Vabysmo 6 mg Solution for Injection

Vabysmo is a bispecific angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of:

• neovascular (wet) age-related macular degeneration (nAMD) (see section 5.1 Pharmacodynamic properties),
• diabetic macular oedema (DME) (see section 5.1),
• macular oedema secondary to retinal vein occlusion (RVO).

General
For intravitreal injection only. Vabysmo must be administered by a qualified physician experienced in intravitreal injections. Each vial should only be used for the treatment of a single eye.

Neovascular (wet) age-related macular degeneration (nAMD)
The recommended dose for Vabysmo is 6 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first 4 doses. Thereafter, an assessment of disease activity based on anatomic and/or visual outcomes is recommended 20 and/or 24 weeks after treatment initiation so that treatment can be individualised. In patients without disease activity, administration of faricimab every 16 weeks (4 months) should be considered. In patients with disease activity, treatment every 8 weeks (2 months) or 12 weeks (3 months) should be considered. If anatomic and/or visual outcomes change, the treatment interval should be adjusted accordingly, and interval reduction should be implemented if anatomic and/or visual outcomes deteriorate (see section 5.1). There is limited safety data on treatment intervals of 8 weeks or less between injections (see section 4.4). Monitoring between the dosing visits should be scheduled based on the patient's status and at the physician's discretion, but there is no requirement for monthly monitoring between injections.

Diabetic macular oedema (DME)
The recommended dose for Vabysmo is 6 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first 4 doses. Thereafter, treatment is individualised using a treat-and-extend approach. Based on the physician's judgement of the patientu2019s anatomic and/or visual outcomes, the dosing interval may be extended up to every 16 weeks (4 months), in increments of up to 4 weeks. If anatomic and/or visual outcomes change, the treatment interval should be adjusted accordingly, and interval reduction should be implemented if anatomic and/or visual outcomes deteriorate (see section 5.1). Treatment intervals shorter than 4 weeks between injections have not been studied. Monitoring between the dosing visits should be scheduled based on the patient's status and at the physician's discretion, but there is no requirement for monthly monitoring between injections.

Macular oedema secondary to retinal vein occlusion (RVO)
The recommended dose for VABYSMO is 6 mg (0,05 mL) administered by intravitreal injection every 4 weeks (monthly); 3 or more consecutive, monthly injections may be needed followed by 6 mg (0,05 mL) via intravitreal injection at intervals of up to every 16 weeks (4 months). Monitoring between the dosing visits should be scheduled based on the patientu2019s status and at the physicianu2019s discretion.

Method of administration
Vabysmo should be inspected visually for particulate matter and discoloration prior to administration. 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. vision loss, eye pain, redness of the eye, photophobia, blurring of vision) without delay. Comprehensive instructions for the administration of Vabysmo are given in the Instructions for Use.

Duration of treatment
Vabysmo is intended for long-term treatment.

Delayed or missed dose
If a dose is delayed or missed, the patient should return to be assessed by physician at the next available visit and continue dosing depending on physicianu2019s discretion. If visual and/or anatomic outcomes indicate that the patient is not benefitting from continued treatment, Vabysmo should be discontinued.

Dose Modifications
No dose modifications of Vabysmo are recommended.

Special populations
Paediatric population
The safety and efficacy of Vabysmo in children and adolescents have not been established.

Elderly use
In the six Phase III clinical studies, approximately 58 % (1,496/2,571) of patients randomized to treatment with Vabysmo were u2265 65 years of age. Population pharmacokinetic analysis has shown an effect of age on ocular pharmacokinetics of faricimab. No dose adjustment is required in patients u2265 65 years of age (see section 4.7 Effects on ability to drive and use machines and 5.2 Pharmacokinetics properties).

Renal impairment
No specific studies in patients with renal impairment have been conducted with Vabysmo. Pharmacokinetic analysis of patients in all clinical studies of which 63 % had renal impairment (mild 38 %, moderate 23 %, and severe 2 %), revealed no differences with respect to systemic pharmacokinetics of faricimab after intravitreal administration of Vabysmo. No dose adjustment is required in patients with renal impairment (see section 5.2 Pharmacokinetics properties).

Hepatic impairment
No specific studies in patients with hepatic impairment have been conducted with Vabysmo. However, no special considerations are needed in this population because metabolism occurs via proteolysis and does not depend on hepatic function. No dose adjustment is required in patients with hepatic impairment (see section 5.2 Pharmacokinetics properties).

Other Special Patient Populations
No special dosage modification is required for any of the populations that have been studied (e.g., elderly, gender, race).

Vabysmo is contraindicated in patients with ocular or periocular infections.

Vabysmo is contraindicated in patients with active intraocular inflammation.

Vabysmo is contraindicated in patients with known hypersensitivity to faricimab or any of the excipients listed in section 6.1. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, erythema, or severe intraocular inflammation.

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

Sugar
Vabysmo contains D sucrose. Patients with the rare hereditary conditions of galactose intolerance lactase deficiency, glucose-galactose malabsorption intolerance should not take Vabysmo. Vabysmo contains D sucrose which may have an effect on the glycaemic control of patients with diabetes mellitus.

Intravitreal injection-related reactions
Intravitreal injections, including those with Vabysmo have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment and retinal tear and iatrogenic traumatic cataract (see section 4.8 Undesirable effects). Proper aseptic injection techniques must always be used when administering Vabysmo. Patients should be instructed to report any symptoms, such as pain, loss of vision, photophobia, blurred vision, floaters, or redness, suggestive of endophthalmitis or any of the above-mentioned events without delay, to permit prompt and appropriate management.

Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of intravitreal injection, including those with Vabysmo. Special precaution is needed in patients with poorly controlled glaucoma (do not inject Vabysmo while the IOP is u2265 30 mmHg). In all cases, both the IOP and perfusion of the optic nerve head and/or vision must be monitored and managed appropriately.

Systemic effects
Systemic adverse events including arterial thromboembolic events have been reported following intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors and there is a theoretical risk that these may be related to VEGF inhibition. A low incidence rate of arterial thromboembolic events was observed in the Vabysmo clinical trials in patients with nAMD, DME, and RVO.

Immunogenicity
As this is a therapeutic protein, there is a potential for immunogenicity with Vabysmo (see section 4.8 Undesirable effects). Patients should be instructed to inform their physician of any signs or symptoms of intraocular inflammation such as vision loss, eye pain, increased sensitivity to light, floaters or worsening eye redness, which might be a clinical sign attributable to hypersensitivity.

Bilateral treatment
The safety and efficacy of Vabysmo administered in both eyes concurrently have not been studied.

Concomitant use of other anti-VEGF
There are no data available on the concomitant use of Vabysmo with anti-VEGF medicinal products in the same eye.

Withholding treatment
Treatment should be withheld in patients with:

• Rhegmatogenous retinal detachment, stage 3 or 4 macular holes, retinal break; treatment should not be resumed until an adequate repair has been performed.
• Treatment related decrease in Best Corrected Visual Acuity (BCVA) of u2265 30 letters compared with the last assessment of visual acuity; treatment should not be resumed earlier than the next scheduled treatment.
• Performed or planned intraocular surgery within the previous or next 28 days; treatment should not be resumed earlier than the next scheduled treatment.

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

Populations with limited data
There is only limited experience in the treatment of DME patients with HbA1c over 10%, patients with high-risk proliferative diabetic retinopathy (DR), or nAMD, DME and RVO patients with active systemic infections. There is also no experience of treatment with Vabysmo in diabetic and RVO patients with uncontrolled hypertension. This lack of information should be considered by the physician when treating such patients.

No drug-drug interaction studies have been performed with Vabysmo.

Women of childbearing potential
Women of childbearing potential should use contraception during treatment with Vabysmo and for at least 3 months following the last dose of Vabysmo.

Pregnancy
There are no data from the use of Vabysmo in pregnant women. No adverse effects were observed in a study in pregnant cynomologus monkeys given Vabysmo intravenously throughout the period of organogenesis at doses achieving more than 500 times the predicted systemic human exposure of Vabysmo after treatment of a single eye (see section 5.2 Pharmacokinetic properties). It is not known whether Vabysmo can cross the placenta or cause harm to the foetus when administered to pregnant women. Based on the mechanism of action of VEGF and Ang-2 inhibitors, there is a potential risk to female reproductive capacity, and to embryo-foetal development. Although the systemic exposure after ocular administration is very low, Vabysmo should not be used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.

Labor and delivery
The safe use of Vabysmo during labor and delivery has not been established.

Breastfeeding
It is not known whether Vabysmo is excreted in human breast milk. No studies have been conducted to assess the impact of Vabysmo on milk production or its presence in breast milk because many drugs are excreted in human milk with the potential for absorption and harm to infant growth and development exists, caution should be exercised when Vabysmo is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the motheru2019s clinical need for Vabysmo and any potential adverse effects on the breastfed child from Vabysmo.

Fertility
No reproductive or fertility studies have been conducted. No effects on reproductive organs or fertility were observed in a 6-month cynomolgus monkey study with Vabysmo. VEGF inhibition has been shown to affect follicular development, corpus luteum function and fertility. Based on the mechanism of action of VEGF and Ang-2 inhibitors, there is a potential risk to female reproductive capacity, and to embryo-foetal development, however the risk is considered low due to the low systemic exposure after ocular administration (see section 5.3 Preclinical safety data).

Drug Abuse and Dependence
There is no evidence that Vabysmo has the potential for drug abuse and dependence.

Vabysmo may have 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.

Paediatric Use
The safety and efficacy of Vabysmo in paediatric patients have not been established.

Elderly Use
In the six Phase III clinical studies, approximately 58 % (1,496/2,571) of patients randomized to treatment with Vabysmo were u2265 65, years of age. No significant differences in efficacy or safety of Vabysmo were seen with increasing age in these studies (see section 4.2 Posology and method of administration and 5.2 Pharmacokinetics properties).

Renal Impairment
No dose adjustment is required in patients with renal impairment (see section 4.2 Posology and method of administration and 5.2 Pharmacokinetics properties).

Hepatic Impairment
The safety and efficacy of Vabysmo in patients with hepatic impairment has not been studied (see section 4.2 Posology and method of administration and 5.2 Pharmacokinetics properties).

Clinical Trials
Summary of safety profile
A total of 4, 489 patients constituted the safety population in the six Phase III clinical studies (2,567 Vabysmo treated patients; 664 in nAMD 1,262 in DME and 641 in RVO). The most serious adverse reactions were uveitis (0.5 %), endophthalmitis (0.4 %), vitritis (0.4 %), retinal tear (0.2 %), rhegmatogenous retinal detachment (0.1 %), and traumatic cataract (< 0.1 %). The most frequently reported adverse reactions in patients treated with VABYSMO were cataract (10 %), conjunctival hemorrhage (7 %), vitreous detachment (4 %), IOP increased (4 %), vitreous floaters (4%), eye pain (3 %) and retinal pigment epithelial tear (nAMD only) (3 %).

Tabulated list of adverse reactions
The safety data described below include all adverse reactions from the pooled data across six Phase III clinical studies in the indications nAMD DME, and RVO with a reasonable possibility of causality attribution to the injection procedure or medicinal product. The adverse reactions are listed according to the MedDRA system organ class and ranked by frequency using the following convention: 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).

Table 1: Summary of adverse reactions occurring in patients treated with Vabysmo in phase III clinical trials

Adverse reactions Frequency category Eye disorders Cataract Common Conjunctival haemorrhage Common Vitreous detachment Common Intraocular pressure increased Common Vitreous floaters Common Retinal pigment epithelial tear (nAMD only) Common Eye pain Common Corneal abrasion Uncommon Eye irritation Uncommon Lacrimation increased Uncommon Eye pruritus Uncommon Ocular discomfort Uncommon Ocular hyperaemia Uncommon Vision blurred Uncommon Iritis Uncommon Visual acuity reduced Uncommon Uveitis Uncommon Endophthalmitis Uncommon Sensation of foreign body Uncommon Vitreous haemorrhage Uncommon Vitritis Uncommon Iridocyclitis Uncommon Conjunctival hyperamia Uncommon Procedural pain Uncommon Retinal tear Uncommon Rhegmatogenous retinal detachment Uncommon Traumatic cataract Rare Visual acuity reduced transiently Rare

Description of selected 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 Vabysmo clinical trials in patients with nAMD, DME and RVO. Across indications no notable difference between the groups treated with Vabysmo and the comparator were observed.

Postmarketing Experience
Rare cases of retinal vasculitis and/or retinal occlusive vasculitis have been spontaneously reported in the post-marketing setting. Retinal vasculitis and retinal occlusive vasculitis have also been reported in patients treated with IVT therapies.

Eye disorders: retinal vasculitis, retinal occlusive vasculitis

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Doses higher than the recommended dosing regimen have not been studied. Overdosing with greater than recommended injection volume may increase intraocular pressure. In the event of an overdose, IOP should be monitored and, if deemed necessary by the treating physician, appropriate treatment should be initiated.