4.1. Therapeutic indications

Ongavia is indicated in adults for:

• The treatment of neovascular (wet) age-related macular degeneration (AMD)

• The treatment of visual impairment due to diabetic macular oedema (DME)

• The treatment of proliferative diabetic retinopathy (PDR)

• The treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)

• The treatment of visual impairment due to choroidal neovascularisation (CNV)

4.2. Posology and method of administration

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

Posology

Adults

The recommended dose for Ongavia in adults is 0.5 mg given as a single intravitreal injection. This corresponds to an injection volume of 0.05 ml. The interval between two doses injected into the same eye should be at least four weeks.

Treatment in adults is initiated with one injection per month until maximum visual acuity is achieved and/or there are no signs of disease activity i.e. no change in visual acuity and in other signs and symptoms of the disease under continued treatment. In patients with wet AMD, DME, PDR and RVO, initially, three or more consecutive, monthly injections may be needed.

Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity, as assessed by visual acuity and/or anatomical parameters.

If, in the physician's opinion, visual and anatomic parameters indicate that the patient is not benefiting from continued treatment, Ongavia should be discontinued.

Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography).

If patients are being treated according to a treat-and-extend regimen, once maximum visual acuity is achieved and/or there are no signs of disease activity, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval should be extended by no more than two weeks at a time for wet AMD and may be extended by up to one month at a time for DME. For PDR and RVO, treatment intervals may also be gradually extended, however there are insufficient data to conclude on the length of these intervals. If disease activity recurs, the treatment interval should be shortened accordingly.

The treatment of visual impairment due to CNV should be determined individually per patient based on disease activity. Some patients may only need one injection during the first 12 months; others may need more frequent treatment, including a monthly injection. For CNV secondary to pathologic myopia (PM), many patients may only need one or two injections during the first year (see section 5.1).

Ranibizumab and laser photocoagulation in DME and in macular oedema secondary to BRVO

There is some experience of ranibizumab administered concomitantly with laser photocoagulation (see section 5.1). When given on the same day, ranibizumab should be administered at least 30 minutes after laser photocoagulation. ranibizumab can be administered in patients who have received previous laser photocoagulation.

Ranibizumab and verteporfin photodynamic therapy in CNV secondary to PM

There is no experience of concomitant administration of ranibizumab and verteporfin.

Special populations

Hepatic impairment

Ranibizumab has not been studied in patients with hepatic impairment. However, no special considerations are needed in this population.

Renal impairment

Dose adjustment is not needed in patients with renal impairment (see section 5.2).

Elderly

No dose adjustment is required in the elderly. There is limited experience in patients older than 75 years with DME.

Paediatric population

The safety and efficacy of ranibizumab in children and adolescents below 18 years of age have not been established. Available data in adolescent patients aged 12 to 17 years with visual impairment due to CNV are described in section 5.1 but no recommendation on a posology can be made.

Method of administration

Single-use vial for intravitreal use only.

Since the volume contained in the vial (0.23 ml) is greater than the recommended dose (0.05 ml for

adults), a portion of the volume contained in the vial must be discarded prior to administration.

Ongavia should be inspected visually for particulate matter and discoloration prior to administration.

For information on preparation of Ongavia, 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) and the availability of sterile paracentesis (if required). The patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see section 4.4). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection, in accordance with local practice.

Adults

In adults the injection needle should be inserted 3.5-4.0 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; a different scleral site should be used for subsequent injections.

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 severe 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.

Intravitreal injection-related reactions

Intravitreous injections, including those with ranibizumab, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see section 4.8). Proper aseptic injection techniques must always be used when administering ranibizumab. In addition, patients should be monitored during the week following the injection to permit early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay.

Intraocular pressure increases

In adults transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of ranibizumab. Sustained IOP increases have also been identified (see section 4.8). Both intraocular pressure and the perfusion of the optic nerve head must be monitored and managed appropriately.

Patients should be informed of the symptoms of these potential adverse reactions and instructed to inform their physician if they develop signs 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).

Bilateral treatment

Limited data on bilateral use of ranibizumab (including same-day administration) do not suggest an increased risk of systemic adverse events compared with unilateral treatment.

Immunogenicity

There is a potential for immunogenicity with Ongavia. Since there is a potential for an increased systemic exposure in subjects with DME, an increased risk for developing hypersensitivity in this patient population cannot be excluded. Patients should also be instructed to report if an intraocular inflammation increases in severity, which may be a clinical sign attributable to intraocular antibody formation.

Concomitant use of other anti-VEGF (vascular endothelial growth factor)

Ranibizumab should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular).

Withholding ranibizumab in adults

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;

• an intraocular pressure of ≥30 mmHg;

• 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 and potentially also other forms of CNV, include a large and/or high pigment epithelial retinal detachment. When initiating ranibizumab therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

Rhegmatogenous retinal detachment or macular holes in adults

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

Populations with limited data

There is only limited experience in the treatment of subjects with DME due to type I diabetes. Ranibizumab has not been studied in patients who have previously received intravitreal injections, in patients with active systemic infections, or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is limited experience of treatment with ranibizumab in diabetic patients with an HbA1c over 108 mmol/mol (12%) and no experience in patients with uncontrolled hypertension. This lack of information should be considered by the physician when treating such patients.

There are insufficient data to conclude on the effect of ranibizumab in patients with RVO presenting irreversible ischaemic visual function loss.

In patients with PM, there are limited data on the effect of ranibizumab in patients who have previously undergone unsuccessful verteporfin photodynamic therapy (vPDT) treatment. Also, while a consistent effect was observed in subjects with subfoveal and juxtafoveal lesions, there are insufficient data to conclude on the effect of ranibizumab in PM subjects with extrafoveal lesions.

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.

There are limited data on safety in the treatment of DME, macular oedema due to RVO and CNV secondary to PM patients with prior history of stroke or transient ischaemic attacks. Caution should be exercised when treating such patients (see section 4.8).

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

No formal interaction studies have been performed.

For the adjunctive use of verteporfin photodynamic therapy (PDT) and ranibizumab in wet AMD and PM, see section 5.1.

For the adjunctive use of laser photocoagulation and ranibizumab in DME and BRVO, see sections 4.2 and 5.1.

In clinical studies for the treatment of visual impairment due to DME, the outcome with regard to visual acuity or central retinal subfield thickness (CSFT) in patients treated with ranibizumab was not affected by concomitant treatment with thiazolidinediones.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception in females

Women of childbearing potential should use effective contraception during treatment.

Pregnancy

For ranibizumab no clinical data on exposed pregnancies are available. Studies in cynomolgus monkeys do not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/foetal development (see section 5.3). The systemic exposure to ranibizumab is low after ocular administration, but due to its mechanism of action, ranibizumab must be regarded as potentially teratogenic and embryo-/foetotoxic. Therefore, ranibizumab should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving a child.

Breast-feeding

Based on very limited data, ranibizumab may be excreted in human milk at low levels. The effect of ranibizumab on a breast-fed newborn/infant is unknown. As a precautionary measure, breast-feeding is not recommended during the use of ranibizumab.

Fertility

There are no data available on fertility.

4.7. Effects on ability to drive and use machines

The treatment procedure may induce temporary visual disturbances, which may affect the ability to drive or use machines (see section 4.8). Patients who experience these signs must not drive or use machines until these temporary visual disturbances subside.

4.8. Undesirable effects

Summary of the safety profile

The majority of adverse reactions reported following administration of ranibizumab are related to the intravitreal injection procedure.

The most frequently reported ocular adverse reactions following injection of ranibizumab are: eye pain, ocular hyperaemia, increased intraocular pressure, vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, increased lacrimation, blepharitis, dry eye and eye pruritus.

The most frequently reported non-ocular adverse reactions are headache, nasopharyngitis and arthralgia.

Less frequently reported, but more serious, adverse reactions include endophthalmitis, blindness, retinal detachment, retinal tear and iatrogenic traumatic cataract (see section 4.4).

The adverse reactions experienced following administration of ranibizumab in clinical trials are summarised in the table below.

Tabulated list of adverse reactions#

The adverse reactions are listed by system organ class and frequency using 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.

Infections and infestations

Very common

Nasopharyngitis

Common

Urinary tract infection*

Blood and lymphatic system disorders

Common

Anaemia

Immune system disorders

Common

Hypersensitivity

Psychiatric disorders

Common

Anxiety

Nervous system disorders

Very common

Headache

Eye disorders

Very common

Vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperaemia, eye pruritus.

Common

Retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract subcapsular, posterior capsule opacification, punctuate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid oedema, eyelid pain, conjunctival hyperaemia.

Uncommon

Blindness, endophthalmitis, hypopyon, hyphaema, keratopathy, iris adhesion, corneal deposits, corneal oedema, corneal striae, injection site pain, injection site irritation, abnormal sensation in eye, eyelid irritation.

Respiratory, thoracic and mediastinal disorders

Common

Cough

Gastrointestinal disorders

Common

Nausea

Skin and subcutaneous tissue disorders

Common

Allergic reactions (rash, urticaria, pruritus, erythema)

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Investigations

Very common

Intraocular pressure increased

# Adverse reactions were defined as adverse events (in at least 0.5 percentage points of patients) which occurred at a higher rate (at least 2 percentage points) in patients receiving treatment with ranibizumab 0.5 mg than in those receiving control treatment (sham or verteporfin PDT).

* observed only in DME population

Product-class-related adverse reactions

In the wet AMD phase III studies, the overall frequency of non-ocular haemorrhages, an adverse event potentially related to systemic VEGF (vascular endothelial growth factor) inhibition, was slightly increased in ranibizumab-treated patients. However, there was no consistent pattern among the different haemorrhages. 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 ranibizumab clinical trials in patients with AMD, DME, PDR, RVO and CNV and there were no major differences between the groups treated with ranibizumab compared to control.

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

Cases of accidental overdose have been reported from the clinical studies in wet AMD and post-marketing data. Adverse reactions associated with these reported cases were intraocular pressure increased, transient blindness, reduced visual acuity, corneal oedema, corneal pain, and eye pain. If an overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the attending physician.