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DEPO-PROVERA (medroxyprogesterone acetate injectable suspension, USP)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Non-medicinal Ingredients

Intramuscular
(IM)

Sterile aqueous suspensions 50 mg/mL and 150 mg/mL

None are clinically relevant

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

DEPO-PROVERA is indicated for:

  • conception control (prevention of pregnancy)
  • treatment of endometriosis

DEPO-PROVERA should be used only if other treatments have been considered to be unsuitable or unacceptable and should be used for the shortest period of time possible. It should be taken into consideration that the return to fertility following treatment with DEPO-PROVERA may be delayed (see WARNINGS AND PRECAUTIONS, General and also WARNINGS AND PRECAUTIONS, Sexual Function/Reproduction).

Since loss of bone mineral density (BMD) may occur in females of child-bearing potential who use DEPO-PROVERA long-term (see WARNINGS AND PRECAUTIONS), a risk/benefit assessment, which also takes into consideration the decrease in BMD that occurs during pregnancy and/or lactation, should be considered. The risks and benefits of treatment should be carefully reevaluated on a regular basis in all users of this drug.

Although there are no studies addressing whether calcium and vitamin D may lessen bone mineral density (BMD) loss in women using DEPO-PROVERA, all patients should have adequate calcium and vitamin D intake. Cessation of smoking and regular weight bearing exercise should be discussed with all patients.

Use in Adolescents (12-18 years)

In adolescents, use of DEPO-PROVERA is only indicated when other contraceptive methods are considered unsuitable or unacceptable, due to unknown long-term effects of bone loss associated with DEPO-PROVERA during the critical period of bone accretion (see WARNINGS AND PRECAUTIONS).

Contraindications

NOT FOR INTRAVENOUS USE

DEPO-PROVERA (medroxyprogesterone acetate) is contraindicated in women with:

  • Known or suspected pregnancy or as a diagnostic test for pregnancy
  • Undiagnosed vaginal and/or urinary tract bleeding
  • Known or suspected carcinoma of the breast
  • Undiagnosed breast pathology
  • Known or suspected progestin-dependent neoplasia
  • History of or actual thrombophlebitis or thromboembolic disorders
  • History of or actual cerebrovascular disorders including cerebral apoplexy
  • History of or actual myocardial infarction or coronary artery disease
  • Presence of severe or multiple risk factor(s) for arterial or venous thrombosis:
    • Severe hypertension (persistent values of ≥160/100 mm Hg)
    • Hereditary or acquired predisposition for venous or arterial thrombosis, such as Factor V Leiden and Prothrombin G20210 A mutation, activated protein C(APC-) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant)
    • Severe dyslipoproteinemia
    • Heavy smoking (>15 cigarettes per day) and over age 35
    • Diabetes mellitus with vascular involvement
  • Any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss of vision or defect in visual fields
  • Current or history of migraine with focal aura
  • Active liver disease or history of or actual benign or malignant liver tumours
  • Hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

DEPO-PROVERA should not be used before menarche.

Serious Warnings and Precautions

The use of DEPO-PROVERA has been associated with loss of bone mineral density (BMD) which may not be completely reversible. Loss of bone mineral density is greater with increasing duration of use.

This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if the use of DEPO-PROVERA during adolescence or early adulthood will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. A study to assess effects of DEPO-PROVERA in adolescent females showed that its use was associated with significant decline in BMD from baseline, and that mean BMD loss at total hip and femoral neck did not fully recover by 60 months (240 weeks) post-treatment. Similarly, in adults, there was only partial recovery of mean BMD at total hip, femoral neck and lumbar spine towards baseline by 24 months post-treatment.

DEPO-PROVERA should be used as indicated only if other treatments have been considered to be unsuitable or unacceptable and should be used for the shortest period of time possible.

The risks and benefits of treatment should be carefully reevaluated on a regular basis in all users of this drug.

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels. Women should be counseled not to smoke.

This product does not protect against sexually transmitted infections (STIs) including HIV/AIDS. For protection against STIs it is advisable to use latex or polyurethane condoms.

 

Warnings And Precautions

General

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 below:
  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.

Counseling when used for conception control:
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.

Carcinogenesis and Mutagenesis

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.

Breast Cancer

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 who currently have or have had breast cancer should not use hormone contraceptives, including DEPO-PROVERA, because breast cancer may be hormonally sensitive. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

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

Cervical Cancer

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.

Cardiovascular

Thromboembolic Disorders
Although DEPO-PROVERA has not been causally associated with the induction of thrombotic or thromboembolic disorders, there have been reports of cerebrovascular and thromboembolic adverse events in obese DEPO-PROVERA women. Women with a prior history of thromboembolic disorders have not been studied in clinical trials and no information is available that would support the safety of DEPO-PROVERA use in this population. 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.

Predisposing Factors for Coronary Artery Disease
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.

Hypertension
There have been reports of cerebro/cardiovascular adverse events in DEPO-PROVERA users who are suffering from hypertension. 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).

Endocrine and Metabolism

Loss of Bone Mineral Density

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. In both adult and adolescent females the decrease in BMD during treatment appears to be substantially reversible after medroxyprogesterone acetate injection is discontinued and ovarian estrogen production increases.

A retrospective cohort study to assess the effect of medroxyprogesterone acetate injection on the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between medroxyprogesterone acetate users and contraceptive users who had no recorded use of medroxyprogesterone acetate. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean = 5.5 years) was 1.41 (95% CI 1.35, 1.47). Among the sub-cohort with data before and after first reported contraceptive treatment (N=166,367), comparisons were made for the follow-up period and also for the 6-month period prior to first reported contraceptive treatment. Comparing medroxyprogesterone acetate users to non-users, the IRR for any fracture ‘before treatment’ (IRR 1.28, 95% CI 1.07, 1.53) was comparable to the IRR ‘after treatment’ (IRR 1.37, 95% CI 1.29, 1.45). The overall results support the conclusion that the higher observed incidence of fractures among medroxyprogesterone acetate users in this study was principally a result of factors other than exposure to medroxyprogesterone acetate.

Long term use:
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: Chronic alcohol and/or tobacco use

  • Chronic use of drugs that can reduce bone mass, e.g., anticonvulsants or corticosteroids
  • Low body mass index or eating disorder, e.g., anorexia nervosa or bulimia
  • Metabolic bone disease
  • Strong family history of osteoporosis

BMD Changes in Adult Women
In a controlled, open-label, non-randomized clinical study (DEPO-PROVERA n=248, placebo n=360), adult women using DEPO-PROVERA (150 mg IM) for up to 5 years for contraception showed spine and hip mean BMD decreases of 5-6%, compared to no significant change in BMD in the control group. The decline in BMD was more pronounced during the first 2 years of use, with smaller declines in subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38% after 1, 2, 3, 4 and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar. Table 1 shows the extent of recovery of BMD for women who received one or more DEPO-PROVERA injections during Years 1 through 5.

Table 1. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (ITT Population*)
*
Intent-to-treat population consisted of patients who enrolled in the study and had BMD measured at screening/baseline and at least one post-baseline time point.
**
medroxyprogesterone acetate group consisted of women who received one or more medroxyprogesterone acetate injections during Years 1 through 5.
***
 The control group consisted of women who did not use Depo-Provera prior to the indicated time point.
Women who took one or more doses of Depo-Provera, and then stopped treatment, entered the Post-therapy phase of the study; BMD results from such subjects would no longer be reported in the on-therapy section of the Table. For Control women, results from Years 6 and 7 are shown in the Post-therapy section.

Time in Study

Lumbar Spine

Total Hip

Femoral Neck

 

Depo-
Provera**

Control***

Depo-
Provera**

Control***

Depo-
Provera**

Control***

1 year

n=135

-2.86%

n=253

0.22%

n=88

-1.56%

n=125

0.95%

n=137

-2.85%

n=254

0.28%

2 years

n=94

-4.11%

n=197

0.29%

n=57

-3.06%

n=94

0.69%

n=95

-3.99%

n=195

-0.22%

3 years

n=71

-4.89%

n=159

0.31%

n=42

-3.89%

n=77

-0.06%

n=72

-4.80%

n=159

-0.23%

4 years

n=59

-4.93%

n=137

0.35%

n=31

-4.52%

n=70

-0.02%

n=58

-5.90%

n=138

-0.53%

5 years

n=33

-5.38%

n=105

0.43%

n=21

-5.16%

n=65

0.19%

n=34

-6.12%

n=106

-0.27%

Post-therapy
Year 1

n=45

-2.42%

n=87

0.28%

n=31

-0.70%

n=54

0.65%

n=45

-3.04%

n=86

-0.27%

Post-therapy
Year 2

n=41

-1.19%

n=66

0.47%

n=25

-0.20%

n=43

0.84%

n=42

-3.11%

n=69

-0.36%

After stopping use of DEPO-PROVERA (150 mg IM), there was progressive recovery of BMD toward baseline values during the 2-year post-therapy period. After 2-years off treatment, the BMD deficit had decreased to approximately 2.1% at the spine and hip. A longer duration of treatment was associated with a less complete BMD recovery observed during the 2–year, post-therapy period.

BMD Changes in Adolescent Females (12-18 years)
An open-label, non-randomized clinical study of DEPO-PROVERA injectable (150 mg IM every 3 months for up to 240 weeks [4.6 years]) in adolescent females (12-18 years) for contraception (DEPO-PROVERA n=177, Control n=237), also showed that DEPO-PROVERA use was associated with a significant decline in BMD from baseline (Table 2). However, adolescent girls in an unmatched control group showed an increase in BMD during this period of growth following menarche. The two cohorts of this open-label study were not matched at baseline for age, race, BMD and other factors that affect the rate of acquisition of BMD.

Table 2. Mean Percent Changes from Baseline Bone Mineral Density (BMD) and Bone Mineral Content (BMC) for Adolescents on DEPO-PROVERA (Regular Users) and Unmatched, Untreated Controls
*
For unmatched control group, PT 60 wk represents 300 wk follow-up; PT 120 wk represents 360 wk follow-up. ** On-treatment results for DEPO-PROVERA group include only subjects who had uninterrupted use of DEPO-PROVERA through each follow-up time point; PT results include all subjects who received ≥1 DEPO-PROVERA injection and had a post-treatment DXA scan. *** Control subjects were not matched for age, race, or other factors affecting bone metabolism; they differed significantly from DEPO-PROVERA subjects and valid comparison of BMD or BMC changes between the groups is not possible. § Maximum observation time was 360 weeks (240 wks + 120 wks) in control group; in DEPO-PROVERA group, PT observation through 180 wks and 240 wks was possible if DEPO-PROVERA treatment time was no more than 180 wks and 120 wks, respectively, for a combined total of 360 wks.

 

DEPO-PROVERA**Unmatched Control***

 

N

% Change (SD)

N

% Change (SD)

Lumbar Spine BMD

    

On Treatment 60 wk

114

-2.5 (2.6)

167

3.4 (3.3)

On Treatment 120 wk

73

-2.7 (3.6)

109

5.3 (5.6)

On Treatment 240 wk

27

-2.1 (5.2)

84

6.4 (6.8)

Post-treatment 60 wk*

70

0.5 (5.6)

67

7.6 (6.7)

Post-treatment 120 wk*

52

2.4 (5.2)

63

9.1 (7.8)

Post-treatment 180 wk

39

3.5 (5.0)

N/A§

N/A§

Post-treatment 240 wk

25

4.7 (5.1)

N/A§

N/A§

Total Hip BMD

    

On Treatment 60 wk

113

-2.8 (3.1)

166

1.2 (2.8)

On Treatment 120 wk

73

-5.4 (3.3)

108

2.2 (4.5)

On Treatment 240 wk

28

-6.4 (5.6)

84

1.7 (5.7)

Post-treatment 60 wk*

71

-2.5 (4.8)

67

2.0 (6.7)

Post-treatment 120 wk*

52

-1.6 (5.0)

62

2.2 (7.0)

Post-treatment 180 wk

39

-0.6 (5.2)

N/A§

N/A§

Post-treatment 240 wk

25

0.3 (5.0)

N/A§

N/A§

Femoral Neck BMD

    

On Treatment 60 wk

113

-3.0 (4.2)

166

1.8 (3.6)

On Treatment 120 wk

73

-5.3 (4.0)

108

2.8 (5.4)

On Treatment 240 wk

28

-5.4 (6.2)

84

1.9 (6.5)

Post-treatment 60 wk*

71

-3.3 (5.9)

67

2.1 (7.3)

Post-treatment 120 wk*

52

-1.7 (5.7)

62

2.5 (7.8)

Post-treatment 180 wk

39

-0.7 (5.9)

N/A§

N/A§

Post-treatment 240 wk

25

-0.8 (6.2)

N/A§

N/A§

Whole Body BMC

    

On Treatment 60 wk

112

0.9 (3.5)

165

4.4 (4.3)

On Treatment 120 wk

73

1.3 (4.8)

109

7.5 (7.1)

On Treatment 240 wk

28

3.6 (8.1)

85

9.3 (8.6)

Post-treatment 60 wk*

67

3.7 (5.3)

66

11.5 (9.9)

Post-treatment 120 wk*

50

5.3 (7.0)

62

12.7 (10.1)

Post-treatment 180 wk

39

6.1 (6.9)

N/A§

N/A§

Post-treatment 240 wk

25

8.7 (6.1)

N/A§

N/A§

Lumbar Spine BMC

    

On Treatment 60 wk

114

-2.68 (3.91)

167

5.98 (5.43)

On Treatment 120 wk

73

-2.11 (5.49)

109

9.62 (9.36)

On Treatment 240 wk

27

-0.27 (8.32)

84

12.44 (12.32)

Total Hip BMC

    

On Treatment 60 wk

113

-1.52 (4.23)

166

2.67 (3.79)

On Treatment 120 wk

73

-4.20 (4.78)

108

4.03 (5.78)

On Treatment 240 wk

28

-4.94 (8.15)

84

3.05 (6.86)

Femoral Neck BMC

    

On Treatment 60 wk

113

-2.83 (5.41)

166

2.92 (4.95)

On Treatment 120 wk

73

-4.45 (5.70)

108

4.11 (7.11)

On Treatment 240 wk

28

-5.26 (7.21)

84

3.72 (9.39)

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 in the Depo-Provera group, mean lumbar spine BMC decreased up to Week 120, but thereafter showed increases toward baseline levels; hip and femoral neck mean BMC was decreased at all time points, while total body BMC was increased compared to baseline at all time points. Mean BMC in the non-Depo-Provera group was increased from baseline at all sites and time points, including total body BMC.

Among subjects who received > 4 injections/60-week period, the mean decrease in lumbar spine BMD was - 2.1 % after 240 weeks; mean decreases for the total hip and femoral neck were -6.4 % and -5.4 %, respectively. Post-treatment follow-up showed that lumbar spine BMD recovered to baseline levels approximately 1 year after treatment was discontinued and that hip BMD recovered to baseline levels approximately 5 years after treatment was discontinued. Femoral neck BMD recovered to post-treatment baseline levels in approximately 5 years. In contrast, unmatched, untreated subjects showed mean BMD increases at 240 weeks of 6.4 %, 1.7 % and 1.9 % for lumbar spine, total hip and femoral neck, respectively.

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 Post-Market Adverse Drug Reactions).

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

Carbohydrate Metabolism
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.

Fluid Retention
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.

Weight Changes
Weight gain may be associated with the use of DEPO-PROVERA (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Weight Gain Experience). 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. 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.

Genitourinary

Irregular Menstrual Patterns
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.

Hematologic

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 >30kg/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.

Hepatic/Biliary/Pancreatic

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.

Immune

Anaphylactic Reactions
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.

Neurologic

CNS Disorders and Convulsions
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.

Migraine and 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).

Ophthalmologic

Ocular Disorders
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.

Peri-operative Considerations

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.

Psychiatric

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.

Sexual Function/Reproduction

Return of Fertility
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.

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%.

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

Special Populations

Pregnant Women:
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 breastfeeding (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 1,000 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.

Although a causal relationship between DEPO-PROVERA and the induction of thrombotic or thromboembolic disorders has not been determined, in post-marketing experience, cases of cerebro/cardiovascular and thromboembolic adverse events occurring 48 hours to 2 months after delivery have been reported. Women should be encouraged to consider a form of contraception that does not increase the risk of the above-noted events in the three months post-partum, if possible.

Nursing Women:

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 which might be ingested by a breastfeeding 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 medroxyprogesterone acetate 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 breastfeeding 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. This discussion should take into account that there have been post-marketing reports of low birth weights and neonatal feeding disorders in children whose mothers were using DEPO-PROVERA while lactating.

Pediatrics

DEPO-PROVERA should not be used before menarche (see CONTRAINDICATIONS). In adolescents, use of DEPO-PROVERA is only indicated when other contraceptive methods are considered unsuitable or unacceptable, due to unknown long-term effects of bone loss associated with DEPO-PROVERA during the critical period of bone accretion.

Other

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

Monitoring and Laboratory Tests

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).

Adverse Reactions

Adverse Drug Reaction Overview

The following adverse reactions have been associated with the use of DEPO-PROVERA:

(A) 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.

(B) 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.

Clinical Trial Adverse Drug Reactions

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 3,905 women receiving DEPO-PROVERA every 3 months, there were a total of 8,467 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%).

(A) Total Adverse Reaction Experience:
Table 3 contains a list of reported side effects, the number of times each side effect was reported and the number and percent of patients who reported each side effect. Table 4 contains the number of side effects reported by month and the number of side effect reports per 100 patients "exposed" by month.

TABLE 3

DEPO-PROVERA EVERY 90 DAYS SIDE EFFECTS

Symptom

No. of Times Reported

No. of Women Reporting

Percent of Women (3,905)

Headache

2187

682

17.46

Abdominal Distress

990

463

11.85

Nervousness

1143

451

11.55

Dizziness

411

232

5.94

Decreased Libido

541

225

5.76

Asthenia

321

177

4.53

Limb Pain & Varicose Vein Pain

311

152

3.89

Nausea

209

138

3.53

Vaginal Discharge

178

120

3.07

Breast Swelling & Tenderness

188

114

2.92

Bloating

170

94

2.41

Edema Peripheral

170

87

2.22

Backache

131

87

2.22

Dysmenorrhea

95

69

1.77

Depression

100

62

1.59

Acne

72

48

1.23

Pruritus Vulvae

67

48

1.23

No Hair Growth, Alopecia

108

46

1.18

Rash

78

41

1.05

Hot Flash

51

40

1.02

Insomnia

54

38

0.97

Genitourinary Infection

45

34

0.87

Eye Discomfort

45

33

0.85

Anorexia

37

29

0.74

Increased Appetite

37

28

0.72

Chest Pain

33

28

0.72

Dysuria

39

28

0.72

Diarrhea

28

25

0.64

Heartburn

26

23

0.59

Galactorrhea

40

22

0.56

Pruritus

28

22

0.56

D&C for Bleeding

21

21

0.54

Pain

25

19

0.49

Somnolence Drowsiness

23

19

0.49

Dyspareunia

21

17

0.43

Dyspnea

30

17

0.43

Abdominal Swelling

25

17

0.43

Allergic Reactions

21

15

0.38

Chloasma

26

13

0.33

Vomiting

16

12

0.31

Constipation

19

11

0.28

Tachycardia

11

10

0.26

Liver disorders NOS, altered liver function

14

10

0.26

Hirsutism

13

10

0.26

Frequency Urination

11

10

0.26

Paraesthesia, Sensory Disturbances

13

9

0.23

According to Table 4, 1,135 (13.40%) of the total 8,467 side effect reports were reported during the first injection period (90 days); during the first two injection periods (first 180 days) 2,070 (24.45%) were reported; 2,826 (33.38%) were reported during the first three injection periods (first 270 days); and 3,536 (41.75%) were reported during the first four injection periods (first 360 days). The number of patients not reporting any side effects was 2,117 (54.2%).

TABLE 4

DEPO-PROVERA EVERY 90 DAYS - SIDE EFFECTS (BY MONTH)

Month

# Pts Entering/Month

# Reports

# Reports/100 Patients

1

3905

355

9.09

2

3670

373

10.16

3

3571

407

11.40

4

3294

290

8.80

5

3084

283

9.18

6

3004

362

12.05

7

2792

249

8.91

8

2634

218

8.28

9

2579

289

11.22

10

2419

224

9.26

11

2299

220

9.57

12

2253

266

11.81

15

1872

212

11.32

18

1659

225

13.56

21

1485

198

13.33

24

1344

194

14.43

27

1180

155

13.14

30

1037

124

11.96

33

927

127

13.70

36

827

128

15.48

39

722

112

15.51

42

664

99

14.91

45

573

84

14.66

48

474

45

9.49

51

412

52

12.62

54

350

46

13.14

57

305

44

14.43

60

263

23

8.75

63

227

19

8.37

66

201

20

9.95

69

184

17

9.24

72

157

17

10.83

75

118

12

9.32

78

91

16

17.58

81

49

3

6.12

84

1

0

0.00

Bleeding Experience:

In U.S. studies of 3,905 women receiving DEPO-PROVERA every 3 months, unpredictable bleeding or spotting were commonly reported during the first few menstrual cycles with frequency, duration and amount of bleeding diminishing gradually. By month 12, amenorrhea was reported by 55% of the women, and by month 24, amenorrhea was reported by 68% of the women using DEPO-PROVERA. Bleeding or spotting persisted for more than 10 days of the month in about 12% of the users. Abnormally heavy or prolonged bleeding occurred in about 1 to 2% of users.

The percent of patients with zero days of bleeding and/or spotting per 30-day month increases with time from start of study, as follows:

Month

Percent Having Zero Bleeding and/or Spotting

3

29.3

12

54.6

24

67.7

36

73.8

48

75.5

60

79.3

72

78.9

Bleeding and/or spotting occurred in the following percentage of the 90 days of the indicated injection period.

Injection Period

Months

Percent of Days with
Bleeding and/or Spotting

First

1 – 3

25.7

Fourth

10 – 12

11.8

Eighth

22 – 24

6.8

Twelfth

34 – 36

4.8

Sixteenth

46 – 48

4.3

Twentieth

58 – 60

4.1

Twenty-fourth

70 – 72

4.3

On 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 1,674 days.

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

Weight Gain Experience:
The U.S. studies of 3,905 women receiving DEPO-PROVERA every 3 months 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. Many studies indicate that weight gain occurs mainly in the first year of use, however, others report a slow and continuing increase which may reach a mean of 8 lbs (3.6 kg) by the end of 2 years. However, some 20 to 40 percent of DEPO-PROVERA users actually lose weight during treatment.

A much higher proportion of patients had an increase as had a decrease of more than 15 pounds. The mean body weight changes from baseline (in pounds) were as follows:

Month

Weight Increase (pounds)

n

12

5.4

1,644

24

8.1

960

36

11.3

567

48

13.8

282

60

14.1

150

72

16.5

109

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

The number of women having had an initial Pap smear taken is 2,052. 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.

(B) Non-Menstrual Adverse Reactions:
The occurrence rates for non-menstrual adverse reactions reported in U.S. studies of 3,905 women receiving DEPO-PROVERA every 3 months are listed below. 2,253 women were in the study for 12 months or more; 827 women were in the study for 36 months or more. The total number of patient-months of experience was 82,384. A total of 2,117 of the 3,905 women (54%) reported no side effects.

SYSTEM ORGAN CLASS

EVENT

General disorders and administration site conditions

Asthenia (5%)

Peripheral edema (2%)

The following adverse events occurred in less than 1% of patients:  Axillary swelling, pain, chills, excessive thirst, fever, pain at injection site

Blood and lymphatic

system disorders

The following adverse events occurred in less than 1% of patients:  Anemia, blood dyscrasia

Cardiac disorders

Chest pain, tachycardia (0.2 - 1.0%)

Eye disorders

Eye discomfort (0.2 - 1.0%)

Gastrointestinal disorders

Abdominal distress (12%)

Nausea (4%)

Bloating (2%)

Anorexia, increased appetite, diarrhea, heartburn, abdominal swelling, vomiting, constipation (0.2 - 1.0%)

The following adverse events occurred in less than 1% of patients:  Gastro-intestinal disturbances, rectal bleeding

Hepatobiliary disorders

Liver disorders NOS, altered liver function (0.2 - 1.0%)

The following adverse event occurred in less than 1% of patients:  Jaundice

Immune system disorders

Allergic reactions (0.2 - 1.0%)

Infections and infestations

Genitourinary infection (0.2 - 1.0%)

Musculoskeletal and connective tissue disorders

Backache (2%)

Limb pain (4%)

Leg cramps, arthralgia (1-5%)

The following adverse events occurred in less than 1% of patients: Osteoporosis

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

The following adverse events occurred in less than 1% of patients: Breast cancer, cervical cancer

Nervous system disorders

Headache (17%)

Dizziness (6%)

Somnolence or drowsiness, paraesthesia, sensory disturbances (0.2 - 1.0%)

The following adverse events occurred in less than 1% of patients:  Syncope, convulsions, paralysis, facial palsy

Pregnancy, puerperium and perinatal conditions

The following adverse events occurred in less than 1% of patients: Unexpected pregnancy, sensation of pregnancy

Psychiatric disorders

Nervousness (12%)

Decreased libido (6%)

Depression (2%)

Anorgasmia (1-5%)

Insomnia (0.2 - 1.0%)

The following adverse event occurred in less than 1% of patients:  Increased libido

Renal and urinary disorders

Dysuria, urinary frequency (0.2 - 1.0%)

Reproductive system and

breast disorders

Breast swelling/tenderness (3%)

Vaginal discharge (3%)

Leukorrhoea (1-5%)

Pelvic pain (1-5%)

Vaginitis (1-5%)

Dysmenorrhea (2%)

Pruritus vulvae (1%)

Galactorrhea, bleeding requiring D&C, dyspareunia (0.2 - 1.0%)

The following adverse events occurred in less than 1% of patients:  Changes in breast size, breast lumps or nipple bleeding, prevention of lactation, vaginal cysts, lack of return to fertility, uterine hyperplasia

Respiratory, thoracic and

mediastinal disorders

Dyspnea (0.2 - 1.0%)

The following adverse events occurred in less than 1% of patients:  Asthma, hoarseness, pulmonary embolus

Skin and subcutaneous tissue disorders

Acne, alopecia, rash (1%)

Hirsutism, pruritus (0.2 - 1%)

Hives (0.2 - 1.0%)

The following adverse events occurred in less than 1% of patients:  Melasma, chloasma, scleroderma, excessive sweating, body odour, dry skin

Vascular disorders

Hot flashes (1%)

The following adverse events occurred in less than 1% of patients: Varicose veins, thrombophlebitis, deep vein thrombosis

Post-Market Adverse Drug Reactions

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.

Blood and lymphatic system disorders: hemolytic anemia, hemorrhagic disorder, sickle cell crisis, splenic infarction, thrombocytopenia, thrombotic thrombocytopenic purpura

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

Congenital and familial/genetic disorders: acute porphyria, in cases of failure of contraception: Trisomy 21, Trisomy 16, Turner’s syndrome

Ear and labyrinth disorders: change in hearing, tinnitus, vertigo

Endocrine disorders: adrenal dysfunction NOS, Cushingoid, estrogen deficiency, hyperthyroidism, hypoglycemia, hypopituitarism, hypothyroidism, thyroiditis

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

Gastrointestinal disorders: acute pancreatitis, dysphagia, intestinal infarction, mouth ulceration, oral mucosal blistering, salivary gland enlargement

General disorders and administration site conditions: fatigue, injection site reactions (including swelling, rash, ulcer, necrosis, edema, infection, abscess), injections site pain/tenderness, injection site persistent atrophy/indentation/dimpling/scar, injection site nodule/lump, malaise, sudden infant death syndrome (exposure-in utero)

Hepatobiliary disorders: Cholangitis, cholelithiasis, gallbladder disorder, hepatitis, hepatomegaly, obstructive jaundice, hepatic failure (with fatal outcome)

Immune system disorders: anaphylactic reaction (with fatal outcome in rare cases), hypersensitivity

Infections and infestations: salpingitis, sepsis, vulval abscess

Investigations: 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

Metabolism and nutrition disorders: cachexia, excessive thirst

Musculoskeletal, connective tissue and bone disorders: joint swelling, muscle weakness, myalgia, osteonecrosis

Neoplasms benign, malignant and unspecified: 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

Nervous system disorders: 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

Pregnancy, peurperium and perinatal conditions: exposure-in-utero: abnormal genitalia, anencephaly, antepartum hemorrhage, blighted ovum, cleft palate, congenital adenomatoid malformation, congenital diaphragmatic hernia, congenital heart defects, congenital megacolon, ear malformation NOS, ectopic pregnancy, esophageal atresia, fetal hydrops, hydrocephalus, hypospadias, intrauterine growth retardation, limb deformity, microcephaly, missed abortion, polydactyly, polyhydramnios, prematurity, single umbilical artery, skull malformation, spina bifida, spontaneous abortion, stillbirth, Talipes, tracheoesophageal fistula

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

Renal and urinary disorders: interstitial nephritis, nephrolithiasis, nephrotic syndrome, proteinuria, renal infarct, urinary retention

Reproductive system and breast disorders: cervical dysplasia, fibrocystic breast disease, menorrhagia, ovarian cyst, premature menopause, uterine cyst, vaginal dysplasia, vaginal mucosal blistering

Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, bronchospasm, epistaxis, laryngeal edema, laryngospasm, oropharyngeal swelling

Skin and subcutaneous tissue disorders: angioedema, erythema multiforme, erythema nodosum, facial edema, lipodystrophy acquired, porphyria aggravated

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

Drug Interactions

Overview

Medroxyprogesterone acetate is metabolized in-vitro primarily by hydroxylation via the CYP3A4.52, 53Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on medroxyprogesterone acetate have not been conducted and therefore the clinical effects of CYP3A4 inducers or inhibitors are unknown.

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.

Drug-Drug Interactions

Aminoglutethimide: 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.

Rifampin: 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.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

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:

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

Dosage And Administration

Recommended Dose and Dosage Adjustment

Conception Control:

The recommended dose for contraception is 150 mg of DEPO-PROVERA 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 breastfeeding. If the woman has chosen to breastfeed, 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 intramuscular injection to maintain contraceptive effectiveness. Intervals between intramuscular injections must not exceed 13 weeks (3 months).

When switching from other contraceptive methods, DEPO-PROVERA should be given in a manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g., patients switching from oral contraceptives should have their first injection of DEPO-PROVERA within 7 days after taking their last active pill).

Endometriosis:
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).

Use in Children:

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

See WARNINGS AND PRECAUTIONS, Loss of Bone Mineral Density for available data for adolescent females (12-18 years).

Missed Dose

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

Administration

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

Overdosage

Overdosage may result in a period of amenorrhea of a variable length and may be followed by irregular menses for several cycles. Very high doses of DEPO-PROVERA (500 mg daily or more) have been associated with corticoid-like activity and with Cushingoid symptoms (e.g. moon face and blood pressure elevation). There is no known therapy for overdosage.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action And Clinical Pharmacology

Pharmacodynamics

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 mechanism 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.

Pharmacokinetics

Table 5. Summary of medroxyprogesterone acetate suspension for injection’s pharmacokinetic parameters in an adult women population

 

Cmax

t½ (h)

AUC0-4

Clearance

Volume of distribution
*
not available

Single 150 mg I.M.

1-7 ng/mL

≈ 1000

NA*

1600-4000 litres/day

20 ± 3 litres

Absorption: Following intramuscular administration, medroxyprogesterone acetate 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 medroxyprogesterone acetate in the circulation is between 4 and 20 days. Following a single 150 mg IM dose of DEPO-PROVERA, medroxyprogesterone acetate 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 medroxyprogesterone acetate 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.

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

Medroxyprogesterone acetate binding occurs primarily to serum albumin; no binding of medroxyprogesterone acetate occurs with sex hormone-binding globulin (SHBG).

Metabolism: 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.
Excretion: The terminal half-life of medroxyprogesterone acetate 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 litres per day. Medroxyprogesterone acetate (as the glucuronide conjugate) is primarily excreted in the feces, via biliary secretion.

Special Populations and Conditions

Hepatic Insufficiency: The effect of hepatic disease on the pharmacokinetics of DEPO-PROVERA is unknown. However, medroxyprogesterone acetate is almost exclusively eliminated by hepatic metabolism and steroid hormones may be poorly metabolized in patients with severe liver insufficiency, (see CONTRAINDICATIONS).

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

Storage And Stability

Protect from freezing. Store upright at controlled room temperature 15° to 30°C. Shake well before using. Keep out of reach of children.

Dosage Forms, Composition And Packaging

Each mL of DEPO-PROVERA contains:

Ingredients (mg)

50 mg/mL

150 mg/mL

Medroxyprogesterone acetate

50

150

Polyethylene Glycol 3350

28.8

28.9

Polysorbate 80

1.9

2.41

Sodium Chloride

8.6

8.68

Methylparaben

1.3

1.37

Propylparaben

0.14

0.15

Water for injection, Sodium Hydroxide, Hydrochloric Acid

q.s.q.s.
DEPO-PROVERA is supplied in 2 strengths.
50 mg/mL5 mL vialsSingle use only
150 mg/mL1 mL vials1 x 1 mL vials; 5 x 1 mL vials

 

Control #: 198801
December 8, 2016

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