英文药名: Depo-provera(Medroxyprogesterone Injection Suspension)

中文药名: 甲羟孕酮（安宫注射悬浮液)

品牌药生产厂家: Not available

药品名称

狄波 - 普维拉注射液Depo-Provera
性状: 醋酸甲羟孕酮的化学名为17-α-羟基-6-α-甲基孕酮醋酸酯。
本品为无菌水性混悬注射剂，除醋酸甲羟孕酮外，还含有聚乙二醇3350，多聚山梨醇酸酯80，氯化钠，羟基甲酸甲酯，羟基甲酸丙酯，注射用水。
药理作用

醋酸甲羟孕酮是一种孕激素，它是孕酮的衍生物。本品是一种没有雌激素活性的孕激素制剂，它的雄激素作用几乎没有。一定量的本药可抑制垂体分泌促性腺激素从而阻止卵泡成熟，造成育龄妇女停止排卵。
一定量的本药可抑制男性莱迪希细胞(Leydig Cell)的功能，即抑制内源性睾丸酮的产生。
口服醋酸甲羟孕酮也可对宫颈粘膜产生典型的孕酮变化(无羊齿样结晶)，并在阴道上皮的成熟指数方面增加中介细胞数。本药对激素依赖性癌症的抗癌活性在药理剂量下是依赖于其对下丘脑-垂体-性腺轴的作用，以及对雌激素受体及激素在组织水平上代谢的影响。
与孕酮相似，醋酸甲羟孕酮会产热，使用治疗某些癌症的大剂量(每天大于500 mg)时，则会出现皮质类固醇样作用。
药代动力学

肌注醋酸甲羟孕酮后，药物缓慢持续低水平释放，大约4-20天血浓度达到高峰，肌注后7-9个月仍可从血中检测到醋酸甲羟孕酮。醋酸甲羟孕酮的蛋白结合率为90-95%，分布容积为20±3升，它可以通过血脑屏障并可经乳汁分泌。尽管醋酸甲羟孕酮有许多代谢产物，但尚不能对它们明确定量，消除半衰期为6周，它主要经胆汁由粪便排泄，大约44%的原型药物由尿液排出。
适应症

避孕(抑制排卵)；治疗子宫内膜异位；治疗更年期血管舒缩症状；作为复发和/或转移性子宫内膜癌或肾癌的辅助和/或姑息疗法；治疗绝经妇女激素依赖性、复发性乳癌。
用法用量

避孕(抑制排卵)
150 mg/次，每3个月深部肌注1次。首次注射应在正常自发月经的头5天之内使用；产后不哺乳妇女产后5日之内即可使用；产后哺乳妇女在产后6周或之前均可使用。
子宫内膜异位
每周50 mg或每2周100 mg肌注1次，至少进行6个月疗程。
更年期血管舒缩症状
每3个月150 mg深部肌注1次。
子宫内膜癌及肾癌
初始剂量为每周肌注400-1000 mg，如果数周或数月内病情改善并稳定，每月维持剂量400 mg就可保持此状况。
乳癌
肌注持续28天，每天500 mg， 然后采用病人能反应的维持剂量，每周2次，每次500 mg。
任何疑问，请遵医嘱！
不良反应

过敏和类过敏性反应；
血栓栓塞症－血栓性静脉炎和肺栓塞；
中枢神经系统 - 紧张、失眠、嗜睡、疲倦、抑郁、眩晕和头痛；
皮肤和粘模 - 荨麻疹，瘙痒、红疹、痤疮、多毛和脱发；
胃肠道 - 恶心；
乳房 - 肿胀和溢乳；
其他 - 发热，体重变化和满月脸。
禁忌症

已知对醋酸甲羟孕酮或其它成分过敏的病人禁用。
注意事项

使用本药前，应对病情作一个评估，评估应排除生殖器官或乳房恶性肿瘤的存在，但对于治疗子宫内膜癌、乳癌或肾癌，以上表述不适用。
尽管尚无本药使用可造成血栓异常的报告，但如发现病人在使用本药中出现此方面的征兆，继续使用前应仔细权衡病情和治疗的需要。
大剂量醋酸甲羟孕酮使用尤其可造成体重增加及体液潴留。对于那些有此症状的病人可能会加重体重增加及体液潴留状况，故应注意。
大剂量醋酸甲羟孕酮在治疗癌症时，有时会出现类柯兴氏综合症，如满月脸、体液潴留，糖不耐受及血压升高。
低剂量醋酸甲羟孕酮对有些病人可能会降低糖耐量，其机理未知。尤其在治疗糖尿病患者时应注意。
有精神抑郁史的病人，接受本药治疗时应严密监测，有些病人会出现类似于经前期抑郁症的情况。
使用本药的病人，当需做子宫内膜或子宫颈组织病理检查时，应告诉病理检验师。
单剂或多剂量使用本药，其长期的抑制排卵作用可造成闭经和/或月经紊乱。
本药的使用会对下列实验室检验有影响：促性腺激素，血浆孕酮浓度，尿雌二醇浓度，血浆睾丸酮浓度(男性)，血浆雌激素浓度(女性)，血浆考的松浓度，糖耐量试验，甲吡酮试验(Metyrapone)。
孕妇及哺乳期妇女用药

不建议怀孕妇女使用孕激素类制剂。
本药用于哺乳期妇女，虽然能在乳汁中分泌，但含量很低。至今没有观察到任何影响婴儿发育的不良作用。
药物相互作用

合用氨基苯乙哌啶酮可显著地降低本药的生物利用度。
用药须知

在使用前，充分振摇以保证混悬液均匀。

规格：150mg/ml 1支 x 1ml (悬浮注射液)

DEPO-PROVERA (medroxyprogesterone acetate) injection, suspension
[Pharmacia and Upjohn Company]

DESCRIPTION

DEPO-PROVERA Sterile Aqueous Suspension contains medroxyprogesterone acetate, which is a derivative of progesterone and is active by the parenteral and oral routes of administration. It is a white to off-white, odorless crystalline powder, stable in air, melting between 200° and 210° C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether and insoluble in water.

The chemical name for medroxyprogesterone acetate is Pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-, (6α)-. The structural formula is:

DEPO-PROVERA for intramuscular injection is available as 400 mg/mL medroxyprogesterone acetate. Each mL of the 400 mg/mL suspension contains:

Medroxyprogesterone acetate .............400 mg
Polyethylene glycol 3350.....................20.3 mg
Sodium sulfate anhydrous ......................11 mg
  with
Myristyl-gamma-picolinium
  chloride ............................................1.69 mg
  added as preservative

When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid.

ACTIONS

Medroxyprogesterone acetate, administered parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative endometrium into secretory endometrium.

Medroxyprogesterone acetate inhibits (in the usual dose range) the secretion of pituitary gonadotropin which, in turn, prevents follicular maturation and ovulation.

Because of its prolonged action and the resulting difficulty in predicting the time of withdrawal bleeding following injection, medroxyprogesterone acetate is not recommended in secondary amenorrhea or dysfunctional uterine bleeding. In these conditions oral therapy is recommended.

INDICATIONS AND USES

Adjunctive therapy and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal carcinoma.

CONTRAINDICATIONS

1. Known or suspected pregnancy or as a diagnostic test for pregnancy
2. Undiagnosed vaginal bleeding
3. Known or suspected malignancy of breast
4. Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease
5. Liver dysfunction or disease
6. Known sensitivity to DEPO-PROVERA (medroxyprogesterone acetate or any of its other ingredients).

WARNINGS

1. Pregnancy

The use of progestational drugs during the first four months of pregnancy is not recommended. Progestational agents have been used beginning with the first trimester of pregnancy in attempts to prevent abortion but there is no evidence that such use is effective. Furthermore, the use of progestational agents, with their uterine-relaxant properties, in patients with fertilized defective ova may cause a delay in spontaneous abortion.

2. Intrauterine Exposure

Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias (5 to 8 per 1,000 male births in the general population) may be approximately doubled with exposure to these drugs. There are insufficient data to quantify the risk to exposed female fetuses, but insofar as some of these drugs induce mild virilization of the external genitalia of the female fetus, and because of the increased association of hypospadias in the male fetus, it is prudent to avoid the use of these drugs during the first trimester of pregnancy.

If the patient is exposed to DEPO-PROVERA Sterile Aqueous Suspension during the first four months of pregnancy or if she becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus.

3. Thromboembolic Disorders

The physician should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, cerebrovascular disorder, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately.

4. Ocular Disorders

Medication should be discontinued pending examination if there is a sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.

5. Lactation

Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the nursing infant has not been determined.

6. Multi-dose Use

Multi-dose use of DEPOPROVERA Sterile Aqueous Suspension from a single vial requires special care to avoid contamination. Although initially sterile, any multi-dose use of vials may lead to contamination unless strict aseptic technique is observed.

PRECAUTIONS

1. Physical Examination

It is good medical practice for all women to have annual history and physical examinations, including women using DEPO-PROVERA Sterile Aqueous Suspension. The physical examination, however, may be deferred until after initiation of DEPO-PROVERA if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

2. Fluid Retention

Because progestational drugs may cause some degree of fluid retention, conditions which might be influenced by this condition, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation.

3. Vaginal Bleeding

In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind and adequate diagnostic measures undertaken.

4. Depression

Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

5. Masking of Climacteric

The age of the patient constitutes no absolute limiting factor although treatment with progestin may mask the onset of the climacteric.

6. Use with Estrogen

Studies of the addition of a progestin product to an estrogen replacement regimen for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of endometrial suggest that 10–13 days of a progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established.

There are possible risks which may be associated with the inclusion of progestin in estrogen replacement regimen, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects.

A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving such therapy.

7. Prolonged Use

The effect of prolonged use of DEPO-PROVERA Sterile Aqueous Suspension at the recommended doses on pituitary, ovarian, adrenal, hepatic, and uterine function is not known.

8. Multi-dose Use

When multi-dose vials are used, special care to prevent contamination of the contents is essential. There is some evidence that benzalkonium chloride is not an adequate antiseptic for sterilizing DEPO-PROVERA Sterile Aqueous Suspension multi-dose vials. A povidone-iodine solution or similar product is recommended to cleanse the vial top prior to aspiration of contents. (See WARNINGS)

DRUG INTERACTIONS

Aminoglutethimide administered concomitantly with DEPO-PROVERA Sterile Aqueous Suspension may significantly depress the serum concentrations of medroxyprogesterone acetate. DEPO-PROVERA users should be warned of the possibility of decreased efficacy with the use of this or any related drugs.

LABORATORY TEST INTERACTIONS

The pathologist should be advised of progestin therapy when relevant specimens are submitted. The following laboratory tests may be affected by progestins including DEPO-PROVERA Sterile Aqueous Suspension:

a)

Plasma and urinary steroid levels are decreased (e.g. progesterone, estradiol, pregnanediol, testosterone, cortisol).

b)

Gonadotropin levels are decreased.

c)

Sex-hormone binding globulin concentrations are decreased.

d)

Protein bound iodine and butanol extractable protein bound iodine may increase. T3 uptake values may decrease.

e)

Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase.

f)

Sulfobromophthalein and other liver function test values may be increased.

g)

The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Long-term intramuscular administration of Medroxyprogesterone acetate (MPA) has been shown to produce mammary tumors in beagle dogs. There is no evidence of a carcinogenic effect associated with the oral administration of MPA to rats and mice. Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.

Medroxyprogesterone acetate at high doses is an anti-fertility drug and high doses would be expected to impair fertility until the cessation of treatment.

INFORMATION FOR THE PATIENT

See Patient Information at end of insert.

ADVERSE REACTIONS

–(See WARNINGS for possible adverse effects on the fetus)
–breakthrough bleeding
–spotting
–change in menstrual flow
–amenorrhea
–headache
–nervousness
–dizziness
–edema
–change in weight (increase or decrease)
–changes in cervical erosion and cervical secretions
–cholestatic jaundice, including neonatal jaundice
–breast tenderness and galactorrhea
–skin sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash
–acne, alopecia and hirsutism
–rash (allergic) with and without pruritis
–anaphylactoid reactions and anaphylaxis
–mental depression
–pyrexia
–fatigue
–insomnia
–nausea
–somnolence

In a few instances there have been undesirable sequelae at the site of injection, such as residual lump, change in color of skin, or sterile abscess.

A statistically significant association has been demonstrated between use of estrogen-progestin combination drugs and pulmonary embolism and cerebral thrombosis and embolism. For this reason patients on progestin therapy should be carefully observed. There is also evidence suggestive of an association with neuro-ocular lesions, e.g. retinal thrombosis and optic neuritis.

The following adverse reactions have been observed in patients receiving estrogen-progestin combination drugs:

–rise in blood pressure in susceptible individuals
–premenstrual syndrome
–changes in libido
–changes in appetite
–cystitis-like syndrome
–headache
–nervousness
–fatigue
–backache
–hirsutism
–loss of scalp hair
–erythema multiforma
–erythema nodosum
–hemorrhagic eruption
–itching
–dizziness

The following laboratory results may be altered by the use of estrogen-progestin combination drugs:

–increased sulfobromophthalein retention and other hepatic function tests
–coagulation tests: increase in prothrombin factors VII, VIII, IX, and X
–metyrapone test
–pregnanediol determinations
–thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values

DOSAGE AND ADMINISTRATION

The suspension is intended for intramuscular administration only.

Endometrial or renal carcinoma— doses of 400 mg to 1000 mg of DEPO-PROVERA Sterile Aqueous Suspension per week are recommended initially. If improvement is noted within a few weeks or months and the disease appears stabilized, it may be possible to maintain improvement with as little as 400 mg per month. Medroxyprogesterone acetate is not recommended as primary therapy, but as adjunctive and palliative treatment in advanced inoperable cases including those with recurrent or metastatic disease.

When multi-dose vials are used, special care to prevent contamination of the contents is essential (See WARNINGS).

HOW SUPPLIED

DEPO-PROVERA Sterile Aqueous Suspension is available as 400 mg/mL in 2.5 mL vials.