英文药名: Lotemax Ophthalmic drops (Loteprednol)

中文药名: 洛替泼诺眼液
药品简介

【药理作用】
本品在眼睛局部给予后,迅速穿透角膜进入前房,转化成为它失活的代谢产物.因此本品不象其他皮质类固醇类药物那样,它的全身毒性很低,而有较强的局部抗炎作用.本品对丁香油引起的家兔角膜炎已被证明具有明显的抗炎活性,用1%的本品可减轻角膜白细胞浸润40.1±4.9%.本品因为能与眼内的糖皮质激素受体结合,故可容易地穿透角膜.它的作用强度大于地塞米松1.5倍.本品眼内的抗炎作用,对用脂多糖或弗氏佐剂造成眼色素层炎的两只家兔模型,用本品其抗炎作用虽然比氟美松弱一点,但能有效的减轻炎症.对另一个慢性眼色素层炎的模型,本品的效果与氟美松一样.另一项实验,在家兔的角膜上施行切开,发现本品对创伤愈合有促进作用. 其抗炎症和抗过敏作用至少与地塞米松一样有效并且形成的疤痕最轻.

【药代动力学】
本品局部应用于家兔眼中,可发现本品和它的代谢产物在结膜,角膜,房水和虹膜睫状体中,然而,本品在血浆中是未被变化的原形药物,浓度最高是在结膜和角膜中,然而,在角膜中代谢物的浓度超过了未变化的原形药物浓度.这意味着角膜是本品代谢生物转化的重要场所. 给犬静注本品5,终末半衰期为2.8小时;分布容量为3.71/;总清除率为0.91/(.虹).在静注给药后无原形药物出现在尿中. 而口服后,只有本品的代谢产物,发现在血浆中.这反应了本品的高首过代谢.在体外血浆结合大于90%.给大鼠服标记的本品和它的代谢产物浓度最高在肝脏和肾脏, 在肺,脑和心脏最低.

【适应症】
季节性,过敏性结合膜炎.

【用法用量】
用.5%的本品混悬液点眼,每天4次.

【临床评价】在12例健康志愿者中进行. 用0.5%本品点眼,每6小时1次,连续28天.未见类固醇类常见的眼内压升高的不良反应.一项随机,双盲,安慰剂对照试验在6例过敏性结合膜炎患者中进行,以含本品0.5%溶液点一只眼,另一只眼用安慰剂.都是1日2次或每日4次,连续28天.发现用本品的红肿明显减轻.另一项类似的试验,在9例患者中进行.用本品(0.1%,0.2%或.3%)点一只眼,用安慰剂点另一只眼.每日4次.发现本品治疗眼红肿明显减轻.并发现用本品浓度0.2%者更为有效.在一项试验中,35例季节性过敏性结膜炎患者随机用本品(02%)或安慰剂每日点眼4次.本品眼球注射两周后治愈率为36%;安慰剂为15%;本品痒感治愈率为58%,安慰剂为38%.说明本品治疗季节性过敏性结膜炎是有效的,并且其安全性与安慰剂相似.在另一项37例因接触性镜刺激引起的巨乳头状结膜炎随机,双盲与安慰剂比较(本品组用05%的本品混悬液),1日4次点眼,连用28天.本品组比安慰剂组明显的改善.而眼内压两组都无变化.

【注意事项】
本品属新型皮质激素类药物,在临床试验中虽未见明显的不良反应,仍应注意观察.
药品中文名称  氯替泼诺混悬滴眼液 

药品名称说明  
药品英文名称  Loteprednol Etabonate Ophthalmic Suspension 
药品中文商品名  露达舒 
药品英文商品名  Lotemax 
中文剂型  滴眼液 
英文剂型  
药品规格  1ml：5mg(0.5%) 
包装规格  2.5ml/瓶；5ml/瓶 
注册证号  H20070003 
原注册证号  
注册证号说明  
分包装文号  
公司中文名称  
公司英文名称  Bausch & Lomb Incorporated 
公司中文地址  
公司英文地址  8500 Hidden River Parkway,Tampa,Florida 33637,USA 
公司中文国别  美国 
公司英文国别  U.S.A. 
生产厂商中文名  
生产厂商英文名  Bausch & Lomb Incorporated 
生产厂国内地址  
生产厂国内地址  8500 Hidden River Parkway,Tampa,Florida 33637,USA 
生产厂中文国别  美国 
生产厂英文国别  U.S.A. 
批准日期  2007-01-10 
注册证效期  2012-01-09 
分包装企业  
分包装地址  
分包批准日  
分包截止日  
产品类别  化学药品 
分包装企业国别  
药品分类  
注册分类  化学药品3.1 
修改时间  2007-09-24 10:42:26

LASEK术后应用露达舒对眼压变化的临床观察
目的:观察准分子激光原位角膜磨镶术(laser epithelial keratomileusis, LASEK)术后露达舒的临床疗效.方法:对200例患者行LASEK手术,分为A组100例200眼术后点用典必殊滴眼液1wk,B组100例200眼术后点用露达舒滴眼液联合托百士滴眼液1wk,术后定期对眼部症状、视力、屈光度、角膜厚度、眼压进行随访观察.结果:A组用药后高眼压12眼(6.0%).B组用药后高眼压3眼(1.5%).两组对照比较P<0.05,有显著差异,点用露达舒滴眼液组眼压增高发病率明显降低.结论:露达舒在LASEK术后应用是安全有效的.

HIGHLIGHTS OF PRESCRIBING I

NFORMATION
These highlights do not include all the information needed to use Lotemax® ointment safely and effectively. See full prescribing information for Lotemax (loteprednol etabonate ophthalmic ointment) 0.5%.
Initial U.S. Approval: 1998
 
INDICATIONS AND USAGE
LOTEMAX ointment is a corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery.
DOSAGE AND ADMINISTRATION
Apply a small amount (approximately ½ inch ribbon) into the conjunctival sac(s) four times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the post-operative period.
 
DOSAGE FORMS AND STRENGTHS
3.5 gram tube filled with loteprednol etabonate ophthalmic ointment, 0.5%
 
CONTRAINDICATIONS
LOTEMAX ointment, as with other ophthalmic corticosteroids, is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. (4)
 
WARNINGS AND PRECAUTIONS
•Intraocular pressure (IOP) increase–Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. If this product is used for 10 days or longer, IOP should be monitored even though it may be difficult in children and uncooperative patients. (5.1)
•Cataracts–Use of corticosteroids may result in posterior subcapsular cataract formation. (5.2)
•Delayed healing–The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. (5.3)
•Bacterial infections–Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. (5.4)
•Viral infections–Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). (5.5)
•Fungal infections–Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. (5.6)
 
ADVERSE REACTIONS
The most common ocular adverse event, reported in approximately 25% of subjects in clinical studies, is anterior chamber inflammation. Other common adverse events, with an incidence of 4-5%, are conjunctival hyperemia, corneal edema, and eye pain. (6)

See 17 for PATIENT COUNSELING INFORMATION 

Revised: 04/2011

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

LOTEMAX® ointment is a corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery.

2 DOSAGE AND ADMINISTRATION

Apply a small amount (approximately ½ inch ribbon) into the conjunctival sac(s) four times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the post-operative period.

3 DOSAGE FORMS AND STRENGTHS

LOTEMAX is supplied sterile in a 3.5 gram tube filled with loteprednol etabonate ophthalmic ointment, 0.5%.

4 CONTRAINDICATIONS

LOTEMAX ointment, as with other ophthalmic corticosteroids, is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures.

5 WARNINGS AND PRECAUTIONS

5.1 Intraocular pressure (IOP) increase

Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. If this product is used for 10 days or longer, IOP should be monitored even though it may be difficult in children and uncooperative patients.

5.2 Cataracts

Use of corticosteroids may result in posterior subcapsular cataract formation.

5.3 Delayed healing

The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids.

The initial prescription and renewal of the medication order beyond 14 days should be made by a physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.

5.4 Bacterial infections

Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated.

5.5 Viral infections

Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex).

5.6 Fungal infections

Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal culture should be taken when appropriate.

5.7 Contact Lens Wear

Patients should not wear contact lenses during their course of therapy with LOTEMAX ointment.

5.8 Amblyopia

LOTEMAX (loteprednol etabonate ophthalmic ointment), 0.5% should not be used in children following ocular surgery.  Its use may interfere with amblyopia treatment by hindering the child’s ability to see out of the operated eye (see Pediatric Use, 8.4).

5.9 Topical ophthalmic use only

Lotemax is not indicated for intraocular administration.

6 ADVERSE REACTIONS

Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.

The most common ocular adverse event reported at approximately 25% in subjects in clinical studies with Lotemax ointment was anterior chamber inflammation. Other common adverse events, with an incidence of 4-5%, were conjunctival hyperemia, corneal edema, and eye pain. Many of these events may have been the consequence of the surgical procedure. The only non-ocular adverse event occurring at ≥ 1% was headache (1.5%).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic effects: Pregnancy Category C. Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, abnormal left common carotid artery, and limb flexures) when administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (150 times the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day (25 times the maximum daily clinical dose). Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate artery at ≥ 5 mg/kg/day doses, and cleft palate and umbilical hernia at ≥ 50 mg/kg/day) and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥ 50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day (25 times the maximum daily clinical dose) during organogenesis did not result in any reproductive toxicity. Loteprednol etabonate was maternally toxic (significantly reduced body weight gain during treatment) when administered to pregnant rats during organogenesis at doses of ≥ 5 mg/kg/day.

Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from the start of the fetal period through the end of lactation, a maternally toxic treatment regimen (significantly decreased body weight gain), gave rise to decreased growth and survival, and retarded development in the offspring during lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol etabonate had no effect on the duration of gestation or parturition when administered orally to pregnant rats at doses up to 50 mg/kg/day during the fetal period.

LOTEMAX should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

8.3 Nursing Mothers

It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when LOTEMAX ointment is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

LOTEMAX (loteprednol etabonate ophthalmic ointment) 0.5% should not be used in children following ocular surgery.  Its use may interfere with amblyopia treatment by hindering the child’s ability to see out of the operated eye.

8.5 Geriatric Use

No overall differences in safety and effectiveness have been observed between elderly and younger patients.

11 DESCRIPTION

LOTEMAX (loteprednol etabonate ophthalmic ointment) 0.5% is a sterile, topical corticosteroid for ophthalmic use. Loteprednol etabonate is a white to off-white powder.

Loteprednol etabonate is represented by the following structural formula:

Chemical Name:

chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate

Each gram contains:

ACTIVE: Loteprednol Etabonate 5 mg (0.5%);

INACTIVES: Mineral Oil and White Petrolatum.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism Of Action

Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. While glucocorticoids are known to bind to and activate the glucocorticoid receptor, the molecular mechanisms involved in glucocorticoid/glucocorticoid receptor-dependent modulation of inflammation are not clearly established. However, corticosteroids are thought to inhibit prostaglandin production through several independent mechanisms.

12.3 Pharmacokinetics

The systemic exposure to loteprednol etabonate following ocular administration of LOTEMAX ointment has not been studied in humans. However, results from a bioavailability study with LOTEMAX suspension in normal volunteers established that plasma concentrations of loteprednol etabonate and Δ¹ cortienic acid etabonate (PJ 91), its primary, inactive metabolite, were below the limit of quantitation (1 ng/mL) at all sampling times. The results were obtained following the ocular administration of one drop in each eye of 0.5% loteprednol etabonate suspension, 8 times daily for 2 days or 4 times daily for 42 days. The maximum systemic exposure to loteprednol following administration of the ointment product dosed four times daily is not expected to exceed exposures attained with LOTEMAX suspension dosed up to two drops four times daily.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay. Treatment of male and female rats with up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (2500 and 1250 times the maximum daily clinical dose, respectively) prior to and during mating did not impair fertility in either gender.

14 CLINICAL STUDIES

In two independent, randomized, multicenter, double-masked, parallel-group, vehicle-controlled studies in 805 subjects meeting a protocol-specified threshold amount of anterior chamber inflammation, LOTEMAX ointment was more effective compared to its vehicle for complete resolution of post-operative anterior chamber cell, flare, and pain following cataract surgery. Primary endpoint was complete resolution of anterior chamber cells and flare (cell count of 0 and no flare) and no pain at post-operative day 8. The individual clinical trial results are provided below.

In the 2 studies, Lotemax had statistically significant higher incidence of complete clearing of anterior chamber cells and flare at post-operative day 8 (24-32% vs. 11-14%) and also had a statistically significant higher incidence of subjects that were pain free at post-operative day 8 (73-78% vs. 41-45%).

16 HOW SUPPLIED/STORAGE AND HANDLING

LOTEMAX (loteprednol etabonate ophthalmic ointment), 0.5% is a sterile ointment supplied in a tin tube with a pink polypropylene cap in the following size:

3.5 gram (NDC 24208-443-35)

Do not use if tamper evident skirt is visible on bottom of cap.

Storage: Store between 15°–25°C (59°–77°F).

Rx only.

17 PATIENT COUNSELING INFORMATION

17.1 Risk of Contamination

Patients should be advised not to touch the eyelid or surrounding areas with the tip of the tube. The cap should remain on the tube when not in use.

Patients should be advised to wash hands prior to using LOTEMAX ointment.

Do not use if tamper evident skirt is visible on bottom of cap.

17.2 Contact Lens Wear

Patients should also be advised not to wear contact lenses during their course of therapy.

17.3 Risk of Secondary Infection

If pain, redness, itching or inflammation becomes aggravated, the patient should be advised to consult a physician.

MANUFACTURER INFORMATION

Bausch & Lomb Incorporated

Tampa, Florida 33637 USA

©Bausch & Lomb Incorporated

U.S. Patent No. 4,996,335

Lotemax is a registered trademark of Bausch & Lomb Incorporated