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普比迪（地诺前列酮）凝胶Prepidil(Dinoprostone Gel)

2011-09-30 01:04:07 作者：新特药房来源：中国新特药网天津分站浏览次数：836 文字大小：【大】【中】【小】

简介： 英文药名: Prepidil(Dinoprostone Gel) 中文药名: 普比迪（地诺前列酮）凝胶生产品牌药厂家: AstraZeneca 药品介绍局部使用前列腺素E2凝胶（地诺前列酮）广泛用于促宫颈成熟。使用前列腺素E2凝胶 ...

关键字：普比迪（地诺前列酮）凝胶

英文药名: Prepidil(Dinoprostone Gel)

中文药名: 普比迪（地诺前列酮）凝胶

生产品牌药厂家: AstraZeneca

药品介绍

局部使用前列腺素E2凝胶（地诺前列酮）广泛用于促宫颈成熟。使用前列腺素E2凝胶后，宫颈结缔组织的变化与足月分娩早期所见到的一样，包括胶原束的溶解和粘膜下层水含量的增加。使用小剂量的前列腺素E2增加了引产成功率，降低了产程延长的发生率，并减少了催产素的用量。

在1992年，FDA批准前列腺素E2凝胶（Prepidil，普比迪）用于足月或近足月有引产适应证的孕妇来促宫颈成熟。这种凝胶装在含有0.5mg地诺前列酮的2.5ml的注射器中。这种宫颈内给药的方式的优点在于：对宫缩的影响小，而对宫颈不成熟的孕妇效果较好。10mg的地诺前列酮阴道栓剂（Cervidil）在1995年也被批准用于促宫颈成熟。栓剂与凝胶相比，其药物释放更慢（0.3mg/h）。

建议这些药物在分娩时或近分娩时使用，因为此时可以进行持续性的宫缩和胎心监测。观察周期为30分钟至2小时。如果观察期间内宫缩和胎心没有变化，则病人可以被转出或出院。当宫缩发生时，通常在第一个小时宫缩比较明显，并在最初4小时内达到高峰。如果规律宫缩持续存在时，应连续监测胎心率并记录生命体征。
使用前列腺素E2和催产素之间的最短安全时间间隔尚未确定。根据生产厂家的说明，应在推迟6-12小时之后再使用催产素引产。

副作用
文献报道子宫过度收缩（即20分钟的总时间中有10分钟的宫缩≥6次）的发生率，宫颈内凝胶（0.5mg量）为1％，而在阴道凝胶（2-5mg量）为5％。当临产后使用前列腺素制剂时，可发生严重的过度收缩或胎儿窘迫，因此在这种情况下一般不使用。一般在凝胶或栓剂给药1小时内会出现子宫过度收缩。宫颈和阴道内冲洗以清除宫颈凝胶的方法认为是无效的。而阴道内凝胶的一个优点，即可以牵拉取出，通常可以减轻这种作用。前列腺素E2的全身副作用包括发热，呕吐和腹泻是可以忽略不计的。

中文通用名称：地诺前列酮
英文通用名称：Dinoprostone
中文其他名称：前列腺素E2, 普洛舒定, 普比迪, 地诺前列腺素, 地诺前列酮栓, 灭菌前列腺素E2溶液, 普贝生, 前列腺素E2栓
英文其他名称： Prostaglandin E2, Prostenon, Prostin E2, Prepidil, Medullin, Enzaprost E, Cerviprost, Minprostin, Dinoprostone Suppositories, Propess, Prostaglandin E2 Suppositories, Sterile Prostaglandine E2 Solution
产品所属分类：女性生殖系统用药\子宫收缩及引产药

适应症：
1.用于中期妊娠及足月妊娠的引产。对妊娠毒血症(先兆子痫、高血压)、妊娠合并心肾疾病、过期妊娠、胎膜早破、高龄初产妇、胎儿宫内发育迟缓等均可使用。
2.用于过期流产、28周前的宫腔内死胎以及良性葡萄胎时排除宫腔内容物。
3.本药凝胶用于有内科或产科并发症而需要引产的足月或近足月孕妇，促进宫颈成熟。

注意事项：
1.禁忌症
(1)对前列腺素过敏者。
(2)多胎经产妇(6胎或以上)、有难产史或创伤性分娩者。
(3)有剖宫产史或子宫手术史者。
(4)有头盆不称、胎位异常、胎儿窘迫、子宫收缩过强或过度反应者。
(5)胎膜已破者禁用本药阴道栓剂。
2.慎用
(1)有贫血史者。
(2)有高血压等心血管病史者。
(3)有糖尿病史者。
(4)有癫痫病史者。
(5)活动性肺病患者。
(6)活动性心脏病患者。
(7)子宫纤维瘤、宫颈硬化、宫颈炎或阴道炎患者。
(8)哮喘患者。
(9)青光眼或持续性眼压高者。
(10)肝、肾功能不良者。
3.药物对妊娠的影响美国药品和食品管理局(FDA)对本药的妊娠安全性分级为C级。
4.药物对哺乳的影响尚不明确。
5.用药前后及用药时应当检查或监测
(1)用药时需严密观察子宫收缩的频率、时间、张力和强度等。
(2)用药时需监测体温、脉搏、血压等。
(3)用药后应监测胎心。

不良反应：
1.用药妇女常见的不良反应有恶心、呕吐、腹泻、发热(常在用药后15-45分钟出现，停药或药栓取出后2-6小时恢复正常)等；少数患者有畏寒、头痛。
2.约10%的妇女在用药后舒张压可降低2.67kPa(20mmHg)，也可出现血压升高。
3.用药后胎儿可出现胎心率改变、胎儿窘迫等。
4.本药静脉滴注时，少数患者可出现类似静脉炎的症状，停药后常自行消失。
5.本药在宫腔内羊膜腔外放置，可导致羊绒炎、胎膜早破等。
6.本药用量过大，可使子宫痉挛及肌张力过高，甚至挛缩，因而可能导致宫颈撕裂、宫颈后方穿孔、子宫破裂或(和)大出血。

给药说明：
1.本药栓剂自冰箱取出后应放至室温后使用。凝胶剂在使用前从冰箱中取出，且不能加温，以免失效。
2.避免用手直接接触无包装的栓剂，以免通过皮肤吸收。
3.放置栓剂后病人应保持卧位姿势10分钟，以使药物吸收。
4.用药前或用药同时服用止吐和止泻药，可降低本药的胃肠道不良反应。
5.必须严密观察宫缩，随时调节用药剂量，防止宫缩过强而致子宫破裂。
6.当出现不良反应时应立即吸氧，并用β肾上腺素能药物或硫酸镁处理子宫过强收缩。
7.动物实验表明，某些前列腺素可致畸，故用本药阴道栓终止妊娠失败后，必须改用其它方法终止妊娠。
8.在流产或分娩后应常规检查宫颈，及时发现宫颈裂伤，并予以修补。

用法用量：
成人
·常规剂量
·静脉滴注
将本药注射液2mg和碳酸钠溶液1mg加入氯化钠注射液10ml中，摇匀后再加入5%葡萄糖注射液500ml中滴注。中期妊娠引产的滴速为4-8μg/min(每分钟15-30滴左右)；足月妊娠引产的滴速为1μg/min。
·宫腔内羊膜腔外给药
将本药注射液2mg和碳酸钠溶液1mg加入氯化钠注射液10ml中，摇匀备用。给药时一次0.2mg，每2小时1次。给药3小时后，亦可酌情加用适量缩宫素，以加速产程进展。
·宫颈给药
促宫颈成熟：孕妇取仰卧位，通过导管将本药凝胶(含0.5mg地诺前列酮)注入宫颈管，低于宫颈内口。注药后至少仰卧15分钟。如宫颈或子宫对初始量无反应，可在6小时后重复给药1次。24小时内最大累积量不超过1.5mg。
·阴道给药
1.流产：本药栓剂，一次20mg，置入阴道内，每3-5小时重复1次，直至流产。给药总量不超过240mg。
2.促宫颈成熟：栓剂3mg于引产前1日晚置入阴道内。
3.足月引产：本药栓剂，首次剂量为3mg，如8小时后无效，可重复3mg。通常3-6mg即有效。
贮法：2-8℃，冰箱内保存。

PREPIDIL - dinoprostone gel
Pharmacia and Upjohn Company
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Prepidil® Gel
dinoprostone cervical gel
For Endocervical Use
DESCRIPTION

PREPIDIL Gel contains dinoprostone as the naturally occurring form of prostaglandin E2 (PGE2) and is designated chemically as (5Z, 11a, 13E, 15S)-11,15-Dihydroxy-9-oxo-prosta-5,13-dien-1-oic acid. The molecular formula is C20H32O5 and the molecular weight is 352.5. Dinoprostone occurs as a white to off-white crystalline powder with a melting point within the range of 65° to 69°C. It is soluble in ethanol, in 25% ethanol in water, and in water to the extent of 130 mg/100 mL. The active constituent of PREPIDIL Gel is dinoprostone 0.5 mg/3 g (2.5 mL gel); other constituents are colloidal silicon dioxide NF (240 mg/3 g) and triacetin USP (2760 mg/3 g).

The structural formula is represented below:

CLINICAL PHARMACOLOGY

PREPIDIL Gel (dinoprostone) administered endocervically may stimulate the myometrium of the gravid uterus to contract in a manner similar to contractions seen in the term uterus during labor. Whether or not this action results from a direct effect of dinoprostone on the myometrium has not been determined. Dinoprostone is also capable of stimulating smooth muscle of the gastrointestinal tract in humans. This activity may be responsible for the vomiting and/or diarrhea that is occasionally seen when dinoprostone is used for preinduction cervical ripening.

In laboratory animals, and also in humans, large doses of dinoprostone can lower blood pressure, probably as a result of its effect on smooth muscle of the vascular system. With the doses of dinoprostone used for cervical ripening this effect has not been seen. In laboratory animals, and also in humans, dinoprostone can elevate body temperature; however, with the dosing used for cervical ripening this effect has not been seen.

In addition to an oxytocic effect, there is evidence suggesting that this agent has a local cervical effect in initiating softening, effacement, and dilation. These changes, referred to as cervical ripening, occur spontaneously as the normal pregnancy progresses toward term and allow evacuation of uterine contents by decreasing cervical resistance at the same time that myometrial activity increases. While not completely understood, biochemical changes within the cervix during natural cervical ripening are similar to those following PGE2-induced ripening. Further, it has been shown that these changes can take place independent of myometrial activity; however, it is quite likely that PGE2 administered endocervically produces effacement and softening by combined contraction-inducing and cervical-ripening properties. There is evidence to suggest that the changes that take place within the cervix are due to collagen degradation resulting from collagenase secretion as a response, at least in part, to PGE2.

Using an unvalidated assay, the following information was determined. When PREPIDIL Gel was administered endocervically to women undergoing preinduction ripening, results from measurement of plasma levels of the metabolite 13,14-dihydro-15-keto-PGE2 (DHK-PGE2) showed that PGE2 was relatively rapidly absorbed and the Tmax was 0.5 to 0.75 hours. Plasma mean Cmax for gel-treated subjects was 433 ± 51 pg/mL versus 137 ± 24 pg/mL for untreated controls. In those subjects in which a clinical response was observed, mean Cmax was 484 ± 57 pg/mL versus 213 ± 69 pg/mL in nonresponders and 219 ± 92 pg/mL in control subjects who had positive clinical progression toward normal labor. These elevated levels in gel-treated subjects appear to be largely a result of absorption of PGE2 from the gel rather than from endogenous sources.

PGE2 is completely metabolized in humans. PGE2 is extensively metabolized in the lungs, and the resulting metabolites are further metabolized in the liver and kidney. The major route of elimination of the products of PGE2 metabolism is the kidneys.

INDICATIONS AND USAGE

PREPIDIL Gel is indicated for ripening an unfavorable cervix in pregnant women at or near term with a medical or obstetrical need for labor induction.

CONTRAINDICATIONS

Endocervically administered PREPIDIL Gel is not recommended for the following:

a.

Patients in whom oxytocic drugs are generally contraindicated or where prolonged contractions of the uterus are considered inappropriate, such as:

cases with a history of cesarean section or major uterine surgery
cases in which cephalopelvic disproportion is present
cases in which there is a history of difficult labor and/or traumatic delivery
grand multiparae with six or more previous term pregnancies cases with non-vertex presentation
cases with hyperactive or hypertonic uterine patterns
cases of fetal distress where delivery is not imminent
in obstetric emergencies where the benefit-to-risk ratio for either the fetus or the mother favors surgical intervention

b.

Patients with hypersensitivity to prostaglandins or constituents of the gel.

c.

Patients with placenta previa or unexplained vaginal bleeding during this pregnancy.

d.

Patients for whom vaginal delivery is not indicated, such as vasa previa or active herpes genitalia.

WARNINGS

FOR HOSPITAL USE ONLY

Dinoprostone, as with other potent oxytocic agents, should be used only with strict adherence to recommended dosages. Dinoprostone should be administered by physicians in a hospital that can provide immediate intensive care and acute surgical facilities.

Women aged 35 years or older, those with complications during pregnancy and those with a gestational age over 40 weeks have been shown to have an increased risk of post-partum disseminated intravascular coagulation. In addition, these factors may further increase the risk associated with labor induction (see ADVERSE REACTIONS, Post-marketing surveillance). Therefore, in these women, use of dinoprostone should be undertaken with caution. Measures should be applied to detect as soon as possible an evolving fibrinolysis in the immediate post-partum phase.

The Clinician should be alert that the intracervical placement of dinoprostone gel may result in inadvertent disruption and subsequent embolization of antigenic tissue causing in rare circumstances the development of Anaphylactoid Syndrome of Pregnancy (Amniotic Fluid Embolism) .

PRECAUTIONS

1. General Precautions

During use, uterine activity, fetal status, and character of the cervix (dilation and effacement) should be carefully monitored either by auscultation or electronic fetal monitoring to detect possible evidence of undesired responses, e.g., hypertonus, sustained uterine contractility, or fetal distress. In cases where there is a history of hypertonic uterine contractility or tetanic uterine contractions, it is recommended that uterine activity and the state of the fetus should be continuously monitored. The possibility of uterine rupture should be borne in mind when high-tone myometrial contractions are sustained. Feto-pelvic relationships should be carefully evaluated before use of PREPIDIL Gel (see CONTRAINDICATIONS).

Caution should be exercised in administration of PREPIDIL Gel in patients with:

asthma or history of asthma
glaucoma or raised intraocular pressure

Caution should be taken so as not to administer PREPIDIL Gel above the level of the internal os. Careful vaginal examination will reveal the degree of effacement which will regulate the size of the shielded endocervical catheter to be used. That is, the 20 mm endocervical catheter should be used if no effacement is present, and the 10 mm catheter should be used if the cervix is 50% effaced. Placement of PREPIDIL Gel into the extra-amniotic space has been associated with uterine hyperstimulation.

As PREPIDIL Gel is extensively metabolized in the lung, liver, and kidney, and the major route of elimination is the kidney, PREPIDIL Gel should be used with caution in patients with renal and hepatic dysfunction.

2. Patients With Ruptured Membranes

Caution should be exercised in the administration of PREPIDIL Gel in patients with ruptured membranes. The safety of use of PREPIDIL Gel in these patients has not been determined.

3. Drug Interactions

PREPIDIL Gel may augment the activity of other oxytocic agents and their concomitant use is not recommended. For the sequential use of oxytocin following PREPIDIL Gel administration, a dosing interval of 6–12 hours is recommended.

4. Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic bioassay studies have not been conducted in animals with PREPIDIL Gel due to the limited indications for use and short duration of administration. No evidence of mutagenicity was observed in the Micronucleus Test or Ames Assay.

5. Pregnancy

Teratogenic Effects

PREGNANCY CATEGORY C

Prostaglandin E2 produced an increase in skeletal anomalies in rats and rabbits. No effect would be expected clinically, when used as indicated, since PREPIDIL Gel is administered after the period of organogenesis. PREPIDIL Gel has been shown to be embryotoxic in rats and rabbits, and any dose that produces sustained increased uterine tone could put the embryo or fetus at risk. See statements under General Precautions.

6. Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

PREPIDIL Gel is generally well-tolerated. In controlled trials, in which 1731 women were entered, the following events were reported at an occurrence of ≥ 1%:

Adverse Reaction	PGE2 (N = 884)	Control (N = 847)
placebo gel or no treatment
Maternal	N (%)	N (%)
Uterine contractile abnormality	58 (6.6)	34 (4.0)
Any gastrointestinal effect	50 (5.7)	22 (2.6)
Back pain	27 (3.1)	0 (0)
Warm feeling in vagina	13 (1.5)	0 (0)
Fever	12 (1.4)	10 (1.2)
Fetal
Any fetal heart rate abnormality	150 (17.0)	123 (14.5)
Bradycardia	36 (4.1)	26 (3.1)
Deceleration
Late	25 (2.8)	18 (2.1)
Variable	38 (4.3)	29 (3.4)
Unspecified	19 (2.1)	19 (2.2)

In addition, in other trials amnionitis and intrauterine fetal sepsis have been associated with extra-amniotic intrauterine administration of PGE2. Uterine rupture has been reported in association with the use of PREPIDIL Gel intracervically. Additional events reported in the literature, associated by the authors with the use of PREPIDIL Gel, included premature rupture of membranes, fetal depression (1 min Apgar < 7), and fetal acidosis (umbilical artery pH < 7.15).

Post-marketing surveillance

Blood and lymphatic system disorders

An increased risk of post-partum disseminated intravascular coagulation has been described in patients whose labor was induced by pharmacological means, either with dinoprostone or oxytocin (see section WARNINGS). The frequency of this adverse event, however, appears to be rare (<1 per 1,000 labors).

DRUG ABUSE AND DEPENDENCE

No drug abuse or drug dependence has been seen with the use of PREPIDIL Gel.

OVERDOSAGE

Overdosage with PREPIDIL Gel may be expressed by uterine hypercontractility and uterine hypertonus. Because of the transient nature of PGE2-induced myometrial hyperstimulation, nonspecific, conservative management was found to be effective in the vast majority of the cases; i.e., maternal position change and administration of oxygen to the mother. β-adrenergic drugs may be used as a treatment of hyperstimulation following the administration of PGE2 for cervical ripening.

DOSAGE AND ADMINISTRATION

NOTE: USE CAUTION IN HANDLING THIS PRODUCT TO PREVENT CONTACT WITH SKIN. WASH HANDS THOROUGHLY WITH SOAP AND WATER AFTER ADMINISTRATION.

PREPIDIL Gel should be brought to room temperature (59° to 86°F; 15° to 30°C) just prior to administration. Do not force the warming process by using a water bath or other source of external heat (eg, microwave oven).

To prepare the product for use remove the protective end cap (to serve as plunger extension) and insert the protective end cap into the plunger stopper assembly in the barrel of syringe. Choose the appropriate length shielded catheter (10 mm or 20 mm) and aseptically remove the sterile shielded catheter from the package. Careful vaginal examination will reveal the degree of effacement which will regulate the size of the shielded endocervical catheter to be used. That is, the 20 mm endocervical catheter should be used if no effacement is present, and the 10 mm catheter should be used if the cervix is 50% effaced. Firmly attach the catheter hub to the syringe tip as evidenced by a distinct click. Fill the catheter with sterile gel by pushing the plunger assembly to expel air from the catheter prior to administration to the patient. Proper assembly of the dosing apparatus is shown below.

To properly administer the product, the patient should be in a dorsal position with the cervix visualized using a speculum. Using sterile technique, introduce the gel with the catheter provided into the cervical canal just below the level of the internal os. Administer the contents of the syringe by gentle expulsion and then remove the catheter. The gel is easily extrudable from the syringe. Use the contents of one syringe for one patient only. No attempt should be made to administer the small amount of gel remaining in the catheter. The syringe, catheter, and any unused package contents should be discarded after use. Following administration of PREPIDIL Gel, the patient should remain in the supine position for at least 15–30 minutes to minimize leakage from the cervical canal. If the desired response is obtained from PREPIDIL Gel, the recommended interval before giving intravenous oxytocin is 6–12 hours. If there is no cervical/uterine response to the initial dose of PREPIDIL Gel, repeat dosing may be given. The recommended repeat dose is 0.5 mg dinoprostone with a dosing interval of 6 hours. The need for additional dosing and the interval must be determined by the attending physician based on the course of clinical events. The maximum recommended cumulative dose for a 24-hour period is 1.5 mg of dinoprostone (7.5 mL PREPIDIL Gel).

HOW SUPPLIED

PREPIDIL Gel is available as a sterile semitranslucent viscous preparation for endocervical application: 0.5 mg PGE2 per 3.0 g (2.5 mL) in syringe. In addition, each package contains two shielded catheters (10 mm and 20 mm tip) enclosed in sterile envelopes. The contents are not guaranteed sterile if envelopes are not intact.

Each 3 gram syringe applicator contains:
dinoprostone, 0.5 mg; colloidal silicon dioxide, 240 mg; triacetin, 2760 mg.

5 × 3 gram syringes NDC 0009-3359-02

PREPIDIL Gel needs to be stored under continuous refrigeration (36° to 46°F; 2° to 8°C).

Rx only

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