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Pagenax

Pagenax

Manufacturer:

Novartis

Distributor:

DKSH
Full Prescribing Info
Contents
Brolucizumab.
Description
One ml solution for injection contains 120 mg of brolucizumab*.
* Brolucizumab is a humanised monoclonal single-chain Fv (scFv) antibody fragment produced in Escherichia coli cells by recombinant DNA technology.
Pagenax 120 mg/ml solution for injection: Each vial contains 27.6 mg brolucizumab in 0.23 ml solution. This provides a usable amount to deliver a single dose of 0.05 ml solution containing 6 mg of brolucizumab.
Excipients/Inactive Ingredients: Sodium citrate, Sucrose, Polysorbate 80, Water for injections.
Action
Pharmacotherapeutic group: Ophthalmologicals, antineovascularisation agents. ATC code: S01LA06.
Pharmacology: Pharmacodynamics: Mechanism of action: Brolucizumab is a humanised monoclonal single chain Fv (scFv) antibody fragment with a molecular weight of ~26 kDa.
Increased levels of signalling through the vascular endothelial growth factor A (VEGF-A) pathway are associated with pathological ocular angiogenesis and retinal oedema. Brolucizumab binds with high affinity to VEGF-A isoforms (e.g. VEGF110, VEGF121, and VEGF165), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A binding, brolucizumab suppresses endothelial cell proliferation, thereby reducing pathological neovascularisation and decreasing vascular permeability.
Pharmacodynamic effects: Neovascular (wet) age-related macular degeneration (AMD) is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal thickening or oedema and/or intraretinal/subretinal haemorrhage, resulting in loss of visual acuity.
In the HAWK and HARRIER studies, related anatomical parameters were part of the disease activity assessments guiding treatment decisions. Reductions in central subfield thickness (CST) and in presence of intraretinal/subretinal fluid (IRF/SRF) or sub-retinal pigment epithelium (sub-RPE) fluid were observed in patients treated with Pagenax as early as 4 weeks after treatment initiation and up to week 48 and week 96.
At week 16, the reduction in CST was statistically significant on Pagenax versus aflibercept in both studies (HAWK: -161 vs. -134 microns; HARRIER: -174 vs. -134 microns). This decrease from baseline in CST was also statistically significant at week 48 (HAWK: -173 vs. -144 microns; HARRIER: -194 vs. -144 microns), and maintained to the end of each study at week 96 (HAWK: -175 vs. -149 microns; HARRIER: -198 vs. -155 microns).
At week 16, the percentage difference in patients with IRF and/or SRF fluid was statistically significant on Pagenax versus aflibercept in both studies (HAWK: 34% vs. 52%; HARRIER: 29% vs. 45%). This difference was also statistically significant at week 48 (HAWK: 31% vs. 45%; HARRIER: 26% vs. 44%), and maintained to the end of each study at week 96 (HAWK: 24% vs. 37%; HARRIER: 24% vs. 39%).
At week 16, the percentage difference in patients with sub-RPE fluid was statistically significant on Pagenax versus aflibercept in both studies (HAWK: 19% vs. 27%; HARRIER: 16% vs. 24%). This difference was also statistically significant at week 48 (HAWK: 14% vs. 22%; HARRIER: 13% vs. 22%), and maintained to the end of each study at week 96 (HAWK: 11% vs. 15%; HARRIER: 17% vs. 22%).
In these studies, for patients treated with Pagenax, reductions in CNV lesion size were observed as early as 12 weeks, and at weeks 48 and 96 after treatment initiation.
Clinical efficacy and safety: The efficacy and safety of Pagenax were assessed in two randomised, multicentre, double-masked, active-controlled Phase III studies (HAWK and HARRIER) in patients with neovascular (wet) AMD. A total of 1,817 patients were treated in these studies for two years (1,088 on Pagenax and 729 on comparator aflibercept). Patient ages ranged from 50 to 97 years, with a mean age of 76 years.
In both studies, after the first three monthly doses (weeks 0, 4 and 8), brolucizumab patients were treated every 12 weeks, with the option of adjusting to a dosing interval every 8 weeks based on disease activity. Disease activity was assessed by a physician during the first 12-week interval (at weeks 16 and 20) and at each subsequent scheduled 12-weekly treatment visit. Patients who showed disease activity (e.g. decreased visual acuity, increased CST and/or presence of IRF/SRF or sub-RPE fluid) at any of these visits were adjusted to an 8-weekly treatment interval. The comparator aflibercept was administered every 8 weeks after the first 3 monthly doses.
Results: The primary efficacy endpoint for the studies was the change from baseline in best corrected visual acuity (BCVA) to week 48, as measured by the early treatment diabetic retinopathy study (ETDRS) letter score, with the primary objective being to demonstrate non-inferiority of Pagenax versus aflibercept. In both studies, Pagenax (administered in an every 12 weeks or an every 8 weeks regimen) demonstrated non-inferior efficacy to aflibercept 2 mg (administered every 8 weeks). The visual acuity gains observed in the first year were maintained in the second year.
Detailed results of both studies are shown in Table 1 and in Figure 1 as follows.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

These visual acuity gains were achieved with 56% and 51% of patients treated with Pagenax 6 mg on a 12-weekly dosing interval at week 48, and with 45% and 39% of patients at week 96 in HAWK and HARRIER, respectively. Among patients identified as eligible for the 12-weekly regimen during the first 12-week interval, 85% and 82% remained on the 12-weekly dosing interval up to week 48. Of patients on the 12-weekly interval at week 48, 82% and 75% remained on the 12-weekly dosing interval up to week 96.
Treatment effects in evaluable subgroups (e.g. age, gender, race, baseline visual acuity, baseline retinal thickness, lesion type, lesion size, fluid status) in each study were generally consistent with the results in the overall populations.
Disease activity was assessed by changes in visual acuity and/or anatomical parameters, including CST and/or presence of IRF/SRF or sub-RPE. Disease activity was assessed throughout the studies. Anatomical parameters of disease activity were decreased at week 48 and at week 96 for Pagenax compared to aflibercept (see 'Pharmacodynamic effects' as previously mentioned).
The percentage difference in patients with disease activity at week 16 was statistically significant on Pagenax versus aflibercept (24% vs 35% in HAWK, p=0.0013; 23% vs 32% in HARRIER, p=0.0021).
In both studies, Pagenax demonstrated clinically meaningful increases from baseline in the pre-specified secondary efficacy endpoint of patient-reported outcomes, reported through the National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in BCVA. Patient-reported outcome benefits were maintained in the second year.
No clinically meaningful differences were found between Pagenax and aflibercept in changes from baseline to week 48 in NEI VFQ-25 total score and subscales (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, colour vision and peripheral vision).
Pharmacokinetics: Pagenax is administered directly into the vitreous to exert local effects in the eye.
Absorption and distribution: After intravitreal administration of 6 mg brolucizumab per eye to patients with nAMD, the geometric mean Cmax of free brolucizumab in the plasma was 49.0 ng/ml (range: 8.97 to 548 ng/ml) and was attained in 1 day.
Biotransformation and elimination: Brolucizumab is a monoclonal antibody fragment and no metabolism studies have been conducted. As a single-chain antibody fragment, free brolucizumab is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF, passive renal elimination and metabolism via proteolysis.
After intravitreal injections, brolucizumab was eliminated with an apparent systemic half-life of 4.4 days. Concentrations were generally near or below the quantitation limit (<0.5 ng/ml) approximately 4 weeks after dosing in most patients. Brolucizumab did not accumulate in the serum when administered intravitreally every 4 weeks.
Special populations: Elderly: There were no relevant differences in systemic pharmacokinetics following intravitreal injection in a study with 22 patients aged 65 to 74 years, 18 patients aged 75 to 84 years and 3 patients aged ≥85 years.
Renal impairment: The systemic pharmacokinetics of brolucizumab was evaluated in nAMD patients with normal renal function (≥90 ml/min [n=21]), with mild (60 to <90 ml/min [n=22]) or moderate (30 to <60 ml/min [n=7]) renal impairment. While the mean systemic clearance values for patients with mild or moderate renal impairment were generally lower than patients with normal renal function, no significant impact of mild and moderate renal impairment on the overall systemic exposure to brolucizumab was observed. No patients with severe (<30 ml/min) renal impairment were studied.
Hepatic impairment: Brolucizumab has not been studied in patients with hepatic impairment. Mild to severe hepatic impairment should have no impact on the overall systemic exposure to brolucizumab, because metabolism occurs via proteolysis and does not depend on hepatic function.
Toxicology: Preclinical safety data: No studies have been conducted on the carcinogenic or mutagenic potential of brolucizumab.
No animal reproduction studies have been conducted.
Indications/Uses
Pagenax is indicated in adults for the treatment of neovascular (wet) age-related macular degeneration (AMD).
Dosage/Direction for Use
Pagenax must be administered by a qualified ophthalmologist experienced in intravitreal injections.
Posology: The recommended dose is 6 mg brolucizumab (0.05 ml solution) administered by intravitreal injection every 4 weeks (monthly) for the first 3 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. The physician may further individualise treatment intervals based on disease activity.
If visual and anatomical outcomes indicate that the patient is not benefiting from continued treatment, Pagenax should be discontinued.
Special populations: Elderly: No dosage adjustment is required in patients aged 65 years or above (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dosage adjustment is required in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: Brolucizumab has not been studied in patients with hepatic impairment. No dosage adjustment is required in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
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: Pagenax is for intravitreal use only.
The solution for injection should be inspected visually prior to administration (see Special precautions for disposal and other handling under Cautions for Usage).
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 Contraindications). 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.
Vial: The vial is for single use only. Each vial should only be used for the treatment of a single eye.
Since the volume contained in the vial (0.23 ml) is greater than the recommended dose (0.05 ml), a portion of the volume contained in the vial must be discarded prior to administration.
Injecting the entire volume of the vial could result in overdose. To expel the air bubble along with excess medicinal product, the air should be carefully expelled from the syringe and the dose adjusted to the 0.05 ml mark (equivalent to 50 μl, i.e. 6 mg brolucizumab).
For instructions on preparation of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage).
Overdosage
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.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Patients with active or suspected ocular or periocular infections.
Patients with active intraocular inflammation.
Special Precautions
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, retinal detachment, retinal vasculitis and/or retinal vascular occlusion: Intravitreal injections, including those with Pagenax, have been associated with endophthalmitis, intraocular inflammation, traumatic cataract and retinal detachment. Proper aseptic injection techniques must always be used when administering Pagenax.
Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of Pagenax (see Precautions and Adverse Reactions).
Patients should be instructed to report any symptoms suggestive of the previously mentioned events without delay.
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 Adverse Reactions). Special precaution is needed in patients with poorly controlled glaucoma (do not inject Pagenax 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 Adverse Reactions). 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 Adverse Reactions).
Concomitant use of other anti-VEGF: There are no data available on the concomitant use of Pagenax 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).
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 with a history of stroke, transient ischaemic attacks or myocardial infarction within the last 3 months. Caution should be exercised 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".
Effects on ability to drive and use machines: Pagenax 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.
Use In Pregnancy & 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. Animal studies are insufficient with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Although the systemic exposure after ocular administration is very low, 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. 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 inhibitiors, there is a potential risk for female reproduction, and to embryofoetal development.
Adverse Reactions
Summary of the safety profile: 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%).
Tabulated list of adverse reactions: Adverse reactions (Table 2) 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 2.)

Click on icon to see table/diagram/image

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 Pagenax 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 categorized 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. (See Table 3.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Immunogenicity: There is a potential for an immune response in patients treated with Pagenax. After dosing with Pagenax for 88 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 23-25% of patients. Among patients with treatment-emergent antibodies, a higher number of intraocular inflammation adverse reactions were observed. The clinical significance of anti-brolucizumab antibodies on safety is unclear at this time. 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. There were no major notable differences between the groups treated with brolucizumab and comparator.
Drug Interactions
No interaction studies have been performed.
Caution For Usage
Instructions for use and handling: Instructions for use of the Pagenax vial kit: Storage and inspection: Store Pagenax in the refrigerator (2°C to 8°C/36°F to 46°F); do not freeze. Keep the vial in the outer carton to protect from light.
After opening the vial, proceed under aseptic conditions.
Pagenax is a clear to slightly opalescent and colorless to slightly brownish-yellow solution.
The solution should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, the vial must not be used and appropriate replacement procedures followed.
The contents of the vial and filter needle are sterile and for single use only. Do not use if the packaging, vial and/or filter needle are damaged or expired.
How to prepare and administer Pagenax: The intravitreal injection procedure must 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 equipment (if required). Adequate anesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection.
For preparation and intravitreal injection the following single use medical devices are needed: A 30G x ½" injection needle, sterile.
A 1 mL syringe with a 0.05 mL dose mark, sterile.
The 5 μm blunt filter needle (18G x 1½", 1.2 mm x 40 mm), sterile.
The injection needle and the syringe are not included in the Pagenax vial kit.
Note: The dose must be set to 0.05 mL.
Ensure that the injection is given immediately after preparation of the dose (Step 8).
Injection procedure: 1 Remove the vial cap and clean the vial septum (e.g. with 70% alcohol swab).
2 Assemble the filter needle onto a 1 mL syringe using aseptic technique.
3 Push the filter needle into the center of the vial septum until the needle touches the bottom of the vial.
4 To withdraw the liquid, hold the vial slightly inclined and slowly withdraw all the liquid from the vial and filter needle.
Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
5 Disconnect the filter needle from the syringe in an aseptic manner and dispose of it.
The filter needle is not to be used for intravitreal injection.
6 Aseptically and firmly assemble a 30G x ½" injection needle onto the syringe.
7 To check for air bubbles, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top.
8 Carefully expel the air from the syringe and adjust the dose to the 0.05 mL mark. The syringe is ready for the injection.
9 Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel.
Note: Any unused medicinal product or waste material should be disposed of in accordance with local regulations.
Commonly asked questions and answers: Q: What if I have difficulty withdrawing sufficient liquid from the vial?
A: Do not shake the vial before withdrawal but let the liquid settle to the bottom of the vial. Ensure the vial is in an upright, slightly inclined position. Slowly withdraw the plunger and wait for the liquid to appear in the syringe barrel. Continue to withdraw slowly to completely empty the vial and the filter needle.
Q: What if I cannot remove all the air bubbles from the liquid?
A: It is important that the liquid is air free. However, tiny air bubbles that are attached to the stopper usually do not detach from the stopper during the injection and therefore do not affect the dose volume.
Special precautions for disposal and other handling: Vial: The vial contains more than the recommended dose of 6 mg. The extractable volume of the vial (0.23 ml) is not to be used in total. The excess volume should be expelled prior to injection. Injecting the entire volume of the vial could result in overdose. The injection dose must be set to the 0.05 ml dose mark, i.e. 6 mg brolucizumab.
The solution should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, the vial must not be used, and appropriate replacement procedures must be followed.
The content of the vial and the filter needle are sterile and for single use only. Do not use if the packaging, vial and/or filter needle are damaged or expired. Detailed instructions for use are provided in the package leaflet.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Storage
Vial: Store in a refrigerator at 2°C to 8°C.
Do not freeze
Keep the vial in the outer carton in order to protect from light.
ATC Classification
S01LA06 - brolucizumab ; Belongs to the class antineovasculatisation agents. Used in the management of neovascular macular degeneration.
Presentation/Packing
Intraocular inj 120 mg/mL (clear to slightly opalescent, colourless to slightly brownish-yellow aqueous solution in vial) x 1's.
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