DEPO-PROVERA 7 Warnings and Precautions

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

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.

Sexually Transmitted Infections:

Some epidemiological evidence on hormonal contraceptive methods and the risk of HIV acquisition suggests a possible increase in risk of HIV acquisition in women who use the depot medroxyprogesterone acetate or DEPO-PROVERA.  However, since the evidence comes from observational studies, which are vulnerable to certain methodological biases, it remains unclear if the association is definitively causal.  If the association between DEPO-PROVERA and HIV acquisition risk is causal, data suggest a likely increase in risk of hazards ratio 1.5 or less.

Women considering using DEPO-PROVERA should be advised about the concerns that DEPO-PROVERA may increase risk of HIV acquisition, about the uncertainty over whether there is a causal relationship, and about how to minimize their risk of acquiring HIV. Women should be counseled that DEPO-PROVERA does not protect against sexually transmitted infections (STIs) including HIV infection (AIDS). Safer sex practices including correct and consistent use of condoms reduce the transmission of STIs through sexual contact, including HIV. The benefits of contraceptive options and their risks must be evaluated individually for each woman.

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 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse 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 2 CONTRAINDICATIONS).

Endocrine and Metabolism

Loss of Bone Mineral Density

Use of DEPO-PROVERA reduces serum estrogen levels and is associated with a statistically 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.

In adolescence, following DEPO-PROVERA use for more than 2 years, subjects did not recover to their baseline BMD level at the femoral neck and total hip even up to 60 months.

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.

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

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 and BMD Recovery Post-treatment 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. There were no significant changes in BMD in the control women over the same period of time. Table 1 shows the extent of recovery of BMD for women who received one or more DEPO-PROVERA injections during Years 1 through 5.

After stopping use of DEPO-PROVERA (150 mg IM), there was partial 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)

The impact of DEPO-PROVERA (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12-18 years). Use of DEPO-PROVERA was associated with a significant decline from baseline in BMD.

Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections per DEPO-PROVERA user was 9.3. The decline in BMD at total hip and femoral neck was greater with longer duration of use (see Table 2). The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).

In general, adolescents increase bone density during the period of growth following menarche, as seen in the untreated cohort. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD and other factors that influence the rate of acquisition of bone mineral density.

BMD Recovery Post-Treatment in Adolescents

Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of DEPO-PROVERA. Table 3 shows the extent of recovery of BMD up to 60 months post-treatment for adolescent women who received DEPO-PROVERA for two years or less compared to more than two years. Post-treatment follow-up showed that, in women treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Subjects treated with DEPO-PROVERA for more than two years did not recover to their baseline BMD level at femoral neck and total hip even up to 60 months post-treatment. Adolescent women in the untreated cohort gained BMD throughout the trial period (data not shown).

Relationship of Fracture Incidence to Use of DEPO-PROVERA (150 mg IM) or Non-Use by Women of Reproductive Age

A retrospective cohort study to assess the association between DEPO-PROVERA injection and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between DEPO-PROVERA users and contraceptive users who had no recorded use of DEPO-PROVERA. 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). It is not known if this is due to DEPO-PROVERA use or to other related lifestyle factors that have a bearing on fracture rate.

In the study, when cumulative exposure to DEPO-PROVERA was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use.

There were very few fractures at skeletal sites known to be related to low BMD in the study and the incidence of these fractures was not found to be higher in DEPO-PROVERA users compared to non-users.  Importantly, this study could not determine whether use of DEPO-PROVERA has an effect on fracture rate later in life.

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 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse 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 8 ADVERSE REACTIONS, 8.2 Clinical Trial Adverse 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 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse 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.

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 7 WARNINGS AND PRECAUTIONS).

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 2 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.

Reproductive Health: Female and Male Potential

• 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.

7.1 Special Populations

7.1.1 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 4 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.

7.1.2 Breast-feeding

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.

7.1.3 Pediatrics

DEPO-PROVERA should not be used before menarche (see 2 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.

7.1.4 Geriatrics 

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

7.1.5 Other

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