XIMLUCI Solution for injection Ref.[50507] Active ingredients: Ranibizumab

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 Ximluci. 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 ranibizumab. 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)

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

Withholding Ximluci 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).

No interaction studies have been performed.

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

For the adjunctive use of laser photocoagulation and Ximluci 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.

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

It is unknown whether ranibizumab is excreted in human milk. Breast-feeding is not recommended during the use of Ximluci.

Fertility

There are no data available on fertility.

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.

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.

^# 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 national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.