Depo-Provera 150 mg/ml

Each ml of suspension contains 150 mg medroxyprogesterone acetate Ph. Eur. For excipients, see section 6.1

Sterile suspension for injection.

Progestogen: for contraception.

Depo-Provera is a long-term contraceptive agent suitable for use in women who have been appropriately counselled concerning the likelihood of menstrual disturbance and the potential for a delay in return to full fertility.

Depo-Provera may also be used for short-term contraception in the following circumstances:

1) For partners of men undergoing vasectomy, for protection until the vasectomy becomes effective.

2) In women who are being immunised against rubella, to prevent pregnancy during the period of activity of the virus.

3) In women awaiting sterilisation.

Since loss of bone mineral density (BMD) may occur in females of all ages who use Depo-Provera injection long-term (see section 4.4 Special Warnings and Special Precautions for Use), a risk/benefit assessment, which also takes into consideration the decrease in BMD that occurs during pregnancy and/or lactation, should be considered.

Use in adolescents (12-18 years)

In adolescents, Depo-Provera may be used, but only after other methods of contraception have been discussed with the patient and considered unsuitable or unacceptable.

It is of the greatest importance that adequate explanations of the long-term nature of the product, of its possible side-effects and of the impossibility of immediately reversing the effects of each injection are given to potential users and that every effort is made to ensure that each patient receives such counselling as to enable her to fully understand these explanations. Patient information leaflets are supplied by the manufacturer. It is recommended that the doctor uses these leaflets to aid counselling of the patient.

Consistent with good clinical practice a general medical as well as gynaecological examination should be undertaken before administration of Depo-Provera and at appropriate intervals thereafter.

The sterile aqueous suspension of Depo-Provera should be vigorously shaken just before use to ensure that the dose being given represents a uniform suspension of Depo-Provera.

Doses should be given by deep intramuscular injection. Care should be taken to ensure that the depot injection is given into the muscle tissue, preferably the gluteus maximus, but other muscle issue such as the deltoid may be used.

The site of injection should be cleansed using standard methods prior to administration of the injection.

Adults:

First injection: To provide contraceptive cover in the first cycle of use, an injection of 150 mg i.m. should be given during the first five days of a normal menstrual cycle. If the injection is carried out according to these instructions, no additional contraceptive cover is required.

Post Partum: To increase assurance that the patient is not pregnant at the time of first administration, this injection should be given within 5 days post partum if not breast-feeding.

There is evidence that women prescribed Depo-Provera in the immediate puerperium can experience prolonged and heavy bleeding. Because of this, the drug should be used with caution in the puerperium. Women who are considering use of the product immediately following delivery or termination should be advised that the risk of heavy or prolonged bleeding may be increased. Doctors are reminded that in the non breast-feeding, post partum patient, ovulation may occur as early as week 4.

If the puerperal woman will be breast-feeding, the initial injection should be given no sooner than six weeks post partum, when the infant's enzyme system is more fully developed. Further injections should be given at 12 week intervals.

Further doses: These should be given at 12 week intervals, however, as long as the injection is given no later than five days after this time, no additional contraceptive measures (e.g. barrier) are required. (N.B. For partners of men undergoing vasectomy a second injection of 150 mg i.m. 12 weeks after the first may be necessary in a small proportion of patients where the partner's sperm count has not fallen to zero.) If the interval from the preceding injection is greater than 89 days (12 weeks and five days) for any reason, then pregnancy should be excluded before the next injection is given and the patient should use additional contraceptive measures (e.g. barrier) for fourteen days after this subsequent injection.

Elderly : Not appropriate.

Children: Depo-Provera is not indicated before menarche (see section 4.1 Therapeutic Indications)

Data in adolescent females (12-18 years) is available (see section 4.4 Special Warnings and Special Precautions for Use). Other than concerns about loss of BMD, the safety and effectiveness of Depo-Provera is expected to be the same for adolescents after menarche and adult females

Switching from other Methods of Contraception

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

Hepatic Insufficiency

The effect of hepatic disease on the pharmacokinetics of Depo-Provera is unknown. As Depo-Provera largely undergoes hepatic elimination it may be poorly metabolised in patients with severe liver insufficiency (see Section 4.3 – Contraindications).

Renal Insufficiency

The effect of renal disease on the pharmacokinetics of Depo-Provera is unknown. No dosage adjustment should be necessary in women with renal insufficiency, since Depo-Provera is almost exclusively eliminated by hepatic metabolism.

Depo-Provera is contra-indicated in patients with a known sensitivity to medroxyprogesterone acetate or any ingredient of the vehicle.

Depo-Provera should not be used during pregnancy, either for diagnosis or therapy.

Depo-Provera is contra-indicated as a contraceptive at the above dosage in known or suspected hormone-dependent malignancy of breast or genital organs.

Depo-Provera is contra-indicated in patients with the presence or history of severe hepatic disease whose liver function test have not returned to normal.

Whether administered alone or in combination with oestrogen, Depo-Provera should not be employed in patients with abnormal uterine bleeding until a definite diagnosis has been established and the possibility of genital tract malignancy eliminated.

Loss of Bone Mineral Density:

Use of DEPO-PROVERA reduces serum estrogen levels and is associated with significant loss of BMD due to the known effect of estrogen deficiency on the bone remodelling system. Bone loss is greater with increasing duration of use, however BMD appears to increase after DEPO-PROVERA is discontinued and ovarian estrogen production increases.

This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of DEPO-PROVERA by younger women will reduce peak bone mass and increase the risk for fracture in later life.

A study to assess the BMD effects of medroxyprogesterone acetate IM (Depo-Provera, DMPA) in adolescent females showed that its use was associated with a significant decline in BMD from baseline. In the small number of women who were followed-up, mean BMD recovered to around baseline values by 1- 3 years after discontinuing treatment. In adolescents, DEPO-PROVERA may be used, but only after other methods of contraception have been discussed with the patients and considered to be unsuitable or unacceptable.

In women of all ages, careful re-evaluation of the risks and benefits of treatment should be carried out in those who wish to continue use for more than 2 years. In particular, in women with significant lifestyle and/or medical risk factors for osteoporosis, other methods of contraception should be considered prior to use of DEPO-PROVERA.

Significant risk factors for osteoporosis include:

• Alcohol abuse 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

• Previous low trauma fracture

• Family history of osteoporosis

A retrospective cohort study using data from the General Practice Research Database (GPRD) reported that women using MPA injections (DMPA), have a higher risk of fracture compared with contraceptive users with no recorded use of DMPA (incident rate ratio 1.41, 95% CI 1.35-1.47 for the five year follow-up period); it is not known if this is due to DMPA, or to other related lifestyle factors which have a bearing on fracture rate. By contrast, in women using DMPA, the fracture risk before and after starting DMPA was not increased (relative risk 1.08, 95% CI 0.92-1.26). Importantly, this study could not determine whether use of DMPA has an effect on fracture rate later in life.

For further information on BMD changes in both adult and adolescent females, as reported in recent clinical studies, refer to section 5.1 (Pharmacodynamic Properties). Adequate intake of calcium and Vitamin D, whether from the diet or from supplements, is important for bone health in women of all ages.

Bone fracture: A retrospective cohort study to assess the effect of MPA injection on the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between DMPA users and contraceptive users who had no recorded use of DMPA. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean = 5.5 years) was 1.41 (95% CI 1.35, 1.47). Among the sub-cohort with data before and after first reported contraceptive treatment (N=166,367), comparisons were made for the follow-up period and also for the 6-month period prior to first reported contraceptive treatment. Comparing DMPA users to non-users, the IRR for any fracture 'before treatment' (IRR 1.28, 95 % CI 1.07, 1.53) was comparable to the IRR 'after treatment' (IRR 1.37, 95% CI 1.29, 1.45). The overall results support the conclusion that the higher observed incidence of fractures among DMPA users in this study was principally a result of factors other than exposure to DMPA .MPA injection should be used as a long-term (e.g., longer than 2 years) birth control method or endometrial treatment only if other birth control methods or endometrial treatments are inadequate. BMD should be evaluated when a female needs to continue use of MPA injection long term. In adolescent females, interpretation of BMD results should take into account patient age and skeletal maturity.

Menstrual Irregularity: The administration of Depo-Provera usually causes disruption of the normal menstrual cycle. Bleeding patterns include amenorrhoea (present in up to 30% of women during the first 3 months and increasing to 55% by month 12 and 68% by month 24); irregular bleeding and spotting; prolonged (>10 days) episodes of bleeding (up to 33% of women in the first 3 months of use decreasing to 12% by month 12). Rarely, heavy prolonged bleeding may occur. Evidence suggests that prolonged or heavy bleeding requiring treatment may occur in 0.5-4 occasions per 100 women years of use. If abnormal bleeding persists or is severe, appropriate investigation should take place to rule out the possibility of organic pathology and appropriate treatment should be instituted when necessary. Excessive or prolonged bleeding can be controlled by the coadministration of oestrogen. This may be delivered either in the form of a low dose (30 micrograms oestrogen) combined oral contraceptive pill or in the form of oestrogen replacement therapy such as conjugated equine oestrogen (0.625-1.25 mg daily). Oestrogen therapy may need to be repeated for 1-2 cycles. Long-term co-administration of oestrogen is not recommended.

Return to Fertility: There is no evidence that Depo-Provera causes permanent infertility. Pregnancies have occurred as early as 14 weeks after a preceding injection, however, in clinical trials, the mean time to return of ovulation was 5.3 months following the preceding injection. Women should be counselled that there is a potential for delay in return to full fertility following use of the method, regardless of the duration of use, however, 83% of women may be expected to conceive within 12 months of the first "missed" injection (i.e. 15 months after the last injection administered). The median time to conception was 10 months (range 4-31) after the last injection.

Cancer Risks: Long-term case-controlled surveillance of Depo-Provera users found 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. A metaanalysis in 1996 from 54 epidemiological studies¹ reported that there is a slight increased relative risk of having breast cancer diagnosed in women who are currently using hormonal contraceptives. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in hormonal contraceptive users, biological effects or a combination of both. The additional breast cancers diagnosed in current users of hormonal contraceptives or in women who have used them in the last ten years are more likely to be localised to the breast than those in women who never used hormonal contraceptives.

Breast cancer is rare among women under 40 years of age whether or not they use hormonal contraceptives.

Results from some epidemiological studies suggest a small difference in risk of the disease in current and recent users compared with never-users. Any excess risk in current or recent DMPA users is small in relation to the overall risk of breast cancer, particularly in young women (see below), and is not apparent after 10 years since last use. Duration of use does not seem to be important.

Possible number of additional cases of breast cancer diagnosed up to 10 years after stopping injectable progestogens*

*based on use for 5 years”

Weight Gain: There is a tendency for women to gain weight while on Depo-Provera therapy. Studies indicate that over the first 1-2 years of use, average weight gain was 5-8 lbs. Women completing 4-6 years of therapy gained an average of 14-16.5 lbs. There is evidence that weight is gained as a result of increased fat and is not secondary to an anabolic effect or fluid retention.

Anaphylaxis: Reports of anaphylactic responses (anaphylactic reactions, anaphylactic shock, anaphylactoid reactions) have been received.

Thrombo-embolic Disorders: Should the patient experience pulmonary embolism, cerebrovascular disease or retinal thrombosis while receiving Depo-Provera, the drug should not be readministered.

Psychiatric Disorders: Patients with a history of endogenous depression should be carefully monitored. Some patients may complain of premenstrual-type depression while on Depo-Provera therapy.

Abscess formation: As with any intramuscular injection, especially if not administered correctly, there is a risk of abscess formation at the site of injection, which may require medical and/or surgical intervention.

Precautions:

History or emergence of the following conditions require careful consideration and appropriate investigation: migraine or unusually severe headaches, acute visual disturbances of any kind, pathological changes in liver function and hormone levels.

Patients with thromboembolic or coronary vascular disease should be carefully evaluated before using Depo-Provera.

A decrease in glucose tolerance has been observed in some patients treated with progestogens. The mechanism for this decrease is obscure. For this reason, diabetic patients should be carefully monitored while receiving progestogen therapy.

Rare cases of thrombo-embolism have been reported with use of Depo-Provera, but causality has not been established.

The effects of medroxyprogesterone acetate on lipid metabolism have been studied with no clear impact demonstrated. Both increases and decreases in total cholesterol, triglycerides and low-density lipoprotein (LDL) cholesterol have been observed in studies.

The use of Depo-Provera appears to be associated with a 15-20% reduction in serum high density lipoprotein (HDL) cholesterol levels which may protect women from cardiovascular disease. The clinical consequences of this observation are unknown. The potential for an increased risk of coronary disease should be considered prior to use.

Doctors should carefully consider the use of Depo-Provera in patients with recent trophoblastic disease before levels of human chorionic gonadotrophin have returned to normal.

Physicians should be aware that pathologists should be informed of the patient's use of Depo-Provera if endometrial or endocervical tissue is submitted for examination.

The results of certain laboratory tests may be affected by the use of Depo-Provera. These include gonadotrophin levels (decreased), plasma progesterone levels (decreased), urinary pregnanediol levels (decreased), plasma oestrogen levels (decreased), plasma cortisol levels (decreased), glucose tolerance test, metyrapone test, liver function tests (may increase), thyroid function tests (protein bound iodine levels may increase and T3 uptake levels may decrease). Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX and X may increase.

Aminoglutethimide administered concurrently with Depo-Provera may significantly depress the bioavailability of Depo-Provera.

Interactions with other medicinal treatments (including oral anticoagulants) have rarely been reported, but causality has not been determined. The possibility of interaction should be borne in mind in patients receiving concurrent treatment with other drugs.

The clearance of medroxyprogesterone acetate is approximately equal to the rate of hepatic blood flow. Because of this fact, it is unlikely that drugs which induce hepatic enzymes will significantly affect the kinetics of medroxyprogesterone acetate. Therefore, no dose adjustment is recommended in patients receiving drugs known to affect hepatic metabolising enzymes.

Doctors should check that patients are not pregnant before initial injection of Depo-Provera, and also if administration of any subsequent injection is delayed beyond 89 days (12 weeks and five days).

Infants from accidental pregnancies that occur 1-2 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.

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.

Medroxyprogesterone acetate and/or its metabolites are secreted in breast milk, but there is no evidence to suggest that this presents any hazard to the child. Infants exposed to medroxyprogesterone via breast milk have been studied for developmental and behavioural effects to puberty. No adverse effects have been noted.

None

In a large clinical trial of over 3900 women, who were treated with Depo-Provera for up to 7 years, the following adverse events were reported.

The following adverse events were commonly (by more than 5% of subjects) reported: menstrual irregularities (bleeding and/or amenorrhoea), weight changes, headache, nervousness, abdominal pain or discomfort, dizziness, asthenia (weakness or fatigue).

Adverse events reported by 1% to 5% of subjects using Depo-Provera were: decreased libido or anorgasmia, backache, leg cramps, depression, nausea, insomnia, leucorrhoea, acne, vaginitis, pelvic pain, breast pain, no hair growth or alopecia, bloating, rash, oedema, hot flushes.

Adverse reactions are listed according to the following categories:

Very Common >10%

Common 1% and < 10%

Uncommon >0.1% and <1%

Rare < 0.1%

Unknown (cannot be estimated from the available data)

Ear and Labyrinth Disorders

Uncommon: Vertigo

Gastrointestinal Disorders

Very common: Abdominal pain or discomfort

Common: Bloating, nausea

Uncommon: Abdominal distension, Gastrointestinal disturbances

Rare: Rectal bleeding

Infection & Infestations

Common: Vaginitis

Metabolism & Nutrition Disorders

Common: Appetite decrease, appetite increase,

Uncommon: weight increase, weight decrease, fluid retention

Musculoskeletal, Connective Tissue & Bone Disorders

Common: backpain,

Uncommon: arthralgia, muscle cramps, pain in limbs

Frequency not known:, Osteoporosis including osteoporotic fractures, loss of bone mineral density, axillary swelling

Nervous System Disorders

Very common: headaches

Common: dizziness

Uncommon: somnolence, migraine, convulsions

Rare: paralysis

Unknown: Syncope

Reproductive System & Breast Disorders

Common: Amenorrhea, breast pain/tenderness, intermenstrual bleeding, menometrorrhagia, menorrhagia, pelvic pain, leucorrhoea,

Uncommon: Vaginal discharge, vulvovaginal dryness, dysmenorrhea, change in breast size, dyspareunia, ovarian cyst, premenstrual syndrome, genitourinary infection, uterine hyperplasia

Rare: breast lumps or nipple bleeding

Frequency not known: Abnormal uterine bleeding (irregular, increase, decrease), galactorrhea, vaginal cysts, prevention of lactation, sensation of pregnancy, lack of return to fertility

Vascular Disorders

Common: Hot flushes

Uncommon: hypertension, varicose veins, thrombophlebitis, pulmonary embolism

Frequency not known: Thromboembolic disorders, deep vein thrombosis

Cardiovascular Disorders

Rare: Tachycardia

Immune System Disorders

Uncommon: Hypersensitivity reactions (e.g. anaphylaxis & anaphylactoid reactions, angioedema)

Hepato-biliary disorders

Uncommon: Abnormal liver enzymes, jaundice

Frequency not known: disturbed liver function

Skin & Subcutaneous Tissue Disorders

Common: Acne, alopecia, rash

Uncommon: Chloasma, dermatitis, ecchymosis, hirsutism, pruritus, melasma, urticaria, oedema

Frequency not known: skin striae, scleroderma,

General Disorders and Administration Site Conditions

Common: Fatigue, injection site reactions (such as pain or abscess), asthenia, paraesthesia

Uncommon: Chest pain, pyrexia

Rare: thirst, hoarseness, paralysis

Frequency not known: facial palsy

Investigations

Uncommon: Cervical smear abnormal

Rare: Decreased glucose tolerance

Psychiatric Disorders

Common: Anorgasmia, depression, nervousness, emotional disturbance, libido decreased, mood disorder, irritability, insomnia

Uncommon: Anxiety

Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps)

Rare: Breast cancer

Blood and lymphatic system disorders

Rare: anaemia

Frequency unknown: blood dyscrasia

Respiratory, thoracic, and mediastinal disorders

Uncommon: dyspnoea

No positive action is required other than cessation of therapy.

Medroxyprogesterone acetate exerts anti-oestrogenic, anti-androgenic and antigonadotrophic effects.

BMD Changes in Adult Women

A study comparing changes in BMD in women using DEPO-PROVERA with women using medroxyprogesterone acetate injection (150 mg IM) showed no significant differences in BMD loss between the two groups after two years of treatment. Mean percent changes in BMD in the DEPO-PROVERA group are listed in Table 1.

Table 1. Mean Percent Change from Baseline in BMD in Women Using DEPO-PROVERA by Skeletal Site

In another controlled, clinical study adult women using medroxyprogesterone acetate injection (150 mg IM) for up to 5 years 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 two 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. Please refer to Table 2 below for further details.

After stopping use of medroxyprogesterone acetate injection (150 mg IM), BMD increased towards baseline values during the post-therapy period. A longer duration of treatment was associated with a slower rate of BMD recovery.

Table 2. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort after 5 Years of Therapy with Medroxyprogesterone acetate 150 mg IM and after 2 Years Post-Therapy or 7 Years of Observation (Control)

*The treatment group consisted of women who received medroxyprogesterone acetate injection (150 mg IM) for 5 years and the control group consisted of women who did not use hormonal contraception for this time period.

** The treatment group consisted of women who received medroxyprogesterone acetate Injection (150 mg IM) for 5 years and were then followed up for 2 years post-use and the control group consisted of women who did not use hormonal contraceptive for 7 years.

BMD Changes in Adolescent Females (12-18 years)

Results from an open-label, non-randomised, clinical study of medroxyprogesterone acetate Injection (150 mg IM every 12 weeks for up to 240 weeks (4.6 years), followed by post–treatment measurements) in adolescent females (12-18 years) also showed that medroxyprogesterone acetate IM use was associated with a significant decline in BMD from baseline. Among subjects who received 4 injections/60-week period, the mean decrease in lumbar spine BMD was - 2.1 % after 240 weeks (4.6 years); mean decreases for the total hip and femoral neck were -6.4 % and -5.4 %, respectively. Post-treatment follow-up showed that, based on mean values, lumbar spine BMD recovered to baseline levels approximately 1 year after treatment was discontinued and that hip BMD recovered to baseline levels approximately 3 years after treatment was discontinued. However, it is important to note that a large number of subjects discontinued from the study, therefore these results are based on a small number of subjects (n=71 at 60 weeks and n=25 at 240 weeks after treatment discontinuation). In contrast, a non-comparable cohort of unmatched, untreated subjects, with different baseline bone parameters from the DMPA users, showed mean BMD increases at 240 weeks of 6.4%, 1.7% and 1.9% for lumbar spine, total hip and femoral neck, respectively.

Parenteral medroxyprogesterone acetate (MPA) is a long acting progestational steroid. The long duration of action results from its slow absorption from the injection site. Immediately after injection of 150 mg/ml MPA, plasma levels were 1.7 ± 0.3 nmol/l. Two weeks later, levels were 6.8 ± 0.8 nmol/l. Concentrations fell to the initial levels by the end of 12 weeks. At lower doses, plasma levels of MPA appear directly related to the dose administered. Serum accumulation over time was not demonstrated. MPA is eliminated via faecal and urinary excretion. Plasma half-life is about six weeks after a single intramuscular injection. At least 11 metabolites have been reported. All are excreted in the urine, some, but not all, conjugated.

Excipients are methylparaben, macrogol 3350, polysorbate 80, propylparaben, sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.

None known.

Syringe: 36 months.

Vial: 18 months

Do not store above 25 ^° C.

Do not freeze.

1 ml disposable syringe with plunger stopper and tip cap. 1 ml vial with stopper and tip cap.

No special instructions are applicable.

Pfizer Limited

Ramsgate Road

Sandwich

CT13 9NJ

UK

PL 00057/0965

Date of Grant: 27 August 1991

Date of Renewal: 6 February 1997

January 2012

Company Reference: DP4_0