*TM Pfizer Enterprises SARL Pfizer Canada Inc., Licensee 8Pfizer Canada Inc., 2006

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

DRUG INTERACTIONS

DOSAGE AND ADMINISTRATION

OVERDOSAGE

ACTION AND CLINICAL PHARMACOLOGY

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING

PART II: SCIENTIFIC INFORMATION 28

PHARMACEUTICAL INFORMATION

CLINICAL TRIALS

DETAILED PHARMACOLOGY

TOXICOLOGY

REFERENCES

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

NOT FOR INTRAVENOUS USE

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.

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. It is unknown if the use of DEPO-PROVERA during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. DEPO-PROVERA should be used as a birth control method or endometrial treatment 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 diseases (STDs) including HIV/AIDS. For protection against STDs it is advisable to use latex condoms.

WARNINGS AND PRECAUTIONS 1 - GENERAL

Thromboembolic and cardiovascular disorders

such as thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis and retinal thrombosis;

Conditions that predispose to venous stasis and vascular thrombosisPeri- operative Considerations below

, 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

Visual defects-partial or complete

Papilledema or ophthalmic (retinal) vascular lesions

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

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.

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.

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.

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.

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.

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).

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).

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.

* * DMPA group consisted of women who received one or more DMPA 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.

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.

Preliminary results from an ongoing, open-label, self-selected, non-randomized clinical study of DEPO-PROVERA injectable (150 mg IM every 12 weeks for up to 5 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). In contrast, most adolescent girls will significantly increase bone density during this period of growth following menarche.

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

* DEPO-PROVERA group consists of "regular users" who received at least 4 injections of DEPO-PROVERA prior to Week 60; 8 injections prior to Week 120; 16 injections prior to Week 240.

* * Control group consists of subjects who did not receive any DEPO-PROVERA prior to the time of the result;

in some cases, control subjects chose to start DEPO-PROVERA after that point but were subsequently excluded from the control group.

+ Treatment and control subjects were not matched for age, gynecologic age or race.

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 Post-Market Adverse Drug Reactions).

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

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.

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 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 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.

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.

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.

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.

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.

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.

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).

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.

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.

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 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.

Cumulative conception rates for women discontinuing use of an IUD, oral contraceptives, or DEPO- PROVERA in order to become pregnant

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%.

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

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 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 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.

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 (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 ug/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.

Pediatrics

Other

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

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).

- 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.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

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

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.

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.

T A B L E 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
T A B L E 3
DEPO-PROVERA EVERY 90 DAYS SIDE EFFECTS
Symptom Anorexia	No. of Times Reported 37	No. of Women Reporting 29	Percent of Women (3,905) 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%).

T A B L E 4
DEPO-PROVERA EVERY 90 DAYS - SIDE EFFECTS (BY MONTH)
Month	# Pts Entering/Mnth	# 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
T A B L E 4
DEPO-PROVERA EVERY 90 DAYS - SIDE EFFECTS (BY MONTH)
Month 33	# Pts Entering/Mnth 927	# Reports 127	# Reports/100 Patients 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%)
SYSTEM ORGAN CLASS	EVENT
	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), malaise, sudden infant death syndrome (exposure-in utero)

Hepatobiliary disorders:

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

Injury, poisoning, and procedural complications:

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

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: antepartum hemorrhage, blighted ovum, ectopic pregnancy, fetal hydrops, intrauterine growth retardation, missed abortion, polyhydramnios, prematurity, spontaneous abortion, stillbirth

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, porphyria aggravated

Vascular disorders:

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

DRUG INTERACTIONS

: 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 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.

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.

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:

DOSAGE AND ADMINISTRATION

Conception Control (prevention of pregnancy): 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).

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 (CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS

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

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

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 facies and blood pressure elevation). There is no known therapy for overdosage.

ACTION AND CLINICAL PHARMACOLOGY

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.

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

Absorption:

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. 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.

Metabolism:

The principal metabolite of medroxyprogesterone acetate that has been identified is a 6a-methyl-6b, 17a, 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 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 litres per day. Medroxyprogesterone acetate (as the glucuronide conjugate) is primarily excreted in the feces, via biliary secretion.

Hepatic Insufficiency:

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

Renal Insufficiency:

STORAGE AND STABILITY

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

DOSAGE FORMS, COMPOSITION AND PACKAGING

Composition: Each mL contains:

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: medroxyprogesterone acetate injectable suspension USP Chemical name: (1) Pregn-4-ene-3,20 dione,17-(acetyloxy)-6-methyl-,(6a)-; (2) 17-Hydroxy-6a-methylpregn-4-ene-3,dione acetate Molecular formula

and molecular mass: C24H34O4 386.53 Structural formula: Physicochemical properties: Medroxyprogesterone acetate is a white to off-white, odourless crystalline powder, stable in air. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in ethanol and methanol, slightly soluble in ether and insoluble in water. The melting point is between 200 and 210EC. The c log P is 1.467.

CLINICAL TRIALS

Conception control

The contraceptive efficacy, safety and acceptability of DEPO-PROVERA (medroxyprogesterone acetate) given as a single intramuscular injection of 150 mg every 90 days has been evaluated in a multicentre study conducted by 54 investigators in the United States.

Protocol

A baseline interview, pelvic examination, weight measurement, blood pressure reading, laboratory study and Papanicolaou smear were carried out. The initial injection of DEPO- PROVERA was given toward the end of, or on the day immediately following, a menstrual period in all subjects. Monthly calendar cards were issued on which to record menstrual periods, instructions were given detailing possible side effects (amenorrhea, irregular bleeding), and appointments were made for follow-up and repeat injections in 3 months. At monthly time intervals, interviews were conducted and monthly calendar cards were collected. At 3-month intervals, subjects reported for repeat injections and body weight and laboratory test performance. At this time interviews were again conducted as to acceptance of therapy, side effects, and signs of pregnancy. Follow-up pelvic examinations, Pap smears and blood pressure measurements were performed 1 year after first injection (at the time of the fifth injection).

Number of Patients and Study Duration

Fifty-four investigators enrolled 3,905 patients into the study. Table 6 contains the number of patients completing at least the stated study month. For example 2,253 patients were in the study for 12 months or more; 827 patients were in the study for 36 months or more. The median study duration was 13 months. The ten-percentile was 3 months, the ninety-percentile 51 months, the minimum 1 month and the maximum 84 months. The total number of patient-months of experience on the drug was 82,384.

Patient Description

The median age of the patients was 26 years; 11.3 percent of the patients were age 19 years or less; 85.7 percent were age 20 through 39 years; 3.0 percent were age 40 years or greater. Caucasians accounted for 54.7 percent of the patient group. The median number of months since last delivery or miscarriage was 6. The median gravida was 3. The median para was 3. 65.3 percent of the patients were abortus zero.

Efficacy Results

In total, 15 (0.38%) of the 3,905 patients dropped out of the study due to method failure (pregnancy). The 12-month cumulative dropout rate (dropouts per 100 women - life table technique) due to pregnancy was 0.32 with a standard error of 0.11. The 12-month pregnancy rate, or failure rate, as calculated by the life table technique is 0.32 per 100 women. The 24-month failure rate is 0.44 per 100 women and the 36-month failure rate is 0.75 per 100 women. Table 7 summarizes cumulative dropout rates due to pregnancy according to the months of the study in which a patient dropped out due to method failure.

Dropouts

Table 8 contains frequency distribution of dropouts by dropout reason. Listed are only those reasons found common to greater than 1.0 percent of the women entering the study.

Continuation Rate

The expected continuation rate for a specific point in time may be calculated by subtracting the dropout rate for all reasons (except protocol completed for the specific point in time), from 100. The life table expected continuation rates for selected points in time are as follows:

Conclusion

DEPO-PROVERA given as a single intramuscular injection of 150 mg every 90 days has been assessed overall as a safe and effective method of contraception and is well tolerated by the majority of patients. The following table shows the reported pregnancy rates for various forms of birth control, including no birth control. The reported rates represent the number of women out of 100 who would become pregnant during the first year of use.

Endometriosis

There has been extensive clinical experience with the use of medroxyprogesterone acetate in the effective treatment of endometriosis, however there are no pivotal clinical trials with DEPO- PROVERA intramuscular formulation.

DETAILED PHARMACOLOGY

Medroxyprogesterone acetate (MPA) induces response in laboratory animals comparable to those caused by progesterone. It is more potent than progesterone and, when injected intramuscularly as a suspension, has a long duration of action. MPA induces glandular development in the endometrium, maintains pregnancy, delays parturition, inhibits ovulation and suppresses oestrus cycles. It is devoid of androgenic and estrogenic activity. In selected animal tests it has some adrenal corticoid-like activity, and in dogs, increases serum growth hormone levels.

Medroxyprogesterone acetate has prolonged progestational effects when administered by intramuscular injection. MPA suppresses the secretion of pituitary gonadotropins which, in turn, prevents follicular maturation, producing long-term anovulation in the reproductive-aged woman. Clinical studies have not shown signs and symptoms of a hypoestrogenic state in women using MPA as a contraceptive. This finding is supported by laboratory measurements showing that circulating estrogen levels in medroxyprogesterone acetate-treated women are similar to those in the early follicular phase of the menstrual cycle. Cyclic patterns of estrogen levels reappear as MPA serum levels decline. MPA suppresses the Leydig cell function in the male (i.e., suppresses endogenous testosterone production). A single dose of 50 mg of parenteral MPA has the equivalent effect of 20 mg of parenteral progesterone given daily for 10 days in producing an optimal secretory change in an estrogen- primed endometrium. This steroid also produces typical progestational changes in the cervical mucus (inhibits ferning), increases the viscosity of cervical mucus thereby increasing the difficulty of sperm penetration of the cervical mucus, and increases the intermediate cell found in the maturation index of the vaginal epithelium. It has been suggested that long-term use of MPA may indirectly decrease high density lipoprotein cholesterol (HDL-C) by decreasing the production of natural estrogen. The purported lowering of mean HDL-C levels in a group of 23 women receiving MPA for 1 year or more was attributed to the drug's suppression of estrogen production. It has been shown, however, that the natural circulating estrogen is not depressed below that of the early follicular phase concentrations after injection of MPA. Women who used MPA for contraception for 4.4 to 10.6 years had no additional suppression of estrogen beyond that observed following the first injection. Another study has shown that long-term use of MPA causes a moderate decrease in triglycerides, HDL cholesterol, HDL cholesterol/total cholesterol ratio and apolipoprotein A1. Total cholesterol, LDL cholesterol and apolipoprotein B were unaffected.

TOXICOLOGY

Rat, Mouse: In 18-month studies, mice given two, 100 or 200 mg/kg (3X, 150X or 300X the human dose) did not show treatment-related neoplasia; even the massive doses produced only minimal toxicity. Rats given two, 100 or 200 mg/kg in 24-month carcinogenicity studies did not show serious adverse effects.

Beagle Dog: Two 7-year toxicity studies in Beagle dogs were conducted using MPA doses ranging from 1X to 25X the human contraceptive dose. MPA (and progesterone) caused anestrus, obesity, increased production of growth hormone, acromegaly, impaired carbohydrate metabolism, multiple endocrinopathy, glomerulopathy, and marked stimulation of the mammary gland resulting in hyperplasia and neoplasia. These tumours were not new histologic types. Progestogen treatment appeared to potentiate the growth of the same types of tumours that would be expected in control dogs, usually the complex or "mixed" type. Mammary carcinomas were found in MPA-treated dogs in both studies and in progesterone-treated dogs in the second study. The Committee on Safety of Medicines (United Kingdom) and three international panels of experts have reviewed the evidence and concluded that the Beagle bitch is not an appropriate model for mammary carcinogenicity testing of progesterone derivatives such as DEPO- PROVERA (medroxyprogesterone acetate). Because of differences between the Beagle bitch and the human female in the sensitivity to and the metabolism of progestogens, positive carcinogenicity studies in the Beagle bitch can no longer be considered as indicative of significant hazard to women.

Rhesus Monkey: In a 10-year toxicology study of MPA in Rhesus monkeys, MPA was administered at 1X, 10X, and 50X the human contraceptive dose. Mammary nodules diagnosed as focal nodular hyperplasia of the mammary gland were found in 3 of the 7 survivors in the 10X group. The lesions showed no signs of malignancy. Because these lesions were both non-progressive and non-invasive and because many lesions of this type are known to appear and then regress, it was concluded that the occurrence of this non-malignant mammary lesion in three MPA-treated monkeys poses no potential threat of breast cancer to women using DEPO-PROVERA as a contraceptive. Lesions diagnosed as endometrial carcinoma were found in 2 of the 12 survivors in the 50X group. These 2 were replacements - 1 was treated for 111 months and the other for 125 months of the 130-month study (based on 28-day months). The lesions were remarkably similar in cell morphology to epithelial plaques which occur in monkeys but not in humans. It is possible that MPA provided a uterine environment that allowed proliferation of an epithelial cell type present in the endometrium of the Rhesus monkey and other non-human primates. Under the influence of progesterone, this epithelial cell type responds to implantation by proliferating and forming an epithelial plaque. The cells comprising this plaque are readily distinguished from normal epithelial cells of the endometrium. Under progesterone or progestogen influence, this epithelial cell type also proliferates and forms a plaque in response to experimentally induced endometrial trauma. Results of electron microscopic studies indicated that the neoplasms were malignant and were epithelial and not mesenchymal in origin, and thus of a type not stimulated by progestogens in women. It has been concluded that, regardless of the cause of these lesions, their occurrence does not signify that DEPO-PROVERA is carcinogenic in women using it as a contraceptive.

Mutagenicity

In 3 different mutagenicity tests, MPA showed no mutagenic properties. MPA was not mutagenic in the Salmonella/Microsome Test (Ames test), it did not induce single-strand breaks in DNA in a DNA damage/alkaline elution assay, and in the micronucleus test MPA at 100X the human contraceptive dose did not induce micronuclei (i.e., it was not clastogenic and did not cause abnormal distribution of chromosomal material).

Reproduction and Teratology

Studies have not demonstrated any impairment of fertility in first or second generation studies. In rats, MPA may have some effect on genital systems, but standard teratologic techniques have shown no effects on nongenital systems. MPA produced cleft palates in rabbits, attributed to that particular species' sensitivity to the drug's glucocorticoid activity.

REFERENCES

Philadelphia: Lippincott Williams & Wilkins; 2005, p.1115. Terblanche J, Goldin AR, Carnbell JAH, Kirsch RE, Louw JH. Liver tumours and the contraceptive pill: controversies in aetiology, diagnosis and management. S Afr Med J 1979:56:932-40. Trussell J, Hatcher RA, Cates W Jr, Stewart FH, Kost K. A guide to interpreting contraceptive efficacy studies. Obstet Gynecol 1990; 76 (II Suppl):558-67. Trussell J, Kost K. Contraceptive failure in the United States: A critical review of the literature. Stud Fam Plan 1987; 18:237-83. Tsunoda SM, Harris RZ, Mroczkowski PJ, Benet LZ. Preliminary evaluation of progestins as inducers of cytochrome P450 3A4 activity in postmenopausal women. In J Clin Pharmacol 1998; 38:1137-43. Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet. 1999; 354:1610-1611. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Cardiovascular disease and use of oral and injectable progestogen- only contraceptives and combined injectable contraceptives. Contraception. 1998; 57:315- 324. World Health Organization. Medical Eligibility Criteria for Contraceptive Use. Third edition. World Health Organization, Geneva, 2004. World Health Organization Special Programme of Research, Development, and Research Training in Human Reproduction; Task Force on Long-Acting Systemic Agents for the Regulation of Fertility: Multinational comparative clinical evaluation of two long-acting injectable steroids: Norethisterone oenanthate and medroxyprogesterone. 2. Bleeding patterns and side effects. Contraception 1978; 17:395-406. World Health Organization Special Programme of Research, Development, and Research Training in Human Reproduction; Multinational comparative clinical trial of long-acting injectable contraceptives: Norethisterone enanthate given in two dosage regimens and depomedroxyprogesterone acetate. Final Report. Contraception 1983; 28:1-20. World Health Organization Special Programme of Research, Development, and Research Training in Human Reproduction; Breast cancer, cervical cancer and depomedroxyprogesterone acetate. Lancet November 1984, 1207-8. World Health Organization Special Programme of Research, Development, and Research Training in Human Reproduction; Depo-medroxyprogesterone acetate (DMPA) and cancer: Memorandum from a World Health Organization meeting. Bulletin of the WHO 1986; 64(3):375-82. World Health Organization, collaborative study of neoplasia and steroid contraceptives. Breast cancer and depo-medroxyprogesterone acetate: a multinational study. Lancet 1991; 338:833-8.

This leaflet is Part III of a three-part "Product Monograph" published when DEPO-PROVERA was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about DEPO-PROVERA. Contact your doctor or pharmacist if you have any questions about the drug.

DEPO-PROVERA contains medroxyprogesterone acetate, a substance similar to (but not the same as) the natural hormone

Prevent the ripening of the egg in the ovaries. When there is no ripe egg to be fertilized by the sperm, pregnancy cannot occur,

Change the lining of the uterus (the endometrium) so that it does not easily receive a fertilized egg,

Cause thickening of the mucus in the cervix, making it more difficult for the sperm to enter the uterus.

The lining of the uterus (womb) is called the endometrium. Part of the endometrium is shed during your menstrual period. In

endometriosis, endometrium-like tissue is found outside the uterus, such as around the uterus, ovaries, intestines and other

tissue can be shed during your period. Some women with endometriosis have symptoms such as painful periods, pelvic pain, pain during intercourse and painful bowel movements.

Endometriosis is a disorder that is dependent on the hormone estrogen. It is thought that DEPO-PROVERA works as a treatment for endometriosis by reducing certain hormone levels in the body, including estrogen levels, and by helping to shrink the endometrium-like tissue.

DEPO-PROVERA is more than 99.7 percent effective for conception control. This means less than one

DEPO-PROVERA is more effective than IUDs, condoms (sometimes called rubber sheaths or prophylactics), diaphragms, or other contraceptive methods as shown in Table 1.

sterilization, and IUDs. How well other methods of contraception work depends in part on how reliably they are used. Faithful users may achieve pregnancy rates in the lower ranges, others may expect pregnancy rates more in the middle of the ranges of those shown in Table 1.

Table 1 shows the reported pregnancy rates for various forms of birth control, including no birth control. The reported rates represent the number of women out of 100 who would become pregnant during the first year of use.

You should not use DEPO-PROVERA if you have or have had any of the following conditions:

DEPO-PROVERA should not be used before menarche (the onset of menstrual periods).

If you wish to become pregnant in the near future, DEPO- PROVERA may not be an appropriate treatment for you. You should discuss alternative treatments with your doctor. (See The Risks of Using DEPO-PROVERA, Return of Fertility.)

density. The longer you use DEPO-PROVERA, the more bone mineral density you may lose. Your bone mineral density may not return completely once you stop using DEPO-PROVERA. This is of particular concern when DEPO-PROVERA is used in adolescence (teenager years) when you should instead be building bone mineral density. Loss of bone mineral density can cause osteoporosis and increase the risk that your bones might break, especially after menopause (the end of menstrual periods).

DEPO-PROVERA should be used as a birth control method or endometrial treatment 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. It is advised that you do not smoke.

DEPO-PROVERA does not protect you against sexually transmitted diseases (STDs), including HIV/AIDS. It is advisable to use latex condoms for this purpose.

Breast cancer or family history of breast cancer, abnormal breast exam or x-ray (mammogram)

DEPO-PROVERA should be used only under the supervision of a doctor, with regular follow-up to identify side effects associated with its use. Your visits may include a blood pressure check, a breast exam, an abdominal exam and a pelvic exam, including a Pap smear. You should talk regularly with your doctor about whether you still need treatment with DEPO-PROVERA. You should only use DEPO-PROVERA if other methods of birth control or endometrial treatments are not right for you.

Because DEPO-PROVERA is a long-acting method of contraception, it takes some time after the last injection for its effect to wear off. This varies from woman to woman. Most women, however, must wait from six to eight months after the last injection to start ovulating, have regular periods, and be able to become pregnant (see THE RISKS OF USING DEPO- PROVERA - Return of Fertility).

density. This can cause weak bones (osteoporosis) that can increase the risk that your bones might break, especially after menopause (the end of menstrual periods). The longer you use DEPO-PROVERA, the more bone mineral density you may lose. Your bone mineral density may not return completely once you stop using DEPO-PROVERA.

treatment should be carefully reevaluated on a regular basis in all users of this drug. If you use DEPO-PROVERA, your doctor may ask you to have a bone test, especially if you have other risk factors for weak bones. You should talk to your doctor about how to reduce the risk of low bone mineral density, and how much calcium and vitamin D you should take.

shows no overall increased risk of ovarian, liver, or cervical cancer. The same examination showed a prolonged, protective effect of reducing the risk of endometrial cancer (cancer of the lining of the uterus) in the population of users.

Women who had ever used DEPO-PROVERA showed no increased risk of breast cancer. And overall, there was no increase in risk of breast cancer with increasing duration of use of DEPO- PROVERA. However, in a certain set of women, those who first took the drug within the previous 4 years and who were under 35 years of age showed a slight increase of breast cancer associated with use of DEPO-PROVERA.

Regular breast examination by a health practitioner and regular breast self-examination are recommended for all women. You should review technique for breast self- examination with your health practitioner.

. It will not prevent the pregnancy from continuing, but may interfere with the normal development of your baby.

To reduce the risk of using DEPO-PROVERA while you are pregnant, get your injection: only within the first five days of the beginning of your normal (menstrual) period, or only within the first five days after giving birth if you are NOT breast-feeding.

Before using DEPO-PROVERA while breast-feeding, talk with your doctor. DEPO-PROVERA should not affect the amount or

quality of your milk. Children whose mothers used DEPO- PROVERA while breast-feeding for about 6 months, showed no

harmful effects up to 14-16 years of age. There is no further information on these children beyond 16 years old.

A very small amount of the medicine in DEPO-PROVERA is transferred to the milk of nursing mothers. It is recommended that DEPO-PROVERA not be used by women who are breast feeding until at least 6 weeks after delivery.

If you are breast feeding, you should discuss the use of DEPO- PROVERA with your doctor so that he/she can help you decide what is best in your situation.

There have been rare cases of heart attack, stroke and blood clots in the legs and lungs in women using DEPO-PROVERA. It is

important for you to recognize the following symptoms and to call your doctor immediately if you:

Have a sudden severe headache with vomiting, blindness or trouble talking, weakness, or numbness in an arm or leg, or get dizzy or faint;

DEPO-PROVERA will not make you infertile. Because DEPO- PROVERA is a long-acting method of contraception, it takes

varies from woman to woman. Most women, however, must wait from six to eight months after the last injection to start ovulating, have regular periods, and be able to become pregnant.

If you stop using DEPO-PROVERA and you do NOT want to become pregnant, start using another method of contraception 3 months after your last injection of DEPO-PROVERA.

If you want to become pregnant, tell your doctor. Fifty-four percent of women who wish to become pregnant do so within six months after their last injection of DEPO-PROVERA. Seventy- six percent of all women become pregnant within one year, and 92% became pregnant within two years. The average time to pregnancy is 9 months after the last injection.

Table 2 shows the percent of women that become pregnant after stopping the use of DEPO-PROVERA, oral contraceptives, and IUDs.

In rare cases, it can take two years or longer for ovulation and regular periods to return, and for you to be able to become pregnant. This delay in return of fertility (after stopping DEPO- PROVERA injections) is not related to how long DEPO- PROVERA has been used. In very rare cases, women have not become pregnant after stopping injections of DEPO-PROVERA. The reason is not known. There are many reasons why women are unable to become pregnant, including increased age and the start of menopause. In the general population, 7 out of every 100 women are unable to get pregnant.

Tell your doctor if you are taking, or begin taking, any other medicines, even medicines you buy without a prescription. Some medicines may interfere with each other in your body.

Drugs that may interact with DEPO-PROVERA include aminoglutethimide and rifampin.

DEPO-PROVERA is injected into muscle - for example, into the fleshy part of the hip (buttocks) or upper arm. For DEPO-

PROVERA to prevent you from getting pregnant, you must get an injection of 150 mg every three months (up to 13 weeks).

If your bleeding pattern is unusual, have a pregnancy test before you receive your first injection.

Do not use DEPO-PROVERA if you are pregnant, or think that you may be pregnant. It will not prevent the pregnancy from continuing, but may interfere with the normal development of your baby. For this reason, get your first injection: only within the first 5 days from the beginning of your (menstrual) period, or only within the first 5 days after giving birth if you are NOT breast-feeding. Before using DEPO-PROVERA while breast- feeding, discuss with your doctor. When this procedure is followed, DEPO-PROVERA will be effective from the day of injection.

If DEPO-PROVERA is given after the first 5 days of the beginning of your (menstrual) period, it may not prevent you from getting pregnant for the first 3 to 4 weeks after the injection. Use another non-hormonal contraceptive method (e.g. condom, diaphragm, sponge, cervical cap, abstinence) during these 3 to 4 weeks.

difficult to get your next injection three months after the last one. This contraceptive method does require you to plan ahead. If scheduling injections every three months would be difficult, then DEPO-PROVERA is probably not the best contraceptive method for you.

You should discuss with your doctor the length of time that you should use DEPO-PROVERA.

Steps After Childbirth, Miscarriage or Therapeutic Abortion If you plan to use DEPO-PROVERA following childbirth, get your injection during the first five days after giving birth if you are NOT breast-feeding. If you choose to breast-feed, discuss with your doctor the possibility of getting pregnant, other possible contraceptives, and when you may start using DEPO-PROVERA. (See WARNINGS AND PRECAUTIONS, Use While Breast- Feeding)

After miscarriage or therapeutic abortion, talk to your doctor about when you may start using DEPO-PROVERA.

You can get your injection up to 13 weeks, or as early as 10 weeks, after your last injection. If you have not had your injection

by the 13th week, you should have a pregnancy test done before any further injections.

The recommended dose is 50 mg once weekly or 100 mg injected into the muscle every 2 weeks for at least 6 months.

case of overdose, contact your physician and/or your local Poison Control Centre.

Some women have side effects from this medicine. Remember, medicines affect different people in different ways. Just because side effects have occurred in other women, this does not mean you will get them. The side effect that occurs most often is change in menstrual patterns.

There have been cases of osteoporosis and fracture (broken bones) associated with the use of DEPO-PROVERA.

DEPO-PROVERA slowly and continuously releases a hormone into your body for about three months. Because of this, you are

not likely to have regular periods. For the first three to six months, most women have irregular, unpredictable or even continuous

may be lighter. This unpredictable bleeding pattern may be inconvenient, but it is normal due to the change DEPO- PROVERA causes in the lining of your uterus. The lining no longer thickens each month and therefore, does not need to be lost as menstrual flow.

As you continue to use DEPO-PROVERA, bleeding generally decreases until most women no longer have monthly periods by the end of the first year of use. The lack of bleeding is NOT a sign of pregnancy. However, if you think you may be pregnant, contact your doctor as soon as possible. Consider using another method of contraception if you think that irregular or complete lack of menstrual periods would upset you.

After you stop using DEPO-PROVERA, the uterine lining will start to thicken again. Periods will start again as soon as the effects of DEPO-PROVERA completely wear off. The time this takes varies from woman to woman.

Very heavy bleeding that persists for several days is NOT a normal effect of DEPO-PROVERA. If this happens, call your doctor immediately.

DEPO-PROVERA. If you notice a large increase in your weight in a short period of time that is not easily explained, tell your doctor.

PROVERA will worsen this condition. If this happens to you, or if you become depressed, tell your doctor.

Just as some women notice bodily changes before their period, you may notice some of the same changes after an injection of

DEPO-PROVERA. Although reported less often than changes in bleeding patterns, the following side effects were reported in

months. Tell your doctor right away if any of the following continue, bother you, or are not easily explained:

The injection itself may cause slight pain and a slight lump may appear under the skin. The lump will usually disappear in a few days.

Other problems were reported by very few of the women in the clinical trials, but some of these could be serious. These include: convulsions, jaundice, urinary tract infections, allergic reactions, fainting, paralysis, osteoporosis, lack of return to fertility, deep vein thrombosis, pulmonary embolus, breast cancer, or cervical cancer. If these or any other problems occur during your use of DEPO-PROVERA, discuss them with your doctor.

This is not a complete list of side effects. If you have any unexpected effects after taking DEPO-PROVERA, contact your doctor or pharmacist.

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

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

This document plus the full product monograph, prepared for health professionals, may be obtained by contacting the sponsor, Pfizer Canada Inc. at: 1-800-463-6001.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Intramuscular	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.

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%

Visit	DEPO-PROVERA * +		Unmatched Controls * * +
	n	Mean % (SD)	n	Mean % (SD)
Total Hip BMD
Week 60	113	-2.72 (3.18)	206	1.31 (2.70)
Week 120	79	-5.29 (3.40)	154	2.00 (4.19)
Week 240	34	-6.91 (4.93)	100	1.83 (5.50)
Femoral Neck BMD
Week 60	113	-2.91 (4.23)	206	1.74 (3.57)
Week 120	79	-5.49 (4.62)	154	2.70 (5.07)
Week 240	34	-6.53 (5.89)	101	2.14 (6.64)
Lumbar Spine BMD
Week 60	114	-2.44 (2.67)	206	3.13 (3.22)
Week 120	80	-2.64 (3.67)	154	4.87 (4.99)
Week 240	35	-2.76 (4.84)	102	6.27 (6.80)
Whole Body BMC
Week 60	115	0.86 (3.52)	207	3.95 (4.20)
Week 120	81	1.34 (4.61)	154	6.91 (6.69)
Week 240	34	3.76 (7.28)	101	9.60 (8.69)
Total Hip BMC
Week 60	113	-1.54 (4.23)	206	2.65 (3.67)
Week 120	79	-4.03 (4.71)	154	3.88 (5.49)
Week 240	34	-5.61 (6.75)	100	3.29 (6.61)
Femoral Neck BMC
Week 60	113	-2.70 (5.26)	206	2.73 (4.81)
Week 120	79	-4.42 (5.92)	154	3.97 (6.77)
Week 240	34	-5.42 (7.23)	101	3.52 (9.11)
Lumbar Spine BMC
Week 60	114	-2.67 (3.90)	206	5.38 (5.26)
Week 120	80	-2.05 (5.33)	154	8.97 (8.43)
Week 240	35	-1.00 (7.27)	102	11.85 (12.20)

	C max	t 1/2 (h)	AUC 0 - 4	Clearance	Volume of distribution
Single 150 mg I.M.	1-7 ng/mL	[?] 1000	NA *	1600-4000 litres/day	20 " 3 litres

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.

50 mg/mL	5 mL vials	Single use only
150 mg/mL	1 mL vials	1 x 1 mL vials; 5 x 1 mL vials, 25 x 1 mL vials
	1 mL disposable pre-filled syringe	1 x 1 mL; 6 x 1 mL; 24 x 1 mL

TABLE 6
DEPO-PROVERA EVERY 90 DAYS NUMBER OF PATIENTS COMPLETING AT LEAST STATED STUDY MONTH
Study Month	No. of Patients	Study Month	No. of Patients	Study Month	No. of Patients
0 - 1	3905	29	1068	57	305
2	3670	30	1037	58	285
3	3571	31	984	59	267
4	3294	32	950	60	263
5	3084	33	927	61	250
6	3004	34	887	62	238
7	2792	35	857	63	227
8	2634	36	827	64	215
9	2576	37	765	65	206
10	2419	38	735	66	201
11	2288	39	622	67	199
12	2253	40	685	68	190
13	2030	41	673	69	184
14	1915	42	664	70	182
15	1872	43	606	71	174
16	1776	44	588	72	157
17	1704	45	573	73	143
18	1659	46	525	74	129
19	1567	47	493	75	118
20	1514	48	474	76	110
21	1485	49	436	77	97
22	1422	50	417	78	91
23	1367	51	412	79	77
24	1344	52	375	80	67
TABLE 6
DEPO-PROVERA EVERY 90 DAYS NUMBER OF PATIENTS COMPLETING AT LEAST STATED STUDY MONTH
Study Month 25	No. of Patients 1251	Study Month 53	No. of Patients 358	Study Month 81	No. of Patients 49
26	1200	54	350	82	23
27	1180	55	326	83	3
28	1116	56	316	84	1
Total Patient-Months Experience: 82,384

T A B L E 7
DEPO-PROVERA EVERY 90 DAYS DROPOUTS/FAILURES (PREGNANCY)
Month	No. of Patients Entering Month	Dropouts	Interval Rate	Cumulative Rate	Standard Error of Cumulative Rate
3	3571	1	0.0003	0.0003	0.0003
4	3294	2	0.0006	0.0009	0.0005
6	3004	2	0.0007	0.0016	0.0007
7	2792	1	0.0004	0.0019	0.0008
9	2576	1	0.0004	0.0023	0.0009
10	2419	1	0.0004	0.0027	0.0010
12	2253	1	0.0004	0.0032	0.0011
15	1872	1	0.0005	0.0037	0.0012
23	1367	1	0.0007	0.0044	0.0014
29	1068	1	0.0009	0.0053	0.0017
33	927	2	0.0022	0.0075	0.0023
39	722	1	0.0014	0.0089	0.0026

T A B L E 8
DEPO-PROVERA EVERY 90 DAYS-REASONS FOR DROPOUT
Reasons	# Women	% of Total Women(n=3905)
Study completed	1086	27.81
Lost to follow-up	774	19.82
Husband objects - inconvenient to come to clinic, to attempt to conceive, objects to expense, personal reasons, no longer requires contraception	568	14.55
Bleeding	326	8.35
Side effects (unspecified)	245	6.27
Moved away	215	5.51
Advice of clinic or private physician	126	3.23
Amenorrhea	86	2.20
Weight gain, excessive	78	2.00
Unknown	68	1.74
Hysterectomy, tubal ligation	61	1.56
Headache	39	1.00

Month	Continuation Rate	Standard Error
12	56.13%	0.80%
24	38.82%	0.81%
36	28.97%	0.78%
48	23.50%	0.77%
60	19.71%	0.79%
72	16.71%	0.83%

DEPO-PROVERA Sterile Aqueous Suspension Reported Pregnancies per 100 Women per Year
Method		Lowest expected	Typical
DEPO-PROVERA		0.3	0.3
Female sterilization		0.2	0.4
Male sterilization		0.1	0.15
Oral Contraceptives (the pill)		0.1- 0.5	3
IUD	Copper T 380A	0.8	3
Condom		2	12
Diaphragm		6	18
Sponge	women who have not had any children	6	18
	women who have had children	9	28
Cap		6	18
Withdrawal		4	18
Periodic abstinence		1-9	20
Spermicides		3	21
Chance (no birth control)		85	85

Table 1 - DEPO-PROVERA Sterile Aqueous Suspension Reported Pregnancies per 100 Women per Year
Method		Lowest expected	Typical
DEPO-PROVERA		0.3	0.3
Female sterilization		0.2	0.4
Male sterilization		0.1	0.15
Oral Contraceptives (the pill)		0.1- 0.5	3
IUD	Copper T 380A	0.8	3
Condom		2	12
Diaphragm		6	18
Sponge	women who have not had any children	6	18
	women who have had children	9	28
Cap		6	18
Withdrawal		4	18
Periodic abstinence		1-9	20
Spermicides		3	21
Chance (no birth control)		85	85

Table 2 - DEPO-PROVERA Sterile Aqueous Suspension. The percent of women that become pregnant after stopping the use of DEPO-PROVERA, oral contraceptives ( A the pill @ ), and intrauterine devices (IUDs)
Months since stopping contraception	DEPO-PROVERA Users	A The Pill @ Users	IUD Users
6	54%	75%	60%
12	76%	85%	76%
24	92%	95%	93%

	IMPORTANT: PLEASE READ
irregular menstrual bleeding	swelling of the hands or feet	shortness of breath
amenorrhea	backache
headache	depression	Sudden partial or complete loss of vision or double vision		[?]
nervousness	insomnia
abdominal cramps	acne
dizziness	pelvic pain
weakness or fatigue	no hair growth or excessive hair loss
		Sudden severe headache or worsening of headache, vomiting, dizziness, fainting, disturbance of vision or speech, or weakness or numbness in the face, arm or leg		[?]
decreased sexual desire	rash
leg cramps	hot flashes
nausea	joint pain
vaginal discharge or irritation	bloating
breast swelling and tenderness

		Unexpected vaginal or urinary tract bleeding	[?]
		Yellowing of the skin or eyes (jaundice)		[?]

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM
Symptom/possible side effect		Talk with your doctor or pharmacist		Stop taking drug and call your doctor or pharmacist
Symptom/possible side effect		Only if severe	In all cases	Stop taking drug and call your doctor or pharmacist
Common	Abdominal pain, nausea or vomiting		[?]
	Persistent sad mood			[?]
	Unusual swelling of the extremities		[?]
Uncommon	Bone fractures (broken bones)			[?]
	Breast lump		[?]
	Convulsions or seizure			[?]
	Crushing chest pain or heaviness			[?]
	Hives, rash, mouth or facial swelling			[?]
	Pain or swelling in the leg			[?]
	Sharp pain in the chest, coughing blood, or sudden			[?]

Date of Revision: July 11, 2006

Control Number: 100711

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

DRUG INTERACTIONS

DOSAGE AND ADMINISTRATION

OVERDOSAGE

ACTION AND CLINICAL PHARMACOLOGY

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING

PART II: SCIENTIFIC INFORMATION 28

PHARMACEUTICAL INFORMATION

CLINICAL TRIALS

DETAILED PHARMACOLOGY

TOXICOLOGY

REFERENCES

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

NOT FOR INTRAVENOUS USE

Serious Warnings and Precautions

WARNINGS AND PRECAUTIONS 1 - GENERAL

Thromboembolic and cardiovascular disorders

Conditions that predispose to venous stasis and vascular thrombosisPeri- operative Considerations below

Visual defects-partial or complete

Papilledema or ophthalmic (retinal) vascular lesions

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

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

Table 1. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (ITT Population *)

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

Pregnant Women:

Nursing Women:

Pediatrics

Other

- FOR CONCEPTION CONTROL

ADVERSE REACTIONS

Blood and lymphatic system disorders:

Cardiac disorders:

Congenital and familial/genetic disorders:

Ear and labyrinth disorders:

Endocrine disorders:

Eye disorders:

Gastrointestinal disorders:

General disorders and administration site conditions:

Hepatobiliary disorders:

Injury, poisoning, and procedural complications:

Immune system disorders:

Infections and infestations:

Investigations:

Metabolism and nutrition disorders:

Musculoskeletal, connective tissue and bone disorders:

Neoplasms benign, malignant and unspecified

Nervous system disorders:

Pregnancy, peurperium and perinatal conditions

Psychiatric disorders:

Renal and urinary disorders

Reproductive system and breast disorders:

Respiratory, thoracic and mediastinal disorders:

Skin and subcutaneous tissue disorders:

Vascular disorders:

DRUG INTERACTIONS

DOSAGE AND ADMINISTRATION

Use in Children:

DEPO-PROVERA should not be used before menarche (CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS

OVERDOSAGE

ACTION AND CLINICAL PHARMACOLOGY

Absorption:

Metabolism:

Excretion:

Hepatic Insufficiency:

Renal Insufficiency:

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING

Composition: Each mL contains:

PHARMACEUTICAL INFORMATION

Drug Substance