Ranibizumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravitreal [preservative free]:

Lucentis: 0.3 mg/0.05 mL (0.05 mL); 0.5 mg/0.05 mL (0.05 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)

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Absorption

Low levels are detected in the serum following intravitreal injection.

Half-Life Elimination

Vitreous: ~9 days

Use: Labeled Indications

Diabetic macular edema: Treatment of diabetic macular edema (DME).

Diabetic retinopathy: Treatment of diabetic retinopathy

Macular degeneration: Treatment of neovascular (wet) age-related macular degeneration (AMD)

Macular edema: Treatment of macular edema following retinal vein occlusion (RVO)

Myopic choroidal neovascularization: Treatment of myopic choroidal neovascularization (mCNV).

Contraindications

Hypersensitivity to ranibizumab or any component of the formulation; ocular or periocular infection

Canadian labeling: Additional contraindications (not in the US labeling): Active intraocular inflammation

Dosage and Administration

Dosing: Adult

Age-related macular degeneration (AMD), neovascular (wet): Intravitreal: 0.5 mg once a month (approximately every 28 days). Frequency may be reduced (eg, 4 to 5 injections over 9 months) after the first 3 injections or may be reduced after the first 4 injections to once every 3 months if monthly injections are not feasible.

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.

Diabetic macular edema (DME): Intravitreal: 0.3 mg once a month (approximately every 28 days); in clinical trials, monthly doses of 0.5 mg were also studied (Massin 2010; Mitchell 2011)

Diabetic retinopathy (DR): Intravitreal: 0.3 mg once a month (approximately every 28 days)

Macular edema following retinal vein occlusion (RVO): Intravitreal: 0.5 mg once a month (approximately every 28 days)

Myopic choroidal neovascularization (mCNV): Intravitreal: 0.5 mg once a month (approximately every 28 days) for up to 3 months; may retreat if necessary.

Dosing: Geriatric

Refer to adult dosing.

Reconstitution

Prefilled syringe: Syringe tray should be opened under sterile conditions. Snap off syringe cap (do not twist or turn) and attach 30 gauge ½ inch needle. Refer to manufacturer labeling for additional detailed information.

Vials: Remove contents from vial using a sterile 5 micron (19-gauge × 1¹/₂-inch) filter needle attached to a 1 mL sterile Luer lock syringe (with marking to measure 0.05 mL). Discard filter needle and replace with a sterile 30 gauge × ¹/₂ inch needle for injection (do not use filter needle for intravitreal injection). Refer to manufacturer labeling for additional detailed information.

Administration

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 labeling for additional detailed information.

Storage

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.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

As reported with AMD, RVO, and DME studies:

>10%:

Cardiovascular: Arterial thromboembolism (AMD trials during first year: 2%; DME trials at 3 years: 11%)

Central nervous system: Foreign body sensation of eye (7% to 16%), headache (6% to 12%)

Hematologic & oncologic: Anemia (4% to 11%)

Neuromuscular & skeletal: Arthralgia (2% to 11%)

Ophthalmic: Conjunctival hemorrhage (47% to 74%), eye pain (17% to 35%), vitreous opacity (7% to 27%), increased intraocular pressure (7% to 24%), blurred vision (5% to 18%), intraocular inflammation (1% to 18%)

Note: Cataract, blepharitis, dry eye syndrome, eye irritation, increased lacrimation, maculopathy, ocular hyperemia, eye pruritus, and vitreous detachment occurred in >10% of patients, but also occurred either in similar percentages to the control or more often in the control in some studies.

Respiratory: Nasopharyngitis (5% to 16%), bronchitis (6% to 11%)

1% to 10%:

Cardiovascular: Peripheral edema (6%), atrial fibrillation (1% to 5%), cerebrovascular accident (AMD trials during 2 years: 3%; DME trials at 3 years: 2%)

Central nervous system: Peripheral neuropathy (1% to 5%)

Endocrine & metabolic: Hypercholesterolemia (3% to 7%)

Gastrointestinal: Nausea (9% to 10%), constipation (8%), gastroesophageal reflux disease (1% to 6%)

Genitourinary: Chronic renal failure (6%)

Immunologic: Antibody formation (1% to 9%), seasonal allergy (8%)

Infection: Influenza (3% to 7%)

Local: Bleeding at injection site (1% to 5%)

Ophthalmic: Retinal degeneration (1% to 8%)

Note: Conjunctival hyperemia, eye discomfort, posterior capsule opacification, and retinopathy occurred in 1% to 10% of patients, but also occurred in similar percentages to the control or more often in the control in some of the studies.

Renal: Renal failure (7%)

Respiratory: Upper respiratory tract infection (9%), cough (5% to 9%), sinusitis (3% to 8%), chronic obstructive pulmonary disease (3% to 6%)

Miscellaneous: Wound healing impairment (1%)

All indications: <1%, postmarketing, and/or case reports: Anterior chamber inflammation, anxiety, back pain, corneal edema, corneal erosion, coronary artery occlusion, decreased visual acuity, dizziness, endophthalmitis, epithelial keratopathy, eye discharge (lid margin), eyelid pain, hypoglycemia, iatrogenic traumatic cataracts, intestinal obstruction, photophobia, retinal pigment epithelium tear, rhegmatogenous retinal detachment, rhinorrhea, urticaria

As reported with choroidal neovascularization secondary to pathologic myopia (not in US labeling):

>10%:

Ophthalmic: Conjunctival hemorrhage (11%)

Respiratory: Nasopharyngitis (11%)

1% to 10%:

Cardiovascular: Hypertension (3%)

Central nervous system: Headache (8%), migraine (2%)

Endocrine & metabolic: Diabetes mellitus (2%)

Gastrointestinal: Abdominal pain (3%), nausea (2%), toothache (2%), vomiting (2%)

Genitourinary: Urinary tract infection (3%), bacteriuria (2%)

Infection: Influenza (2%)

Local: Bleeding at injection site (4%)

Neuromuscular & skeletal: Back pain (2%), herniated disk (2%), limb pain (2%), osteoporosis (2%)

Ophthalmic: Punctate keratitis (8%), vitreous opacity (5%), dry eye syndrome (4%), eye pain (4%), increased intraocular pressure (3%), blepharitis (2%), conjunctivitis (2%), eyelid edema (2%), retinal hole without detachment (2%)

Respiratory: Upper respiratory tract infection (3%), pharyngitis (2%)

<1%: Allergic conjunctivitis, arthralgia, bronchitis, cataract, conjunctival edema, corneal erosion, cough, eye irritation, hepatic insufficiency, hypercholesterolemia, hypersensitivity, increased intracranial pressure, iridocyclitis, ocular hyperemia, pain at injection site, retinal hemorrhage, sciatica, tendonitis, uveitis, viral conjunctivitis (adenovirus), vitreous detachment

Warnings/Precautions

Concerns related to adverse effects:

• Endophthalmitis/retinal detachment: Intravitreous injections may be associated with endophthalmitis and retinal detachments. Proper aseptic injection techniques should be used. Patients should be monitored for potential infection and report any signs of infection (eg, eye pain or redness, photophobia, blurred vision) immediately.
• 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 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.
• 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).

Disease-related concerns:

• Diabetic macular edema (DME) and diabetic retinopathy (DR): Pooled analysis of trials involving DME and DR patients 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.

Monitoring Parameters

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.

Pregnancy

Pregnancy Considerations

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 information specific to use of ranibizumab in pregnancy, are limited (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; Zehtner 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).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience dry eyes, floater in the eye, or foreign body sensation in eye. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or tvision changes)signs of a heart attack (chest pain; pain in arms, back, neck, jaw, or abdomen; shortness of breath; cold sweats; severe dizziness; passing out; or severe nausea or vomiting), vision changes, eye pain, severe eye irritation, eyelid swelling, eye discharge, bleeding in eye, eye redness, or sensitivity to light (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.