The implant has been associated with a 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab. Many of these events were associated with conjunctival retractions or erosions. Appropriate conjunctiva management and early detection with surgical repair of conjunctival retractions or erosion may reduce the risk of endophthalmitis. In clinical trials, 2% of patients receiving an implant experienced at least 1 episode of endophthalmitis.
Note: In the United States, Byooviz (ranibizumab-nuna) and Cimerli (ranibizumab-eqrn) are approved as biosimilars to Lucentis (ranibizumab). In Canada, Byooviz is approved as a biosimilar to Lucentis; refer to the Canadian product monograph for biosimilar-specific labeled indications. Initial and follow-up visits to assess clinical outcomes should occur every ~4 weeks with an experienced ophthalmology team (Ref).
Age-related macular degeneration, neovascular (wet):
Lucentis and ranibizumab biosimilars: Intravitreal (injection): 0.5 mg once a month (approximately every 28 days). After 3 or 4 consecutive monthly doses, dosing interval may be extended (eg, once every 3 months or once monthly as needed based on response) with regular assessment (ie, "treat and extend" strategy); "treat and extend" strategies should only be done under the supervision of an experienced ophthalmology team (Ref).
Note: A regimen averaging 4 to 5 doses over 9 months is expected to maintain visual acuity and an every-3-month dosing regimen has reportedly resulted in a ~5 letter (1 line) loss of visual acuity over 9 months, as compared to monthly dosing which may result in an additional ~1 to 2 letter gain.
Susvimo: Intravitreal (implant): 2 mg (0.02 mL of 100 mg/mL solution) delivered continuously with refills administered every 24 weeks (approximately every 6 months). Supplemental intravitreal injections (Lucentis) of 0.5 mg (0.05 mL of 10 mg/mL solution) may be administered to the affected eye while implant is in place, if needed.
Missed refill exchange: Administer as soon as possible and perform subsequent refills 24 weeks (~6 months) thereafter.
Diabetic macular edema: Lucentis and Cimerli only: Intravitreal (injection): 0.3 mg once a month (approximately every 28 days); in clinical trials, monthly doses of 0.5 mg were also studied (Ref). After 3 consecutive monthly doses (if using the 0.5 mg dose), dosing interval may be extended (eg, by 2 to 4 weeks) based on response with regular assessment (ie, "treat and extend" strategy); "treat and extend" strategies should only be done under the supervision of an experienced ophthalmology team (Ref).
Diabetic retinopathy: Lucentis and Cimerli only: Intravitreal (injection): 0.3 mg once a month (approximately every 28 days).
Macular edema following retinal vein occlusion: Lucentis and ranibizumab biosimilars: Intravitreal (injection): 0.5 mg once a month (approximately every 28 days). After 3 consecutive monthly doses, dosing interval may be extended based on response with regular assessment (ie, "treat and extend" strategy) (Ref). "Treat and extend" strategies should only be done under the supervision of an experienced ophthalmology team (Ref).
Myopic choroidal neovascularization: Lucentis and ranibizumab biosimilars: Intravitreal (injection): 0.5 mg once a month (approximately every 28 days) for up to 3 months; may retreat if necessary.
No dosage adjustment necessary.
There are no dosage adjustments provided in the manufacturer's labeling. However, significant systemic exposure is not expected.
Implant (Susvimo): Refill-exchange modifications for adverse reactions:
Intraocular inflammation ≥1 plus cells or flare, infectious endophthalmitis, local infections of either eye, severe systemic infection, or sight-threatening events (eg, rhegmatogenous retinal detachment, unexplained vision loss, vitreous hemorrhage): Withhold refill-exchange.
Observed damage to the implant: Withhold refill-exchange and consider implant removal.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults receiving injection unless otherwise specified.
>10%:
Cardiovascular: Arterial thromboembolism (≤11%)
Hematologic & oncologic: Anemia (1% to 11%)
Immunologic: Antibody development (implant: 12%; injection: 1% to 9%)
Nervous system: Headache (implant: 7%; injection: 3% to 12%)
Neuromuscular & skeletal: Arthralgia (2% to 11%)
Ophthalmic: Blepharitis (3% to 12%), blurred vision (≤18%), cataract (2% to 28%), conjunctival hemorrhage (implant: 72%; injection: 47% to 74%), conjunctival hyperemia (implant: 26%; injection: 1% to 7%), dry eye syndrome (3% to 12%), eye irritation (7% to 15%), eye pain (implant: 10%; injection: 17% to 35%), eye pruritus (1% to 12%), foreign body sensation of eye (implant: 7%; injection: 7% to 16%), increased intraocular pressure (7% to 24%), increased lacrimation (2% to 14%), intraocular inflammation (1% to 18%), iritis (implant: 23%; including anterior chamber inflammation), maculopathy (5% to 11%), ocular hyperemia (5% to 11%), visual disturbance (≤18%), vitreous detachment (implant: 6%; injection: 4% to 21%), vitreous opacity (implant: 9%; injection: 7% to 27%)
Respiratory: Bronchitis (4% to 11%), nasopharyngitis (5% to 16%)
1% to 10%:
Cardiovascular: Atrial fibrillation (1% to 5%), peripheral edema (2% to 6%)
Endocrine & metabolic: Hypercholesterolemia (1% to 7%)
Gastrointestinal: Constipation (3% to 8%), gastroesophageal reflux disease (1% to 6%), nausea (1% to 10%)
Hypersensitivity: Seasonal allergy (2% to 8%)
Infection: Influenza (3% to 7%)
Local: Bleeding at injection site (1% to 5%)
Nervous system: Cerebrovascular accident (≤5%; including hemorrhagic stroke and ischemic stroke), peripheral neuropathy (1% to 5%)
Ophthalmic: Conjunctival abnormalities (conjunctival erosion or retraction; implant: ≤4%), conjunctival edema (implant: 5%), corneal abrasion (implant: 4%), corneal disease (implant: 4%), corneal edema (implant: 4%), encapsulated/cystic bleb (conjunctival; implant: ≤9%), endophthalmitis (implant: 2%), eye discomfort (2% to 7%), hypotony of eye (implant: 6%), inadvertent filtering bleb (conjunctival; implant: ≤9%), retinal degeneration (1% to 8%), retinopathy (2% to 10%), secondary cataract (2% to 7%), vitreous hemorrhage (implant: 5%)
Renal: Chronic renal failure (6%), renal failure syndrome (1% to 7%)
Respiratory: Chronic obstructive pulmonary disease (1% to 6%), cough (1% to 9%), sinusitis (3% to 8%), upper respiratory tract infection (2% to 9%)
Miscellaneous: Wound healing impairment (1%)
Frequency not defined (all formulations): Ophthalmic: Decreased visual acuity, rhegmatogenous retinal detachment
Postmarketing (all formulations): Ophthalmic: Retinal pigment epithelium tear
Hypersensitivity to ranibizumab or any component of the formulation; ocular or periocular infection; active intraocular inflammation (implant only).
Canadian labeling: Additional contraindications (not in the US labeling): Intravitreal injection: Active intraocular inflammation.
Concerns related to adverse effects:
• Conjunctival effects: Implant: Conjunctival bleb, erosion, and retraction have occurred and may lead to endophthalmitis; surgical intervention may be needed. Ensure appropriate intraoperative handling of the conjunctiva and Tenon’s capsule during implantation.
• Endophthalmitis/retinal detachment: Intravitreous injections and implants may be associated with endophthalmitis and retinal detachments, resulting in vision loss. Proper aseptic injection techniques should be used. Areas of abnormal vitreo-retinal adhesion or retinal breaks should be treated prior to inserting the implant. Patients should be monitored for potential infection and report any signs of infection (eg, eye pain or redness, photophobia, blurred vision) immediately; early detection and prompt treatment should occur.
• Hypersensitivity reactions: Hypersensitivity may present as severe intraocular inflammation; instruct patients to report intraocular inflammation that increases with severity. Rare hypersensitivity reactions (including anaphylaxis) have been associated with another vascular endothelial growth factor (VEGF) inhibitor, pegaptanib, occurring within several hours of use; monitor closely. Equipment and appropriate personnel should be available for monitoring and treatment of anaphylaxis.
• Increased intraocular pressure: Prior to and following intravitreal injection, intraocular pressure may increase. Onset is seen within 60 minutes postinjection. Monitor intraocular pressure before and after injection and manage accordingly.
• Septum dislodgement: Implant: Implant damage where the septum has dislodged into the implant body has been reported. Use appropriate handling (avoiding twisting and/or rotation) and insertion of the refill needle into the septum to minimize risk. Discontinue treatment if septum dislodgement occurs and consider implant removal if the benefits outweigh the risks.
• Thromboembolic events: Risk of thromboembolic events, particularly stroke, may be increased following intravitreal administration of VEGF inhibitors. Use caution in patients with known risk factors (eg, history of stroke, TIA).
• Visual acuity: Implant: A decrease in visual acuity on average of 4 letters in the first month and 2 letters in the second month was observed postoperatively following initial implantation.
• Vitreous hemorrhage: Implant: Vitreous hemorrhages resulting in vision loss and requiring vitrectomy may occur. Most cases occurred within the first month postoperatively and many resolved spontaneously. Risk may be increased in patients on antithrombotic therapy; temporarily withhold antithrombotic medications prior to implantation.
Disease-related concerns:
• Diabetic macular edema and diabetic retinopathy: Pooled analysis of trials involving patients with diabetic macular edema and diabetic retinopathy revealed a higher incidence of fatal events in patients treated with ranibizumab compared to control (3% in patients treated with 0.3 mg in the first 2 years compared to 1% in the control). Overall, the incidence of fatalities was consistent with deaths normally observed in patients with advanced diabetic complications; however, a potential association between fatal events and intravitreal administration of VEGF inhibitors cannot be excluded.
Dosage form specific:
• Implant: Appropriate use: For intravitreal use via surgical ocular implant only by a health care provider experienced in vitreoretinal surgery; do not administer as a bolus intravitreal injection. Minimize air bubbles within the implant reservoir. Do not use implant if air bubbles greater than one-third of the widest diameter of the implant are present during initial fill or excess air is present after initial fill; discard syringe and needle if excess air is present in the syringe and needle during refill-exchange procedure; if excess air is present after the refill-exchange, consider repeating procedure. If implant becomes dislocated, immediate surgical intervention is necessary; adhering to the scleral incision length and appropriate targeting of the pars plana during laser ablation may reduce the risk of dislocation. Use caution when performing ophthalmic procedures (eg, B-scan ophthalmic ultrasound, gonioscopy, scleral depression) that may cause deflection of the implant resulting in injury.
• Interchangeability: The implant vial is not interchangeable with other ranibizumab products.
Other warnings/precautions:
• MRI: The implant is considered magnetic resonance conditional. Instruct patient to inform health care provider and show implant card prior to MRI.
Systemic absorption with subsequent suppression of systemic vascular endothelial growth factor (VEGF) concentrations after intravitreal VEGF inhibitor administration has been reported (Hoerster 2013; Sato 2012; Wu 2017). Ranibizumab has been associated with less systemic VEGF suppression as compared to bevacizumab (Hoerster 2013; Wu 2017). Short- and long-term implications of systemic exposure are unknown; monitoring is recommended.
Ocular complications following intravitreal ranibizumab in preterm neonates with retinopathy of prematurity have been reported; complications described include cataract formation and endophthalmitis. Cataract formation was reported in a retrospective review and a randomized, open-label study (Chan 2016; Stahl 2019). In the retrospective review, 1 patient developed a cataract following injection 0.5 mm post-limbus; all other patients received injection 1 mm post-limbus with no additional cataract formation (Chan 2016). Endophthalmitis and an orbital infection developed 6 days after intravitreal ranibizumab in a patient who was treated for conjunctivitis and a staphylococcal periocular infection 11 days prior to ranibizumab with complete resolution; in addition the patient received prophylactic topical antibiotics 3 days immediately prior to ranibizumab; the authors concluded that preceding periocular infection should exclude neonates from receiving intravitreal ranibizumab (Stahl 2019).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravitreal:
Cimerli: Ranibizumab-eqrn 0.3 mg/0.05 mL (6 mg/mL) (0.05 mL); Ranibizumab-eqrn 0.5 mg/0.05 mL (10 mg/mL) (0.05 mL)
Solution, Intravitreal [preservative free]:
Byooviz: Ranibizumab-nuna 0.5 mg/ 0.05 mL (0.05 mL)
Lucentis: 0.3 mg/0.05 mL (0.05 mL [DSC]); 0.5 mg/0.05 mL (0.05 mL [DSC])
Susvimo (Implant 1st Fill): 10 mg/0.1 mL (0.1 mL)
Susvimo (Implant Refill): 10 mg/0.1 mL (0.1 mL)
Solution Prefilled Syringe, Intravitreal [preservative free]:
Lucentis: 0.3 mg/0.05 mL (0.05 mL); 0.5 mg/0.05 mL (0.05 mL)
No
Solution (Byooviz Intravitreal)
0.5 mg/0.05 mL (per 0.05 mL): $1,356.00
Solution (Cimerli Intravitreal)
0.3 mg/0.05 mL (per 0.05 mL): $979.20
0.5 mg/0.05 mL (per 0.05 mL): $1,632.00
Solution (Susvimo (Implant 1st Fill) Intravitreal)
10MG/0.1ML (per 0.1 mL): $9,600.00
Solution (Susvimo (Implant Refill) Intravitreal)
10MG/0.1ML (per 0.1 mL): $9,600.00
Solution Prefilled Syringe (Lucentis Intravitreal)
0.3 mg/0.05 mL (per 0.05 mL): $1,404.00
0.5 mg/0.05 mL (per 0.05 mL): $2,340.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravitreal:
Byooviz: 2.3 mg/0.23 mL (0.23 mL)
Lucentis: 2.3 mg/0.23 mL (0.23 mL)
Solution Prefilled Syringe, Intravitreal:
Lucentis: 1.65 mg/0.165 mL (0.165 mL)
Intravitreal:
Implant (Susvimo): For intravitreal use via surgical ocular implant only by a health care provider experienced in vitreoretinal surgery; do not administer as a bolus intravitreal injection. Do not shake. Adequate anesthesia and a topical broad-spectrum antimicrobial agent should be administered prior to the procedure. Implant should be filled aseptically with ranibizumab (over 5 to 10 seconds) immediately prior to insertion; no more than 30 minutes should pass between initial fill and surgical insertion. Refer to the complete instructions included in the insertion tool assembly carton for the initial fill, implant procedure, refill exchange, and proper removal. After insertion, instruct patient to keep head above shoulder for the rest of the day; sleep with head on 3 or more pillows during the day and the night after surgery; do not remove eye shield until instructed to do so by health care provider; wear eye shield at bedtime for at least 7 days following implant insertion; do not push on the eye, rub the eye, or touch the area of the eye where the implant is inserted for 30 days following surgery; and do not participate in strenuous activities until 1 month after implant insertion.
Injection (prefilled syringe [Lucentis], vial [Lucentis and ranibizumab biosimilars]): For ophthalmic intravitreal injection only. Each vial or prefilled syringe should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial or prefilled syringe should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before ranibizumab is administered to the other eye. Adequate anesthesia and a topical broad-spectrum antimicrobial agent should be administered prior to the procedure. Refer to manufacturer's labeling for additional detailed information.
Ophthalmic: For intravitreal injection only; injection of undiluted ranibizumab solution using a 30 gauge, 1/2-inch needle should be performed by an experienced and qualified ophthalmologist (Huang 2017; Kang 2018; Wu 2017; Zhang 2017; Lucentis European Medicines Agency 2020). Ranibizumab prefilled syringes do not allow measurement of doses smaller than 0.3 mg and 0.5 mg and therefore should not be used for treatment of neonates. Use a new vial and supplies for treatment of second eye, if indicated. Topical anesthetics and topical antiseptics (eg, povidone-iodine, 5% Betadine) were administered to neonates undergoing retinopathy of prematurity treatment; some studies also administered topical antibiotics ranging from 1 dose to 7 days following ranibizumab injection (Chan 2016; Huang 2017; Kang 2018; Wu 2017; Zhang 2017).
Diabetic macular edema (Lucentis and Cimerli only): Treatment of diabetic macular edema.
Diabetic retinopathy (Lucentis and Cimerli only): Treatment of diabetic retinopathy.
Macular degeneration:
Lucentis and ranibizumab biosimilars: Treatment of neovascular (wet) age-related macular degeneration (AMD).
Susvimo: Treatment of neovascular (wet) AMD in patients who have previously responded to at least 2 intravitreal injections of a vascular endothelial growth factor inhibitor medication.
Macular edema (Lucentis and ranibizumab biosimilars): Treatment of macular edema following retinal vein occlusion.
Myopic choroidal neovascularization (Lucentis and ranibizumab biosimilars): Treatment of myopic choroidal neovascularization.
Note: In the United States, Byooviz (ranibizumab-nuna) and Cimerli (ranibizumab-eqrn) are approved as biosimilars to Lucentis (ranibizumab). In Canada, Byooviz is approved as a biosimilar to Lucentis; refer to the Canadian product monograph for biosimilar-specific labeled indications.
Ranibizumab may be confused with bevacizumab, ramucirumab
Inhibits CYP2J2 (weak)
There are no known significant interactions.
Evaluate pregnancy status prior to use in patients who may become pregnant; confirm the patient is not pregnant prior to starting treatment. Patients who can become pregnant should use effective contraception prior to the initial dose, during treatment, and for at least 3 months after the last monthly intravitreal injection (Naderan 2021; Peracha 2016) or at least 12 months after the last the 24-week implant.
Ranibizumab is a vascular endothelial growth factor (VEGF) inhibitor; VEGF is required to achieve and maintain normal pregnancies. Reports of intravitreal VEGF inhibitor use in pregnancy (Peracha 2016; Naderan 2021), and outcome data specific to use of ranibizumab in pregnancy are limited (Akkava 2019; Fossum 2018; Jouve 2015; Penčák 2022; Sakai 2022; Sarhianaki 2012). Based on studies in nonpregnant adults, VEGF inhibitors can alter systemic concentrations of VEGF and placental growth factor following intravitreal administration (Peracha 2016; Zehetner 2015). Until additional data are available, use during the first trimester should be avoided and use later in pregnancy should be based on patient specific risks versus benefits (Peracha 2016; Polizzi 2015).
Ranibizumab can be detected in breast milk (Juncal 2020).
Case reports have evaluated the presence of ranibizumab and VEGF-A concentrations in breast milk.
• Data related to the presence of ranibizumab in breast milk are available from 2 patients treated with intravitreal ranibizumab for myopic choroidal neovascularization (CNV). The first patient was 16 months postpartum and stopped breastfeeding prior to the dose; breast milk was not pumped outside of the study visits. The second patient was 1 month postpartum and continued breastfeeding during treatment. For both patients, breast milk was collected prior to and on days 1 through 7, then at intervals up to 28 days following the injection. Ranibizumab was detected in the breast milk of the patient who stopped breastfeeding on the third day after the injection (34.7 ng/mL), with concentrations increasing over time. VEGF-A concentrations decreased from 22.8 ng/mL at baseline to 12.3 ng/mL on day 1, with a further decrease to 4.9 ng/mL on day 28. The patient who continued breastfeeding regularly did not have detectable concentrations of ranibizumab in breast milk and VEGF-A concentrations did not change (Juncal 2020).
• VEGF-A breast milk concentrations were also measured in a lactating patient, 6 months postpartum, administered 4 intravitreal injections of ranibizumab 0.5 mg for idiopathic CNV. This patient stopped breastfeeding for 3 days after each treatment but expressed breast milk to maintain lactation. VEGF-A breast milk concentrations decreased within 6 to 12 hours after each injection, then increased to pre-injection concentrations within 24 hours. Ranibizumab concentrations were not evaluated (Huang 2022).
• Neither paper evaluated possible effects to a breastfed infant (Huang 2022; Juncal 2020).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Intraocular pressure (prior to and 30 minutes following injection via tonometry); consider checking for perfusion of the optic nerve head immediately following injection; signs of infection/inflammation (for first week following injection); retinal perfusion, endophthalmitis; visual acuity. Perform a dilated slit lamp exam and/or dilated indirect ophthalmoscopy to inspect the implant for dislodgement prior to and after the refill-exchange procedure. Monitor implant and tissue overlying the implant routinely for signs and symptoms of conjunctival blebs, conjunctival erosion, conjunctival retraction, endophthalmitis, implant dislocation, rhegmatogenous retinal detachment, and vitreous hemorrhage.
Ranibizumab is a recombinant humanized monoclonal antibody fragment which binds to and inhibits human vascular endothelial growth factor A (VEGF-A). Ranibizumab inhibits VEGF from binding to its receptors and thereby suppressing neovascularization and slowing vision loss.
Absorption: Low levels are detected in the serum following intravitreal injection.
Half-life elimination: Implant: ~25 weeks; vitreous: ~9 days.
Time to peak: Implant: 26 days (range: 1 to 89 days).
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