Provera
WARNING
DESCRIPTION
ACTIONS
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
PATIENT INFORMATION
WARNING FOR WOMEN
THE USE OF PROVERA (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 200º and 210ºC. 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 medroxyprogesterone 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.
Medroxyprogesterone acetate, administered orally or parenterally in the recommended doses to women with
adequate endogenous estrogen, transforms proliferative into secretary 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.
1. 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.
2. 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.
3. 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.
4. 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.
5. Usage in pregnancy is not recommended (See WARNING Box).
6. 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 vaginurn, 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.
Carcinogenesis, 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.
Information for the Patient
See Patient Information at end of insert.
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 cholestatic jaundice
spotting anaphylactoid reactions
change in menstrual and anaphylaxis
flow rash (allergic) with
amenorrhea and without
edema pruritus
change in weight mental depression
(increase or pyrexia
decrease) insomnia
changes in cervical nausea
erosion and cervical somnolence
secretions
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 estrogenprogestin combination drugs:
rise in blood pres- fatigue
sure in susceptible backache
individuals hirsutism
premenstrual-like loss of scalp hair
syndrome erythema multiforme
changes in libido erythema nodosum
changes in appetite hemorrhagic
cystitis-like syndrome eruption
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.
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 secretary
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 secretary 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™ 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 epidemioloical case-
control study. Am J Epidemiol 90:365-380, 1969.
The text of the patient insert for progesterone and progesterone-like drugs is set forth below.
PROVERA Tablets contain medroxyprogesterone acetate a progesterone. The information below is that which
the U.S. Food and Drug Administration requires be provided for all patients taking progesterones. The
information below relates only to the risk to the unborn child associated with use of progesterone during
pregnancy. For further information on the use, side effects and other risks associated with this product, ask your
doctor.
Progesterone 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.
Caution: Federal law prohibits dispensing without prescription.
The Upjohn Company
Kalamazoo, MI 49001, USA
Revised January 1992
812 584 409
691015