4.1. Therapeutic indications

Beovu is indicated in adults for the treatment of

• neovascular (wet) age‑related macular degeneration (AMD) (see section 5.1),

• visual impairment due to diabetic macular oedema (DME) (see section 5.1).

4.2. Posology and method of administration

Beovu must be administered by a qualified ophthalmologist experienced in intravitreal injections.

Posology

Wet AMD

Treatment initiation - loading

The recommended dose is 6 mg brolucizumab (0.05 ml solution) administered by intravitreal injection every 4 weeks (monthly) for the first 3 doses.. A disease activity assessment is suggested 16 weeks (4 months) after treatment start.

Alternatively, 6 mg brolucizumab (0.05 ml solution) may be administered every 6 weeks for the first 2 doses. A disease activity assessment is suggested 12 weeks (3 months) after treatment start. A third dose may be administered based on disease activity as assessed by visual acuity and/or anatomical parameters at week 12.

Maintenance treatment

After the last loading dose, the physician may individualise treatment intervals based on disease activity as assessed by visual acuity and/or anatomical parameters. In patients without disease activity, treatment every 12 weeks (3 months) should be considered. In patients with disease activity, treatment every 8 weeks (2 months) should be considered. 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 (1 month) at a time (see section 5.1). There are limited data on treatment intervals longer than 20 weeks (5 months). The treatment interval between two doses of Beovu should not be less than every 8 weeks (2 months) (see sections 4.4).

If visual and anatomical outcomes indicate that the patient is not benefiting from continued treatment, Beovu should be discontinued.

DME

The recommended dose is 6 mg brolucizumab (0.05 ml solution) administered by intravitreal injection every 6 weeks for the first 5 doses. Thereafter, the physician may individualise treatment intervals based on disease activity as assessed by visual acuity and/or anatomical parameters. In patients without disease activity, treatment every 12 weeks (3 months) should be considered. In patients with disease activity, treatment every 8 weeks (2 months) should be considered. After 12 months of treatment, in patients without disease activity, treatment intervals up to 16 weeks (4 months) could be considered (see sections 4.4 and 5.1).

If visual and anatomical outcomes indicate that the patient is not benefiting from continued treatment, Beovu should be discontinued.

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

Brolucizumab has not been studied in patients with hepatic impairment. No dose adjustment is required in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of brolucizumab in children and adolescents below 18 years of age have not been established. No data are available.

Method of administration

Beovu is for intravitreal use only.

The solution for injection should be inspected visually prior to administration (see section 6.6).

The intravitreal 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 patient's 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.

Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, sterile equipment for paracentesis should be available.

Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis (e.g. eye pain, redness of the eye, photophobia, blurring of vision) without delay.

Pre‑filled syringe

The pre‑filled syringe is for single use only. Each pre‑filled syringe should only be used for the treatment of a single eye.

Since the volume contained in the pre‑filled syringe (0.165 ml) is greater than the recommended dose (0.05 ml), a portion of the volume contained in the pre‑filled syringe must be discarded prior to administration.

Injecting the entire volume of the pre‑filled syringe could result in overdose. To expel the air bubble along with excess medicinal product, the plunger should be slowly depressed until the edge below the dome of the rubber stopper is aligned with the 0.05 ml dose mark (equivalent to 50 µl, i.e. 6 mg brolucizumab).

4.3. Contraindications

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.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Endophthalmitis, intraocular inflammation, traumatic cataract, retinal detachment, retinal tear, retinal vasculitis, and/or retinal vascular occlusion

Intravitreal injections, including those with Beovu, have been associated with endophthalmitis, intraocular inflammation, traumatic cataract, retinal detachment and retinal tear (see section 4.8). Proper aseptic injection techniques must always be used when administering Beovu.

Patients should be instructed to report any symptoms suggestive of the above‑mentioned events without delay.

Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion

Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, has been reported with the use of Beovu (see sections 4.3 and 4.8). A higher number of intraocular inflammation events were observed among patients with treatment-emergent antibodies. After investigation, retinal vasculitis and/or retinal vascular occlusion were found to be immune‑mediated events. Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, may occur following the first intravitreal injection and at any time of treatment. These events were observed more frequently at the beginning of the treatment.

Based on clinical studies these events were more frequent in female patients treated with Beovu than male patients (e.g. 5.3% females vs. 3.2% males in HAWK and HARRIER) and in Japanese patients.

In patients developing these events, treatment with Beovu should be discontinued and the events should be promptly managed. Patients treated with Beovu with a medical history of intraocular inflammation and/or retinal vascular occlusion (within 12 months prior to the first brolucizumab injection) should be closely monitored, since they are at increased risk of developing retinal vasculitis and/or retinal vascular occlusion.

The interval between two Beovu doses during maintenance treatment should not be less than 8 weeks considering that a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion was reported in patients with nAMD who received Beovu every 4 week maintenance dosing in a clinical study compared to patients who received Beovu every 8 or 12 week maintenance dosing in the pivotal Phase III clinical studies.

Intraocular pressure increases

Transient increases in intraocular pressure have been seen within 30 minutes of intravitreal injection with vascular endothelial growth factor (VEGF) inhibitors, including brolucizumab (see section 4.8). Special precaution is needed in patients with poorly controlled glaucoma (do not inject Beovu while the intraocular pressure is ≥30 mmHg). Both intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately.

Bilateral treatment

The safety and efficacy of brolucizumab administered in both eyes concurrently have not been studied.

Immunogenicity

As this is a therapeutic protein, there is a potential for immunogenicity with brolucizumab (see section 4.8). Patients should be instructed to inform their physician if they develop symptoms such as eye pain or increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in their vision, or increased sensitivity to light (see section 4.8).

Concomitant use of other anti‑VEGF

There are no data available on the concomitant use of Beovu with other anti‑VEGF medicinal products in the same eye. Brolucizumab should not be administered concurrently with other anti‑VEGF medicinal products (systemic or ocular) (see section 4.5).

Withholding treatment

In intravitreal anti‑VEGF treatments, the dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of:

• a decrease in best‑corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity;

• a retinal break;

• a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50% of the total lesion area;

• performed or planned intraocular surgery within the previous or next 28 days.

Retinal pigment epithelial tear

Risk factors associated with the development of a retinal pigment epithelial tear after anti‑VEGF therapy for wet AMD include a large and/or high pigment epithelial retinal detachment. When initiating brolucizumab therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

Rhegmatogenous retinal detachment or macular holes

Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.

Systemic effects following intravitreal use

Systemic adverse events, including non‑ocular haemorrhages and arterial thromboembolic events, have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with AMD and DME with a history of stroke, transient ischaemic attacks or myocardial infarction within the last 3 months. Caution should be exercised when treating such patients.

Populations with limited data

There is limited experience with Beovu treatment in diabetic patients with HbA1c greater than 10% or with proliferative diabetic retinopathy. There is also no experience of treatment with Beovu in diabetic patients with uncontrolled hypertension. This lack of information should be considered by the physician when treating such patients.

Sodium content

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

Polysorbate 80 content

This medicinal product contains 0.01 mg polysorbate 80 per dose (0.05 ml). Polysorbates may cause allergic reactions. Patients need to be instructed to tell their doctor if they have any known allergies.

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

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment with brolucizumab and for at least one month after the last dose when stopping treatment with brolucizumab.

Pregnancy

There are no or limited amount of data from the use of brolucizumab in pregnant women. A study in pregnant cynomolgus monkeys did not indicate any harmful effects with respect to reproductive toxicity. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Although the systemic exposure after ocular administration is very low due to its mechanism of action, there is a potential risk to embryofoetal development. Therefore, brolucizumab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.

Breast‑feeding

It is unknown whether brolucizumab is excreted in human milk. In a reproductive toxicity study, brolucizumab was not detected in the maternal milk or infant serum of cynomolgus monkeys (see section 5.3). A risk to the breast‑fed newborn/infant cannot be excluded. Brolucizumab is not recommended during breast‑feeding and breast‑feeding should not be started for at least one month after the last dose when stopping treatment with brolucizumab. A decision must be made whether to discontinue breast‑feeding or to abstain from brolucizumab therapy, taking into account the benefit of breast‑feeding for the child and the benefit of therapy for the woman.

Fertility

No reproductive or fertility studies have been conducted. VEGF inhibition has been shown to affect follicular development, corpus luteum function and fertility. Based on the mechanism of action of VEGF inhibitors, there is a potential risk for female reproduction.

4.7. Effects on ability to drive and use machines

Beovu has a minor influence on the ability to drive and use machines due to possible temporary visual disturbances following the intravitreal injection and the associated eye examination. Patients should not drive or use machines until visual function has recovered sufficiently.

4.8. Undesirable effects

Summary of the safety profile

Wet AMD

For wet AMD, a total of 1 088 patients treated with brolucizumab constituted the safety population in two Phase III studies. Of these, 730 patients were treated with the recommended dose of 6 mg.

The most frequently reported adverse reactions were reduced visual acuity (7.3%), cataract (7.0%), conjunctival haemorrhage (6.3%) and vitreous floaters (5.1%).

The most serious adverse reactions were blindness (0.8%), endophthalmitis (0.7%), retinal artery occlusion (0.8%) and retinal detachment (0.7%).

DME

For DME, a total of 558 patients treated with brolucizumab constituted the safety population in two Phase III studies. Of these, 368 patients were treated with the recommended dose of 6 mg.

The most frequently reported adverse reactions were cataract (9.0%), conjunctival haemorrhage (6.5%) and intraocular pressure increased (5.4%).

The most serious adverse reactions were cataract (9.0%), , retinal vascular occlusion (1.1%), retinal artery occlusion (0.8%) and endophthalmitis (0.5%).

Tabulated list of adverse reactions

The adverse reactions experienced following administration of Beovu in clinical studies are summarised in Table 1 below.

Adverse reactions (Table 1) are listed according to the MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Frequency categories for each adverse reaction are based on the following convention: 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Frequencies of adverse reactions in clinical studies

MedDRA System organ class

Frequency category*

Immune system disorders

Hypersensitivity (including urticaria, rash, pruritus, erythema)

Common

Eye disorders

Visual acuity reduced

Common

Retinal haemorrhage

Common

Uveitis

Common

Iridocyclitis

Common

Iritis

Common

Retinal vascular occlusion

Common

Vitreous haemorrhage

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

Blindness

Uncommon

Endophthalmitis

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

Anterior chamber flare

Uncommon

Corneal oedema

Uncommon

Retinal vasculitis

Uncommon

Scleritis**

Uncommon

*The frequency category for each adverse reaction is based on the most conservative incidence rate from either pooled nAMD or pooled DME Phase III pivotal studies.

**including episcleritis

Description of selected adverse reactions

Immunogenicity

There is a potential for an immune response in patients treated with Beovu.

Wet AMD

After dosing with Beovu for 88 weeks, treatment‑emergent anti‑brolucizumab antibodies were detected in 23–25% of patients.

DME

After dosing with Beovu for 96 weeks, treatment‑emergent anti‑brolucizumab antibodies were detected in 16-23% of patients.

Among AMD and DME patients with treatment‑emergent antibodies, a higher number of intraocular inflammation adverse reactions were observed. After investigation, retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, were found to be immune‑mediated adverse events related to exposure to Beovu (see section 4.4). Anti‑brolucizumab antibodies were not associated with an impact on clinical efficacy.

Product‑class‑related adverse reactions

There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate of arterial thromboembolic events was observed in the brolucizumab clinical studies in patients with AMD and DME. There were no major notable differences between the groups treated with brolucizumab and comparator.

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

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.