Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, CT13 9NJ, UK
Hypersensitivity to medroxyprogesterone acetate or to any of excipients listed in section 6.1.
Depo-Provera should not be used during pregnancy, either for diagnosis or therapy.
Depo-Provera is contraindicated as a contraceptive at the above dosage in known or suspected hormone-dependent malignancy of breast or genital organs.
Depo-Provera is contraindicated in patients with the presence or history of severe hepatic disease whose liver function tests 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.
Assessment of women prior to starting hormonal contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.
Use of depot medroxyprogesterone acetate intramuscular (DMPA-IM) reduces serum oestrogen levels and is associated with significant loss of BMD due to the known effect of oestrogen deficiency on the bone remodelling system. Bone loss is greater with increasing duration of use; however BMD appears to increase after DMPA-IM is discontinued and ovarian oestrogen 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 DMPA-IM by younger women will reduce peak bone mass and increase the risk for fracture in later life i.e. after menopause.
A study to assess the BMD effects of DMPA-IM (Depo-Provera) in adolescent females showed that its use was associated with a statistically significant decline in BMD from baseline. After discontinuing DMPA-IM in adolescents, return of mean BMD to baseline values required 1.2 years at the lumbar spine, 4.6 years at the total hip and at least 3.4 years at the femoral neck (see section 5.1). However in some participants, BMD did not fully return to baseline during follow-up and the long-term outcome is not known in this group. 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.
A large observational study of predominantly adult female contraceptive users showed that use of DMPA-IM did not increase risk for bone fractures. Importantly, this study could not determine whether use of DMPA has an effect on fracture rate later in life (see section 5.1 – Relationship of fracture incidence to use of DMPA-IM by women of reproductive age).
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:
For further information on BMD changes in both adult and adolescent females, refer to section 5.1.
Adequate intake of calcium and Vitamin D, whether from the diet or from supplements, is important for bone health in women of all ages.
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 co-administration 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.
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*
| Age at last use of DMPA | No of cases per 10,000 women who are never-users | Possible additional cases per 10,000 DMPA users |
|---|---|---|
| 20 | Less than 1 | Much less than 1 |
| 30 | 44 | 2-3 |
| 40 | 160 | 10 |
* 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 re-administered.
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.
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
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.
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.
Women should be counselled 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.
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.
Medroxyprogesterone acetate (MPA) is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted and therefore the clinical effects of CYP3A4 inducers or inhibitors are unknown.
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 acetate via breast milk have been studied for developmental and behavioural effects to puberty. No adverse effects have been noted.
Depo-Provera may cause headaches and dizziness. Patients should be advised not to drive or operate machinery if affected.
The table below provides a listing of adverse drug reactions with frequency based on all-causality data from clinical studies that enrolled more than 4200 women who received DMPA for contraception for up to 7 years. Those most frequently (>5%) reported adverse drug reactions were weight increased (69%), weight decreased (25%), headache (16%), nervousness (11%), abdominal pain or discomfort (11%), dizziness (6%), and decrease in libido (6%).
The following lists of adverse reactions are listed within the organ system classes, under headings of frequency (number of patients expected to experience the reaction), using the following categories: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Rare: Breast cancer
Rare: Anaemia, Blood disorder
Uncommon: Drug hypersensitivity
Rare: Anaphylactic reaction, Anaphylactoid reaction, Angioedema
Uncommon: Increased appetite, decreased appetite
Very common: Nervousness
Common: Depression, Libido decreased
Uncommon: Insomnia
Rare: Anorgasmia, Emotional disturbance, Effective disorder, Irritability, Anxiety
Very common: Headache
Common: Dizziness
Uncommon: Seizure, Somnolence, Paraesthesia
Rare: Migraine, Paralysis, Syncope
Rare: Vertigo
Rare: Tachycardia
Uncommon: Hot flush
Rare: Embolism and thrombosis, Deep vein thrombosis, Thrombophlebitis, Hypertension, Varicose veins
Uncommon: Dyspnoea
Rare: Pulmonary embolism
Very common: Abdominal pain, Abdominal discomfort
Common: Nausea, Abdominal distension
Rare: Rectal haemorrhage, Gastrointestinal disorder
Uncommon: Hepatic function abnormal
Rare: Jaundice, Hepatic enzyme abnormal
Common: Alopecia, Acne, Rash
Uncommon: Hirsutism, Urticaria, Pruritus, Chloasma
Rare: Lipodystrophy acquired*, Dermatitis, Ecchymosis, Scleroderma, Skin striae
Common: Back pain, Pain in extremity
Rare: Arthralgia, Muscle spasms, Osteoporosis, Osteoporotic fractures
Common: Vaginal discharge, Breast tenderness, Dysmenorrhea, Genitourinary tract infection
Uncommon: Dysfunctional uterine bleeding (irregular, increase, decrease, spotting, Galactorrhoea Pelvic pain, Dyspareunia, Suppressed lactation
Rare: Vaginitis, Amenorrhoea, Breast pain, Metrorrhagia, Menometrorrhagia, Menorrhagia,Vulvovaginal dryness, Breast atropy, Ovarian cyst, Premenstrual syndrome, Endometrial hyperplasia, Breast mass, Nipple exudate bloody, Vaginal cyst, Breast enlargement, Lack of return to fertility, Sensation of pregnancy
Common: Odema/Fluid retention, Asthenia
Uncommon: Chest pain
Rare: Pyrexia, Fatigue, Injection site reaction*, Injection site persistent atrophy/indentation/dimpling*, Injection site nodule/lump*, Injection site pain/tenderness* Thirst, Dysphonia, VIIth nerve paralysis, Axillary swelling
Very common: Weight increased, Weight decreased
Rare: Bone density decreased, Glucose tolerance decreased, Cervical smear abnormal
* ADR identified post-marketing
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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