UPTERA

Ranibizumab is a recombinant humanized

IgG1 kappa isotype monoclonal antibody fragment directed against human vascular endothelial growth factor A (VEGF-A), which is a glycoprotein implicated in the pathophysiology of age-related macular degeneration. 2, 7 Ranibizumab is used to treat various ocular disorders with abnormal growth of blood vessels, such as neovascular (wet) age-related macular degeneration.

The development of ranibizumab first began after bevacizumab, another anti-VEGF anticancer drug, was discovered to inhibit neovascularization and used in the off-label treatment of neovascular age-related macular degeneration for intravenous injection.

In order to improve drug delivery to the target organ, ranibizumab is available for intravitreal use.

Ranibizumab was initially approved by the

FDA in 2006 2 and by the European Commission (EC) in 2007.

It is marketed under the brand names LUCENTIS and SUSVIMO.

BYOOVIZ, a biosimilar of LUCENTIS, was approved by Health Canada in March 2022, making it the first and only biosimilar drug of ranibizumab available in Canada.

In August 2022, other biosimilars CIMERLI, RAIVISIO, and RANOPTO were approved by the FDA, EC, and Health Canada respectively. 12, 13, 15.

Ranibizumab injection for intravitreal use is indicated to treat Neovascular (wet) Age-related Macular Degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization by the FDA. 7, 11 Ranibizumab injection for intravitreal use via ocular implant is used to treat Neovascular (wet) Age-related Macular Degeneration (AMD) in patients who have responded to at least two intravitreal injections of a VEGF inhibitor.

In Canada, ranibizumab is approved to treat adult patients with neovascular (wet) age-related macular degeneration (AMD) and visual impairment due to diabetic macular edema, macular edema secondary to retinal vein occlusion, choroidal neovascularisation (CNV) secondary to pathologic myopia (PM), and choroidal neovascularisation (CNV) secondary to ocular conditions other than AMD or PM, including but not limited to angioid streaks, postinflammatory retinochoroidopathy, central serous chorioretinopathy or idiopathic chorioretinopathy.

In Europe, ranibizumab is also approved for the treatment of similar ophthalmological conditions, including neovascular (wet) age-related macular degeneration (AMD), visual impairment due to diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), and visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO) or choroidal neovascularisation (CNV) for adults and retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 3+) or AP-ROP (aggressive posterior ROP) disease for preterm infants.

Ranibizumab is a vascular endothelial growth factor (VEGF-A) inhibitor used to manage ocular diseases with abnormal angiogenesis.

It inhibits the formation of new blood vessels or neovascularization.

Ultimately, ranibizumab works to slow down the loss of vision and causes significant visual improvement in patients with ocular degenerative disorders, such as age-related macular degeneration.

It can also reduce retinal thickness.

As ranibizumab has one binding site for VEGF, two drug molecules bind to one VEGF dimer.

Ranibizumab lacks the

Fc region of an antibody, which may prevent the drug from causing intraocular inflammation following intravitreal injection.

Ranibizumab rapidly penetrates through the retina to reach the choroid after intravitreal injection.

Following monthly intravitreal administration of 0.5 mg ranibizumab in patients with neovascular (wet) age-related macular degeneration, the mean C max (±SD) was 1.7 (± 1.1) ng/mL.

Following an implant insertion, the mean (±SD) C max of ranibizumab was 0.48 (±0.17) ng/mL and median T max was 26 days, with a range of one to 89 days.

The apparent volume of the central compartment (Vd/F) is 2.77 L.

Ranibizumab is not shown to accumulate in serum.

Due to its small size from lacking the Fc region of an antibody, ranibizumab achieves enhanced diffusion into the retina and choroid. 3, 5.

The metabolism of ranibizumab has not been studied.

Since it is a monoclonal antibody fragment, ranibizumab is expected to undergo catabolism.

There is no information available.

The estimated average vitreous elimination half-life is approximately nine days following intravitreal injection.

The half-life of ranibizumab implant is approximately 25 weeks.

In patients with retinal vein occlusion or diabetic macular edema, the apparent clearance (CL/F) of ranibizumab was 24.8 L/day.

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There is no information available regarding the LD 50 values of ranibizumab.

There is also limited clinical experience of ranibizumab overdose: concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been administered to patients, with no additional unexpected adverse reactions that were observed.

• Ocular or periocular infections.

• Hypersensitivity 4.1 Ocular or Periocular.

Infections CIMERLI is contraindicated in patients with ocular or periocular infections. 4.2 Hypersensitivity CIMERLI is contraindicated in patients with known hypersensitivity to ranibizumab products or any of the excipients in CIMERLI.

Hypersensitivity reactions may manifest as severe intraocular inflammation.

For ophthalmic intravitreal injection only.

• Neovascular (Wet) Age-Related Macular Degeneration (AMD) : CIMERLI 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).

• Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment.

• Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses.

Patients should be assessed regularly.

• Macular Edema Following Retinal Vein Occlusion (RVO) : CIMERLI 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).

• Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) : CIMERLI 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).

• Myopic Choroidal Neovascularization (mCNV) : CIMERLI 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be initially administered by intravitreal injection once a month (approximately 28 days) for up to three months.

Patients may be retreated if needed. 2.1 General Dosing Information FOR OPHTHALMIC INTRAVITREAL INJECTION.

A 5-micron sterile filter needle (19-gauge × 1-1/2 inch), a 1-mL Luer lock syringe and a 30-gauge × 1/2 inch sterile injection needle are needed but not included. 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD) CIMERLI 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).

Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment.

In the 9 months after three initial monthly doses, less frequent dosing with 4-5 doses on average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional average 1-2 letter gain.

Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses.

Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average.

Patients should be assessed regularly. 2.3 Macular Edema Following Retinal Vein Occlusion (RVO) CIMERLI 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).

RVO-1 and RVO-2, patients received monthly injections of ranibizumab for 6 months.

In spite of being guided by optical coherence tomography and visual acuity re-treatment criteria, patients who were then not treated at Month 6 experienced on average, a loss of visual acuity at Month 7, whereas patients who were treated at Month 6 did not.

Patients should be treated monthly. 2.4 Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) CIMERLI 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days). 2.5 Myopic Choroidal Neovascularization (mCNV) CIMERLI 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be initially administered by intravitreal injection once a month (approximately 28 days) for up to 3 months.

Patients may be retreated if needed. 2.6 Preparation for Administration Vial: Using aseptic technique, all of the CIMERLI vial contents are withdrawn through a 5-micron (19-gauge × 1-1/2 inch), sterile filter needle attached to a 1 mL syringe (not included).

The filter needle should be discarded after withdrawal of the vial contents and should not be used for intravitreal injection.

The filter needle should be replaced with a sterile 30-gauge × 1/2 inch needle for the intravitreal injection.

Use aseptic technique to carry out the following preparation steps: 1.

• a 5-micron sterile filter needle (19-gauge × 1-1/2 inch).

• a 1 mL sterile Luer lock syringe (with marking to measure 0.05 mL).

• a sterile injection needle (30-gauge × 1/2-inch) 2.

Before withdrawal, disinfect the outer part of the rubber stopper of the vial. 3.

Place a 5-micron filter needle (19-gauge × 1-1/2 inch) onto a 1 mL Luer lock syringe using aseptic technique. 4.

Push the filter needle into the center of the vial stopper until the needle touches the bottom edge of the vial. 5.

Withdraw all the liquid from the vial, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. 6.

Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. 7.

The filter needle should be discarded after withdrawal of the vial contents and must not be used for the intravitreal injection. 8.

Attach a 30-gauge × 1/2-inch sterile injection needle firmly onto the syringe by screwing it tightly onto the Luer lock.

Carefully remove the needle cap by pulling it straight off.

Do not wipe the needle at any time. 9.

Hold the syringe with the needle pointing up.

If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top. 10.

Hold the syringe at eye level, and carefully push the plunger rod until the plunger tip is aligned with the line that marks 0.05 mL on the syringe.

Image 2.7 Administration The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent).

Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection.

Prior to and 30 minutes following the intravitreal injection, patients should be monitored for elevation in intraocular pressure using tonometry.

Monitoring may also consist of a check for perfusion of the optic nerve head immediately after the injection.

Patients should also be monitored for and instructed to report any symptoms suggestive of endophthalmitis without delay following the injection.

Each vial should only be used for the treatment of a single eye.

If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter needle, and injection needles should be changed before CIMERLI is administered to the other eye.

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

(ranibizumab-eqrn) injection is a colorless to pale yellow solution supplied in:

• Each CIMERLI 0.5 mg carton (NDC 61314-625-94) contains a single-dose, 2-mL glass vial with a BLUE CAP designed to deliver 0.05 mL of 10 mg/mL ranibizumab-eqrn solution.

• Each CIMERLI 0.3 mg carton (NDC 61314-624-94) contains a single-dose, 2-mL glass vial with a WHITE CAP designed to deliver 0.05 mL of 6 mg/mL ranibizumab-eqrn solution.

CIMERLI should be refrigerated at 2°C to 8°C (36°F to 46°F).

Do not use beyond the expiry date stamped on the label.

CIMERLI vials from light and store in the original carton until time of use.

should be refrigerated at 2°C to 8°C (36°F to 46°F).

Do not use beyond the expiry date stamped on the label.

CIMERLI vials from light and store in the original carton until time of use.

There are no adequate and well-controlled studies of ranibizumab products administered in pregnant women.

Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses 13-times the predicted human exposure (based on maximal serum trough levels [C max ]) after a single eye treatment at the recommended clinical dose.

No skeletal abnormalities were observed at serum trough levels equivalent to the predicted human exposure after a single eye treatment at the recommended clinical dose.

Animal reproduction studies are not always predictive of human response, and it is not known whether ranibizumab products can cause fetal harm when administered to a pregnant woman.

Based on the anti-VEGF mechanism of action for ranibizumab products, treatment with ranibizumab products may pose a risk to human embryofetal development.

CIMERLI should be given to a pregnant woman only if clearly needed.

An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys.

Pregnant animals received intravitreal injections of ranibizumab every 14 days starting on Day of gestation, until Day at doses of 0, 0.125, and 1 mg/eye.

Skeletal abnormalities including incomplete and/or irregular ossification of bones in the skull, vertebral column, and hindlimbs and shortened supernumerary ribs were seen at a low incidence in fetuses from animals treated with 1 mg/eye of ranibizumab.

The 1 mg/eye dose resulted in trough serum ranibizumab levels up to 13 times higher than predicted C max levels with single eye treatment in humans.

No skeletal abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which resulted in trough exposures equivalent to single eye treatment in humans.

No effect on the weight or structure of the placenta, maternal toxicity, or embryotoxicity was observed.

The safety and effectiveness of

CIMERLI in pediatric patients have not been established.

In the clinical studies, approximately 76% (2449 of 3227) of patients randomized to treatment with ranibizumab were ≥ 65 years of age and approximately 51% (1644 of 3227) were ≥ 75 years of age.

No notable differences in efficacy or safety were seen with increasing age in these studies.

Age did not have a significant effect on systemic exposure.