WARNING
- Bleeding Irregularities
Most women using DEPO-PROVERA 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 ruleout the possibility or organic pathology, and
appropriate treatment should be instituted when necessary.
As women continue using DEPO-PROVERA Contraceptive Injection,
fewer experience irregular bleeding and more experience
amenorrhea. By month 12 amenorrhea was reported by 55%
of women, and by month 24amenorrhea was reported by
68% of women using DEPO-PROVERA Contraceptive Injection.
2
- Bone Mineral Density Changes
Use of DEPO-PROVERA 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.
- Cancer Risks
Long-term case-controlled surveillance of users of DEPO-PROVERA
Contraceptive Injection found slight or no increased
overall risk of breast cancer 3 and no overall
increased risk of ovarian, 4 liver, 5
or cervical 6 cancer and a prolonged,
protective effect of reducing the risk of endometrial
7 cancer in the population of users.
A pooled analysis 14 from two case-control
studies, the World Health Organization Study 3
and the New Zealand Study 13 , reported
the relative risk (RR) of breast cancer for women who
had ever used DEPO-PROVERA Contraceptive Injection as
1.1 (95% confidence interval (Cl) 0.97 to 1.4). Overall,
there was no increase in risk with increasing duration
of use of DEPO-PROVERA Contraceptive Injection. The
RR of breast cancer for women of all ages who had initiated
use of DEPO-PROVERA Contraceptive Injection within the
previous 5 years was estimated to be 2.0 (95% Cl 1.5
to 2.8).
The World Health Organization Study 3 , a
component of the pooled analysis 14 described
above, showed an increased RR of 2.19 (95% Cl 1.23 to
3.89) of breast cancer associated with use of DEPO-PROVERA
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 DEPO-PROVERA Contraceptive Injection was only 1.2
(95% Cl 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% Cl 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 of 2.19 means that women whose first exposure to
drug was within the previous 4 years and who are under
35 years of agvaluee have a 2.19-fold (95% Cl 1.23 to
3.89-fold) increased risk of breast cancer relative
to nonusers. The National Cancer Institute 8 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 DEPO-PROVERA Contraceptive Injection
in women who were first exposed before the age of 35
years (RR 1.22 to 1.28 and 95% Cl 0.93 to 1.70). The
overall, nonsignificant relative rate of invasive squamous-cell
cervical cancer in women who ever used DEPO-PROVERA
Contraceptive Injection was estimated to be 1.11 (95%
Cl 0.96 to 1.29). No trends in risk with duration of
use or times since initial or most recent exposure were
observed.
- 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.
- 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.
- Unexpected Pregnancies
To ensure that DEPO-PROVERA 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 DEPO-PROVERA 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. 9,10
A significant increase in incidence of polysyndactyly
and chromosomal anomalies was observed among infants
of users of DEPO-PROVERA 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 DEPO-PROVERA Contraceptive Injection, and
the chance effects due to multiple statistical comparisons,
make a causal association unlikely. 11
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 hypospadias (five to eight 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 because 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.
To ensure that DEPO-PROVERA 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 ).
- Ectopic Pregnancy
Health-care providers should be alert to the possibility
of an ectopic pregnancy among women using DEPO-PROVERA
Contraceptive Injection who become pregnant or complain
of severe abdominal pain.
- Lactation
Detectable amounts of drug have been identified in the
milk of mothers receiving DEPO-PROVERA Contraceptive
Injection. In nursing mothers treated with DEPO-PROVERA
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.
- Anaphylaxis and Anaphylactoid Reaction
Anaphylaxis and anaphylactoid reaction have been reported
with the use of DEPO-PROVERA Contraceptive Injection.
If an anaphylactic reaction occurs appropriate therapy
should be instituted. Serious anaphylactic reactions
require emergency medical treatment.
PRECAUTIONS
GENERAL
- Physical Examination
It is good medical practice for all women to have annual
history and physical examinations, including women using
DEPO-PROVERA Contraceptive Injection. 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.
- 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.
- Weight Changes
There is a tendency for women to gain weight while on
therapy with DEPO-PROVERA Contraceptive Injection. From
an initial average body weight of 136 lb, women who
completed 1 year of therapy with DEPO-PROVERA 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.
- Return of Fertility
DEPO-PROVERA Contraceptive Injection has a prolonged
contraceptive effect. In a large US study of women who
discontinued use of DEPO-PROVERA 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 DEPO-PROVERA Contraceptive
Injection to become pregnant and who were lost to follow-up
or changed their mind.
- 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 DEPO-PROVERA Contraceptive
Injection. Association with drug use or pre-existing
conditions is not clear.
- Carbohydrate Metabolism
A decrease in glucose tolerance has been observed in
some patients on DEPO-PROVERA Contraceptive Injection
treatment. The mechanism of this decrease is obscure.
For this reason, diabetic patients should be carefully
observed while receiving such therapy.
- Liver Function
If jaundice develops, consideration should be given
to not readministering the drug.
- Protection Against Sexually Transmitted Diseases
Patients should be counseled that this product does
not protect against HIV infection (AIDS) and other sexually
transmitted diseases.
DRUG INTERACTIONS
Aminoglutethimide administered concomitantly with the
DEPO-PROVERA Contraceptive Injection may significantly
depress the serum concentrations of medroxyprogesterone
acetate. 12 Users of DEPO-PROVERA Contraceptive
Injection 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 Contraceptive Injection:
- Plasma and urinary steroid levels are decreased (eg,
progesterone, estradiol, pregnanediol, testosterone,
cortisol).
- Gonadotropin levels are decreased.
- Sex-hormone-binding-globulin concentrations are decreased.
- Protein-bound iodine and butanol extractable protein-bound
iodine may increase.
T 3 -uptake values may decrease.
- Coagulation test values for prothrombin (Factor II),
and Factors VII, VIII, IX, and X may increase.
- Sulfobromopthalein and other liver function test values
may be increased.
- 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
See "
WARNINGS
" section 3.
PREGNANCY
Pregnancy Category X. See "
WARNINGS
" section 6.
NURSING MOTHERS
See "
WARNINGS
" section 8.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not
been established. See " WARNINGS " section 6.
INFORMATION FOR THE PATIENT
See Patient Labeling.
Patient labeling is included with each single-dose vial
and prefilled syringe of DEPO-PROVERA Contraceptive Injection
to help describe its characteristics to the patient. It
is recommended that prospective users be given this labeling
and be informed about the risks and benefits associated
with the use of DEPO-PROVERA 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 DEPO-PROVERA
Contraceptive Injection continues, without other therapy
being required.
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