ranibizumab intravitreal implant (Rx)

>10%

Conjunctival hemorrhage (72%)

Conjunctival hyperemia (26%)

Iritis (23%)

1-10%

Eye pain (10%)

Vitreous floaters (9%)

Conjunctival bleb/ filtering bleb leak (9%)

Foreign body sensation in eyes (7%)

Headache (7%)

Hypotony of eye (6%)

Vitreous detachment (6%)

Vitreous hemorrhage (5%)

Conjunctival edema (5%)

Corneal disorder (4%)

Corneal abrasion (4%)

Corneal edema (4%)

Contraindications

Ocular or periocular infections

Active intraocular inflammation

Hypersensitivity to ranibizumab or product excipients

Cautions

Rhegmatogenous retinal detachments (eg, pneumatic retinopexy, vitrectomy, or laser photocoagulation) occurred and may result in vision loss; if this occurs, delay refill-exchange if retinal detachment or retinal break is present; carefully evaluate retinal periphery and treat any suspected areas of abnormal vitreoretinal adhesion or retinal breaks before inserting the implant

In clinical trials, the device has dislocated/subluxated into the vitreous cavity or has extended outside the vitreous cavity into or beyond the subconjunctival space; device dislocation requires urgent surgical intervention

Conjunctival erosions or retractions have been associated with increased risk of endophthalmitis; especially when implant is exposed; perform surgical intervention (eg, conjunctival/Tenon’s capsule repair) is recommended if conjunctival erosion or retraction with or without exposure of the implant flange is present

Conjunctival blebs may require surgical management to avoid further complications, especially if implant septum is no longer identifiable due to the conjunctival bleb

Visual acuity was decreased by 4 letters on average in the first postoperative month and 2 letters on average in the second postoperative month following initial implantation

Use caution when performing ophthalmic procedures (eg, B-scan ophthalmic ultrasound, scleral depression, gonioscopy) that may cause deflection of the implant and subsequent injury

Endophthalmitis

• Risk of endophthalmitis or retinal detachment with intravitreous injections; cases more prevalent in intravitreal implant
• Always use proper aseptic injection technique when administering therapy
• Monitor and treat promptly to reduce the risk of vision loss and maximize recovery
• Patients should not have an active or suspected ocular or periocular infection or severe systemic infection at the time of any implant or refill procedure
• Appropriate intraoperative handling followed by secure closure of the conjunctiva and Tenon’s capsule, and early detection and surgical repair of conjunctival erosions or retractions may reduce the risk of endophthalmitis

Air bubbles in implant reservoir

• Minimize air bubbles within implant reservoir as they may cause slower drug release
• During initial fill procedure, if an air bubble is present, it must be ≤1/3 of the widest diameter of the implant; if excess air is observed after initial fill, do not use the implant
• During refill-exchange procedure, if excess air is present in the syringe and needle do not use the syringe and needle; if excess air bubbles are observed after the refill-exchange procedure, consider repeating the refill-exchange procedure.

Vitreous hemorrhages

• Vitreous hemorrhages may result in temporary vision loss; vitrectomy may be needed in the case of a non-clearing vitreous hemorrhage
• Patients on antithrombotic medication (eg, oral anticoagulants, aspirin, nonsteroidal anti-inflammatory drugs) may be at increased risk of vitreous hemorrhage; temporarily hold antithrombotic medications before implant insertion
• Delay dose (refill-exchange) in the event of sight-threatening vitreous hemorrhage
• Use of pars plana laser ablation and perform scleral cauterization to reduce the risk of vitreous hemorrhage

Septum dislodgement

• Appropriate handling and insertion of refill needle into septum (avoid twisting and/or rotation) required to minimize risk of septum dislodgement
• Implant damage where the septum has dislodged into implant body reported
• Perform a dilated slit lamp exam and/or dilated indirect ophthalmoscopy to inspect the implant in vitreous cavity through the pupil before and after refill-exchange procedure to identify if septum dislodgement has occurred
• Discontinue treatment following septum dislodgement and consider implant removal should benefit outweigh the risk

Pregnancy

There are no adequate and well-controlled studies of ranibizumab intravitreal implant in pregnant females

Based on mechanism of action, treatment may pose a risk to human embryofetal development

Animal data

• Administration of ranibizumab to pregnant monkeys during organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses up to 41 times of the human exposure

Contraception

• Females of reproductive potential: Use effective contraception during treatment and for at least 12 months after the last dose

Infertility

• No studies on the effects of ranibizumab on fertility have been conducted and it is not known whether ranibizumab can affect reproduction capacity
• Based on mechanism of action, treatment may pose a risk to reproductive capacity

Lactation

No data are available on drug presence in human milk, its effects on breastfed infants, or its effects on milk production/excretion

Use drug with caution when administering to nursing females

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Recombinant humanized monoclonal antibody binds and inhibits human vascular endothelial growth factor (VEGF-A)

Binding to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation

Absorption

Peak plasma concentration: 0.48 ng/mL

Peak plasma time: 26 days

No accumulation in serum when administered with refills every 24 weeks

Elimination

Excretion profile for ranibizumab following administration is unknown

Intravitreal injection preparation

Transfer dose from 100 mg/mL-vial to 1-mL Luer lock syringe by using a 5-micron filter needle (not included in kit) to withdraw all contents of vial; do NOT use initial fill needle for this step

With filter needle attached, hold syringe with needle pointing up

Gently tap syringe with your finger to allow any air bubbles rise to the top

Slowly push plunger rod until air is fully expelled from syringe and needle

Remove and discard filter needle

Attach initial fill needle (34-gauge, with integrated 5-micron filter and blue cap; provided in kit)

Carefully remove cap by pulling straight off; do NOT wipe needle at any time

Gently tap syringe to remove bubbles; expel air and set dose

Use the syringe within 15 minutes of removing all air to avoid drug from drying in the needle and impeding fluid flow

Load syringe into carrier; do not hold or push on the plunger of the syringe while inserting needle into the implant septum

Under the microscope, slowly administer ranibizumab into the ocular implant by slightly tilting the carrier upwards; implant should be filled over ~5 to 10 seconds, to help avoid air entrapment in the implant reservoir

If solution is leaking from implant at a different location (eg, side of the implant), do not use the ocular implant

Inspect ocular implant under the microscope to ensure that implant is completely full of drug solution; ≤30 minutes should pass between initial fill of the implant and insertion into the patient’s eye to ensure that the release control element remains saturated

Remove syringe and guide sleeve from carrier by pulling back on the syringe; dispose used syringe and guide sleeve in accordance with local requirements

Slide insertion tool handle into carrier; do not withdraw handle and implant until eye is ready for insertion

Implant properties

• Implant holds 0.02 mL of drug, and is secured within the sclera, by the extrascleral flange that remains visible through the conjunctiva following insertion
• Implant septum is self-sealing interface through which ranibizumab is administered to fill the implant

Intravitreal Implant Administration

Do not administer ranibizumab as a bolus intravitreal injection; do not substitute ranibizumab intravitreal implant with other ranibizumab products

See complete instructions for implant initial fill and ocular refill-exchange procedure in the prescribing information

Following procedures must be performed under aseptic conditions

• Initial fill and ocular implant insertion and implant removal procedures by a physician experienced in vitreoretinal surgery
• Ocular implant must be surgically implanted in the eye or removed from the eye (if medically necessary) in an operating room
• Refill-exchange procedures by a physician experienced in ophthalmic surgery

Handling

Do not reprocess, resterilize, or reuse

Do not use if sterility has been compromised or contents have been dropped, damaged, or tampered with

Do not use past expiration date printed on label

Do not open sealed tray until time of use

Avoid contact between sharp surgical instruments and implant

Storage

Initial needle kit

• Refrigerate at 2-8ºC (36-46ºF)
• Do not freeze
• Protect from light
• Do NOT shake
• Initial fill needle has been sterilized with electron beam processing

Unused vials

• Refrigerate at 2-8ºC (36-46ºF)
• Do not freeze
• Protect from light
• Do NOT shake
• Before use, may be kept at 9-30ºC (48-86ºF) for up to 24 hr provided it is protected from light

Implant, insertion tool assembly, refill needle, and explant tool

• Store at room temperature 15-25ºC (59-77ºF)
• Implant and insertion tool assembly has been sterilized with ethylene oxide gas
• Refill needle and explant tool have been sterilized with electron beam processing