Melvizo Product Monograph

Recent Major Label Changes

Table of Contents

Sections or subsections that are not applicable at the time of authorization are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ...................................................................................................................... 2

Part 1: Healthcare Professional Information .......................................................................... 4

1 Indications ..................................................................................................................... 4

1.1 Pediatrics ............................................................................................................... 4

1.2 Geriatrics ............................................................................................................... 4

2 Contraindications .......................................................................................................... 4

4 Dosage and Administration ......................................................................................... 5

4.1 Dosing Considerations .......................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment ..................................................... 5

4.4 Administration ........................................................................................................ 7

4.5 Missed Dose .......................................................................................................... 9

5 Overdose ........................................................................................................................ 9

6 Dosage Forms, Strengths, Composition, and Packaging ......................................... 9

7 Warnings and Precautions ......................................................................................... 10

General ......................................................................................................................... 10

Driving and Operating Machinery .................................................................................. 10

Immune ......................................................................................................................... 10

Ophthalmologic ............................................................................................................. 10

Renal ............................................................................................................................. 11

Reproductive Health ...................................................................................................... 11

7.1 Special Populations ............................................................................................. 12

7.1.1 Pregnancy ........................................................................................................ 12

7.1.2 Breastfeeding ................................................................................................... 12

7.1.3 Pediatrics ......................................................................................................... 12

7.1.4 Geriatrics ......................................................................................................... 12

8 Adverse Reactions ...................................................................................................... 12

8.1 Adverse Reaction Overview ................................................................................ 12

8.2 Clinical Trial Adverse Reactions .......................................................................... 13

8.3 Less Common Clinical Trial Adverse Reactions ................................................. 50

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data .......................................................................................................... 51

8.5 Post-Market Adverse Reactions .......................................................................... 52

9 Drug Interactions ........................................................................................................ 53

9.2 Drug Interactions Overview ................................................................................. 53

9.4 Drug-Drug Interactions ........................................................................................ 53

9.5 Drug-Food Interactions ........................................................................................ 53

9.6 Drug-Herb Interactions ........................................................................................ 53

9.7 Drug-Laboratory Test Interactions ....................................................................... 53

10 Clinical Pharmacology ................................................................................................ 53

10.1 Mechanism of Action ....................................................................................... 53

10.2 Pharmacodynamics ......................................................................................... 54

10.3 Pharmacokinetics ............................................................................................ 54

11 Storage, Stability, and Disposal ................................................................................ 55

12 Special Handling Instructions .................................................................................... 55

Part 2: Scientific Information ................................................................................................. 56

13 Pharmaceutical Information ....................................................................................... 56

14 Clinical Trials ............................................................................................................... 57

14.1 Clinical Trials by Indication .............................................................................. 57

15 Microbiology ................................................................................................................ 75

16 Non-Clinical Toxicology ............................................................................................. 75

17 Supporting Product Monographs .............................................................................. 83

Patient Medication Information ............................................................................................. 84

Part 1: Healthcare Professional Information

MELVIZO (ranibizumab) is a biosimilar biologic drug (biosimilar) to Lucentis. A biosimilar is a biologic drug that was granted authorization based on a demonstration of similarity to a version previously authorized in Canada, known as the reference biologic drug.

1 Indications

MELVIZO (ranibizumab injection) is indicated for:

• the treatment of neovascular (wet) age-related macular degeneration (AMD).
• the treatment of visual impairment due to diabetic macular edema (DME).
• the treatment of visual impairment due to macular edema secondary to retinal vein occlusion (RVO).
• the treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM).
• the treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to ocular conditions other than AMD or PM, including but not limited to angioid streaks, post- inflammatory retinochoroidopathy, central serous chorioretinopathy or idiopathic chorioretinopathy.

Indications have been granted on the basis of similarity between MELVIZO and the reference biologic drug Lucentis.

1.1 Pediatrics

Health Canada has not authorized MELVIZO for pediatric use due to insufficient data on safety and efficacy in this sub-population. Limited data from 5 adolescent patients aged 13 to 17 years with visual impairment due to CNV are available.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): No dose adjustment is necessary in the elderly.

2 Contraindications

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.
• Patients with active or suspected ocular or periocular infections.
• Patients with active intraocular inflammation.

4 Dosage and Administration

4.1 Dosing Considerations

• Single-use vial for intravitreal use only. Use of more than one injection from a vial can lead to contamination and subsequent infection. MELVIZO (ranibizumab injection) vials do not contain any preservative agent (see 6 Dosage Forms, Strengths, Composition, and Packaging).
• MELVIZO (ranibizumab injection) must be administered by a qualified ophthalmologist experienced in intravitreal injections.

4.2 Recommended Dose and Dosage Adjustment

Health Canada has not authorized an indication for pediatric use.

The recommended dose for MELVIZO 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 should not be shorter than 1 month.

Treatment of wet AMD

MELVIZO 0.5 mg is recommended to be administered by intravitreal injection once a month. Treatment may be reduced to one injection every 3 months after the first three injections if monthly dosing is not feasible. Compared to monthly dosing, dosing every 3 months will lead to an approximate 5-letter (1 line) loss of visual acuity benefit, on average, over the following 9 months. Patients should be evaluated regularly.

MELVIZO treatment is initiated with a loading phase of one injection per month for three consecutive months, followed by a maintenance phase in which patients should be monitored for visual acuity on a regular basis. If the patient experiences a loss of greater than 5 letters in visual acuity (Early Treatment Diabetic Retinopathy Study (ETDRS) or one Snellen line equivalent), or clinical or diagnostic evidence of disease activity, MELVIZO should be administered.

Treatment of visual impairment due to DME

Treatment is given monthly and continued until maximum visual acuity is achieved, confirmed by stable visual acuity for three consecutive monthly assessments performed while on MELVIZO treatment.

Thereafter patients should be monitored monthly for visual acuity.

Treatment is resumed with monthly injections when monitoring indicates a loss of visual acuity due to DME and continued until stable visual acuity is reached again for three consecutive monthly assessments.

MELVIZO and laser photocoagulation in DME:

In clinical trials, ranibizumab was administered concomitantly with laser photocoagulation, as well as in patients who have received previous laser photocoagulation. When given on the same day, MELVIZO should be administered at least 30 minutes after laser photocoagulation.

Treatment of visual impairment due to macular edema secondary to RVO

Treatment is given monthly and continued until maximum visual acuity is achieved, confirmed by stable visual acuity for three consecutive monthly assessments performed while on MELVIZO treatment.

Thereafter patients should be monitored monthly for visual acuity.

Treatment is resumed with monthly injections when monitoring indicates a loss of visual acuity due to macular edema secondary to RVO and continued until stable visual acuity is reached again for three consecutive monthly assessments.

MELVIZO and laser photocoagulation in Branch RVO (BRVO):

MELVIZO can be safely administered concomitantly with laser photocoagulation. When given on the same day, MELVIZO should be administered at least 30 minutes after laser photocoagulation.

Treatment of visual impairment due to CNV secondary to PM

Treatment is initiated with a single injection.

If monitoring reveals signs of disease activity, e.g. reduced visual acuity and/or signs of lesion activity, further treatment is recommended.

Monitoring for disease activity may include clinical examination, optical coherence tomography (OCT) or fluorescein angiography (FA).

While many patients may only need one or two injections during the first year, some patients may need more frequent treatment (see 14 Clinical Trials). Therefore, monitoring is recommended monthly for the first two months and at least every three months thereafter during the first year. After the first year, the frequency of monitoring should be determined by the treating physician.

There is no clinical trial experience of concomitant administration of ranibizumab and other medical agents/procedures in patients diagnosed with pathologic myopia.

There are limited data on treatment with ranibizumab in patients previously treated with verteporfin PDT.

Treatment of visual impairment due to CNV

Treatment is initiated with a single injection.

If monitoring reveals signs of disease activity, e.g. reduced visual acuity and/or signs of lesion activity, further treatment is recommended.

Monitoring for disease activity may include clinical examination, optical coherence tomography (OCT) or fluorescein angiography (FA).

Frequent monitoring is recommended, the treating physician should determine frequency of monitoring.

4.4 Administration

As with all medicinal products for parenteral use, MELVIZO should be inspected visually for particulate matter and discolouration prior to administration.

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). 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 2 Contraindications). Adequate anesthesia 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 guidelines.

For the intravitreal injection, a 30G x ½ inch injection needle should be used.

Vial

Vials are for single use only. After injection any unused product must be discarded.

The vial is sterile. Do not use the vial if the packaging is damaged. The sterility of the vial cannot be guaranteed unless the packaging seal remains intact. Do not use the vial if the solution is discoloured, cloudy, or contains particulates.

To prepare MELVIZO for intravitreal administration in adults, please adhere to the following instructions:

A.	1. Before withdrawal, the outer part of the rubber stopper of the vial should be disinfected. 2. Assemble the 5 micrometer filter needle (included in MELVIZO needles pack, but not included in MELVIZO vial only pack) onto the 1 mL syringe (not included in MELVIZO pack) using aseptic technique. Push the blunt filter needle into the centre of the vial stopper until the needle touches the bottom edge of the vial. 3. Withdraw all the liquid from the vial, keeping the vial in an upright position, slightly inclined to ease complete withdrawal.
B.	4. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. 5. Leave the blunt filter needle in the vial and
	disconnect the syringe from the blunt filter needle. The filter needle should be discarded after withdrawal of the vial contents and should not be used for the intravitreal injection.
C.	6. Aseptically and firmly assemble the 30G x ½ inch injection needle(included in MELVIZO needles pack, but not included in MELVIZO vial only pack) onto the syringe. 7. Carefully remove the cap from the injection needle without disconnecting the injection needle from the syringe. Note: Grip at the hub of the injection needle while removing the cap.
D.	8. Carefully expel the air from the syringe and adjust the dose to the 0.05 mL mark on the syringe. The syringe is ready for injection. Note: Do not wipe the injection needle. Do not pull back on the plunger.
E	9. 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. 10. The injection volume of 0.05 mL is then delivered. 11. The scleral site should be rotated for subsequent injections. 12. After injection, do not recap the needle or detach it from the syringe. Dispose of the used syringe together with the needle in a sharps disposal container or in accordance with local requirements.

4.5 Missed Dose

If a planned injection is missed, the patient should return to be assessed by physician as soon as possible and continue dosing depending on physician’s discretion.

5 Overdose

Because MELVIZO (ranibizumab injection) is administered by qualified ophthalmologists experienced in intravitreal injections, the likelihood of an overdose is very low. Cases of accidental overdose (injection of volumes greater than the recommended 0.05 mL MELVIZO) have been reported from the clinical studies and post-marketing data. Adverse reactions most frequently associated with these reported cases were intraocular pressure increased and eye pain. If an overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the attending physician.

6 Dosage Forms, Strengths, Composition, and Packaging

To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 1 Dosage Forms, Strengths, Composition, and Packaging

MELVIZO (ranibizumab injection) is a sterile, clear colourless to pale yellow and preservative- free aqueous solution for injection.

Packaging

Vial + filter needle + injection needle pack

Single-use glass vial (colourless type I glass) with chlorobutyl rubber stopper containing 2.3 mg ranibizumab in 0.23 mL solution for injection. One pack contains one vial, one filter needle for withdrawal of the vial contents and one injection needle.

Vial only

Single-use glass vial (colourless type I glass) with chlorobutyl rubber stopper containing 2.3 mg ranibizumab in 0.23 mL solution for injection. One pack contains one vial.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada's toll-free number, 1-844 POISON-X (1-844-764-7669).

7 Warnings and Precautions

General

Treatment with MELVIZO (ranibizumab injection) is for intravitreal injection only.

Driving and Operating Machinery

The ranibizumab treatment procedure may induce temporary visual disturbances, which may affect the ability to drive or use machines (see 8 Adverse Reactions). Patients who experience these signs must not drive or use machines until these temporary visual disturbances subside.

Immune

Hypersensitivity

As with all therapeutic proteins, there is a potential for immunogenicity with ranibizumab. Patients should be instructed to report if an intraocular inflammation increases in severity, which may be a clinical sign attributable to intraocular antibody formation. There is a theoretical risk of hypersensitivity reactions including anaphylaxis/anaphylactoid reactions or angioedema which may occur with the use of ranibizumab (see Immunogenicity).

Ranibizumab has not been studied in patients with active systemic infections.

Ophthalmologic

Endophthalmitis and Retinal Detachments

Intravitreal injections, including those with ranibizumab, have been associated with endophthalmitis, intraocular inflammation, hypopyon, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see 8 Adverse Reactions). 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 aforementioned events without delay.

Retinal Vasculitis and Retinal Occlusive Vasculitis

Retinal vasculitis and retinal occlusive vasculitis have been reported with the use of ranibizumab, typically in the presence of intraocular inflammation or treatment with other intravitreal agents. Discontinue treatment with ranibizumab in patients who develop these events. Patients experiencing any change in vision following treatment should talk to their healthcare professional without delay.

Increases in Intraocular Pressure

Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of ranibizumab (see 8 Adverse Reactions). Sustained IOP increases have also been reported. Both intraocular pressure and the perfusion of the optic nerve head must therefore be monitored and managed appropriately. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection and / or tonometry within 30 minutes following the injection.

Ranibizumab has not been studied in patients who have previously received other types of intravitreal injections. Ranibizumab should not be administered concurrently with other anti- VEGF agents (systemic or ocular).

Bilateral treatment

Available data do not suggest an increased risk of systemic adverse events with bilateral treatment. The efficacy of ranibizumab therapy administered to both eyes concurrently has not been studied.

Ranibizumab has not been studied in patients with concurrent eye conditions such as retinal detachment or macular hole.

Additional experience has been gained from post-approval studies on a limited number of patients with prior episodes of RVO and of patients with ischemic branch RVO (BRVO) and central RVO (CRVO). In patients with RVO presenting with clinical signs of irreversible ischemic visual function loss, treatment is not recommended.

Renal

Systemic exposure to ranibizumab may be increased in patients with renal impairment (see 10 10 Clinical Pharmacology – Special Populations and Conditions). The clinical significance of increased systemic exposure to ranibizumab is unknown.

Reproductive Health

Women of Childbearing Potential

Women of childbearing potential should use effective contraception during treatment.

• Fertility

  There is no fertility data available.

Systemic effects

Thromboembolic events

Although there was a low rate of arterial thromboembolic events (ATEs) observed in the ranibizumab clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The risk of stroke may be greater in patients with known risk factors, including history of prior stroke or transient ischemic attack (see 8 Adverse Reactions). Therefore, these patients should be carefully evaluated by their physician to determine whether treatment with ranibizumab is appropriate, and the benefit outweighs the potential risk. Patients who suffer a thromboembolic event while being treated with ranibizumab should be carefully evaluated by their physician who will assess if continuation of ranibizumab treatment is appropriate, i.e., if the benefit to the patient outweighs the risk.

Non-ocular hemorrhages

Non-ocular hemorrhages have been reported following intravitreal injection of VEGF inhibitors, including ranibizumab in clinical trials for adults (see 8 Adverse Reactions), and there is a potential risk that these may relate to VEGF inhibition.

7.1 Special Populations

7.1.1 Pregnancy

No clinical data concerning exposure to ranibizumab during human pregnancy are available.

Studies in cynomolgus monkeys do not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/fetal development (see 16 Non-Clinical Toxicology). 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-/fetotoxic. Therefore, ranibizumab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the fetus. 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.

7.1.2 Breastfeeding

Based on limited data, ranibizumab is present in human milk following the intravitreal administration of ranibizumab in lactating women and may suppress VEGF levels in breast milk. The effects of VEGF suppression in breast milk on the breastfed infant or the effects of ranibizumab on milk production/excretion are unknown. As a precautionary measure, breast-feeding is not recommended during the use of MELVIZO.

7.1.3 Pediatrics

Pediatrics (< 18 years of age)

Health Canada has not authorized MELVIZO for pediatric use due to insufficient data on safety and efficacy in this sub-population. Limited data from 5 adolescent patients aged 13 to 17 years with visual impairment due to CNV are available.

7.1.4 Geriatrics

Geriatrics (≥ 65 years of age): No dose adjustment is necessary in the elderly.

8 Adverse Reactions

The adverse drug reaction profiles reported in clinical studies that compared MELVIZO to the reference biologic drug Lucentis were comparable. The description of adverse reactions in this section is based on clinical experience with the reference biologic drug.

8.1 Adverse Reaction Overview

Serious adverse events related to the injection procedure included endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see 7 Warnings and Precautions).

Other serious ocular events observed among ranibizumab-treated patients included intraocular inflammation (with frequency from 3.3% to 11.7% in the wet AMD trials) and increased intraocular pressure (with frequency from 6.6% to 18.8% in the wet AMD trials) (see 7 Warnings and Precautions).

Overall, ocular and non-ocular events in the DME, RVO, PM and CNV trials were reported with a frequency and severity similar to those seen in the wet-AMD trials.

In the RESOLVE trial in patients with DME, all serious ocular and non-ocular adverse events reported in patients receiving ranibizumab (pooled data) occurred at a frequency of <1%, with the exception of endophthalmitis and hypoglycemia, which both occurred in 2.0% of patients treated with ranibizumab. Serious ocular events other than those listed above observed among ranibizumab treated patients in the RESOLVE trial include retinal artery occlusion, retinal ischemia and vitreous hemorrhage. In the RESTORE trial, the only serious ocular adverse events that occurred in ranibizumab treated patients was cataract, which occurred in 1.7% of patients treated with ranibizumab 0.5 mg and laser. There were no ocular serious adverse events reported in patients treated with ranibizumab monotherapy and no reports of endophthalmitis overall in the study. All serious non-ocular adverse events reported in the ranibizumab arms occurred at a frequency of <1%, with the exception of angina pectoris, coronary artery disease, fall, and pulmonary embolism which each occurred at a frequency of 1.7% in patients treated with ranibizumab monotherapy, as well as hypertension which occurred in 1.7% of patients treated with ranibizumab and laser.

All serious ocular and non-ocular adverse events reported in the RVO trials during the 6-month treatment period in patients receiving ranibizumab (pooled data) occurred at a frequency of <1%. Serious ocular events, other than those listed above for the wet-AMD and DME trials, observed among ranibizumab treated patients in the RVO trials include blindness unilateral, corneal abrasion, corneal edema, iris neovascularization, macular edema, retinal vascular disorder, retinal vascular occlusion and retinal vein occlusion. No serious intraocular inflammation adverse events occurred in the RVO trials.

In the PM trial, all serious ocular and non-ocular adverse events reported in patients receiving ranibizumab also occurred at a frequency of <1%. The serious ocular events observed among ranibizumab treated patients, which were not listed above for the wet-AMD, DME and RVO trials, were corneal erosion and retinoschisis. No serious intraocular inflammation adverse events occurred in the PM trial.

In the CNV trial there were no serious ocular adverse events reported in the study eye or in the fellow treated eye in patients receiving ranibizumab. None of the non-ocular SAEs were suspected to be related to study treatment or ocular injection.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Wet AMD Population

A total of 1,315 patients constituted the safety population in the three phase III studies in wet AMD, FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER) with 24 months exposure to ranibizumab and four hundred and forty (440) patients were treated with the recommended dose of 0.5 mg.

The common ocular and non-ocular adverse events with suspected relationship to ranibizumab treatment occurring in ≥ 1% of patients receiving treatment with ranibizumab 0.5 mg in at least one of the three controlled wet AMD phase III studies FVF2598g (MARINA; 2-year data), FVF2587g (ANCHOR; 2-year data) and FVF3192g (PIER; 2-year data) are summarized in Table 2 and Table 3 below.

The common ocular and non-ocular adverse events, regardless of treatment relationship to ranibizumab, with a difference in incidence rate of ≥ 2% between patients receiving treatment with 0.5 mg ranibizumab and the control group in at least one of the three controlled wet AMD phase III studies FVF2598g (MARINA; 2-year data), FVF2587g (ANCHOR; 2-year data) and FVF3192g (PIER; 2-year data) are summarized in Table 4 below.

Furthermore, the ocular and non-ocular adverse events, regardless of relationship to ranibizumab treatment, occurring in ≥ 1% of patients receiving ranibizumab 0.5 mg in the controlled wet AMD phase III studies FVF2598g (MARINA; 2-year data), FVF2587g (ANCHOR; 2-year data) and FVF3192g (PIER; 2-year data) (pooled data) are summarized in Table 5 and Table 6 below.

Table 2 Ocular Adverse Events in the Study Eye with Suspected Relationship to Ranibizumab Treatment Studies MARINA (FVF2598g), ANCHOR (FVF2587g) and PIER (FVF3192g) Safety Population Adverse Events with Incidence Rate ≥ 1% for Ranibizumab 0.5 mg in at Least One Study

Table 3 Non-Ocular Adverse Events with Suspected Relationship to Ranibizumab Treatment Studies MARINA (FVF2598g), ANCHOR (FVF2587g) and PIER (FVF3192g) Safety Population Adverse Events with Incidence Rate ≥ 1% for Ranibizumab 0.5 mg in at Least One Study

Multiple occurrences of the same event were counted once in the overall incidence.

Table 4 Ocular (in the study eye) and Non-ocular Adverse Events, regardless Relationship to Treatment, with a Difference in Incidence Rate ≥ 2% between Ranibizumab 0.5 mg and the Control in at Least One Study Studies MARINA (FVF2598g), ANCHOR (FVF2587g) and PIER (FVF3192g) Safety Population

Table 5 Ocular Adverse Events in The Study Eye regardless of Relationship to Treatment by System Organ Class and Preferred Term (2-year Incidence at Least 1.0% in Ranibizumab 0.5 mg Group) in MARINA, ANCHOR, and PIER (Pooled Data) Safety Population

Table 6 Non-ocular Adverse Events regardless of Relationship to Treatment by System Organ Class and Preferred Term (2-year Incidence at Least 1.0% in Ranibizumab 0.5 mg Group) in MARINA, ANCHOR, and PIER (Pooled Data) Safety Population

Arterial thromboembolic events, as defined by the ANTIPLATELET TRIALISTS’ COLLABORATION (APTC), including vascular deaths, non-fatal myocardial infarctions, non- fatal ischemic strokes and non-fatal haemorrhagic strokes, have been linked to the systemic availability of highly potent vascular endothelial growth factor (VEGF) inhibitors. When the first-year data from all three phase III studies (MARINA, ANCHOR and PIER) were combined, the overall incidence of arterial thromboembolic events was higher for patients treated with ranibizumab 0.5 mg (2.5%) compared with control arm (1.1%). When the second year data from all three phase III (MARINA, ANCHOR and PIER) were combined, the overall incidence of arterial thromboembolic events was similar for patients with ranibizumab 0.5 mg (4.1%) compared with the control arm (3.6%). For (fatal and non-fatal) cerebrovascular accidents (CVAs) the results were not consistent across studies. In the MARINA study, there was a slight numerical imbalance between ranibizumab 0.5 mg (1.3%) and the control arm (0.4%) during the first year, which was still present at the end of the 2-year treatment period (3.3% for 0.5 mg vs. 1.3% for sham treatment). The CVA incidence rate in the MARINA, ANCHOR study and PIER study are shown in Table 7. Although there was a low annual rate of arterial thromboembolic events observed in the ranibizumab (a VEGF inhibitor) clinical trials, there was no imbalance between treatment groups (Table 8). There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors.

Table 7 Cerebrovascular Accident (CVA) Rates (Fatal and Non-fatal), Safety Populations (2-year Cumulative Data)

Control

0.3 mg Ranibizumab

0.5 mg Ranibizumab

MARINA – 1 yr

1/236 (0.4%)

1/238 (0.4%)

3/239 (1.3%)

MARINA – 2 yr

3/236 (1.3%)

3/238 (1.3%)

8/239 (3.3%)

ANCHOR – 1 yr

1/143 (0.7%)

1/137 (0.7%)

1/140 (0.7%)

ANCHOR - 2 yr

2/143 (1.4%)

3/137 (2.2%)^a

0/140 (0.0%)

PIER – 1 yr

0/62 (0.0%)

0/59 (0.0%)

0/61 (0.0%)

PIER -2 yr^b

0/62 (0.0%) (before crossover) 1/39 (2.6%) (after crossover)

0/59 (0.0%)

0/61 (0.0%)

^a Includes one serious adverse event of cerebral infarction (Year 1), one adverse event of ischemic stroke (Year 2) and one non-serious adverse event of cerebral ischemia (Year 2)

^b After the month 12 visit in the study, patients in the sham-injection group could crossover to the ranibizumab 0.5 mg group for the remainder of the study.

Table 8 Arterial Thromboembolic Events (ATE) as Defined by the Antiplatelet Trialists’ Collaboration (APTC), Safety Populations (2-year Cumulative Data)

Control

0.3 mg Ranibizumab

0.5 mg Ranibizumab

MARINA – 1 yr

2/236 (0.8%)

4/238 (1.7%)

5/239 (2.1%)

MARINA – 2 yr

9/236 (3.8%)

11/238 (4.6%)

11/239 (4.6%)

ANCHOR – 1 yr

3/143 (2.1%)

3/137 (2.2%)

6/140 (4.3%)

ANCHOR 2 yr

6/143 (4.2%)

6/137 (4.4%)

7/140 (5.0%)

PIER – 1 yr

0/62 (0.0%)

0/59 (0.0%)

0/61 (0.0%)

PIER -2 yr^a

1/62 (1.6%) (before crossover) 1/39 (2.6%) (after crossover)

1/59 (1.7%)

0/61 (0.0%)

^a After the month 12 visit in the study, patients in the sham-injection group could crossover to the ranibizumab 0.5 mg group for the remainder of the study.

The SAILOR study, FVF 3689g, was a Phase IIIb, Multicenter Study to Evaluate the Safety and Tolerability of Ranibizumab in Naive and Previously Treated Subjects with Choroidal Neovascularization (CNV) Secondary to Age-Related Macular Degeneration (AMD).

In the study, an interim analysis including data from almost 2400 patients (randomized to the two doses of ranibizumab 0.3 mg and ranibizumab 0.5 mg in a 1:1 ratio) with an average follow-up period of 230 days was performed. The overall incidence of CVAs (fatal and non-fatal) was found to be 1.1% for ranibizumab 0.5 mg compared with 0.3% for ranibizumab 0.3 mg (p=0.021). The rate of deaths from all causes was (1.6% on 0.5 mg vs. 0.6% on 0.3 mg, p=0.029) whereas the differences in the rate of vascular deaths (0.7% on 0.5 mg vs. 0.4% on 0.3 mg) and in the rate of combined APTC events (1.7% on 0.5 mg vs. 1.1% on 0.3 mg) were smaller.

A second interim analysis which was based on an average follow-up time of 335 days showed that the difference in the incidence of CVAs had decreased with increasing exposure to ranibizumab treatment (1.3% on 0.5 mg vs. 0.6% on 0.3 mg). The same applied to the difference in the overall death rate (2.0% on 0.5 mg vs. 1.3% on 0.3 mg).

Upon final analysis of the incidence in strokes in SAILOR study, there exists a trend towards a higher stroke rate in the 0.5 mg group compared to the 0.3 mg group. The respective 95% CIs for the overall stroke rate were wide (0.3% to 1.3% for the 0.3 mg group vs. 0.7% to 2.0% for the 0.5 mg group). The number of strokes was small for both dose groups, and there is not sufficient evidence to conclude (or rule out) that there is a true difference in stroke rates among the treatment groups. Forty-nine deaths were reported, with 20 deaths in the 0.3-mg group (1.7%) and 29 deaths in the 0.5-mg group (2.4%). Of these, 21 were classified as vascular deaths, 11 in the 0.3-mg group (0.9%) and 10 in the 0.5-mg group (0.8%).

DME population

The safety of ranibizumab was studied in a one-year sham-controlled trial (study D2201 - RESOLVE) and in a one year laser-controlled trial (study D2301 - RESTORE) conducted respectively in 102 and 235 ranibizumab-treated patients with visual impairment due to DME (see 14 Clinical Trials – Treatment of visual impairment due to DME). The safety population is grouped by the actual treatment received and is comprised of the safety-evaluable patients from the two studies who received at least one dose of study drug (a total of 496 patients). Overall, ocular and non-ocular events in the RESOLVE and RESTORE trials were reported with a frequency and severity similar to those seen in the wet-AMD trials. The most common ocular adverse events in patients receiving ranibizumab monotherapy (pooled data) were eye pain (14.3%), conjunctival hemorrhage (14.3%), intraocular pressure increased (10.1%), conjunctival hyperemia (5.5%), and foreign body sensation in eyes (5.1%). The most common non-ocular events were nasopharyngitis (9.7%), hypertension (7.4%) and influenza (5.1%).

The common ocular and non-ocular adverse events with suspected relationship to ranibizumab treatment occurring in ≥ 1% of patients receiving treatment with ranibizumab (any group) in at least one of the two studies RESOLVE and RESTORE are summarized in Table 9 and Table 10 below.

The common ocular and non-ocular adverse events, regardless of treatment relationship to ranibizumab, with a difference in incidence rate of > 2% between patients receiving treatment with ranibizumab (any group) and the control group in at least one of the two studies RESOLVE and RESTORE are summarized in Table 11 below.

Table 9 Ocular Adverse Events in the Study Eye with Suspected Relationship to Ranibizumab Treatment Studies RESOLVE and RESTORE Safety Population Adverse Events with Incidence Rate ≥ 1% For Ranibizumab (Any Group) in at Least One Study

^†The RESOLVE study (D2201) consisted of an exploratory part (Group A) and a confirmatory part (Group B) (see 14 Clinical Trials - Treatment of visual impairment due to DME). For the purpose of the safety analyses, only data on the overall population (Group A+B) is presented.

^‡Patients in the 6 mg/ml group received an actual dose of 0.3 mg or 0.6 mg ranibizumab, and patients in the 10 mg/ml group received an actual dose of 0.5 mg or 1.0 mg ranibizumab.

Table 10 Non-ocular Adverse Events with Suspected Relationship to Ranibizumab Treatment Studies RESOLVE and RESTORE Safety Population Adverse Events with Incidence Rate ≥ 1% for Ranibizumab (any group) in at Least One Study

^†The RESOLVE study (D2201) consisted of an exploratory part (Group A) and a confirmatory part (Group B) (see 14 Clinical Trials - Treatment of visual impairment due to DME). For the purpose of the safety analyses, only data on the overall population (Group A+B) is presented.

^‡Patients in the 6 mg/ml group received an actual dose of 0.3 mg or 0.6 mg ranibizumab, and patients in the 10 mg/ml group received an actual dose of 0.5 mg or 1.0 mg ranibizumab.

Table 11 Ocular (in the study eye) and Non-ocular Adverse Events, regardless Relationship to Treatment, with a Difference in Incidence Rate > 2% between Ranibizumab (any group) and the Control, and at a Higher Rate in the Ranibizumab Group, in at Least One Study Studies RESOLVE and RESTORE Safety Population

^†The RESOLVE study (D2201) consisted of an exploratory part (Group A) and a confirmatory part (Group B) (see 14 Clinical Trials - Treatment of visual impairment due to DME). For the purpose of the safety analyses, only data on the overall population (Group A+B) is presented.

^‡Patients in the 6 mg/ml group received an actual dose of 0.3 mg or 0.6 mg ranibizumab, and patients in the 10 mg/ml group received an actual dose of 0.5 mg or 1.0 mg ranibizumab

There was no significant imbalance in the incidence rate of arterial thromboembolic events in the RESOLVE and RESTORE studies between the ranibizumab and control arms. In the RESOLVE study, 3 patients reported arterial thromboembolic events in the 10 mg/mL ranibizumab arm (5.9%) and 2 in sham arm (4.1%). One of the 3 events in the treatment arm (retina artery occlusion) was classified as an ATE, however the event was reported to occur due to the pressure caused by the intraocular injection, not due to an arterial thromboembolic event. In the RESTORE study, arterial thromboembolic events were reported in 4 patients in the ranibizumab arm (3.5%), 4 patients in the ranibizumab + laser arm (3.3%), and in 3 patients in the laser arm (2.7%).

A meta-analysis of pooled safety data from completed, randomized, double masked global studies showed a higher incidence rate of non-serious, non-ocular wound infection/inflammation in DME patients treated with ranibizumab 0.5 mg (1.85/100 patient years) compared to control (0.27/100 patient years). The relationship to ranibizumab remains unknown.

RVO population

The safety of ranibizumab was studied in two 12-month trials (BRAVO and CRUISE) conducted respectively in 264 and 261 ranibizumab-treated patients with visual impairment due to macular edema secondary to Branch RVO (BRVO) and Central RVO (CRVO) (see 14 Clinical Trials – Treatment of visual impairment due to macular edema secondary to RVO). The safety population comprises all patients from the BRAVO and CRUISE studies who received at least 1 injection of study drug. Ocular and non-ocular events in the BRAVO and CRUISE trials were reported with a frequency and severity similar to those seen in the wet-AMD trials, with no new safety signals identified from the RVO population. The most commonly reported ocular events in the ranibizumab groups during the 6-month treatment period were conjunctival hemorrhage, retinal exudates, and eye pain. The most common non-ocular adverse event reported overall during the treatment period was hypertension (8.1% in the sham group vs. 6.0% and 5.0% in the 0.3 mg and 0.5 mg groups, respectively). Overall, the cumulative 12-month safety profile of ranibizumab in both studies was consistent with that observed at month 6.

The ocular and non-ocular adverse events occurring in ≥ 1% of patients receiving ranibizumab in the controlled RVO phase III studies BRAVO and CRUISE (pooled data) are summarized in Table 12 and Table 13 below.

Table 12 Ocular Adverse Events in the Study Eye Regardless of Relationship to Treatment, during the 6-Month Treatment Period, by Primary System Organ Class and Preferred Term (at Least 1.0% in Ranibizumab Group) in BRAVO and CRUISE (pooled data) Safety Population

Table 13 Non-ocular Adverse Events regardless of Relationship to Treatment, during the 6-month Treatment Period, by System Organ Class and Preferred Term (at Least 1.0% in Ranibizumab Monotherapy Group) in BRAVO and CRUISE (Pooled Data) Safety Population

Sinusitis occurred in 5/260 (1.9%) of patients on sham and in 8/259 (3.1%) of patients on 0.5 mg of ranibizumab in the pooled BRAVO and CRUISE trials.

There was no significant imbalance in the incidence rate of arterial thromboembolic events during the 6-month treatment period of the BRAVO and CRUISE studies between the ranibizumab and control arms. In the BRAVO study, the rate of APTC arterial thromboembolic events during the 6-month treatment period was similar between treatment groups, with 1 subject (0.8%) in the sham group experiencing a non-fatal hemorrhagic cerebrovascular accident, no subjects in the 0.3-mg group experiencing an arterial thromboembolic event, and 2 subjects (1.5%) in the 0.5-mg group experiencing one arterial thromboembolic event each (non-fatal myocardial infarction and fatal hemorrhagic cerebrovascular accident). In the CRUISE study, the rate of APTC arterial thromboembolic events during the 6-month treatment period were also balanced between treatment groups, with 1 subject (0.8%) in the sham group, 1 subject (0.8%) in the 0.3-mg group, and 1 subject (0.8%) in the 0.5-mg group experiencing one such event each (non-fatal myocardial infarction). Low rates of these events (<2.5%) were observed at 12 months in both 0.3 and 0.5-mg groups.

The long term safety profile of ranibizumab observed in the BRIGHTER and CRYSTAL 24-month studies was consistent with the known ranibizumab safety profile (see 14 Clinical Trials, Post-marketing studies).

PM population

The safety data of ranibizumab as studied in the 12-month clinical study (RADIANCE), which included 224 ranibizumab-treated patients with PM (see 14 Clinical Trials – Treatment of visual impairment due to CNV secondary to PM). The safety population includes all randomized patients who received at least 1 application of study treatment (ranibizumab (sham) and/or vPDT (sham)) and had at least 1 post-baseline safety assessment during the study. Ocular and non-ocular events in this trial were reported with a frequency and severity consistent with those seen in the wet-AMD trials. Up to Month 12, the most frequently reported ocular adverse events following ranibizumab treatment were conjunctival hemorrhage, punctate keratitis, intraocular pressure increased, eye pain, and injection site hemorrhage. The most common non-ocular adverse events up to Month 12 in the ranibizumab groups were nasopharyngitis, headache, hypertension, upper respiratory tract infection, urinary tract infection, back pain, influenza and abdominal pain.

The ocular and non-ocular adverse events occurring in ≥ 1% of patients receiving ranibizumab in the controlled PM phase III study are summarized in Table 14 and Table 15 below.

Table 14 Ocular adverse events of the study eye up to Month 12, regardless of relationship to treatment, by primary system organ class and preferred term (at least 1.0% in ranibizumab groups [Group I and II]) in study RADIANCE (Safety Set)

PDT = photodynamic therapy

Table 15 Non-ocular adverse events up to Month 12, regardless of relationship to treatment, by primary system organ class and preferred term (at least 1.0% in ranibizumab groups [Groups I and II]) in study RADIANCE (Safety Set)

PDT = photodynamic therapy

CNV population

The safety of ranibizumab was studied in a 12-month clinical study (MINERVA), which included 171 ranibizumab-treated patients with visual impairment due to CNV (see 14 Clinical Trials – Treatment of visual impairment due to CNV). The safety profile in these patients was consistent with that seen in previous clinical trials with ranibizumab. The safety population includes those adult patients who received at least one application of study treatment and had at least one post-baseline safety assessment. Safety and tolerability of ranibizumab 0.5 mg were compared to safety and tolerability of sham injections up to Month 2 and over time up to Month 12 (overall safety).

Up to Month 12, the most commonly reported ocular adverse events were conjunctival hemorrhage (7 (5.9%) ranibizumab patients and 6 (11.5%) sham with ranibizumab patients), choroidal neovascularization (3 (2.5%) ranibizumab patients and 0 sham with ranibizumab patients), visual acuity reduced (3 (2.5%) ranibizumab patients and 1 (1.9%) sham with ranibizumab patients) and conjunctivitis (2 (1.7%) ranibizumab patients and 3 (5.8%) sham with ranibizumab patients). The most commonly reported non-ocular adverse event up to Month 12 was nasopharyngitis (14 (11.8%) ranibizumab patients and 9 (17.3%) sham with ranibizumab patients).

The ocular and non-ocular adverse events occurring in ≥ 1% of patients receiving ranibizumab in the controlled CNV phase III study are summarized in Table 16 and Table 17 below.

Table 16 Ocular adverse events of the study eye up to Month 12, regardless of relationship to treatment, by primary system organ class and preferred term (at least 1.0% in ranibizumab groups) in study MINERVA (Safety Set)

Table 17 Non-ocular adverse events up to Month 12, regardless of relationship to treatment, by primary system organ class and preferred term (at least 1.0% in ranibizumab groups) in study MINERVA (Safety Set)

In the study MINERVA (Safety Set), only 1 patient (0.8%) in the ranibizumab arm experienced a non-ocular risk of non-myocardial arterial thromboembolic events up to Month 2.

8.3 Less Common Clinical Trial Adverse Reactions

Adults

The adverse events with suspected relationship to ranibizumab treatment listed below are events that occurred at an incidence of < 1.0%. The safety data described below also includes procedure and potential drug related ocular (in the study eye) and non-ocular adverse events.

Cardiac disorders: Arrhythmia, atrial fibrillation, coronary artery occlusion, myocardial infarction.

Ear and labyrinth disorders: Ear pain.

Eye disorders: Abnormal sensation in eye, angle closure glaucoma, anterior chamber disorder, anterior chamber inflammation, anterior chamber flare, blepharitis, blindness, cataract, cataract subcapsular, conjunctival edema, conjunctival hyperemia, conjunctivitis, conjunctivitis allergic, corneal deposits, corneal edema, corneal epithelium defect, corneal erosion, corneal striae, dellen, detachment of retinal pigment epithelium, diplopia, endophthalmitis, episcleritis, erythema of eyelid, eye allergy, eye discharge, eye hemorrhage, eye irritation, eye swelling, eyelid edema, eyelid irritation, eyelid pain, eyelid ptosis, glaucoma, hyphema, iridocyclitis, iris adhesions, iritis, keratitis, keratopathy, lenticular pigmentation, lid margin discharge, macular degeneration, maculopathy, metamorphosia, ocular discomfort, photophobia, photopsia, pigmentary glaucoma, posterior capsule opacification, pupillary reflex impaired, retinal artery occlusion, retinal cyst, retinal disorder, retinal scar, retinal tear, scleral hyperemia, subretinal fibrosis, uveitis, visual acuity reduced, visual impairment, vitreous detachment, vitreous degeneration, vitreous hemorrhage, vitreous opacities, vitreous prolapse.

Gastrointestinal disorders: Intestinal obstruction, nausea.

General disorders and administration site conditions: Asthenia, facial pain, influenza like illness, injection site irritation, injection site pain, pain.

Hepatobiliary disorders: Hepatic function abnormal.

Immune system disorders: Drug hypersensitivity.

Infections and infestations: Adenoviral conjunctivitis, endophthalmitis, hypopyon, influenza, sinusitis.

Injury, poisoning and procedural complications: Cataract traumatic, contusion, corneal abrasion, eye injury, scratch.

Investigations: Intraocular pressure decreased.

Metabolism and nutrition disorders: Hypoglycemia.

Musculoskeletal and connective tissue disorders: Arthralgia, back pain, pain in jaw.

Nervous System disorders: Cerebral hemorrhage, dizziness, hyperaesthesia, intracranial pressure increased, presyncope.

Psychiatric disorders: Anticipatory anxiety, anxiety.

Respiratory, thoracic and mediastinal disorders: Cough, dyspnea, increased upper airway secretion, rhinorrhea, wheezing.

Skin and subcutaneous tissue disorders: Dermatitis allergic, lichenoid ketatosis, urticaria.

Vascular disorders: Arterial thrombosis limb.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Wet AMD population:

There were no findings to suggest a relationship between ranibizumab and the development of clinically significant abnormalities.

RVO population:

There were no findings to suggest a relationship between ranibizumab and the development of clinically significant abnormalities. There was no imbalance among treatment groups regarding the hematology and biochemistry post-baseline values.

PM population:

There were no findings to suggest a relationship between ranibizumab and the development of clinically significant abnormalities. There was no imbalance among treatment groups regarding the hematology and biochemistry post-baseline values.

CNV population:

Overall, there were no meaningful shifts in laboratory parameters over 12 months in the MINERVA study. There were no patients with newly occurring notable values or with reported laboratory abnormalities which were classified as serious adverse events.

8.5 Post-Market Adverse Reactions

The common ocular and non-ocular adverse drug reactions been reported with an incidence rate of ≥ 1.0% of the total adverse reactions reported in Phase IV clinical trials and with marketed use of ranibizumab in wet AMD are summarized in Table 18 below.

Table 18 Ranibizumab Post-Market Ocular and Non-ocular Adverse Reactions: Phase IV Studies [SECURE (CRFB002A2402) and EVEREST (CBPD952A2308)], Literature Cases and Spontaneous Reports. Adverse Reactions with Incidence Rate ≥ 1% of Total Adverse Reactions Reported (N=4074)

⁺ Preferred terms summarized: Rash, Erythema, Urticaria, Pruritus and Pruritus generalized

9 Drug Interactions

9.2 Drug Interactions Overview

For the adjunctive use of verteporfin photodynamic therapy (PDT) and ranibizumab injection in wet AMD and PM, see 14.1 Clinical Trials by Indication.

For the adjunctive use of laser photocoagulation and ranibizumab in DME, see 14.1 Clinical Trials by Indication and 4 Dosage and Administration – Treatment of Visual Impairment Due to DME sections.

For the adjunctive use of laser photocoagulation and ranibizumab in BRVO, see 14.1 Clinical Trials by Indication and 4 Dosage and Administration – Treatment of Visual Impairment Due to macular edema secondary to RVO sections.

9.4 Drug-Drug Interactions

Interactions with other drugs have not been established.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 Clinical Pharmacology

10.1 Mechanism of Action

Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor-A (VEGF-A). Ranibizumab is designed to penetrate all retinal layers. It binds with high affinity to all active VEGF-A isoforms (e.g. VEGF₁₁₀, VEGF₁₂₁ and VEGF₁₆₅), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2. Binding of VEGF-A to its receptors leads to endothelial cell proliferation and neovascularisation, as well as vascular leakage, which are thought to contribute to the progression of the neovascular form of age-related macular degeneration, of macular edema causing visual impairment in diabetes and retinal vein occlusion, and of choroidal neovascularization secondary to pathologic myopia.

10.2 Pharmacodynamics

The pharmacology of ranibizumab has been evaluated in several in vitro assays and in vivo animal studies. Ranibizumab binds with high affinity to the human VEGF isoforms (K_D: ≤ 192 pM for VEGF₁₁₀, VEGF₁₂₁, and VEGF₁₆₅), inhibits VEGF-induced HUVEC proliferation (IC₅₀: ≤ 0.56 nM) and tissue factor expression (IC₅₀: 0.31 nM), and does not bind to complement C1q and Fc gamma receptors that mediate complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, respectively. Ranibizumab also inhibits VEGF-induced changes in vascular permeability in a guinea pig skin model (IC₅₀: ≤ 1.2 nM). In the non-human primate model of laser-induced CNV, intravitreal injection of ranibizumab alone at 0.5 mg/eye can prevent formation of clinically significant CNV membranes and decreases leakage of already formed CNV membranes. Ranibizumab in combination with verteporfin PDT causes a reduction in CNV leakage compared to verteporfin PDT alone, irrespective of the order of treatment.

10.3 Pharmacokinetics

Following monthly intravitreal administration of ranibizumab injection to patients with neovascular AMD, serum concentrations of ranibizumab were generally low. Maximum serum levels (Cmax), measured after single administration and estimated using population pharmacokinetics (PK) for repeated administration, were generally below the ranibizumab concentration necessary to inhibit the biological activity of VEGF by 50% (11-27 ng/mL, as assessed in an in vitro cellular proliferation assay). Following single administration, Cmax was dose proportional over the dose range of 0.05 to 1.0 mg/eye. Serum ranibizumab concentrations in RVO patients were similar to those observed in wet AMD patients. Although the PK data suggest that serum ranibizumab levels remain below the level necessary to inhibit the biological activity of VEGF by 50%, an assessment of additional time points around the C_max would be required to confirm that serum ranibizumab levels do not exceed this threshold at any timepoint upon monthly intravitreal injection of 0.5 mg ranibizumab in humans.

Based on analysis of limited population pharmacokinetics data from patients with wet AMD treated with the 0.5 mg dose, serum ranibizumab Cmax, attained approximately 1 day after dosing, is predicted to generally range between 0.79 and 2.90 ng/mL, and Cmin is predicted to generally range between 0.07 and 0.49 ng/mL.

Special Populations and Conditions

• Pediatrics: No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in pediatric patients.
• Geriatrics (65 years or above): No dose adjustment is required in the elderly.
• Sex: No special considerations are needed.
• Hepatic Insufficiency: No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in patients with hepatic impairment.

• Renal Insufficiency: No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in patients with renal impairment. In a population

  • pharmacokinetic analysis of neovascular AMD patients, 68% (136 of 200) had renal impairment (46.5% mild [50-80 mL/min], 20% moderate [30-50 mL/min], and 1.5% severe [<30 mL/min]). In RVO patients, 48.2% (253 of 525) had renal impairment (36.4% mild, 9.5% moderate and 2.3% severe). Systemic clearance was slightly lower in patients with mild and moderate renal impairment. Three patients with severe renal impairment had a clearance that was reduced by approximately 42%. The clinical significance of these findings is unknown.

11 Storage, Stability, and Disposal

Vial

Store in a refrigerator (2°C - 8°C). DO NOT FREEZE.

Keep the vial in the outer carton in order to protect from light.

Prior to use, the unopened vial may be stored at room temperatures up to a maximum of 30°C for a period up to 60 days.

Any unused product or waste material should be disposed of in accordance with local requirements.

12 Special Handling Instructions

Do not use if particles, discolouration or cloudiness are evident.

Vials are for single use only.

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

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Proper name:

Ranibizumab

Chemical name:

Immunoglobulin G1, anti-(human vascular endothelial growth factor) Fab fragment (human-mouse monoclonal rhuFab V2 γ1- chain), disulfide with human-mouse monoclonal rhuFab V2 κ- chain

Molecular formula and molecular mass:

The molecular weight of the light and of the heavy chain deduced from the amino acid sequence is 23,433 and 24,957 Da, respectively. The molecular weight of the Fab fragment is 48 kDa and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product.

Structural formula:

Ranibizumab is a humanised monoclonal antibody fragment produced in Escherichia coli cells by recombinant DNA technology. It consists of a 214-residue light chain linked by a disulfide bond at its C-terminus to the 231-residue N-terminal segment of the heavy chain. The expected amino acid sequences of the heavy and light chains are shown below. Ranibizumab is not glycosylated.

Physicochemical properties:

a sterile, clear colourless to pale yellow and preservative- free aqueous solution for injection.

Pharmaceutical standard:

In-house standard

Heavy Chain of MELVIZO

001 EVQLVESGGG LVQPGGSLRL SCAASGYDFT HYGMNWVRQA PGKGLEWVGW INTYTGEPTY

061 AADFKRRFTF SLDTSKSTAY LQMNSLRAED TAVYYCAKYP YYYGTSHWYF DVWGQGTLVT

121 VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL

181 QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSCDKTH L 231

Light Chain of MELVIZO

001 DIQLTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP GKAPKVLIYF TSSLHSGVPS

061 RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSTVPWTFGQ GTKVEIKRTV AAPSVFIFPP

121 SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT

181 LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC 214

Cysteine residue: Underlined letters

Variable region: Bold letters

Product Characteristics

The drug substance (DS) manufacturing process of MELVIZO involves pre-culture, main culture, harvest of the cell culture fluid (primary downstream process), purification, and dispensing, resulting in highly purified DS of MELVIZO.

The drug product (DP) manufacturing process of MELVIZO involves drug substance (DS) thawing, bioburden reduction filtration and DS pooling/mixing, sterile filtration, and aseptic filling/stoppering/crimping.

14 Clinical Trials

14.1 Clinical Trials by Indication

Treatment of Wet AMD

In wet AMD, the clinical safety and efficacy of ranibizumab injection have been assessed in three randomized, double-masked, sham¹- or active-controlled studies in patients with neovascular AMD. A total of 1,323 patients (879 active and 444 control) were enrolled in these studies.

¹ The sham ranibizumab injection control procedure involved anesthetising the eye in a manner identical to a ranibizumab intravitreal injection. The tip of a needleless syringe was then pressed against the conjunctiva and the plunger of the needleless syringe depressed.

In study FVF2598g (MARINA), patients with minimally classic or occult with no classic choroidal neovascularisation (CNV) received monthly intravitreal injections of ranibizumab 0.3 mg or 0.5 mg or sham injections. A total of 716 patients were enrolled in this study (sham, 238; ranibizumab 0.3 mg, 238; ranibizumab 0.5 mg, 240). Data are available up to the end of Month 24.

In study FVF2587g (ANCHOR), patients with predominantly classic CNV lesions received either: 1) monthly intravitreal injections of ranibizumab 0.3 mg and sham photodynamic therapy (PDT); 2) monthly intravitreal injections of ranibizumab 0.5 mg and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Sham or active verteporfin PDT was given with the initial ranibizumab injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of vascular leakage. A total of 423 patients were enrolled in this study (sham, 143; ranibizumab 0.3 mg, 140; ranibizumab 0.5 mg, 140). Data are available up to the end of Month 24.

Study FVF3192g (PIER) was a randomized, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of ranibizumab in patients with neovascular AMD (with or without a classic CNV component). Data are available up to the end of Month 12. Patients received ranibizumab 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months. A total of 184 patients were enrolled in this study (ranibizumab 0.3 mg, 60; ranibizumab 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study.

In both studies MARINA and ANCHOR the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all ranibizumab-treated patients (90-96%) depending on study and dose maintained their visual acuity (see Table 19 and Figure 1). In study FVF3192g (PIER), the primary efficacy endpoint was mean change in BCVA from baseline at Month 12 (see Figure 2). In both dose groups, visual acuity was maintained, on average.

Table 19 Overview of the Primary Endpoints by Study, Randomized Subjects, with Last Observation Carried Forward (LOCF) Method to Impute Missing Data

^#Best Corrected Visual Acuity

Randomized subjects = all subjects randomized. Note for Study ANCHOR, ranibizumab 0.5 mg group, 140 subjects were randomized, however one subject did not have a BCVA baseline value, therefore, data from 139 patients are included in the results for this group.

Patient withdrawal rates (control, 0.3 mg ranibizumab, 0.5 mg ranibizumab):

• MARINA 1 year (discontinued study on or prior to Month 12): 8.8%, 2.5%, 2.5%
• MARINA 2 year (discontinued from study): 20.2%, 11.8%, 10.4%
• ANCHOR 1 year (discontinued study on or prior to Month 12): 7.0%, 7.1%, 3.6%
• ANCHOR 2 year (discontinued from study): 23.1%, 16.4%, 17.1%
• PIER 1 year (discontinued study on or prior to Month 12): 12.7%, 1.7%, 3.3%

The sham ranibizumab injection control procedure involved anesthetising the eye in a manner identical to a ranibizumab intravitreal injection. The tip of a needleless syringe was then pressed against the conjunctiva and the plunger of the needleless syringe depressed.

Figure 1 Mean Change in Visual Acuity from Baseline to Month 24 in Study FVF2598g (MARINA) and Study FVF2587g (ANCHOR), Randomized Subjects

Ranibizumab 0.5 (N=240): +6.6

Ranibizumab 0.3 (N=238): +5.4

Sham (N=238): -14.9

PDT = photodynamic therapy

Note: The LOCF method was used to impute missing data. Vertical bars are ± 1 standard error of the mean

Randomized subjects = all subjects randomized. Note for Study ANCHOR, ranibizumab 0.5 mg, 140 subjects were randomized, however one subject did not have a BCVA baseline value, therefore, data from 139 patients are included in the results for this group.

Patient withdrawal rates (control, 0.3 mg ranibizumab, 0.5 mg ranibizumab):

• MARINA 1 year (discontinued study on or prior to Month 12): 8.8%, 2.5%, 2.5%
• MARINA 2 year (discontinued from study): 20.2%, 11.8%, 10.4%
• ANCHOR 1 year (discontinued study on or prior to Month 12): 7.0%, 7.1%, 3.6%
• ANCHOR 2 year (discontinued from study): 23.1%, 16.4%, 17.1%

The sham ranibizumab injection control procedure involved anesthetising the eye in a manner identical to a ranibizumab intravitreal injection. The tip of a needleless syringe was then pressed against the conjunctiva and the plunger of the needleless syringe depressed.

Figure 2 Mean Change in Visual Acuity from Baseline to Month 12 in Study FVF3192g (PIER), Randomized Subjects

Randomized subjects = all subjects randomized

Patient withdrawal rates (control, 0.3 mg ranibizumab, 0.5 mg ranibizumab):

• PIER 1 year (discontinued study on or prior to Month 12): 12.7%, 1.7%, 3.3%

The sham ranibizumab injection control procedure involved anesthetising the eye in a manner identical to a ranibizumab intravitreal injection. The tip of a needleless syringe was then pressed against the conjunctiva and the plunger of the needleless syringe depressed.

Thirty-four percent (34%) to 40% of ranibizumab-treated patients in studies MARINA and ANCHOR, (0.5 mg) experienced a clinically significant, sustained improvement in vision, defined as gaining 15 or more letters at 24 months (p<0.01), regardless of lesion type. Twenty- five percent (25%) to 36% of ranibizumab-treated patients (0.3 mg) experienced a clinically significant, sustained improvement in vision (Table 20). In both studies, mean changes in BCVA from baseline at Month 24 demonstrated an improvement of vision by 6.6-11.3 letters (0.5 mg) and 5.4-8.5 letters (0.3 mg) respectively. The gain in BCVA was essentially achieved after the first 3 injections with ranibizumab (at Month 3) and maintained until Month 24 in both studies.

In PIER, almost all ranibizumab-treated patients (90%) maintained their visual acuity at Month

In study FVF3192g (PIER), the proportion of patients who lost fewer than 15 letters of BCVA at Month 12 was 90% on 0.5 mg and 83% on 0.3mg.

Table 20 Overview of the Main Secondary Endpoints by Study, Randomized Subjects, with Last Observation Carried Forward (LOCF) Method to Impute Missing Data

^# Best Corrected Visual Acuity

Randomized subjects = all subjects randomized. Note for Study ANCHOR, ranibizumab 0.5 mg, 140 subjects were randomized, however one subject did not have a BCVA baseline value, therefore, data from 139 patients are included in the results for this group.

Patient withdrawal rates (control, 0.3 mg ranibizumab, 0.5 mg ranibizumab):

• MARINA 1 year (discontinued study on or prior to Month 12): 8.8%, 2.5%, 2.5%
• MARINA 2 year (discontinued from study): 20.2%, 11.8%, 10.4%
• ANCHOR 1 year (discontinued study on or prior to Month 12): 7.0%, 7.1%, 3.6%
• ANCHOR 2 year (discontinued from study): 23.1%, 16.4%, 17.1%
• PIER 1 year (discontinued study on or prior to Month 12): 12.7%, 1.7%, 3.3%

The sham ranibizumab injection control procedure involved anesthetising the eye in a manner identical to a ranibizumab intravitreal injection. The tip of a needleless syringe was then pressed against the conjunctiva and the plunger of the needleless syringe depressed.

Patients in the groups treated with ranibizumab had minimal observable CNV lesion growth, on average. At Month 12, the mean change in the total area of the CNV lesion was 0.1 to 0.3 disc area for ranibizumab versus 2.3 to 2.6 disc area for the control arms. Results from both trials indicated that continued ranibizumab-treatment may be of benefit also in patients who lost 15 letters of best-corrected visual acuity (BCVA) in the first year of treatment.

The size of the lesion did not significantly affect the results. In general, patients with poor visual acuity (<20/200) at the onset of treatment experienced a benefit of treatment. However, neovascular AMD that has evolved into lesions characterised by subretinal fibrosis and advanced geographic atrophy is not likely to respond to ranibizumab.

In MARINA and ANCHOR, at month 12 patients treated with ranibizumab reported, on average, a statistically (p<0.01) and clinically meaningful improvement in their ability to perform activities related to near vision (such as reading; MARINA: 0.5 mg ranibizumab: + 10.4 point increase; 0.3 mg ranibizumab: + 9.4 point increase; ANCHOR: 0.5 mg ranibizumab: + 9.1 point increase; 0.3 mg ranibizumab: + 6.6 point increase), distance vision (such as driving; MARINA: 0.5 mg ranibizumab: + 7.0 point increase; 0.3 mg ranibizumab: + 6.7 point increase; ANCHOR: 0.5 mg ranibizumab: + 9.3 point increase; 0.3 mg ranibizumab: + 6.4 point increase) and vision– specific dependency (such as seeing faces; MARINA: 0.5 mg ranibizumab: + 6.8 point increase; 0.3 mg ranibizumab: + 3.6 point increase; ANCHOR: 0.5 mg ranibizumab: + 8.9 point increase; mg ranibizumab: + 7.6 point increase), as measured by the National Eye Institute (NEI) Visual Functioning Questionnaire-25 (VFQ-25). Sham-treated patients reported a decrease in their ability to perform these activities (MARINA: near vision:

• 2.6 point decrease; distance vision: -5.9 point decrease; vision-specific dependency: -4.7 point decrease) and verteporfin PDT-treated patients reported a small increase or decrease (ANCHOR: near vision: + 3.7 point increase; distance vision: + 1.7 point increase; vision-specific dependency: - 1.4 point decrease).

In MARINA, this increase from baseline in each of the three VFQ-25 subscales at Month 12 was maintained at Month 24 for ranibizumab-treated patients, while in the sham-injection group the mean change from baseline decreased further from Month 12 to Month 24 in each of these subscales. Therefore, the treatment benefit of ranibizumab over the sham control at Month 24 was greater than that at Month 12.

In the verteporfin PDT group, the mean improvement from baseline in the near activities and distance activities subscale scores at Month 12 were lost at Month 24, while the mean decrease from baseline in the vision-specific dependency subscale score at Month 12 was maintained at Month 24. These changes between Months 12 and 24 within each treatment group resulted in either maintained or greater treatment benefit of ranibizumab over verteporfin PDT compared with Month 12, while the treatment benefit of ranibizumab in the vision-specific dependency subscale was smaller at Month 24 compared with Month 12 (p-values ranging from 0.0023 to 0.0006).

Treatment of visual impairment due to DME

Clinical efficacy of ranibizumab in patients with visual impairment secondary to diabetic macular edema (DME) was assessed in the randomized, double-masked, controlled study D2301 (RESTORE). Clinical safety of ranibizumab has been assessed in the randomized, double-masked, controlled studies D2301 (RESTORE) and D2201 (RESOLVE).

Table 21 Summary of Patient Demographics for Clinical Trials in Visual Impairment due to DME

† a. There is only limited experience in the treatment of subjects with DME due to Type I diabetes.

b. There is limited experience in patients older than 75 years of age with DME.

c. Patients with the HbA1c > 10% were not included in the clinical trial.

‡ prn: pro re nata (as needed)

In study D2301 (RESTORE), a total of 345 patients with visual impairment due to macular edema were enrolled to receive either initial intravitreal injection of ranibizumab 0.5 mg as monotherapy and sham laser photocoagulation, combined ranibizumab 0.5 mg and laser photocoagulation, or sham injection and laser photocoagulation monotherapy. Treatment with ranibizumab was started with monthly intravitreal injections. Treatment was suspended when visual acuity stability was observed over the last three consecutive visits. The treatment was reinitiated when there was a reduction in BCVA due to DME progression. Laser photocoagulation was administered at baseline, and then as needed based on ETDRS criteria.

The primary efficacy endpoint was mean average change in BCVA from Month 1 to Month 12 compared to baseline. The 12-month results demonstrate statistically significant superiority of ranibizumab as monotherapy or adjunctive to laser photocoagulation compared to laser control, on both primary and secondary endpoints of visual acuity, and on the effect on central retinal thickness (CRT). Clinical significance of the effect on central retinal thickness in this population is unknown. A rapid improvement in BCVA was observed as early as the first follow-up visit and was maintained through the 12-month period (Figure 3). The mean average change in BCVA over 12 months showed an improvement of 5.4 and 4.9 letters, respectively, for ranibizumab and ranibizumab adjunctive to laser compared to laser monotherapy, and in the laser arm, a maintenance of the baseline BCVA of about + 1 letter over the 12 months study period.

The results of the primary endpoint are detailed below in Table 22 and illustrated in Figure 3.

Table 22 Outcomes at Month 12 in Study D2301 (RESTORE), Full Analysis Set, with Last Observation Carried Forward (LOCF)

^b p<0.0001

Figure 3 Mean BCVA Change from Baseline over Time in Study D2301 (RESTORE)

The results for the key secondary efficacy endpoints based on BCVA were consistent with those obtained for the primary endpoint and showed statistically significant treatment differences in ranibizumab treated patients compared to laser. At Month 12, the mean BCVA improvement compared to baseline for patient treated with ranibizumab and ranibizumab adjunctive to laser was 6.8 and 6.4 letters, compared to 0.9 letters in the laser treated patients. The proportion of ranibizumab treated patients who gained at least 15 letters from baseline at 12 months was 22.6% (ranibizumab) and 22.9% (ranibizumab + laser) compared to 8.2% in laser control.

The improvement in the visual acuity outcomes was also accompanied by a rapid and sustained decrease in the macular edema as assessed by the central retinal thickness. Clinical significance of the effect on central retinal thickness in this population is unknown.

In study D2201 (RESOLVE), a total of 151 patients with macular center involvement causing visual impairment were enrolled to receive either: 1) initial intravitreal injection of ranibizumab

0.3 mg (6 mg/mL formulation) and then monthly injection until treatment success or futility was observed (51 patients); 2) initial intravitreal injection of ranibizumab 0.5 mg (10 mg/mL formulation) and then monthly injection until treatment success or futility was observed (51 patients); 3) initial sham injection and then monthly sham injections when needed following the same treatment criteria (49 patients). The initial ranibizumab dose could be doubled at any time during the study after the first injection if the investigator evaluated that response to treatment was not sufficiently achieved. The dose doubling was achieved by doubling of the injection volume from 0.05 to 0.1 mL. Laser photocoagulation rescue treatment was allowed at any time in the study in the active and control arms after month 3 of the study, based on the investigators’ opinion.

Treatment of visual impairment due to macular edema secondary to RVO

Clinical safety and efficacy of ranibizumab in patients with visual impairment due to macular edema secondary to RVO have been assessed in the randomized, double-masked, controlled studies BRAVO and CRUISE.

In the BRAVO study, a total of 397 patients with visual impairment due to macular edema secondary to Branch RVO were enrolled to receive either 0.3 mg or 0.5 mg intravitreal ranibizumab or sham1 injections. Laser photocoagulation standard of care was allowed in all three arms and was administered, based on protocol defined criteria, as rescue treatment beginning at Month 3. A proportion of 57.6% of patients in the sham-control arm and 20.1% and 21.4% in the ranibizumab-treated arms (0.3 mg and 0.5 mg, respectively) received at least one laser treatment during the first 6 months of the study.

After 6 months, the patients in the sham-control arm were crossed-over to 0.5 mg ranibizumab. The proportion of patients receiving at least one laser treatment during the entire 12 months study period was as follows: 61.4% in the sham/0.5 mg ranibizumab arm, 41.0% in the 0.3 mg ranibizumab arm, and 34.4% in the 0.5 mg ranibizumab arm.

The primary endpoint was the mean change from baseline in best-corrected visual acuity (BCVA) at Month 6: treatment with 0.5 mg ranibizumab, on average, showed a statistically significant improvement of 18.3 letters compared to a gain of 7.3 letters in the control group (p<0.0001). Improvement in BCVA was rapid (as early as day 7, p<0.0001), and sustained over the next months through Month 12 (secondary endpoint), with a mean improvement from baseline in BCVA score at Month 12 of 18.3 letters for the 0.5 mg ranibizumab group, compared to 12.1 letters for the sham/0.5 mg group.

Statistically significant improvements were also observed in key secondary endpoints at Month 6, and sustained to Month 12. At month 6, 61.1% of the patients in the 0.5 mg ranibizumab group gained ≥15 letters in visual acuity score from baseline compared with 28.8% of patients in the sham group, which represents an estimated difference of 31.3% between the two groups. At month 12, 60.3% of the patients in the 0.5 mg ranibizumab group gained ≥15 letters in visual acuity score from baseline compared with 43.9% of patients in the sham/0.5 mg ranibizumab arm. For the crossover sham/0.5-mg group, improvements in visual acuity were also observed during the 6-month observation period.

Table 23 BCVA Primary Efficacy Outcome at Month 6 (BRAVO), Randomized Patients, with Last Observation Carried Forward Method (LOCF) to Impute Missing Data

a: Early Treatment Diabetic Retinopathy Study

b: p<0.0001

Figure 4 Mean Change from Baseline BCVA over Time to Month 6 (BRAVO)

In the CRUISE study, a total of 392 patients with visual impairment due to macular edema secondary to Central RVO were enrolled to receive either 0.3 mg or 0.5 mg intravitreal ranibizumab or sham injections. After 6 months, the patients in the sham-control arm were crossed-over to 0.5 mg ranibizumab.

The primary endpoint was the mean change from baseline in BCVA at Month 6: treatment with

0.5 mg ranibizumab, on average, showed a statistically significant improvement of 14.9 letters compared to 0.8 letter gain in the control group (p<0.0001). Improvement in BCVA was rapid (as early as day 7, p<0.0001), and sustained over the next months through month 12, with a mean improvement from baseline in BCVA score at Month 12 of 13.9 letters for the 0.5 mg ranibizumab group, compared to 7.3 letters for the sham/0.5 mg group.

Statistically significant improvements were also observed in key secondary endpoints at Month 6 and sustained through Month 12. At month 6, 47.7% of the patients in the 0.5 mg ranibizumab group gained ≥15 letters in visual acuity score from baseline compared with 16.9% of patients in the sham group, which represents an estimated difference of 30.3% between the two groups. At month 12, 50.8% of the patients in the 0.5 mg ranibizumab group gained ≥15 letters in visual acuity score from baseline compared with 33.1% of patients in the sham/0.5 mg ranibizumab arm. For the crossover sham/0.5 mg group, improvements in visual acuity were also observed during the 6-month observation period.

Table 24 BCVA Primary Efficacy Outcome at Month 6 (CRUISE), Randomized Patients, with Last Observation Carried Forward Method (LOCF) to Impute Missing Data

a: Early Treatment Diabetic Retinopathy Study

b: p<0.0001

Figure 5 Mean Change from Baseline BCVA over Time to Month 6 (CRUISE)

In both studies, the improvement in the visual acuity outcomes were accompanied by a rapid and sustained decrease in the macular edema as assessed by the central retinal thickness, both at Month 6 and Month 12.

In both studies, the improvement in visual acuity outcomes seen with ranibizumab treatment at both 6 and 12 months was accompanied by patient-reported benefits as measured by the National Eye Institute Visual Function Questionnaire (NEI VFQ-25), and particularly in the sub-scales related to near and distance activities, as pre-specified secondary efficacy endpoints.

In BRAVO and CRUISE, patients treated with ranibizumab achieved statistically significant improvements at Month 6 in near activities (BRAVO: ranibizumab 0.5 mg: +13.7; sham: +7.3; p=0.0002; CRUISE: ranibizumab 0.5 mg: +9.3; sham: +5.1; p=0.0099) and distance activities (BRAVO: ranibizumab 0.5 mg: +11.3; sham: +6.3; p=0.0014; CRUISE: ranibizumab 0.5 mg:

+6.7; sham: +2.8; p=0.0199). In both studies, this increase from baseline in each of the two VFQ-25 subscales at Month 6 was sustained at Month 12.

Post-marketing studies

The long term (24 month) clinical safety and efficacy of ranibizumab in patients with visual impairment due to macular edema secondary to RVO were assessed in the BRIGHTER (BRVO) and CRYSTAL (CRVO) studies. In both studies, subjects received a 0.5 mg ranibizumab PRN dosing regimen driven by individualized stabilization criteria.

BRIGHTER was a 3-arm, randomized, active-controlled study that compared 0.5 mg ranibizumab given as monotherapy or in combination with adjunctive laser photocoagulation, to laser photocoagulation alone. After 6 months, subjects in the laser monotherapy arm could receive 0.5 mg ranibizumab. CRYSTAL was a single-arm study with 0.5 mg ranibizumab monotherapy.

The key outcome measures from BRIGHTER and CRYSTAL are shown in the Table below.

Table 25 Outcomes at Month 6 and 24 (BRIGHTER and CRYSTAL)

* Starting at Month 6 treatment with ranibizumab 0.5 mg was allowed (24 patients were treated with laser only).

The effect of visual improvement was observed in all patients treated with 0.5 mg ranibizumab monotherapy regardless of their disease duration in both BRIGHTER and CRYSTAL.

Treatment of visual impairment due CNV secondary to PM

The clinical safety and efficacy of ranibizumab in patients with visual impairment due to CNV in PM have been assessed based on the 12-month data of the randomized, double-masked, controlled pivotal study F2301 (RADIANCE) which was designed to evaluate two different dosing regimens of 0.5 mg ranibizumab given as intravitreal injection in comparison to verteporfin photodynamic therapy PDT (vPDT). PM is characterized by abnormal and progressive elongation of the eyeball, usually to an axial length greater than 26 mm and refractive error of more than -6.0 Diopters, with concomitant degenerative changes in the posterior segment of the eye such as posterior staphyloma, chorioretinal atrophy, Bruch’s membrane (lacquer) cracks, subretinal hemorrhage, retinal detachment, and CNV.

Table 26 Summary of Patient Demographics for Clinical Trials in Visual Impairment due to CNV Secondary to PM

^†Patients in the vPDT were allowed to receive ranibizumab treatment as of Month 3.

The 277 patients were randomized to one of the following arms:

• Group I (ranibizumab 0.5 mg, dosing regimen driven by “stability” criteria defined as no change in best corrected visual acuity (BCVA) compared to two preceding monthly evaluations)
• Group II (ranibizumab 0.5 mg, dosing regimen driven by “disease activity” criteria defined as vision impairment attributable to intra-or-subretinal fluid or active leakage due to the CNV lesion as assessed by OCT and/or FA)
• Group III (vPDT - patients were allowed to receive ranibizumab treatment as of Month 3)

Over the 12 months of the study patients received on average 4.6 injections (median 4.0, range 1- 12) in Group I and 3.5 (median 2.0, range 1-12) injections in Group II. In Group II (in which patients received the recommended treatment regimen based on disease activity, see 4 Dosage and Administration), 50.9% of patients required 1 or 2 injections, 34.5% required 3 to 5 injections and 14.7% required 6 to 12 injections over the 12-month study period. In Group II, 62.9% of patients did not require injections in the second 6 months of the study.

The primary efficacy endpoint was the mean average change in BCVA from baseline to Month

1 through Month 3. Both ranibizumab treatment arms demonstrated statistically significant superior efficacy compared with vPDT: the mean average BCVA score of the study eye from Month 1 to Month 3 exceeded baseline by 10.5 letters (Group I; min-max: -19.3 to +31.0) and

10.6 letters (Group II; min-max: -8.3 to +32.0) in the ranibizumab groups and by 2.2 letters in the vPDT group (min-max: -24.7 to +24.3). The treatment benefit was maintained for the 12- month duration of the study. The mean average change in BCVA from baseline to Month 1 through Month 12 was 12.8 letters and 12.5 letters in Group I and Group II, respectively.

Table 27 Primary Efficacy Outcome at Month 3 in Study RADIANCE, Randomized Patients, with Modified Last Observation Carried Forward (LOCF) Method

^† Comparative control up to Month 3. Patients randomized to vPDT were allowed to receive ranibizumab treatment as of Month 3, as per Investigator discretion (in Group III, 38 patients received ranibizumab from Month 3 onwards)

a: p<0.00001 comparison with vPDT control

Results for secondary endpoint were consistent with those of the primary endpoint. The time course of mean change BCVA from baseline through Month 12 showed a rapid improvement, most of it reached by Month 2. The improvement in BCVA continued through Month 12 achieving a mean change in BCVA of about 14 letters gain in both ranibizumab arms (Figure 6). At Month 3, the proportion of patients who gained ≥10 letters (or reached a BCVA of ≥84 letters) from baseline was 61.9% and 65.5% in Group I and II, compared to 27.3% in the vPDT group; and the proportion of patients who gained ≥15 letters (or ≥84 letters total) was 38.1% and 43.1% in Group I and II, compared to 14.5% in the vPDT group. At Month 12, the proportion of patients who gained ≥10 letters (or ≥84 letters total) from baseline was 69.5% and 69.0% in Group I and II; and the proportion of patients who gained ≥15 letters (or ≥84 letters total) from baseline was 53.3% and 51.7% in Group I and II, respectively.

Figure 6 Mean Change from Baseline BCVA over Time up to Month 12 (RADIANCE)

BL = baseline; SE = standard error of the mean.

Patients randomized to vPDT were allowed to receive ranibizumab from Month 3 onwards.

There are limited data regarding treatment with ranibizumab in PM patients with extrafoveal lesions.

The improvement of vision was accompanied by a reduction in central retinal thickness; however, the clinical significance of this is yet to be determined.

Treatment of visual impairment due to CNV

The clinical safety and efficacy of ranibizumab in patients with visual impairment due to CNV secondary to etiologies other than wet AMD and PM have been assessed based on a Phase 3 multi-center study G2301 (MINERVA), which was randomized, double-masked, sham controlled for 2 months followed by an open-label extension of 10 months.

Table 28 Summary of Patient Demographics for Clinical Trials in Visual Impairment due to CNV

In this study, 178 adult patients were randomized in a 2:1 ratio to one of the following arms, stratified by the presence of angioid streaks at baseline (yes/no):

• ranibizumab 0.5 mg at baseline followed by an individualized dosing regimen based on evidence of disease activity.
• sham injection at baseline followed by an individualized treatment regimen based on evidence of disease activity.

Starting at Month 2, all patients received open-label individualised treatment with ranibizumab based on disease activity. The primary endpoint was assessed by the best corrected visual acuity (BCVA) change from baseline to Month 2.

The primary outcome measure, demonstrated statistically superior efficacy in ranibizumab- treated patients compared to patients randomized to sham (Table 29).

Table 29 Change in Visual Acuity at Month 2 in study MINERVA

n is the number of patients with data available in the analysis

⁽¹⁾ Analyzed using MMRM, which contains scheduled visit, the type of underlying pathophysiologic mechanism (angioid streaks vs. others) and treatment group as fixed effect factors, centered baseline BCVA as a continuous covariate and treatment group by visit and visit by centered baseline BCVA interactions.

The mean BCVA change from baseline over time to Month 12 is shown in Figure 7.

Figure 7 Mean BCVA Change from Baseline over Time up to Month 12 (MINERVA)

A difference was observed in the change from baseline to Month 2 in BCVA (13.0 letters vs 4.2 letters) for the 2 age groups (patients <= 60 years vs patients > 60 years, respectively).

A subgroup analysis for the primary variable was conducted using the following subgroups of type of underlying ocular pathophysiological mechanism (baseline etiology) in the study eye: (i) angioid streaks; (ii) post-inflammatory retinochoroidopathy; (iii) idiopathic chorioretinopathy;

(iv) central serous chorioretinopathy (CSC) and (v) miscellaneous (any etiology that does not belong to the above subgroups). The subgroups were based on data entered in the eCRF, and the definition of each baseline etiology subgroup was determined prior to database lock. Within the “Miscellaneous” baseline etiology subgroup, there were 15 different etiologies causing CNV. In total, the study enrolled patients with 19 different etiologies. Results from the subgroup analysis for the primary variable by baseline etiology are shown in Table 30, and suggest that the treatment effect varies by baseline etiology.

Table 30 Overall Results on Change in Visual Acuity and per Baseline Etiology at Month 2 (MINERVA)

^a comprises CNV etiologies which do not fall under the other subgroups

* number of patients with data available in the analysis

The mean number of ranibizumab injections given in the study eye over 12 months was 5.8 (range 1-12) in the ranibizumab arm versus 5.4 (range 1-10) over 10 months in those patients in the sham with ranibizumab group. In the sham arm, 7 out of 59 patients did not receive any treatment with ranibizumab in the study eye during the 12-month period.