英文药名: Lucentis (Ranibizumab Injections)

中文药名: 兰尼单抗注射剂

药品介绍

FDA已批准Genentech公司的湿性老年性黄斑病变(age-related macular degeneration，简称AMD）治疗药Lucentis.
AMD是导致55岁以上人群失明的主要原因，据估计，全球共有2500万人遭受AMD的困扰。全球的AMD治疗药市值约达6亿美元。在最终阶段的试验中，Lucentis已显示出对这种疾病的疗效。
通过批准后，Lucentis将是第三个进入美国市场的AMD药，其他两种同类药物分别为诺华公司的Visudyne和辉瑞公司的Macugen。

Ranibizumab是首个每月用药1次,能够使90%湿性AMD患者保持视力的药物。
Ranibizumab是一种分子实体药物,含有一种活性物质,是FDA批准的第一个启用新格式处方药物包装说明书的药物,以便为医师和消费者提供简明的处方信息。
AMD可引起严重且不可逆的视力丧失,患者视网膜异常血管增生、渗出,最终影响中心视力,是55岁以上人群的主要致盲原因。湿性AMD占所有AMD的10%,大多数未经治疗的湿性AMD患者视功能受损,80%伴随的视力丧失归因于湿性AMD。
Ranibizumab具有阻止新生血管增生及渗出的作用。3项多中心、随机研究显示,眼内注射ranibizumab治疗AMD安全有效。患者每月接受1次眼内注射,共12个月,几乎95%患者的视力得以维持(其中1/3的患者视力改善),对照组约为60%。一项使用ranibizumab对患者进行24个月治疗的研究表明,患者视力仍保持稳定。
Ranibizumab最常见的不良事件包括结膜出血、眼痛、飞蚊症、眼内压升高及炎症。严重的副作用罕见,且常与注射操作有关,包括眼内炎、视网膜剥离、视网膜撕裂和外伤性白内障。

处方信息摘要
这些亮点不包括所有需要使用Lucentis的安全和有效的信息。查看完整的Lucentis的处方信息。
Lucentis的（兰尼）注射液，玻璃体使用的解决方案

美国初始认证：2006年
 
适应症
Lucentis的适应症是用于新生血管（湿）年龄相关性黄斑变性病人的治疗。
 
剂量和用法
眼科玻璃体腔内注射仅
Lucentis的0.5毫克（0.05毫升），则建议由每月一次眼内。
虽然效果较差，治疗可减少到一次注射后的第一个四，每三个月注射，如果每月注射是行不通的。相对于持续每月给药，给药每3个月，将导致大约5个字母（1线）视力利益的损失，平均在以下9个月。患者应定期评估。

剂型和优势
10毫克/在一个玻璃体内注射单用小瓶毫升溶液
 
禁忌
眼或眼周感染
超敏反应
 
警告部分
眼内炎和视网膜脱离玻璃体腔内注射后可能会发生。应监测患者在注射后的周。
眼内压力增加人们已经注意到，玻璃体内注射后60分钟。
 
不良反应
最常见的（报告≥6％，比对照组Lucentis的治疗的受试者高）不良reations是结膜出血，眼痛，玻璃体漂浮物，增加眼内压，眼内发炎

 HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use lucentis safely and effectively. See full prescribing information for lucentis.
lucentis (Ranibizumab)  injection, solution for intravitreal use
Initial U.S. Approval: 2006
 
INDICATIONS AND USAGE
LUCENTIS is indicated for the treatments of patients with neovascular (wet) age‑related macular degeneration ( 1).

DOSAGE AND ADMINISTRATION
FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY ( 2.1)
LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by intravitreal injection once a month ( 2.2).
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 ( 2.2).
 
DOSAGE FORMS AND STRENGTHS
10 mg/mL solution in a single-use vial for intravitreal injection ( 3)
 
CONTRAINDICATIONS
Ocular or periocular infections ( 4.1)
Hypersensitivity ( 4.2)
 
WARNINGS SECTION
Endophthalmitis and retinal detachments may occur following intravitreal injections. Patients should be monitored during the week following the injection ( 5.1).
Increases in intraocular pressure have been noted within 60 minutes of intravitreal injection ( 5.2).

ADVERSE REACTIONS
The most common adverse reations (reported ≥ 6% higher in LUCENTIS-treated subjects than control subjects) are conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation 
 
1. INDICATIONS AND USAGE

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

2. DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.

2.2 Dosing

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 (14.2)].

2.3 Preparation for Administration

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.

2.4 Administration

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 forendophthalmitis.  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).

3. Dosage Forms and Strengths

Single-use glass vial designed to provide 0.05 mL of 10 mg/mL solution for intravitreal injection.

4. CONTRAINDICATIONS

4.1 Ocular or Periocular Infections

LUCENTIS is contraindicated in patients with ocular or periocular infections.

4.2 Hypersensitivity

LUCENTIS is contraindicated in patients with known hypersensitivity to ranibizumab or any of the excipients in LUCENTIS. Hypersensitivity reactions may manifest as severe intraocular inflammation.

5. Warnings and Precautions

5.1 Endophthalmitis and Retinal Detachments

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 addition, patients should be monitored during the week following the injection to permit early treatment should an infection occur [see Dosage and Administration ( 2.3, 2.4) and Patient Counseling Information (17)].

5.2 Increases in Intraocular Pressure

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 (2.4)].

5.3 Thromboembolic events

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 (6.3)].

6. ADVERSE REACTIONS

6.1 Injection Procedure

Serious adverse reactions related to the injection procedure occurring in <0.1% of intravitreal injections included endophthalmitis [see Warnings and Precautions (5.1)], rhegmatogenous retinal detachments, and iatrogenic traumatic cataracts.

6.2 Clinical Studies Experience‑ Ocular Reactions

Other serious ocular adverse reactions observed among LUCENTIS‑treated patients occurring in <2% of patients included intraocular inflammation and increased intraocular pressure [see Warning and Precautions (5.1, 5.2)].

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) administrered monthly by intravitreal injection (Studies 1 and 2) [see Clinical Studies (14.1)], 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 (14.2)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one 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 reactions that were reported with LUCENTIS treatment, for which the point estimates were higher in the LUCENTIS group compared with the control group. 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.

Table 1

Adverse Reaction	LUCENTIS	Control
Conjunctival hemorrhage	77%–43%	66%–29%
Eye pain	37%–17%	33%–11%
Vitreous floaters	32%–3%	10%–3%
Intraocular pressure increased	24%–8%	7%–3%
Intraocular inflammation	18%–5%	11%–3%
Eye irritation	19%–4%	20%–6%
Cataract	16%–5%	16%–6%
Foreign body sensation in eyes	19%–6%	14%–6%
Lacrimation increased	17%–3%	16%–0%
Eye pruritis	13%–0%	12%–3%
Visual disturbance	14%–0%	9%–2%
Blepharitis	13%–3%	9%–4%
Ocular hyperemia	10%–5%	10%–1%
Maculopathy	10%–3%	11%–3%
Dry eye	10%–3%	8%–5%
Ocular discomfort	8%–0%	5%–0%
Conjunctival hyperemia	9%–0%	7%–0%
Posterior capsule opacification	8%–0%	5%–0%

6.3 Clinical Studies Experience‑ Non‑Ocular Reactions

Table 2 shows the most frequently reported non-ocular adverse reactions that were reported with LUCENTIS treatment, for which the point estimates were higher in the LUCENTIS group compared with the control group. 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.

Table 2

Adverse Reaction	LUCENTIS	Control
Hypertension/elevated blood pressure	23%–5%	23%–8%
Nasopharyngitis	16%–5%	13%–5%
Arthralgia	11%–3%	9%–0%
Headache	15%–2%	10%–3%
Bronchitis	10%–3%	8%–2%
Cough	10%–3%	7%–2%
Anemia	8%–3%	8%–0%
Nausea	9%–2%	6%–4%
Sinusitis	8%–2%	6%–4%
Influenza	10%–2%	5%–1%

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 (5.3)].

6.4 Immunogenicity

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.

7. Drug Interactions

Drug interaction studies have not been conducted with LUCENTIS.

LUCENTIS intravitreal injection has been used adjunctively with verteporfin photodynamic therepy (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.

8. Use in Specific Populations

8.1 Pregnancy

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

8.3 Nursing Mothers

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.

8.4 Pediatric Use

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

8.5 Geriatric Use

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.

8.6 Patients with Renal Impairment

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 a 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.

8.7 Patients with Hepatic Dysfunction

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 dysfuntion.

10. OVERDOSAGE

Planned initial single doses of ranibizumab injection 1.0 mg were associated with clinically significant intraocular inflammation in 2 of 2 patients injected.  However, 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.

11. DESCRIPTION

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% α,α‑trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Neovascular AMD is associated with foveal retinal thickening as assessed by optical coherence tomography (OCT) and leakage from choroidal neovascularization (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 (14.2)].

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.

12.3 Pharmacokinetics

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 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.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

14. CLINICAL STUDIES

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.

14.1 Study 1 and Study 2

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 treaments 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.

Table 3:  Outcomes at Month 12 and Month 24 in Study 1

Outcome Measure	Month	Sham n=238	LUCENTIS 0.5 mg n=240	Estimated Difference * (95% CI)
Adjusted estimate based on the stratified model. p < 0.01.
Loss of<15 letters in visual acuity (%)†	Month 12	62%	95%	32% (26%, 39%)
	Month 24	53%	90%	37% (29%, 44%)
Gain of≥15 letters in visual acuity (%)†	Month 12	5%	34%	29% (22%, 35%)
	Month 24	4%	33%	29% (23%, 35%)
Mean change in visual acuity(letters) (SD)†	Month 12	–10.5 (16.6)	+7.2 (14.4)	17.5 (14.8, 20.2)
	Month 24	–14.9 (18.7)	+6.6 (16.5)	21.1 (18.1, 24.2)

Table 4:  Outcomes at Month 12 in Study 2

Outcome Measure	Verteporfin PDT n=143	LUCENTIS 0.5 mg n=140	Estimated Difference * (95% CI)
* Adjusted estimate based on the stratified model. † p < 0.01.
Loss of <15 letters in visual acuity (%) †	64%	96%	33% (25%, 41%)
Gain of ≥15 letters in visual acuity (%) †	6%	40%	35% (26%, 44%)
Mean change in visual acuity(letters) (SD) †	–9.5 (16.4)	+11.3 (14.6)	21.1 (17.5, 24.6)

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.

14.2 Study 3

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 (seeFigure 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.

16. HOW SUPPLIED/STORAGE AND HANDLING

Each LUCENTIS carton, NDC 50242-080-01, contains a 0.2 mL fill of 10 mg/mL ranibizumab in a 2‑cc glass vial; 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 (2.4)]. VIALS ARE FOR SINGLE EYE USE ONLY.

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.

17. 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 Warning and Precautions (5.1)].