LUCENTIS™ (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A). Ranibizumab has a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product.

LUCENTIS is a sterile, colorless to pale yellow solution in a single-use glass vial. LUCENTIS is supplied as a preservative-free, sterile solution in a single-use glass vial designed to deliver 0.05 mL of 10 mg/mL LUCENTIS aqueous solution with 10 mM histidine HCl, 10%, -trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.

LUCENTIS is indicated for the treatment of patients with neovascular (wet) age-related macular degeneration.

FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.

LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by intravitreal injection once a month.

Although less effective, treatment may be reduced to one injection every three months after the first four injections if monthly injections are not feasible. Compared to continued monthly dosing, dosing every 3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months. Patients should be evaluated regularly [see CLINICAL STUDIES].

Using aseptic technique, all (0.2 mL) of the LUCENTIS vial contents are withdrawn through a 5-micron 19-gauge filter needle attached to a 1-cc tuberculin syringe. 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. The contents should be expelled until the plunger tip is aligned with the line that marks 0.05 mL on the syringe.

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.

Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven days following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay. 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, and injection needles should be changed before LUCENTIS 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).

LUCENTIS should be refrigerated at 2°-8°C (36°-46°F). DO NOT FREEZE. Do not use beyond the date stamped on the label. LUCENTIS vials should be protected from light. Store in the original carton until time of use.

DOSAGE FORMS AND STRENGTHS

Single-use glass vial designed to deliver 0.05 mL of 10 mg/mL.

STORAGE AND HANDLING

Each LUCENTIS carton, NDC 50242-080-01, contains one 2-cc glass vial of ranibizumab, one 5-micron, 19-gauge 1-1/2-inch filter needle for withdrawal of the vial contents, one 30-gauge 1/2-inch injection needle for the intravitreal injection, and one package insert [see DOSAGE AND ADMINISTRATION ]. VIALS ARE FOR SINGLE EYE USE ONLY.

Serious adverse events related to the injection procedure have occurred in <0.1% of intravitreal injections, including endophthalmitis [see WARNINGS AND PRECAUTIONS ], rhegmatogenous retinal detachments, and iatrogenic traumatic cataracts.

Other serious ocular adverse events observed among LUCENTIS-treated patients occurring in <2% of patients included intraocular inflammation and increased intraocular pressure [see WARNINGS AND PRECAUTIONS].

The available safety data include exposure to LUCENTIS in 874 patients with neovascular age-related macular degeneration in three double-masked, controlled studies with dosage regimens of 0.3 mg (375 patients) or 0.5 mg (379 patients) administered monthly by intravitreal injection (Studies 1 and 2) [see CLINICAL STUDIES ] and dosage regimens of 0.3 mg (59 patients) or 0.5 mg (61 patients) administered once a month for 3 consecutive doses followed by a dose administered once every 3 months (Study 3) [see CLINICAL STUDIES ].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.

Table 1 shows the most frequently reported ocular adverse events that were reported with LUCENTIS treatment. The ranges represent the maximum and minimum rates across all three studies for control, and across all three studies and both dose groups for LUCENTIS.

Clinical Trials Experience Non-Ocular Events

Table 2 shows the most frequently reported non-ocular adverse events with LUCENTIS treatment. The ranges represent the maximum and minimum rates across all three studies for control, and across all three studies and both dose groups for LUCENTIS.

The rate of arterial thromboembolic events in the three studies in the first year was 2.1% of patients (18 out of 874) in the combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS compared with 1.1% of patients (5 out of 441) in the control arms of the studies. In the second year of Study 1, the rate of arterial thromboembolic events was 3.0% of patients (14 out of 466) in the combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS compared with 3.2% of patients (7 out of 216) in the control arm [see WARNINGS AND PRECAUTIONS].

The pre-treatment incidence of immunoreactivity to LUCENTIS was 0%-3% across treatment groups. After monthly dosing with LUCENTIS for 12 to 24 months, low titers of antibodies to LUCENTIS were detected in approximately 1%-6% of patients. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to LUCENTIS in an electrochemiluminescence assay and are highly dependent on the sensitivity and specificity of the assay. The clinical significance of immunoreactivity to LUCENTIS is unclear at this time, although some patients with the highest levels of immunoreactivity were noted to have iritis or vitritis.

Drug interaction studies have not been conducted with LUCENTIS.

LUCENTIS intravitreal injection has been used adjunctively with verteporfin photodynamic therapy (PDT). Twelve of 105 (11%) patients developed serious intraocular inflammation; in 10 of the 12 patients, this occurred when LUCENTIS was administered 7 days (±2 days) after verteporfin PDT.

Intravitreal injections, including those with LUCENTIS, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique should always be used when administering LUCENTIS. In ddition, patients should be monitored during the week following the injection to permit early treatment should an infection occur [see DOSAGE AND ADMINISTRATION and Patient Counseling Information ].

Increases in intraocular pressure have been noted within 60 minutes of intravitreal injection with LUCENTIS. Therefore, intraocular pressure as well as the perfusion of the optic nerve head should be monitored and managed appropriately [see DOSAGE AND ADMINISTRATION ].

Although there was a low rate (<4%) of arterial thromboembolic events observed in the LUCENTIS clinical trials, there is a theoretical risk of arterial thromboembolic events following intravitreal use of inhibitors of VEGF [see ADVERSE REACTIONS ].

Pregnancy Category C. Animal reproduction studies have not been conducted with ranibizumab. It is also not known whether ranibizumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. LUCENTIS should be given to a pregnant woman only if clearly needed.

It is not known whether ranibizumab is excreted in human milk. Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when LUCENTIS is administered to a nursing woman.

The safety and effectiveness of LUCENTIS in pediatric patients has not been established.

In the controlled clinical studies, approximately 94% (822/879) of the patients randomized to treatment with LUCENTIS were ≥ 65 years of age and approximately 68% (601/879) were ≥ 75 years of age. No notable difference in treatment effect was seen with increasing age in any of the studies. Age did not have a significant effect on systemic exposure in a population pharmacokinetic analysis after correcting for creatinine clearance.

No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in patients with renal impairment. Sixty-eight percent of patients (136 of 200) in the population pharmacokinetic analysis had renal impairment (46.5% mild, 20% moderate, and 1.5% severe). Reduction in ranibizumab clearance is minimal in patients with renal impairment and is considered clinically insignificant. Dose adjustment is not expected to be needed for patients with renal impairment.

No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in patients with hepatic impairment. Dose adjustment is not expected to be needed for patients with hepatic dysfunction.

Intravitreal injections, including those with LUCENTIS, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique should always be used when administering LUCENTIS. In ddition, patients should be monitored during the week following the injection to permit early treatment should an infection occur [see DOSAGE AND ADMINISTRATION and Patient Counseling Information ].

Increases in intraocular pressure have been noted within 60 minutes of intravitreal injection with LUCENTIS. Therefore, intraocular pressure as well as the perfusion of the optic nerve head should be monitored and managed appropriately [see DOSAGE AND ADMINISTRATION ].

Although there was a low rate (<4%) of arterial thromboembolic events observed in the LUCENTIS clinical trials, there is a theoretical risk of arterial thromboembolic events following intravitreal use of inhibitors of VEGF [see ADVERSE REACTIONS ].

Pregnancy Category C. Animal reproduction studies have not been conducted with ranibizumab. It is also not known whether ranibizumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. LUCENTIS should be given to a pregnant woman only if clearly needed.

It is not known whether ranibizumab is excreted in human milk. Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when LUCENTIS is administered to a nursing woman.

The safety and effectiveness of LUCENTIS in pediatric patients has not been established.

In the controlled clinical studies, approximately 94% (822/879) of the patients randomized to treatment with LUCENTIS were ≥ 65 years of age and approximately 68% (601/879) were ≥ 75 years of age. No notable difference in treatment effect was seen with increasing age in any of the studies. Age did not have a significant effect on systemic exposure in a population pharmacokinetic analysis after correcting for creatinine clearance.

No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in patients with renal impairment. Sixty-eight percent of patients (136 of 200) in the population pharmacokinetic analysis had renal impairment (46.5% mild, 20% moderate, and 1.5% severe). Reduction in ranibizumab clearance is minimal in patients with renal impairment and is considered clinically insignificant. Dose adjustment is not expected to be needed for patients with renal impairment.

No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in patients with hepatic impairment. Dose adjustment is not expected to be needed for patients with hepatic dysfunction.

Planned initial single doses of ranibizumab injection 1.0 mg were associated with clinically significant intraocular inflammation in 2 of 2 patients injected. With an escalating regimen of doses beginning with initial doses of ranibizumab injection 0.3 mg, doses as high as 2.0 mg were tolerated in 15 of 20 patients.

LUCENTIS is contraindicated in patients with ocular or periocular infections.

LUCENTIS is contraindicated in patients with known hypersensitivity to ranibizumab or any of the excipients in LUCENTIS.

Ranibizumab binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF₁₁₀. VEGF-A has been shown to cause neovascularization and leakage in models of ocular angiogenesis and is thought to contribute to the progression of the neovascular form of age-related macular degeneration (AMD). The binding of ranibizumab 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.

Neovascular AMD is associated with foveal retinal thickening as assessed by optical coherence tomography (OCT) and leakage from CNV as assessed by fluorescein angiography.

In Study 3, foveal retinal thickness was assessed by OCT in 118/184 patients. OCT measurements were collected at baseline, Months 1, 2, 3, 5, 8, and 12. In patients treated with LUCENTIS, foveal retinal thickness decreased, on average, more than the sham group from baseline through Month 12. Retinal thickness decreased by Month 1 and decreased further at Month 3, on average. Foveal retinal thickness data did not provide information useful in influencing treatment decisions [see CLINICAL STUDIES ].

In patients treated with LUCENTIS, the area of vascular leakage, on average, decreased by Month 3 as assessed by fluorescein angiography. The area of vascular leakage for an individual patient was not correlated with visual acuity.

In animal studies, following intravitreal injection, ranibizumab was cleared from the vitreous with a half-life of approximately 3 days. After reaching a maximum at approximately 1 day, the serum concentration of ranibizumab declined in parallel with the vitreous concentration. In these animal studies, systemic exposure of ranibizumab is more than 2000-fold lower than in the vitreous.

In patients with neovascular AMD, following monthly intravitreal administration, maximum ranibizumab serum concentrations were low (0.3 ng/mL to 2.36 ng/mL). These levels were below the concentration of ranibizumab (11 ng/mL to 27 ng/mL) thought to be necessary to inhibit the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay. The maximum observed serum concentration was dose proportional over the dose range of 0.05 to 1.0 mg/eye. Based on a population pharmacokinetic analysis, maximum serum concentrations of 1.5 ng/mL are predicted to be reached at approximately 1 day after monthly intravitreal administration of LUCENTIS 0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the estimated average vitreous elimination half-life was approximately 9 days. Steady-state minimum concentration is predicted to be 0.22 ng/mL with a monthly dosing regimen. In humans, serum ranibizumab concentrations are predicted to be approximately 90, 000-fold lower than vitreal concentrations.

No carcinogenicity or mutagenicity data are available for ranibizumab injection in animals or humans.

No studies on the effects of ranibizumab on fertility have been conducted.

The safety and efficacy of LUCENTIS were assessed in three randomized, double-masked, sham- or active-controlled studies in patients with neovascular AMD. A total of 1323 patients (LUCENTIS 879, Control 444) were enrolled in the three studies.

In Study 1, patients with minimally classic or occult (without classic) CNV lesions received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections. Data are available through Month 24. Patients treated with LUCENTIS in Study 1 received a mean of 22 total treatments out of a possible 24 from Day 0 to Month 24.

In Study 2, patients with predominantly classic CNV lesions received one of the following: 1) monthly LUCENTIS 0.3 mg intravitreal injections and sham PDT; 2) monthly LUCENTIS 0.5 mg intravitreal injections and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Sham PDT (or active verteporfin PDT) was given with the initial LUCENTIS (or sham) intravitreal injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of leakage. Data are available through Month 12. Patients treated with LUCENTIS in Study 2 received a mean of 12 total treatments out of a possible 13 from Day 0 through Month 12.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all LUCENTIS-treated patients (approximately 95%) maintained their visual acuity. 34%-40% of LUCENTIS-treated patients experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months. The size of the lesion did not significantly affect the results. Detailed results are shown in the tables below.

Figure 1 : Mean Change in Visual Acuity from Baseline to Month 24 in Study 1 and to Month 12 in Study 2

Patients in the group treated with LUCENTIS had minimal observable CNV lesion growth, on average. At Month 12, the mean change in the total area of the CNV lesion was 0.1-0.3 DA for LUCENTIS versus 2.3-2.6 DA for the control arms. The use of LUCENTIS beyond 24 months has not been studied.

Study 3 was a randomized, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of LUCENTIS in patients with neovascular AMD (with or without a classic CNV component). Data are available through Month 12. Patients received LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months. A total of 184 patients were enrolled in this study (LUCENTIS 0.3 mg, 60; LUCENTIS 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study. Patients treated with LUCENTIS in Study 3 received a mean of 6 total treatments out of possible 6 from Day 0 through Month 12. In Study 3, the primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline (see Figure 2). After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every three months with LUCENTIS lost visual acuity, returning to baseline at Month 12. In Study 3, almost all LUCENTIS-treated patients (90%) maintained their visual acuity at Month 12.

PATIENT COUNSELING INFORMATION

In the days following LUCENTIS administration, patients are at risk of developing endophthalmitis. If the eye becomes red, sensitive to light, painful, or develops a change in vision, the patient should seek immediate care from an ophthalmologist [see WARNINGS AND PRECAUTIONS].

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

RANIBIZUMAB - INTRAOCULAR

(ra-ni-BIZ-oo-mab)

COMMON BRAND NAME(S): Lucentis

USES: This medication is used to treat a certain serious eye condition (age-related macular degeneration). It is used to help prevent decreased vision and blindness. Ranibizumab works by slowing the growth of abnormal new blood vessels in the eye and decreasing leakage from these blood vessels.

HOW TO USE: This medication is given by injection into the affected eye(s) by a health care professional. The affected eye is numbed before each injection. After the injection, you will remain in the doctor's office for a while, and your eye will be monitored.

Dosage is based on your medical condition and response to treatment. This medication is usually given once a month or as directed by your doctor. If you are not able to have monthly injections, your doctor may change your schedule after the first few injections to once every 3 months.

Use this medication regularly to get the most benefit from it.

Tell your doctor if your condition does not improve or if it worsens.

SIDE EFFECTS: Mild discomfort and increased tears may occur in the affected eye(s). If either of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication may infrequently increase your risk for developing a certain serious eye condition (endophthalmitis), especially during the first week after receiving a dose. Tell your doctor immediately if you notice any of these symptoms in the affected eye(s): pain, redness, sensitivity to light, sudden change in vision.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of tongue/lips/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before receiving ranibizumab, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have a certain medical condition. Before using this medicine, consult your doctor or pharmacist if you have: a current eye infection.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. However, this medication is unlikely to pass into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: products applied to the eye (e.g., eyedrops).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: This medication may be harmful if swallowed. If swallowing or overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Your doctor will schedule periodic eye exams to monitor your progress and check for side effects.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule.

STORAGE: Store this product in the original package in the refrigerator between 36-46 degrees F (2-8 degrees C) away from light. Do not freeze. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.