CONTRAINDICATIONS
Oral Tablets
1. Thrombophlebitis, thromboembolic disorders, cerebral apoplexy or patients
with a past history of these conditions.
2. Liver dysfunction or disease.
3. Known or suspected malignancy of breast or genital organs.
4. Undiagnosed vaginal bleeding.
5. Missed abortion.
6. As a diagnostic test for pregnancy.
7. Known sensitivity to medroxyprogesterone acetate.
Sterile Aqueous Suspension and Contraceptive Injection
1. Known or suspected pregnancy or as a diagnostic test for pregnancy.
2. Undiagnosed vaginal bleeding.
3. Known or suspected malignancy of the 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 medroxyprogesterone acetate or any of the inactive
ingredients.
WARNINGS
Oral 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should be withdrawn.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 neonate and infant has not been
determined.
5. Usage in pregnancy is not recommended (See BOXED WARNING).
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.
Sterile Aqueous Suspension
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 1000 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
medroxyprogesterone acetate sterile aqueous suspension during the first four
months of pregnancy or if she becomes pregnant while taking this durg, 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 medroxyprogesterone acetate 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.
Contraceptive Injection
1. Bleeding Irregularities: Most women using medroxyprogesterone acetate
contraceptive injection experience disruption of menstrual bleeding patterns.
Altered menstrual bleeding patterns include irregular or unpredictable bleeding or
spotting, or rarely, heavy or continuous bleeding. If abnormal bleeding persists or
is severe, appropriate investigation should be instituted to rule out the possibility of
organic pathology, and appropriate treatment should be instituted when necessary.
As women continue using medroxyprogesterone acetate contraceptive injection, fewer
experience irregular bleeding and more experience amenorrhea. By month 12
amenorrheas was reported by 55% of women, and by month 24 amenorrhea was
reported by 68% of women using medroxyprogesterone acetate contraceptive injection.5
2. Bone Mineral Density Changes: Use of medroxyprogesterone acetate
contraceptive injection may be considered among the risk factors for development
of osteoporosis. The rate of bone loss is greatest in the early years of use and then
subsequently approaches the normal rate of age related fall.
3. Cancer Risks: Long-term case-controlled surveillance of users of
medroxyprogesterone acetate contraceptive injection found slight or no increased
overall risk of breast cancer7 and no overall increased risk of ovarian,8 liver,9 or
cervical10 cancer and a prolonged, protective effect of reducing the risk of
endometrial11 cancer in the population of users.
A pooled analysis18 from two case-control studies, the World Health Organization
Study7 and the New Zealand Study,17 reported the relative risk (RR) of breast cancer
for women who had ever used medroxyprogesterone acetate contraceptive injection as
1.1 (95% confidence interval [CI] 0.97 to 1.4). Overall, there was no increase in risk
with increasing duration of use of medroxyprogesterone acetate contraceptive injection.
The RR of breast cancer for women of all ages who had initiated use of
medroxyprogesterone acetate contraceptive injection within the previous 5 years was
estimated to be 2.0 (95% CI 1.5 to 2.8).
The World Health Organization Study,7 a component of the pooled analysis18 described
above, showed an increased RR of 2.19 (95%) CI 1.23 to 3.89) of breast cancer
associated with use of medroxyprogesterone acetate contraceptive injection in women
whose first exposure to drug was within the previous 4 years and who were under 35
years of age. However the overall RR for ever-users of medroxyprogesterone acetate
contraceptive injection was only 1.2 (95% CI 0.96 to 1.52).
Note: A RR of 1.0 indicates neither an increased nor a decreased risk of cancer
associated with the use of the drug, relative to no use of the drug. In the case of the
subpopulation with a RR of 2.19, the 95% CI is fairly wide and does not include the
value of 1.0, thus inferring an increased risk of breast cancer in the defined subgroup
relative to nonusers. The value of 2.19 means that women whose first exposure to drug
was within the previous 4 years and who are under 35 years of age have a 2.19-fold
(95% C.I. 1.23- to 3.89-fold) increased risk of breast cancer relative to nonusers. The
National Cancer Institute12 reports an average annual incidence rate for breast cancer for
US women, all races, age 30 to 34 years of 26.7 per 100,000. A RR of 2.19 thus,
increases the possible risk from 26.7 to 58.5 cases per 100,000 women. The attributable
risk, thus, is 31.8 per 100,000 women per year.
A statistically insignificant increase in RR estimates of invasive squamous-cell cervical
cancer has been associated with the use of medroxyprogesterone acetate contraceptive
injection in women who were first exposed before the age of 35 years (RR 1.22 to 1.28
and 95% CI 0.93 to 1.70). The overall, nonsignificant relative rate of invasive
squamous-cell cervical cancer in women who ever used medroxyprogesterone acetate
contraceptive injection was estimated to be 1.11 (95% CI 0.96 to 1.29). No trends in
risk with duration of use or times since initial or most recent exposure were observed.
4. Thromboembolic Disorders: The physician should be alert to the earliest
manifestations of thrombotic disorders (thrombophlebitis, pulmonary embolism,
cerebrovascular disorders, and retinal thrombosis). Should any of these occur or
be suspected, the drug should not be readministered.
5. Ocular Disorders: Medication should not be readministered 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 not be readministered.
6. Unexpected Pregnancies: To ensure that medroxyprogesterone acetate
contraceptive injection is not administered inadvertently to a pregnant woman, the
first injection must be given ONLY during the first 5 days of a normal menstrual
period; ONLY within the first 5-days postpartum if not breast-feeding, and if
exclusively breast-feeding, ONLY at the sixth postpartum week (see DOSAGE
AND ADMINISTRATION).
Neonates from unexpected pregnancies that occur 1 to 2 months after injection of
medroxyprogesterone acetate contraceptive injection may be at an increased risk of low
birth weight, which, in turn, is associated with an increased risk of neonatal death. The
attributable risk is low because such pregnancies are uncommon.13, 14
A significant increase in incidence of polysyndactyly and chromosomal anomalies was
observed among infants of users of medroxyprogesterone acetate contraceptive injection,
the former being most pronounced in women under 30 years of age. The unrelated nature
of these defects, the lack of confirmation from other studies, the distant preconceptual
exposure to medroxyprogesterone acetate contraceptive injection, and the chance effects
due to multiple statistical comparisons, make a causal association unlikely.15
Neonates exposed to medroxyprogesterone acetate in utero and followed to
adolescence, showed no evidence of any adverse effects on their health including their
physical, intellectual, sexual or social development.
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 hypospadia (5 to 8 per 1000 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 because some of these drugs induce
mild virilization of the external genitalia of the female fetus and because of the increased
association of hypospadia in the male fetus, it is prudent to avoid use of these drugs
during the first trimester of pregnancy.
To ensure that medroxyprogesterone acetate contraceptive injection is not administered
inadvertently to a pregnant woman, it is important that the first injection be given only
during the first 5 days after the onset of a normal menstrual period within 5 days
postpartum if not breast-feeding and if breast-feeding, at the sixth week postpartum (see
DOSAGE AND ADMINISTRATION).
7. Ectopic Pregnancy: Health-care providers should be alert to the possibility of
an ectopic pregnancy among women using medroxyprogesterone acetate
contraceptive injection who become pregnant or complain of severe abdominal
pain.
8. Lactation: Detectable amounts of drug have been identified in the milk of
mothers receiving medroxyprogesterone acetatecontraceptive injection. In nursing
mothers treated with medroxyprogesterone acetate contraceptive injection, milk
composition, quality, and amount are not adversely affected. Neonates and infants
exposed to medroxyprogesterone from breast milk have been studied for
developmental and behavioral effects through puberty. No adverse effects have
been noted.
9. Anaphylaxis and Anaphylactoid Reaction: Anaphylaxis and anaphylactoid
reaction have been reported with the use of medroxyprogesterone acetate
contraceptive injection. If an anaphylactic reaction occurs appropriate therapy
should be instituted. Serious anaphylactic reactions require emergency medical
treatment.
PRECAUTIONS
Oral Tablets
1. The pretreatment physical examination should include special reference to
breast and pelvic organs, as well as Papanicolaou smear.
2. 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.
3. 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.
4. 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. Any possible influence of prolonged progestin therapy on pituitary, ovarian,
adrenal, hepatic or uterine functions awaits further study.
6. 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.
7. The age of the patient constitutes no absolute limiting factor although treatment
with progestins may mask the onset of the climacteric.
8. The pathologist should be advised of progestin therapy when relevant
specimens are submitted.
9. 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.
10. 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.
11. Aminoglutethimide administered concomitantly with medroxyprogesterone
acetate tablets may significantly depress the bioavailability of
medroxyprogesterone acetate.
12. Safety and effectiveness in pediatric patients below the age of 12 years have
not been established.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term intramuscular
administration of medroxyprogesterone acetate 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 medroxyprogesterone acetate 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 PACKAGE INSERT.
Sterile Aqueous Suspension
1. Physical Examination: It is good medical practice for all women to have
annual history and physical examinations, including women using
medroxyprogesterone acetate contraceptive injection. The physical examination,
however, may be deferred until after initation of medroxyprogesterone acetate
sterile aqueous suspension 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 cervial 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 endometria 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 decreas is
obscure. For this reason, diabetic patients should be carefully observed while
receiving such therapy.
7. Prolonged Use: The effect of prolonged use of medroxyprogesterone acetate
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
medroxyprogesterone acetate 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.)
Contraceptive Injection
1. Physical Examination: It is good medical practice for all women to have
annual history and physical examination, including women using
medroxygrogesterone acetate congtraceptive injection. The physical examination,
however, may be deferred until after initiation of medroxygrogesterone acetate
contraceptive injection 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, inlcuding 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 that might be influenced by this condition, such as epilepsy,
migraine, asthma, and cardiac or renal dysfunction, require careful observation.
3. Weight Changes: There is a tendency for women to gain weight while on
therapy with medroxyprogesterone acetate contraceptive injection. From an initial
average body weight of 136 lb, women who completed 1 year of therapy with
medroxyprogesterone acetate contraceptive injection gained an average of 5.4 lb.
Women who completed 2 years of therapy gained an average of 8.1 lb.
Women who completed 4 years gained an average of 13.8 lb. Women who completed 6
years gained an average of 16.5 lb. Two percent of women withdrew from a large-scale
clinical trial because of excessive weight gain.
4. Return of Fertility: Medroxyprogesterone acetate contraceptive injection has a
prolonged contraceptive effect. In a large U.S. study of women who discontinued
use of medroxyprogesterone acetate contraceptive injection to become pregnant,
data are available for 61% of them. Based on Life-Table analysis of these data, it
is expected that 68% of women who do become pregnant may conceive within 12
months, 83% may conceive within 15 months, and 93% may conceive within 18
months from the last injection. The median time to conception for those who do
conceive is 10 months following the last injection with a range of 4 to 31 months,
and is unrelated to the duration of use. No data are available for 39% of the
patients who discontinued medroxyprogesterone acetate contraceptive injection to
become pregnant and who were lost to follow-up or changed their mind.
5. CNS Disorders and Convulsions: Patients who have a history of psychic
depression should be carefully observed and the drug not be readministered if the
depression recurs.
There have been a few reported cases of convulsions in patients who were treated with
medroxyprogesterone acetate contraceptive injection. Association with drug use or
pre-existing conditions is not clear.
6. Carbohydrate Metabolism: A decrease in glucose tolerance has been
observed in some patients on medroxyprogesterone acetate contraceptive
injection treatment. The mechanism of this decrease is obscure. For this reason,
diabetic patients should be carefully observed while receiving such therapy.
7. Liver Function: If jaundice develops, consideration should be given to not
readministering the drug.
8. Protection Against Sexually Transmitted Diseases: Patients should be
counseled that this product does not protect against HIV infection (AIDS) and
other sexually transmitted diseases.
Carcinogenesis: See WARNINGS, Cancer.
Pregnancy Category X: See WARNINGS, Lactation.
Nursing Mothers: See WARNINGS, Lactation.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
See WARNINGS, Unexpected Pregnancies.
Information for the Patient: Patient labeling is included with each single-dose vial and
prefilled syringe of medroxyprogesterone acetate contraceptive injection to help describe
its characteristics to the patient (see PATIENT PACKAGE INSERT). It is
recommended that prospective users be given this labeling and be informed about the
risks and benefits associated with the use of medroxyprogesterone acetate contraceptive
injection, as compared with other forms of contraception or with no contraception at all.
It is recommended that physicians or other health- care providers responsible for those
patients advise them at the beginning of treatment that their menstrual cycle may be
disrupted and that irregular and unpredictable bleeding or spotting results, and that this
usually decreases to the point of amenorrhea as treatment with medroxyprogesterone
acetate contraceptive injection continues, without other therapy being required.
Laboratory Test Interactions
Sterile Aqueous Suspension and Contraceptive Injection
The pathologist should be advised of progestin therapy when relevant specimens are
submitted.
The following laboratory tests may be affected by progestins including
medroxyprogesterone acetate:
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.