction

Effect on medicinal product levels

Cmax

AUC

Cmin

Clinical comments

ANGIOTENSIN-II RECEPTOR BLOCKERS

Losartan

50 mg single dose

↑ losartan

2.51

(2.00, 3.15)

1.56

(1.28, 1.89)

--

No dose adjustment is required.

↑ losartan carboxylic acid

2.18

(1.88, 2.53)

↔

--

Valsartan

80 mg single dose

(Inhibition of OATP1B1/3)

↑ valsartan

1.36

(1.17, 1.58)

1.31

(1.16, 1.49)

--

No dose adjustment is required.

ANTIARRHYTHMICS

Digoxin

0.5 mg single dose

(Inhibition of P-gp)

↑ digoxin

1.72

(1.45, 2.04)

1.48

(1.40, 1.57)

--

Caution and therapeutic concentration monitoring of digoxin is recommended.

ANTICOAGULANTS

Dabigatran etexilate

150 mg single dose

(Inhibition of P-gp)

↑ dabigatran

2.05

(1.72, 2.44)

2.38

(2.11, 2.70)

--

Co-administration is contraindicated (see section 4.3).

ANTICONVULSANTS

Carbamazepine

200 mg twice daily

(Induction of P-gp/CYP3A)

↓ glecaprevir

0.33

(0.27, 0.41)

0.34

(0.28, 0.40)

--

Co-administration may lead to reduced therapeutic effect of Glecaprevir/Pibrentasvir and is contraindicated (see section 4.3).

↓ pibrentasvir

0.50

(0.42, 0.59)

0.49

(0.43, 0.55)

--

Phenytoin, phenobarbital, primidone

Not studied.

Expected: ↓ glecaprevir and ↓ pibrentasvir

ANTIMYCOBACTERIALS

Rifampicin

600 mg single dose

(Inhibition of OATP1B1/3)

↑ glecaprevir

6.52

(5.06, 8.41)

8.55

(7.01, 10.4)

--

Co-administration is contraindicated (see section 4.3).

↔ pibrentasvir

↔

↔

--

Rifampicin 600 mg once dailya

(Induction of P-gp/BCRP/CYP3A)

↓ glecaprevir

0.14

(0.11, 0.19)

0.12

(0.09, 0.15)

--

↓ pibrentasvir

0.17

(0.14, 0.20)

0.13

(0.11, 0.15)

--

ETHINYL-OESTRADIOL-CONTAINING PRODUCTS

Ethinyloestradiol (EE)/Norgestimate

35 µg/250 µg once daily

↑ EE

1.31

(1.24, 1.38)

1.28

(1.23, 1.32)

1.38

(1.25, 1.52)

Co-administration of Glecaprevir/Pibrentasvir with ethinyloestradiol-containing products is contraindicated due to the risk of ALT elevations (see section 4.3).

No dose adjustment is required with levonorgestrel, norethidrone or norgestimate as contraceptive progestagen.

↑ norelgestromin

↔

1.44

(1.34, 1.54)

1.45

(1.33, 1.58)

↑ norgestrel

1.54

(1.34, 1.76)

1.63

(1.50, 1.76)

1.75

(1.62, 1.89)

EE/Levonorgestrel

20 µg/100 µg once daily

↑ EE

1.30

(1.18, 1.44)

1.40

(1.33, 1.48)

1.56

(1.41, 1.72)

↑ norgestrel

1.37

(1.23, 1.52)

1.68

(1.57, 1.80)

1.77

(1.58, 1.98)

HERBAL PRODUCTS

St. John's wort (Hypericum perforatum)

(Induction of P-gp/CYP3A)

Not studied.

Expected: ↓ glecaprevir and ↓ pibrentasvir

Co-administration may lead to reduced therapeutic effect of Glecaprevir/Pibrentasvir and is contraindicated (see section 4.3).

HIV-ANTIVIRAL AGENTS

Atazanavir + ritonavir

300/100 mg once dailyb

↑ glecaprevir

≥4.06

(3.15, 5.23)

≥6.53

(5.24, 8.14)

≥14.3

(9.85, 20.7)

Co-administration with atazanavir is contraindicated due to the risk of ALT elevations (see section 4.3).

↑ pibrentasvir

≥1.29

(1.15, 1.45)

≥1.64

(1.48, 1.82)

≥2.29

(1.95, 2.68)

Darunavir + ritonavir

800/100 mg once daily

↑ glecaprevir

3.09

(2.26, 4.20)

4.97

(3.62, 6.84)

8.24

(4.40, 15.4)

Co-administration with darunavir is not recommended.

↔ pibrentasvir

↔

↔

1.66

(1.25, 2.21)

Efavirenz/emtricitabine/tenofovir disoproxil fumarate 600/200/300 mg once daily

↑ tenofovir

↔

1.29

(1.23, 1.35)

1.38

(1.31, 1.46)

Co-administration with efavirenz may lead to reduced therapeutic effect of Glecaprevir/Pibrentasvir and is not recommended. No clinically significant interactions are expected with tenofovir disoproxil fumarate.

The effect of efavirenz/emtricitabine/tenofovir disoproxil fumarate on glecaprevir and pibrentasvir was not directly quantified within this study, but glecaprevir and pibrentasvir exposures were significantly lower than historical controls.

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

(P-gp, BCRP, and OATP inhibition by cobicistat, OATP inhibition by elvitegravir)

↔ tenofovir

↔

↔

↔

No dose adjustment is required.

↑ glecaprevir

2.50

(2.08, 3.00)

3.05

(2.55, 3.64)

4.58

(3.15, 6.65)

↑ pibrentasvir

↔

1.57

(1.39, 1.76)

1.89

(1.63, 2.19)

Lopinavir/ritonavir 400/100 mg twice daily

↑ glecaprevir

2.55

(1.84, 3.52)

4.38

(3.02, 6.36)

18.6

(10.4, 33.5)

Co-administration is not recommended.

↑ pibrentasvir

1.40

(1.17, 1.67)

2.46

(2.07, 2.92)

5.24

(4.18, 6.58)

Raltegravir

400 mg twice daily

(Inhibition of UGT1A1)

↑ raltegravir

1.34

(0.89, 1.98)

1.47

(1.15, 1.87)

2.64

(1.42, 4.91)

No dose adjustment is required.

HCV-ANTIVIRAL AGENTS

Sofosbuvir

400 mg single dose

(P-gp/BCRP inhibition)

↑ sofosbuvir

1.66

(1.23, 2.22)

2.25

(1.86, 2.72)

--

No dose adjustment is required.

↑ GS-331007

↔

↔

1.85

(1.67, 2.04)

↔ glecaprevir

↔

↔

↔

↔ pibrentasvir

↔

↔

↔

HMG-COA REDUCTASE INHIBITORS

Atorvastatin

10 mg once daily

(Inhibition of OATP1B1/3, P-gp, BCRP, CYP3A)

↑ atorvastatin

22.0

(16.4, 29.5)

8.28

(6.06, 11.3)

--

Co-administration with atorvastatin and simvastatin is contraindicated (see section 4.3).

Simvastatin

5 mg once daily

(Inhibition of OATP1B1/3, P-gp, BCRP)

↑ simvastatin

1.99

(1.60, 2.48)

2.32

(1.93, 2.79)

--

↑ simvastatin acid

10.7

(7.88, 14.6)

4.48

(3.11, 6.46)

--

Lovastatin

10 mg once daily

(Inhibition of OATP1B1/3, P-gp, BCRP)

↑ lovastatin

↔

1.70

(1.40, 2.06)

--

Co-administration is not recommended. If used, lovastatin should not exceed a dose of 20 mg/day and patients should be monitored.

↑ lovastatin acid

5.73

(4.65, 7.07)

4.10

(3.45, 4.87)

--

Pravastatin

10 mg once daily

(Inhibition of OATP1B1/3)

↑ pravastatin

2.23

(1.87, 2.65)

2.30

(1.91, 2.76)

--

Caution is recommended. Pravastatin dose should not exceed 20 mg per day and rosuvastatin dose should not exceed 5 mg per day.

Rosuvastatin

5 mg once daily

(Inhibition of OATP1B1/3, BCRP)

↑ rosuvastatin

5.62

(4.80, 6.59)

2.15

(1.88, 2.46)

--

Fluvastatin, Pitavastatin

Not studied.

Expected: ↑ fluvastatin and ↑ pitavastatin

Interactions with fluvastatin and pitavastatin are likely and caution is recommended during the combination. A low dose of the statin is recommended at the initiation of the DAA treatment.

IMMUNOSUPPRESSANTS

Ciclosporin

100 mg single dose

↑ glecaprevirc

1.30

(0.95, 1.78)

1.37

(1.13, 1.66)

1.34

(1.12, 1.60)

Glecaprevir/Pibrentasvir is not recommended for use in patients requiring stable ciclosporin doses > 100 mg per day.

If the combination is unavoidable, use can be considered if the benefit outweighs the risk with a close clinical monitoring.

↑ pibrentasvir

↔

↔

1.26

(1.15, 1.37)

Ciclosporin

400 mg single dose

↑ glecaprevir

4.51

(3.63, 6.05)

5.08

(4.11, 6.29)

--

↑ pibrentasvir

↔

1.93

(1.78, 2.09)

--

Tacrolimus

1 mg single dose

(CYP3A4 and P-gp inhibition)

↑ tacrolimus

1.50

(1.24, 1.82)

1.45

(1.24, 1.70)

--

The combination of Glecaprevir/Pibrentasvir with tacrolimus should be used with caution. Increase of tacrolimus exposure is expected. Therefore, a therapeutic drug monitoring of tacrolimus is recommended and a dose adjustment of tacrolimus made accordingly.

↔ glecaprevir

↔

↔

↔

↔ pibrentasvir

↔

↔

↔

PROTON PUMP INHIBITORS

Omeprazole

20 mg once daily

(Increase gastric pH value)

↓ glecaprevir

0.78

(0.60, 1.00)

0.71

(0.58, 0.86)

--

No dose adjustment is required.

↔ pibrentasvir

↔

↔

--

Omeprazole

40 mg once daily (1 hour before breakfast)

↓ glecaprevir

0.36

(0.21, 0.59)

0.49

(0.35, 0.68)

--

↔ pibrentasvir

↔

↔

--

Omeprazole

40 mg once daily (evening without food)

↓ glecaprevir

0.54

(0.44, 0.65)

0.51

(0.45, 0.59)

--

↔ pibrentasvir

↔

↔

--

VITAMIN K ANTAGONISTS

Vitamin K antagonists

Not studied.

Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Glecaprevir/Pibrentasvir.

DAA=direct acting antiviral

a. Effect of rifampicin on glecaprevir and pibrentasvir 24 hours after final rifampicin dose.

b. Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported.

c. HCV-infected transplant recipients who received a median ciclosporin dose of 100 mg per day had increased glecaprevir exposures to 2.4-fold of those not receiving ciclosporin.

Additional drug-drug interaction studies were performed with the following medical products and showed no clinically significant interactions with Glecaprevir/Pibrentasvir: abacavir, amlodipine, buprenorphine, caffeine, dextromethorphan, dolutegravir, emtricitabine, felodipine, lamivudine, lamotrigine, methadone, midazolam, naloxone, norethindrone or other progestin-only contraceptives, rilpivirine, tenofovir alafenamide and tolbutamide.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of glecaprevir or pibrentasvir in pregnant women.

Studies in rats/mice with glecaprevir or pibrentasvir do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Maternal toxicity associated with embryo-foetal loss has been observed in the rabbit with glecaprevir which precluded evaluation of glecaprevir at clinical exposures in this species (see section 5.3). As a precautionary measure, Glecaprevir/Pibrentasvir use is not recommended in pregnancy.

Breast-feeding

It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk (for details see section 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Glecaprevir/Pibrentasvir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of glecaprevir and/or pibrentasvir on fertility are available. Animal studies do not indicate harmful effects of glecaprevir or pibrentasvir on fertility at exposures higher than the exposures in humans at the recommended dose (see section 5.3).

4.7. Effects on ability to drive and use machines

Glecaprevir/Pibrentasvir has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

In pooled Phase 2 and 3 clinical studies of adult subjects receiving Glecaprevir/Pibrentasvir with genotype 1, 2, 3, 4, 5 or 6 HCV infection the most commonly reported adverse reactions (incidence ≥ 10%) were headache and fatigue. Less than 0.1% of subjects treated with Glecaprevir/Pibrentasvir had serious adverse reactions (transient ischaemic attack). The proportion of subjects treated with Glecaprevir/Pibrentasvir who permanently discontinued treatment due to adverse reactions was 0.1%.

Tabulated list of adverse reactions

The following adverse reactions were identified in registrational Phase 2 and 3 studies in HCV-infected adults with or without cirrhosis treated with Glecaprevir/Pibrentasvir for 8, 12 or 16 weeks, or during post-marketing experience. The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) or not known (cannot be estimated from the available data).

Table 5: Adverse reactions identified with Glecaprevir/Pibrentasvir

Frequency

Adverse reactions

Immune system disorders

Uncommon

angioedema

Nervous system disorders

Very common

headache

Gastrointestinal disorders

Common

diarrhoea, nausea

Skin and subcutaneous tissue disorders

Not known

pruritus

General disorders and administration site conditions

Very common

fatigue

Common

asthenia

Investigations

Common

elevation in total bilirubin

Description of selected adverse reactions

Adverse reactions in subjects with severe renal impairment including subjects on dialysis

The safety of Glecaprevir/Pibrentasvir in subjects with chronic kidney disease (including subjects on dialysis) and genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection with compensated liver disease (with or without cirrhosis) was assessed in adults in EXPEDITION-4 (n=104) and EXPEDITION-5 (n=101). The most common adverse reactions in subjects with severe renal impairment were pruritus (17%) and fatigue (12%) in EXPEDITION-4 and pruritus (14.9%) in EXPEDITION-5.

Adverse reactions in subjects with liver or kidney transplant

The safety of Glecaprevir/Pibrentasvir was assessed in 100 post-liver or -kidney transplant adult recipients with genotypes 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overall safety profile in transplant recipients was comparable to that observed in subjects in the Phase 2 and 3 studies. Adverse reactions observed in greater than or equal to 5% of subjects receiving Glecaprevir/Pibrentasvir for 12 weeks were headache (17%), fatigue (16%), nausea (8%) and pruritus (7%).

Safety in HCV/HIV-1 co-infected subjects

The overall safety profile in HCV/HIV-1 co-infected adult subjects (ENDURANCE-1 and EXPEDITION-2) was comparable to that observed in HCV mono-infected adult subjects.

Paediatric population

The safety of Glecaprevir/Pibrentasvir in HCV GT1-6 infected adolescents is based on data from a Phase 2/3 open-label study in 47 subjects aged 12 years to < 18 years treated with Glecaprevir/Pibrentasvir tablets for 8 to 16 weeks (DORA Part 1). The adverse reactions observed were comparable with those observed in clinical studies of Glecaprevir/Pibrentasvir in adults.

The safety of Glecaprevir/Pibrentasvir in HCV GT1-6 infected children aged 3 to less than 12 years is based on data from a Phase 2/3 open-label study in 80 subjects aged 3 to < 12 years treated with weight-based Glecaprevir/Pibrentasvir coated granules for 8, 12, or 16 weeks (DORA Part 2). The pattern of adverse reactions observed was comparable with that observed in clinical studies of Glecaprevir/Pibrentasvir film-coated tablets in adolescents and adults. Diarrhoea, nausea and vomiting occurred at a slightly higher frequency in paediatric subjects compared to adolescents (adverse reactions: 3.8% vs. 0%, 3.8% vs. 0%, and 7.5% vs. 2.1% respectively).

Serum bilirubin elevations

Elevations in total bilirubin of at least 2x upper limit normal (ULN) were observed in 1.3% of subjects related to glecaprevir-mediated inhibition of bilirubin transporters and metabolism. Bilirubin elevations were asymptomatic, transient, and typically occurred early during treatment. Bilirubin elevations were predominantly indirect and not associated with ALT elevations. Direct hyperbilirubinemia was reported in 0.3% of subjects.

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:

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

4.9. Overdose

The highest documented doses administered to healthy volunteers is 1 200 mg once daily for 7 days for glecaprevir and 600 mg once daily for 10 days for pibrentasvir. Asymptomatic serum ALT elevations (> 5x ULN) were observed in 1 out of 70 healthy subjects following multiple doses of glecaprevir (700 mg or 800 mg) once daily for ≥ 7 days. In case of overdose, the patient should be monitored for any signs and symptoms of toxicities (see section 4.8). Appropriate symptomatic treatment should be instituted immediately. Glecaprevir and pibrentasvir are not significantly removed by haemodialysis.