Depo-Provera

Interactions with herbal products have not been established.

Aminoglutethimide administered concomitantly with DEPO-PROVERA (medroxyprogesterone acetate) may significantly depress the serum concentration of medroxyprogesterone acetate. Users of DEPO-PROVERA should be warned of the possibility of decreased efficacy with the use of this or any related drugs.

Interactions with food have not been established.

The results of one study indicated that intramuscularly administered medroxyprogesterone acetate may induce or activate the CYP3A4 enzyme system, leading to an increased metabolism of many CYP3A4 substrates.

Rifampin can increase the metabolism of exogenously administered progestational agents. Norethindrone has specifically been affected; a reduction of plasma concentrations has occurred. The extent to which rifampin may alter the metabolism of other progestogens remains to be determined; the possibility of an interaction should be considered.

Certain endocrine and possibly liver function tests may be affected by treatment with DEPO-PROVERA. Therefore, if such tests are abnormal in a woman taking DEPO-PROVERA, it is recommended that they be repeated 6 to 12 months after the drug has been withdrawn.

The clinical chemist or pathologist should be advised of progestogen therapy when a woman's blood or tissue specimens are submitted for laboratory diagnosis or biochemical analysis.

The following laboratory tests may be affected by the use of DEPO-PROVERA: (a) Gonadotropin levels—inhibition of the midcycle LH surge; (b) Plasma progesterone levels—inhibition of ovulation and thus the postovulatory rise of progesterone; (c) Plasma estrogen levels—do not exceed early-to-mid-proliferative phase levels; (d) Plasma cortisol levels—not significantly affected by the dose used for contraception; (e) Glucose tolerance test—occasionally some degree of glucose intolerance may develop; (f) Plasma lipid concentrations—decrease in high density lipoprotein cholesterol (HDL-C) in some studies. The clinical relevance of this has yet to be determined; (g) Urinary pregnanediol levels. (Note: DEPO-PROVERA does not interfere with the assay of human chorionic gonadotropin (HCG) either chemically or pharmacologically.)

DEPO-PROVERA should not be used before menarche (see Contraindications and Warnings and Precautions).

See Warnings and Precautions, Loss of Bone Mineral Density for available data for adolescent females (12-18 years).

The recommended dose of DEPO-PROVERA is 50 mg weekly or 100 mg every 2 weeks intramuscularly for at least 6 months. It should be noted that return of ovulation may be delayed following this therapy due to the depot properties of the drug (see Warnings and Precautions).

The recommended dose for contraception is 150 mg of DEPO-PROVERA (medroxyprogesterone acetate) every 3 months, administered by deep intramuscular injection. To increase assurance that the woman is not pregnant at the time of the first administration, it is recommended that this injection be given only within the 5 five days of the onset of a normal menstrual period or, only within the first 5 days post-partum if not breast-feeding. If the woman has chosen to breast-feed, discuss the risks of pregnancy and possible risks of DEPO-PROVERA to determine the most appropriate course of action for the individual woman (see Warnings and Precautions).

If administered within the first 5 days after the onset of a normal menstrual period, DEPO-PROVERA is effective from the day of injection. When DEPO-PROVERA is given later in the menstrual cycle it may not be effective for the first 3 to 4 weeks after the injection and another method of contraception (non-hormonal) should be used during this time.

After miscarriage or first trimester therapeutic abortion, the injection is normally given within 5 days of the procedure and no extra precautions are required. After a late (second trimester) abortion, some further delay is recommended to reduce the risk of heavy and prolonged bleeding, therefore, the first injection should not be given until 4 weeks after the procedure.

The woman must return every 10 to 13 weeks for a repeat injection to maintain contraceptive effectiveness. Intervals between injections must not exceed 13 weeks (3 months).

DEPO-PROVERA is intended for intramuscular administration only. Immediately before use, the sterile aqueous suspension should be vigorously shaken to assure that the dose being administered represents a uniform suspension.

If an injection is not given within 13 weeks a pregnancy test should be done before any further treatment with DEPO-PROVERA.

macular edema, optic ischemic neuropathy, optic neuritis, papilloedema, ptosis, retinal vein occlusion, vision loss, visual changes.

adrenal dysfunction NOS, Cushingoid, estrogen deficiency, hyperthyroidism, hypoglycemia, hypopituitarism, hypothyroidism, thyroiditis.

joint swelling, muscle weakness, myalgia, osteonecrosis.

acute respiratory distress syndrome, bronchospasm, epistaxis, laryngeal edema, laryngospasm, oropharyngeal swelling.

amnesia, anosmia, ataxia, balance disorder, benign intracranial hypertension, cerebral hemorrhage, cerebral ischemia/infarct, cerebral venous thrombosis, cerebrovascular accident, confusion, dysarthria, dysgeusia, memory loss, migraine, myoclonus, Parkinsonism, seizures, speech disorder, stroke (with fatal outcome), third nerve palsy, transient ischemic attack, tremor.

angioedema, erythema multiforme, erythema nodosum, facial edema, porphyria aggravated.

acute porphyria, in cases of failure of contraception: Trisomy 21, Trisomy 16, Turner's syndrome.

salpingitis, sepsis, vulval abscess.

Laboratory assays were performed on a sample of women, rather than on all women. There were no clinically significant changes in any of the hematology, urine or serum chemistry variables that were monitored.

The number of women having had an initial Pap smear taken is 2052. Ten (10) patients dropped from the study due to a Grade IV Pap smear, while 4 patients dropped out due to a Grade III Pap smear.

One hundred and ninety four (194) patients reported no bleeding or spotting from first injection to the end of their participation in the study. The median number of days of no spotting or bleeding for these 194 women was 120 days. The minimum number of days of no spotting or bleeding was 30 and the maximum was 1674 days.

Thirteen (13) patients reported bleeding and/or spotting every day from first injection to the end of their participation in the study.

Occurrence Rates for Non-menstrual Adverse Reactions Reported in U.S. Studies of 3905 Women Receiving DEPO-PROVERA Every 3 Months

arterial thrombosis, embolism, Henoch-Schonlein purpura, postural hypotension, venous thrombosis (including rare cases with fatal outcome).

acute leukemia, benign breast neoplasm, benign hydatidiform mole, fibroadenoma of breast, Hodgkin's disease, kidney neoplasm, malignant melanoma, meningioma, neurofibroma, ovarian cancer, squamous cell carcinoma of the cervix, uterine leiomyoma.

coagulation Factor X decreased, decreased blood folate, decreased blood pressure, decreased estrogen, decreased testosterone, elevated blood creatinine, hypernatremia, hypokalemia, increased alanine aminotransferase, increased alkaline phosphatase, increased blood pressure, increased creatine phosphokinase, increased triglycerides, leukocytosis, weight decreased.

hemolytic anemia, hemorrhagic disorder, sickle cell crisis, splenic infarction, thrombocytopenia, thrombotic thrombocytopenic purpura.

acute psychosis, agitation, anxiety, attention deficit/hyperactivity disorder, dysphemia, eating disorder, irritability, mood swings, paranoia, suicidality.

acute pancreatitis, dysphagia, intestinal infarction, mouth ulceration, oral mucosal blistering, salivary gland enlargement.

cervical dysplasia, fibrocystic breast disease, menorrhagia, ovarian cyst, premature menopause, uterine cyst, vaginal dysplasia, vaginal mucosal blistering.

In post-marketing experience, there have been cases of osteoporosis including osteoporotic fractures reported in patients taking DEPO-PROVERA. Patient age ranged from 16 years to 48 years. Other adverse events reported during post-marketing experience, regardless of causality and frequency, are listed below. It should be noted that the nature of post-marketing surveillance makes it difficult to determine if a reported event was actually caused by DEPO-PROVERA.

cachexia, excessive thirst.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In clinical studies of 3905 women receiving DEPO-PROVERA every 3 months, there were a total of 8467 side effect reports. Headache, abdominal distress, nervousness, dizziness and decreased libido were reported in greater than 5.0 percent of study patients. Thrombophlebitis was reported by 4 women (0.10%).

bradycardia, myocardial infarction, palpitations, pericarditis, possible exacerbation of prolonged QT interval syndrome (with fatal outcome), supraventricular tachycardia.

fatigue, injection site reactions (including swelling, rash, ulcer, necrosis, edema, infection, abscess), malaise, sudden infant death syndrome (exposure-in-utero).

change in hearing, tinnitus, vertigo.

interstitial nephritis, nephrolithiasis, nephrotic syndrome, proteinuria, renal infarct, urinary retention.

exposure in utero: abnormal genitalia, anencephaly, cleft palate, congenital adenomatoid malformation, congenital diaphragmatic hernia, congenital heart defects, congenital megacolon, ear malformation NOS, esophageal atresia, hydrocephalus, hypospadias, limb deformity, microcephaly, polydactyly, single umbilical artery, skull malformation, spina bifida, Talipes, tracheoesophageal fistula.

cholangitis, cholelithiasis, gallbladder disorder, hepatitis, hepatomegaly, obstructive jaundice, hepatic failure (with fatal outcome).

exposure-in-utero: antepartum hemorrhage, blighted ovum, ectopic pregnancy, fetal hydrops, intrauterine growth retardation, missed abortion, polyhydramnios, prematurity, spontaneous abortion, stillbirth.

The following adverse reactions have been associated with the use of DEPO-PROVERA (medroxyprogesterone acetate):

1. Irregular Menstrual Patterns: The most common adverse reactions associated with the use of DEPO-PROVERA for contraception is the disruption of menstrual patterns. This includes irregular or unpredictable bleeding or spotting, or rarely heavy or continuous bleeding.

   
   

2. Non-Menstrual Adverse Reactions: Other than menstrual changes, weight gain, headache and abdominal discomfort are the most common side effects.

   
   

   In a few instances there have been undesirable sequelae at the site of injection, such as a residual lump, change in colour of the skin or a sterile abscess.

   
   

   Anaphylactic and anaphylactoid reactions have been reported on rare occasions.

anaphylactic reaction (with fatal outcome in rare cases), hypersensitivity.

Each mL contains: medroxyprogesterone acetate 150 mg. Nonmedicinal ingredients: hydrochloric acid, methylparaben, polyethylene glycol, polysorbate, propylparaben, sodium chloride, sodium hydroxide and water for injection. Vials of 1 mL, boxes of 1, 5 and 25.

Each mL contains: medroxyprogesterone acetate 50 mg. Nonmedicinal ingredients: hydrochloric acid, methylparaben, polyethylene glycol, polysorbate, propylparaben, sodium chloride, sodium hydroxide and water for injection. Vials of 5 mL, boxes of 1. Single use only.

If feasible, hormonal contraceptives should be discontinued and an alternative method substituted at least four weeks prior to elective surgery of a type associated with an increase in risk of thromboembolism and during prolonged immobilization. Hormonal contraceptives should not be resumed until the first menstrual period after hospital discharge following surgery or following prolonged immobilization.

After stopping use of DEPO-PROVERA (150 mg IM), there was partial recovery of BMD toward baseline values during the 2-year post-therapy period. A longer duration of treatment was associated with a less complete BMD recovery observed during the 2-year, post-therapy period.

Use of DEPO-PROVERA reduces serum estrogen levels and is associated with significant loss of BMD as bone metabolism accommodates to a lower estrogen level. This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if the use of DEPO-PROVERA by younger women will reduce peak bone mass and increase the risk for osteoporotic fractures in later life. A study to assess the reversibility of loss of BMD in adolescent females is ongoing.

BMD should be monitored in women using DEPO-PROVERA for longer than 2 years, or earlier as clinically appropriate. In adolescent females, interpretation of BMD results should take into account patient age and skeletal maturity. If a clinically significant decrease in BMD is detected, treatment with DEPO-PROVERA should be reconsidered.

Use of DEPO-PROVERA should be considered a risk factor for osteoporosis. The use of DEPO-PROVERA should be considered in light of a patient's possible other risk factors for osteoporosis (including metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids).

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.

To increase assurance that the woman is not pregnant at the time of the first administration, it is recommended that the first injection be given only within the first 5 days of the onset of a normal menstrual period or, only within the first 5 days post-partum if not breast-feeding (see Dosage and Administration).

Infants from unexpected pregnancies that occurred 1 to 2 months after injection of DEPO-PROVERA 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.

A significant increase in incidence of polysyndactyly and chromosomal anomalies was observed among infants of users of DEPO-PROVERA, 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 and the chance effects due to multiple statistical comparisons, make a causal association unlikely.

Children 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 intra-uterine 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. Although there are insufficient data to quantify the risk to exposed female fetuses, some of these drugs induce mild virilization of the external genitalia of the female fetus. Because of these changes, it is prudent to avoid the use of progestogens during the first trimester of pregnancy.

Disruption of menstrual patterns is common following the administration of DEPO-PROVERA. This includes irregular or unpredictable bleeding or spotting, or rarely heavy or continuous bleeding. If undiagnosed vaginal bleeding occurs, or if abnormal bleeding persists or is severe, appropriate investigation should be instituted to rule out the possibility of organic pathology, and appropriate treatment instituted if necessary.

As women continue to use DEPO-PROVERA, fewer experience irregular bleeding patterns and more experience amenorrhea. By month 12, amenorrhea was reported by 55% of women, and by month 24, amenorrhea was reported by 68% of women using DEPO-PROVERA.

Because of the prolonged effect following intramuscular injection of DEPO-PROVERA, re-establishment of menstruation may be delayed and difficult to predict. For this reason, DEPO-PROVERA is not recommended for treatment of secondary amenorrhea or functional uterine bleeding. For these conditions, oral progestogen therapy is recommended.

Liver function tests should be performed periodically in women who are suspected of, or who are at risk of, having hepatic disease. The physician should be alert to the earliest manifestations of impaired liver function. Should this occur or be suspected, the treatment should not be continued. The woman's status should be re-evaluated at appropriate intervals. If jaundice develops, consideration should be given to discontinue the drug.

Patients who have had jaundice, including a history of cholestatic jaundice during pregnancy or during use of oral contraceptives should be given hormonal contraceptives only with great care and under close observation.

Preliminary data from a small number of adolescents have shown only partial recovery of BMD during the 2-year, post-use observation period. Follow-up bone measurements for the treatment-free period are ongoing. The Product Monograph will be updated once final results are available.

In addition to BMD results, Table 2 also shows the % changes (vs baseline) in Bone Mineral Content (BMC). Whole body BMC is a measure of the overall mineral content of the skeleton. Unlike the adult skeleton, that of the adolescent is growing in size. Therefore, while examination of BMD changes is generally sufficient for understanding the adult subject, both BMD and BMC should be assessed together in the adolescent. The results in Table 2 indicate that adolescents who chose DEPO-PROVERA increased whole body BMC at a slower rate than adolescents who initially chose abstinence or non-hormonal contraception and may have elected non-DEPO-PROVERA hormonal contraception (e.g., oral contraceptives) after the initial visit. BMC measurements of the specific skeletal sites (total hip, femoral neck and lumbar spine) in adolescents taking DEPO-PROVERA showed decreases that are similar in magnitude to the decreases in BMD seen at those sites. Preliminary results obtained from all users of DEPO-PROVERA (defined as adolescents who took one or more doses of DEPO-PROVERA, and then stopped the treatment) show that BMC increases during the 2 year post-use observation period after treatment is stopped. The full extent of BMC recovery has not been defined and follow-up measurements for the treatment-free period are on-going. The Product Monograph will be updated once final results are available.

In post-marketing experience, there have been cases of osteoporosis including osteoporotic fractures reported in patients taking DEPO-PROVERA. Patient age ranged from 16 years to 48 years (see Adverse Reactions, Post-Market Adverse Drug Reactions).

There is no evidence that DEPO-PROVERA causes infertility. A large study of return of fertility shows that women conceived 9 months on average after the last injection, or 5.5 months after discontinuing (discontinuance is assumed to be 15 weeks after the last injection). In addition, the number of users who had conceived within 2 years of discontinuing their method of contraception (92% of DEPO-PROVERA users had conceived within 2 years after discontinuing compared with 93% for users of the IUD and 95% for users of oral contraceptives) were comparable. Discuss this information with women who intend to conceive in the next 1 to 2 years.

Cigarette smoking increases the risk of serious cardiovascular side effects and mortality. Convincing data are available to support an upper age limit of 35 years for hormonal contraceptive use by women who smoke.

Other women who are independently at high risk for cardiovascular disease include those who suffer from or have a family history of diabetes, hypertension or an abnormal lipid profile. Whether hormonal contraceptives accentuate this risk is unclear.

There have been post-market reports of cardiovascular events, including heart attack and stroke (e.g. medullary infarction in a heavy smoker) in women using DEPO-PROVERA (see Adverse Reactions, Post-Market Adverse Drug Reactions). Generally, it is not clear if the risk of cardiovascular events is different for users of DEPO-PROVERA than for non-users.

Weight gain may be associated with the use of DEPO-PROVERA (see Adverse Reactions). The majority of studies report a mean weight gain of 5.4 lbs (2.5 kg) at the end of 1 year, but only 2% of women discontinued treatment due to excessive weight gain (see Adverse Reactions, Clinical Trial Adverse Drug Reactions, Weight Gain Experience). Many studies indicate that weight gain occurs mainly in the first year of use, however, others do report a slow and continuing increase which may reach a mean of 8 lbs (3.6 kg) by the end of 2 years. Some 20 to 40 percent of DEPO-PROVERA users actually lose weight during treatment.

Discontinue medication at the earliest manifestation of:

1. Thromboembolic and cardiovascular disorders such as thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis and retinal thrombosis;

   
   

2. Conditions that predispose to venous stasis and vascular thrombosis, such as immobilization after accidents or confinement to bed during long-term illness. Other non-hormonal methods of contraception should be used until regular activities are resumed. For use of hormonal contraceptives when surgery is contemplated, see Peri-Operative Considerations:

   
   

3. Visual defects-partial or complete

   
   

4. Papilledema or ophthalmic (retinal) vascular lesions

   
   

5. Severe headache of unknown etiology or worsening of pre-existing migraine headache.

The onset or exacerbation of migraine or the development of headaches with a new pattern that is recurrent, persistent or severe requires discontinuation of hormonal contraceptives and evaluation of the cause.

Women with migraine headache who take hormonal contraceptives may be at increased risk of stroke (see Contraindications).

Patients with essential hypertension whose blood pressure is well controlled may be given hormonal contraceptives but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, cessation of medication is necessary (see also Contraindications).

A decrease in glucose tolerance has been observed in some women receiving DEPO-PROVERA. The mechanisms of this decrease are obscure. For this reason, diabetic women should be carefully observed while receiving DEPO-PROVERA.

A statistically insignificant increase in RR estimates of invasive squamous-cell cervical cancer has been associated with the use of DEPO-PROVERA 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 DEPO-PROVERA 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.

Clinical suppression of adrenocortical functions has not been observed at low dose levels used for contraception (ovulation suppression).

The World Health Organization Study, a component of a pooled analysis, showed an increased RR of 2.19 (95% CI 1.23 to 3.89) of breast cancer associated with the use of DEPO-PROVERA 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 women who have ever used DEPO-PROVERA 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% CI 1.23 to 3.89-fold) increased risk of breast cancer relative to nonusers. The National Cancer Institute 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.]

Women receiving DEPO-PROVERA should be counselled regarding the importance of breast self-examination. Clinical breast examination should be performed at regular intervals.

It is very important that adequate explanations of the long-term nature of DEPO-PROVERA as a contraceptive be given to each woman prior to her first injection. The possible side effects including BMD changes, changes in menstrual cycle and the relatively slow return of fertility should be emphasized. Every effort should be made to ensure that each woman receives such counseling as to enable her to understand fully these explanations and the possible consequences. A detailed Patient Information leaflet that describes the actions, benefits, risks and adverse effects of this contraceptive should be made available to each woman before she makes the decision to use DEPO-PROVERA for conception control.

Long-term, case-controlled surveillance of users of DEPO-PROVERA found slight or no increased overall risk of breast cancer and no overall increased risk of ovarian, liver, or cervical cancer and a prolonged, protective effect of reducing the risk of endometrial cancer in the population of users.

Anaphylactic and anaphylactoid reactions have occasionally been reported in women treated with DEPO-PROVERA. If an anaphylactic reaction occurs, appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.

In the perimenopausal population, age constitutes no absolute limiting factor, although treatment with a progestogen may mask the onset of the climacteric.

Before prescribing DEPO-PROVERA, 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.

DEPO-PROVERA should not be used before menarche (see Contraindications).

In some cases, women have not become pregnant after stopping injections of DEPO-PROVERA. It is not known whether DEPO-PROVERA or other factors resulted in a change in the ability to conceive. Many reasons exist for such changes, including increased age and the onset of menopause. The infertility rate in the normal population is 7%.

Women who have a history of mental depression should be carefully observed and this drug discontinued if serious depression re-occurs. Some women may complain of premenstrual like depression while on DEPO-PROVERA therapy

There have been post-market reports of arterial and venous thromboembolism (VTE) in women using DEPO-PROVERA (see Adverse Reactions, Post-Market Adverse Drug Reactions). Generally, it is not clear if the risk of arterial and venous thromboembolism is different for users of DEPO-PROVERA than for non-users.

Generalized risk factors for venous thromboembolism include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index >30 kg/m²) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking. The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma.

Before DEPO-PROVERA is used, a thorough history and physical examination should be performed, including a blood pressure determination. Breasts, liver, extremities and pelvic organs should be examined. A Papanicolaou smear should be taken if the patient has been sexually active. The first follow-up visit should be three months after the initiation of therapy. Thereafter, examinations should be performed at least once a year, or more frequently if indicated. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. At each visit, examination should include those procedures that were done at the initial visit, as outlined above or as per the recommendations of the Canadian Task force on the Periodic Health Examination.

Bone mineral density (BMD) should be monitored in women using DEPO-PROVERA for longer than 2 years, or earlier as clinically appropriate. In adolescent females, interpretation of BMD results should take into account patient age and skeletal maturity. If a clinically significant decrease in BMD is detected, treatment with DEPO-PROVERA should be reconsidered (see Warnings and Precautions, Loss of Bone Mineral Density ).

There have been few reported cases of convulsions in patients who were treated with DEPO-PROVERA. Association with DEPO-PROVERA use or pre-existing conditions is not clear. Women with known seizure disorders, including epilepsy, require careful observation.

Since progestogens may cause some degree of fluid retention, conditions that might be influenced by this factor, such as migraine, asthma, or cardiac or renal dysfunction, require careful observation.

Physicians should investigate the possibility of an ectopic pregnancy among women using DEPO-PROVERA who complain of severe abdominal pain.

Detectable amounts of progestogen have been identified in the milk of mothers receiving DEPO-PROVERA. Two studies have indicated that the maximum amount of medroxyprogesterone acetate (MPA) which might be ingested by a breast-feeding infant whose mother is receiving DEPO-PROVERA for contraception would be 1.0 to 1.5 μg/day (or 0.0015 mg/day, 0.045 mg/month, 0.27 mg over 6 months which is about 0.05 mg/kg over 6 months for a 5.5 kg baby). If absorption properties between adult and infant are comparable, this amount would be too low to suppress pituitary function in the infant. No adverse effects related to lactation itself or infant growth were reported in studies where DEPO-PROVERA was started 1-4 days, 7 days or within 6 weeks postpartum.

In nursing mothers treated with DEPO-PROVERA, milk composition, quality and amount are not adversely affected.

To date, no adverse effects have been observed in children whose mothers were using DEPO-PROVERA while lactating. A study of children exposed to MPA with median observation periods of 14-16 years, indicated no incidence of adverse effects on physical growth, mental growth and development of general health status. However, the long-term effects on the child are not fully understood. It is recommended that DEPO-PROVERA not be administered until 6 weeks postpartum in women who are breast feeding to avoid risk of exposure of the neonate to steroid hormones. The physician and woman should discuss the risks of pregnancy versus the risks to the child, if DEPO-PROVERA is used during lactation, to determine the most appropriate course of action for the individual woman.

The effect of hepatic disease on the pharmacokinetics of DEPO-PROVERA is unknown.

Medroxyprogesterone acetate is approximately 90 to 95 percent protein bound. Volume of distribution is reported as 20±3 L. It crosses the blood-brain barrier and is secreted in breast milk.

Following intramuscular administration, MPA is slowly released from the injection site, resulting in low, but persistent levels of drug and drug-related materials in the circulation. On average, the time required to obtain a maximum concentration of MPA in the circulation is between 4 and 20 days. Following a single 150 mg IM dose of DEPO-PROVERA, medroxyprogesterone acetate (MPA) concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL.

Circulating levels of MPA can be detected for as long as 7 to 9 months. Increasing the injection volume of medroxyprogesterone acetate produces an increased rate of absorption and higher serum levels; however, extent of absorption is not affected.

The terminal half-life of MPA is approximately 30 to 60 hours. The elimination half-life following intramuscular administration is approximately 6 weeks, reflecting the prolonged absorption of the drug from the intramuscular injection site. The levels then decrease exponentially until they become undetectable (<100 pg/mL) between 120 to 200 days following injection. Plasma clearance is reported as approximately 1600-4000 L per day. Medroxyprogesterone acetate (as the glucuronide conjugate) is primarily excreted in the feces, via biliary secretion.

The effect of renal disease on the pharmacokinetics of DEPO-PROVERA is unknown.

The principal metabolite of medroxyprogesterone acetate that has been identified is a 6α-methyl-6β, 17α, 21-trihydroxy-4-pregnene-3, 20-dione-17-acetate, which is excreted in the urine. Numerous other metabolites of medroxyprogesterone acetate have been reported; however, these have not been well quantified. Metabolism may be influenced by the route of administration as well as the physical state of the drug.

DEPO-PROVERA (medroxyprogesterone acetate) is a long-acting progestational steroid (progestogen) derived from a natural source (soybeans). Its long duration of action is a result of slow absorption from the injection site. DEPO-PROVERA does not contain estrogen.

For conception control, DEPO-PROVERA inhibits the secretion of gonadotropins which, in turn, prevents follicular maturation and ovulation, and results in endometrial thinning. Additional progestational effects that may contribute to the contraceptive effectiveness of DEPO-PROVERA include the transformation and maintenance of an endometrium hostile to implantation, and thickening of cervical mucus making sperm penetration of the cervix more difficult.

DEPO-PROVERA administered parenterally to women with adequate endogenous estrogen transforms proliferative endometrium into secretory endometrium.

Endometriosis is an estrogen-dependent disorder in women of reproductive age that is characterized by the presence of endometrial-like tissue (glands and stoma) outside the uterine lining. The putative mechanisms of action of DEPO-PROVERA in the treatment of endometriosis is by inhibition of gonadotropin production, induction of decidualization followed by atrophy of endometriotic implants, prevention of follicular maturation and ovulation and decrease in circulating estrogen levels.