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.
Retinopathy of prematurity (ROP): Limited data available: Preterm infants: Intravitreal: 0.2 mg as a single intravitreal injection in the affected eye(s); dose may be repeated up to 2 times at minimum of 28-day intervals (Stahl 2019; Lucentis European Medicines Agency 2020). In a randomized open-label study, 2 doses of ranibizumab (0.1 mg vs 0.2 mg) and laser therapy were compared in preterm infants with ROP (zone I [stage 1+, 2+, 3, or 3+], zone II stage 3+, or aggressive posterior ROP) (total n=214; 0.2 mg group n=70; 0.1 mg group n=76; laser therapy n=68). Treatment success, defined as survival without active ROP, unfavorable structural outcomes, or need for alternate treatment, was higher in the ranibizumab 0.2 mg group compared to the laser therapy group (80% vs 66%), although it did not reach statistical significance. All groups included patients who experienced unfavorable structural outcomes with the most in the laser group (7 patients) and the fewest in the ranibizumab 0.2 mg group (1 patient). There was 1 case each of cataract formation and endophthalmitis reported in patients receiving ranibizumab; both were thought to be related to ranibizumab injection (Stahl 2019). Doses ranging from 0.1 to 0.3 mg have been reported in the literature (Huang 2017; Stahl 2018; Stahl 2019; Zhang 2017).
Note: Product selection: Ranibizumab is available in multiple concentrations (eg, in the US market: 10 mg/mL and 6 mg/mL). In most ROP trials, ranibizumab 10 mg/mL was used for doses ranging from 0.1 to 0.3 mg/dose, which equates to dose volumes of 0.01 to 0.03 mL/dose (Chan 2016; Huang 2017; Kang 2018; Stahl 2018; Wu 2017; Zhang 2017); only one study used ranibizumab 6 mg/mL for doses of 0.12 mg, which equates to 0.02 mL/dose (Stahl 2018); data are lacking for dose volumes >0.03 mL.
(For additional information see "Ranibizumab (including biosimilars): Drug information")
Note: In the United States, Byooviz (ranibizumab-nuna) is approved as a biosimilar to Lucentis (ranibizumab). 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 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 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.
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); 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
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravitreal:
Lucentis: 2.3 mg/0.23 mL (0.23 mL)
Solution Prefilled Syringe, Intravitreal:
Lucentis: 1.65 mg/0.165 mL (0.165 mL)
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).
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 [Byooviz, Lucentis]): 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.
Implant (Susvimo): Store initial fill needle kit at 2°C to 8°C (36°F to 46°F); do not freeze; protect from light. Store 100 mg/mL vial at 2°C to 8°C (36°F to 46°F); do not freeze; protect from light. Unopened vial may be stored at 9°C to 30°C (48°F to 86°F) for ≤24 hours if protected from light. Store implant, insertion tool assembly, refill needle, and explant tool at 15°C to 25°C (59°F to 77°F).
Prefilled syringe (Lucentis), vials (Byooviz, Lucentis): Store in original carton under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light. Do not freeze. Keep prefilled syringe in sealed tray until ready to use.
Treatment of diabetic macular edema, diabetic retinopathy, macular edema following retinal vein occlusion, myopic choroidal neovascularization, and neovascular age-related macular degeneration (All indications: FDA approved in adults); has also been used for retinopathy of prematurity.
Ranibizumab may be confused with bevacizumab, ramucirumab
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).
Inhibits CYP2J2 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Evaluate pregnancy status prior to use in patients who may become pregnant. 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), and data specific to use of ranibizumab in pregnancy, are limited (Akkava 2019; Fossum 2018; Jouve 2015; 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 information is 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).
Vital signs (eg, BP, heart rate, respiratory rate) throughout the procedure (Wu 2017); intraocular pressure (prior to and 30 minutes following injection); retinal artery or optic nerve perfusion (immediately following procedure) (Huang 2017; Wu 2017); signs and symptoms of infection or ocular inflammation; disease progression; consider short and long-term monitoring for sequelae of systemic absorption (Wu 2017).
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).
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 (Lucentis Intravitreal)
0.3 mg/0.05 mL (per 0.05 mL): $1,404.00
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
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