The following information is published by
the manufacturer of synthetic progesterone:
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.
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:
Contrastingly, the molecule for Natural Progesterone looks like this:
This is the molecule made by the female body and the exact same molecule
found in a Properly Formulated Natural Progesterone cream. Dr. John Lee,of California,
U.S.A., used natural progesterone creams in his practice for 19
years. He states in his books that natural progesterone is remarkably safe and
free of side-effects when administered in a proper cream formulation.
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.
Secondary amenorrhea; abnormal uterine bleeding
due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine
cancer.
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.
Missed abortion.
As a diagnostic test for pregnancy.
Known sensitivity to PROVERA Tablets.
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.
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.
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.
Information for the Patient
See Patient Information at end of insert.
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.
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).
1. Royal College of General Practitioners: Oral contraception
and thromboembolic disease. J Coll Gen Pract 13:267-279, 1967.
2.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.
3.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.
4.Sartwell PE, Masi AT, Arthes FG, et al: Thromboembolism and oral contraceptives:
An epidemiological case-control study. Am J Epidemiol 90:365-380, 1969.
The text of the patient insert for medroxyprogesterone acetate and progesterone-like
drugs is set forth below.
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 here.
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