Vsiqq 120 mg/mL Solution for injection

VSIQQ is indicated for the treatment of:

• Neovascular (wet) age-related macular degeneration (AMD).
• Diabetic macular edema (DME).

Posology

VSIQQ must be administered by a qualified medical practitioner.

Age-related Macular Degeneration (Wet AMD)

Treatment initiation u2013 loading

The recommended dose is 6 mg (0,05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first three doses. Alternatively, VSIQQ may be administered every 6 weeks for the first two doses, and a third dose may be administered 6 weeks later based on an assessment of disease activity.

Maintenance treatment

After the last loading dose, VSIQQ is administered every 12 weeks (3 months). The medical practitioner may then individualise treatment intervals based on disease activity as assessed by visual acuity and/or anatomical parameters. The treatment interval could be as frequent as every 8 weeks (2 months) (see section 5.1). If patients are being treated according to a treat-and-extend regimen and there are no signs of disease activity, the treatment intervals could be extended stepwise until signs of disease activity recur. The treatment interval should be extended or shortened by no more than 4 weeks at a time. However, the interval between two doses should not be less than every 8 weeks (2 months) (see section 4.4).

Diabetic Macular Edema (DME)

The recommended dose for VSIQQ is 6 mg (0,05 mL) administered by intravitreal injection every 6 weeks for the first five doses. Thereafter, VSIQQ is administered every 12 or 16 weeks (3 or 4 months). Treatment intervals should be determined by the physician and should be based on disease activity as assessed by visual acuity and/or anatomic parameters. In patients with disease activity, treatment every 8 weeks (2 months) could be considered (see section 5.1).

Special populations

Hepatic impairment

No dosage regimen adjustment is required in patients with hepatic impairment (see section 5.2).

Renal impairment

No dosage regimen adjustment is required in patients with renal impairment (see section 5.2).

Elderly (age 65 years and over)

No dose adjustment is required in patients aged 65 years or above (see section 5.2).

Paediatric population

The safety and efficacy of VSIQQ in children and adolescents below 18 years of age have not been established.

Method of administration

VSIQQ is for intravitreal use only. VSIQQ should be inspected visually prior to administration (see section 6.6). The injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). Sterile paracentesis equipment should be available as a precautionary measure. The patientu2019s medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see section 4.3). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection. The injection needle should be inserted 3,5 to 4,0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0,05 mL is then delivered slowly; a different scleral site should be used for subsequent injections.

The safety and efficacy of VSIQQ administered in both eyes concurrently have not been studied and is not recommended. The vial is for single use only. Each vial should only be used for the treatment of a single eye.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Patients with active or suspected ocular or periocular infections.
• Patients with active intraocular inflammation.
• Pregnancy and lactation, see section 4.6

Endophthalmitis, retinal detachment, retinal vasculitis and/or retinal vascular occlusion

Intravitreal injections, including those with VSIQQ, have been associated with endophthalmitis and retinal detachment. Proper aseptic injection techniques must always be used when administering VSIQQ. Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of VSIQQ (see section 4.3 and section 4.8). These immune mediated adverse events may occur following the first intravitreal injection. Discontinue treatment with VSIQQ in patients who develop these events. Patients treated with VSIQQ who experience intraocular inflammation may be at risk of developing retinal vasculitis and/or retinal vascular occlusion and should be closely monitored. Patients should be instructed to report any symptoms suggestive of the above-mentioned events without delay. In a Phase IIIa clinical study (MERLIN), patients with nAMD who received VSIQQ every 4-week maintenance dosing experienced a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion than patients who received VSIQQ every 8- or 12-week maintenance dosing in the pivotal Phase III clinical studies (HAWK and HARRIER). The interval between two VSIQQ doses during maintenance treatment should not be less than 8 weeks (see section 4.2).

Intraocular pressure increases

Transient increases in intraocular pressure have been seen within 30 minutes of injection, similar to those observed with intravitreal administration of other VEGF inhibitors (see section 4.8). Sustained intraocular pressure increases have also been reported with VSIQQ. Both intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately. VSIQQ contains sucrose which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take VSIQQ.

No formal interaction studies have been performed.

Women of childbearing potential/ Contraception in males and females

Females of childbearing potential should use effective contraception (methods that result in less than 1 % pregnancy rates) during treatment with VSIQQ and for at least one month after the last dose when stopping treatment with VSIQQ.

Pregnancy

A study in pregnant cynomolgus monkeys did not indicate any harmful effects with respect to pre- or postnatal development at approximately 6-times the human exposure based on serum C max (see Animal data). However, based on the anti-VEGF mechanism of action, brolucizumab must be regarded as potentially teratogenic and embryo/foetotoxic. Therefore, brolucizumab should not be used during pregnancy. See section 4.3.

Animal data

In an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus monkeys, brolucizumab was administered to all animals by intravitreal (IVT) injection to one eye at doses of 3 or 6 mg once every 4 weeks until delivery. One additional injection was administered to a subset of animals 28 days post-partum and had blood and milk collected for toxicokinetic evaluations. There was no impact of IVT administration of brolucizumab on embryo-foetal development, pregnancy or parturition, or on the survival, growth, or postnatal development of offspring. This represents an exposure approximately 6-times the human exposure (based on serum C max) at the proposed clinical dose of 6 mg.

Breastfeeding

Because of the potential for adverse drug reactions in the breastfed new-born/infant, breastfeeding is not recommended during treatment and for at least one month after the last dose when stopping treatment with VSIQQ. See section 4.3. In an ePPND study, brolucizumab was not detected in the maternal milk or infant serum of cynomolgus monkeys.

Fertility

VEGF inhibition has been shown to affect follicular development, corpus luteum function and fertility. Based on the mechanism of action of VSIQQ, there is a potential risk for female reproduction, and to embryofoetal development.

Patients may experience temporary visual disturbances after an intravitreal injection with VSIQQ and the associated eye examination and should therefore be advised not to drive or use machinery until visual function has recovered sufficiently.

a. Summary of the safety profile

Wet AMD population

A total of 1 088 patients treated with brolucizumab constituted the safety population in the two Phase III studies (HAWK and HARRIER) with a cumulative 96 weeks exposure to VSIQQ and 730 patients treated with the recommended dose of 6 mg (see section 5.1). The most frequently reported adverse drug reactions (in > 5 % of patients treated with VSIQQ) were reduced visual acuity (7,3 %), cataract (7,0 %), conjunctival haemorrhage (6,3 %) and vitreous floaters (5,1 %). Less common serious adverse drug reactions reported in < 1 % of the patients treated with VSIQQ were endophthalmitis, blindness, retinal artery occlusion and retinal detachment.

DME population

The safety of VSIQQ was studied in two, Phase III active controlled studies (KESTREL and KITE) conducted respectively in 368 patients with visual impairment due to DME treated with the recommended dose of brolucizumab 6 mg for 100 weeks. The ocular and non-ocular events in the KESTREL and KITE studies were reported with a frequency and severity similar to those seen in the wet AMD trials. Retinal vascular occlusion was reported in four patients (1,1 %) treated with VSIQQ and two patients (0,5 %) treated with aflibercept 2 mg. Retinal vasculitis was reported in one patient (0,3 %) treated with VSIQQ and no patients treated with aflibercept 2 mg. The adverse drug reactions of iridocyclitis and vitreous haemorrhage were observed at a higher frequency (category of common) in the pooled DME Phase III studies as compared to the pooled nAMD Phase III studies (category of uncommon). In addition, the adverse drug reaction retinal vascular occlusion was observed at a frequency category of common in the pooled DME Phase III studies.

b. Tabulated summary of adverse reactions

Adverse reactions from the HAWK and HARRIER clinical studies (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common ( u2265 1/10), common ( u2265 1/100 to < 1/10), uncommon ( u2265 1/1,000 to < 1/100), rare ( u2265 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Table 1 Frequencies of adverse drug reactions in clinical studies

System organ class Frequency category Eye disorders Visual acuity reduced Common Retinal haemorrhage Common Uveitis Common Iritis Common Vitreous detachment Common Retinal tear Common Cataract Common Conjunctival haemorrhage Common Vitreous floaters Common Eye pain Common Intraocular pressure increase Common Conjunctivitis Common Retinal pigment epithelial tear Common Vision blurred Common Corneal abrasion Common Punctate keratitis Common

Endophthalmitis Uncommon Blindness Uncommon Retinal artery occlusion Uncommon Retinal detachment Uncommon Conjunctival hyperaemia Uncommon Lacrimation increased Uncommon Abnormal sensation in eye Uncommon Detachment of retinal pigment epithelium Uncommon Vitritis Uncommon Anterior chamber inflammation Uncommon Iridocyclitis Uncommon Anterior chamber flare Uncommon Corneal oedema Uncommon Vitreous haemorrhage Uncommon

Immune system disorders Hypersensitivity a) Common a) Including urticaria, rash, pruritus, erythema

Adverse drug reactions from spontaneous reports and literature cases (frequency not known)

The following adverse drug reactions have been derived from post-marketing experience with VSIQQ via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Table 2 Adverse drug reactions from spontaneous reports and literature (frequency not known) Eye disorders Retinal vascular occlusion, retinal vasculitis

c. Description of selected adverse reactions

Intraocular inflammation

Based on clinical studies, intraocular inflammation related adverse events, including retinal vasculitis and retinal vascular occlusion, were reported more frequently in female patients treated with VSIQQ than male patients (e.g., 5,3 % females vs. 3,2 % males in HAWK and HARRIER). The results of a retrospective real world evidence analysis in nAMD patients who were evaluated for up to 6 months after initiating treatment with VSIQQ suggest that patients with a medical history of intraocular inflammation and/or retinal vascular occlusion in the year prior to treatment with VSIQQ were more likely to present with similar events after VSIQQ injection, as compared to nAMD patients with no history of these events.

Immunogenicity

There is a potential for an immune response in patients treated with VSIQQ. The immunogenicity of VSIQQ was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to VSIQQ in immunoassays. Wet AMD The pre-treatment incidence of anti-brolucizumab antibodies was 35 u2013 52 %. After dosing with VSIQQ for 88 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 23 u2013 25 % of patients. DME The pre-treatment incidence of anti-brolucizumab antibodies was 64 %. After dosing with VSIQQ for 96 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 16 to 23 % of patients. In wet AMD and DME, anti-brolucizumab antibodies were not associated with an impact on clinical efficacy. Among patients with treatment-emergent antibodies, a higher number of intraocular inflammation events were observed. Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, are immune mediated adverse events related to exposure to VSIQQ. This treatment emergent antibody response may develop following the first intravitreal injection (see section 4.4).

Overdosing with greater than recommended injection volume may increase intraocular pressure. In the event of overdose, intraocular pressure should therefore be monitored and, if deemed necessary by the treating physician, appropriate treatment should be initiated.