Following are Contraindicataions, Warnings, Precautions, and Adverse
Reactions published by the manufaturer of
"Sythetic Progesterone" (medroxy-progesterone
acetate)
Provera
(Medroxyprogesterone Acetate)
Warning: The use of Medroxyprogesterone
Acetate during the first four months of pregnancy is NOT recommended.
Progestational agents have been used beginning with
the first trimester of pregnancy in an attempt to prevent habitual abortion.
There is no adequate evidence that such use is effective when such drugs
are given during the first four months of pregnancy. Furthermore, in the
vast majority of women, the cause of abortion is a defective ovum, which
progestational agents could not be expected to influence. In addition,
the use of progestational agents, with their uterine-relaxant properties,
in patients with fertilized defective ova may cause a delay in spontaneous
abortion. Therefore, the use of such drugs during the first four months of
pregnancy is not recommended.
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 PROVERA Tablets (medroxyprogesterone acetate)
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.
Description
PROVERA Tablets contain medroxyprogesterone acetate,
which is a derivative of progesterone. 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 in 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-, (6a)-. The structural formula is:
Each PROVERA tablet for oral administration contains
2.5 mg, 5 mg or 10 mg of medroxy-progesterone acetate. Inactive ingredients:
calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose,
talc. The 2.5 mg tablet contains FD&C Yellow no. 6.
The information contained in the box only is not from
the manufaturer of synthetic progesterone
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Medroxyprogesterone acetate, administered orally or parenterally
in the recommended doses to women with adequate endogenous estrogen, transforms
proliferative into secretory endometrium. Androgenic and anabolic effects have
been noted, but the drug is apparently devoid of significant estrogenic activity.
While parenterally administered medroxyprogesterone acetate inhibits gonadotropin
production, which in turn prevents follicular maturation and ovulation, available
data indicate that this does not occur when the usually recommended oral dosage
is given as single daily doses.
Indications and usage
Secondary amenorrhea; abnormal uterine bleeding due to
hormonal imbalance in the absence of organic pathology, such as fibroids
or uterine cancer.
Contraindications for Medroxyprogesterone Acetate
Thrombophlebitis, thromboembolic disorders, cerebral apoplexy or patients with a past history of these conditions.
Liver dysfunction or disease.
Known or suspected malignancy of breast or genital organs.
Undiagnosed vaginal bleeding. 5.Missed abortion.
As a diagnostic test for pregnancy.
Known sensitivity to PROVERA Tablets.
Warnings for Medroxyprogesterone Acetate
The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately.
Beagle dogs treated with medroxyprogesterone acetate developed mammary nodules some of which were malignant. Although nodules occasionally appeared in control animals, they were intermittent in nature, whereas the nodules in the drug-treated animals were larger, more numerous, persistent, and there were some breast malignancies with metastases. Their significance with respect to humans has not been established.
Discontinue medication pending examination if there is 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.
Detectable amounts of progestin have been identified in the milk of mothers receiving the drug. The effect of this on the nursing infant has not been determined.
Usage in pregnancy is not recommended (See WARNING Box).
Retrospective studies of morbidity and mortality in Great Britain and studies of morbidity in the United States have shown a statistically significant association between thrombophlebitis, pulmonary embolism, and cerebral thrombosis and embolism and the use of oral contraceptives.1-4 The estimate of the relative risk of thromboembolism in the study by Vessey and Doll3 was about sevenfold, while Sartwell and associates4 in the United States found a relative risk of 4.4, meaning that the users are several times as likely to undergo thromboembolic disease without evident cause as nonusers. The American study also indicated that the risk did not persist after discontinuation of administration, and that it was not enhanced by long continued administration. The American study was not designed to evaluate a difference between products.
Precautions for Medroxyprogesterone Acetate
The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.
Because progestogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation.
In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.
Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
Any possible influence of prolonged progestin therapy on pituitary, ovarian, adrenal, hepatic or uterine functions awaits further study.
A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination drugs. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving progestin therapy.
The age of the patient constitutes no absolute limiting factor although treatment with progestins may mask the onset of the climacteric.
The pathologist should be advised of progestin therapy when relevant specimens are submitted.
Because of the occasional occurrence of thrombotic disorders, (thrombophlebitis, pulmonary embolism, retinal thrombosis, and cerebrovascular disorders) in patients taking estrogen-progestin combinations and since the mechanism is obscure, the physician should be alert to the earliest manifestation of these disorders.
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 endometrium 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 additional risks which may be associated with the inclusion of progestin in estrogen replacement regimen. The potential risks include adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects.
Aminoglutethimide administered concomitantly with PROVERA may significantly depress the bioavailability of PROVERA.
Carcinogenes, Mutagenesis, Impairment of Fertility
Long-term intramuscular administration of PROVERA has
been shown to produce mammary tumors in beagle dogs (see WARNINGS). There
was no evidence of a carcinogenic effect associated with the oral
administration of PROVERA 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 antifertility drug and
high doses would be expected to impair fertility until the cessation of
treatment.
Adverse reactions to Medroxyprogesterone Acetate
Pregnancy-(See WARNING Box for possible adverse
effects on the fetus).
Breast-Breast tenderness or galactorrhea has been reported rarely.
Skin-Sensitivity reactions consisting of urticaria, pruritus, edema
and generalized rash have occurred in an occasional patient. Acne,
alopecia and hirsutism have been reported in a few cases.
Thromboembolic Phenomena-Thromboembolic phenomena including
thrombophlebitis and pulmonary embolism have been reported.
The following adverse reactions have been observed in women taking
progestins including PROVERA Tablets: breakthrough bleeding, spotting,
change in menstrual flow, amenorrhea, edema, change in weight (increase
or decrease), changes in cervical erosion and cervical secretions,
cholestatic jaundice, anaphylactoid reactions and anaphylaxis, rash
(allergic) with and without pruritus, mental depression, pyrexia,
insomnia, nausea, somnolence.
A statistically significant association has been demonstrated between
use of estrogen-progestin combination drugs and the following serious
adverse reactions: thrombophlebitis; pulmonary embolism and cerebral
thrombosis and embolism. For this reason patients on progestin therapy
should be carefully observed.
Although available evidence is suggestive of an association, such a
relationship has been neither confirmed nor refuted for the following
serious adverse reactions: neuro-ocular lesions, eg, 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, fatigue, backache, hirsutism, premenstrual-like syndrome,
loss of scalp hair, erythema multiforme, changes in libido, erythema
nodosum, changes in appetite, hemorrhagic eruption, cystitis-like syndrome,
headache, itching, nervousness, dizziness.
In view of these observations, patients on progestin therapy should be
carefully observed.
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
determination. Thyroid function: increase in PBI, and butanol extractable
protein bound iodine and decrease in T3 uptake values.
Dosage and administration for Medroxyprogesterone Acetate
Secondary Amenorrhea-PROVERA Tablets may be given
in dosages of 5 to 10 mg daily for from 5 to 10 days. A dose for inducing
an optimum secretory transformation of an endometrium that has been
adequately primed with either endogenous or exogenous estrogen is 10
mg of PROVERA daily for 10 days. In cases of secondary amenorrhea,
therapy may be started at any time. Progestin withdrawal bleeding
usually occurs within three to seven days after discontinuing PROVERA
therapy.
Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of
Organic Pathology-Beginning on the calculated 16th or 21st day of the
menstrual cycle, 5 to 10 mg of medroxyprogesterone acetate may be given
daily for from 5 to 10 days. To produce an optimum secretory transformation
of an endometrium that has been adequately primed with either endogenous
or exogenous estrogen, 10 mg of medroxyprogesterone acetate daily for 10
days beginning on the 16th day of the cycle is suggested. Progestin
withdrawal bleeding usually occurs within three to seven days after
discontinuing therapy with PROVERA. Patients with a past history of
recurrent episodes of abnormal uterine bleeding may benefit from planned
menstrual cycling with PROVERA.
How supplied
PROVERA Tablets are available in the following
strengths and package sizes:
2.5 mg (scored, round, orange)
Bottles of 30 NDC 0009-0064-06
Bottles of 100 NDC 0009-0064-04
5 mg (scored, hexagonal, white)
Bottles of 30 NDC 0009-0286-32
Bottles of 100 NDC 0009-0286-03
10 mg (scored, round, white)
Bottles of 30 NDC 0009-0050-09
Bottles of 100 NDC 0009-0050-02
Bottles of 500 NDC 0009-0050-11
DOSEPAK-3 Unit of Use (10) NDC 0009-0050-12
Store at controlled room temperature
15-30 C (59-86 F).
References
Royal College of General Practitioners: Oral contraception and thromboembolic disease. J Coll Gen Pract 13:267-279, 1967.
Inman WHW, Vessey MP: Investigation of deaths from pulmonary, coronary, and cerebral thrombosis and embolism in women of child- bearing age. Br Med J 2:193-199, 1968.
Vessey MP, Doll R: Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 2:651-657, 1969.
Sartwell PE, Masi AT, Arthes FG, et al: Thromboembolism and oral contraceptives: An epidemiological case-control study. Am J Epidemiol 90:365-380, 1969.
Patient information
PROVERA Tablets contain medroxyprogesterone
acetate a synthetic progesterone.
The information below is that which the U.S. Food and Drug Administration
requires be provided for all patients taking medroxyprogesterone acetates.
The information below relates only to the risk to the unborn child associated
with use of medroxyprogesterone acetate during pregnancy. For further information
on the use, side effects and other risks associated with this product, ask your
doctor or read the information
WARNING FOR WOMEN
Medroxyprogesterone acetate or progesterone-like drugs
have been used to prevent miscarriage in the first few months of pregnancy.
No adequate evidence is available to show that they are effective for this
purpose. Furthermore, most cases of early miscarriage are due to causes which
could not be helped by these drugs.
There is an increased risk of minor birth defects in children whose mothers
take this drug during the first 4 months of pregnancy. Several reports suggest
an association between mothers who take these drugs in the first trimester of
pregnancy and genital abnormalities in male and female babies. The risk to the
male baby is the possibility of being born with a condition in which the opening
of the penis is on the underside rather than the tip of the penis (hypospadias).
Hypospadias occurs in about 5 to 8 per 1,000 male births and is about doubled
with exposure to these drugs. There is not enough information to quantify the
risk to exposed female fetuses, but enlargement of the clitoris and fusion of
the labia may occur, although rarely.
Therefore, since drugs of this type may induce mild masculinization of the
external genitalia of the female fetus, as well as hypospadias in the male
fetus, it is wise to avoid using the drug during the first trimester of
pregnancy.
These drugs have been used as a test for pregnancy but such use is no longer
considered safe because of possible damage to a developing baby. Also, more
rapid methods for testing for pregnancy are now available.
If you take PROVERA and later find you were pregnant when you took it, be sure
to discuss this with your doctor as soon as possible.
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