DEPO-PROVERA®
Medroxyprogesterone acetate USP, 150mg/ml injection
Presentation
Depo-Provera is a white aqueous suspension containing Medroxyprogesterone acetate USP 150mg/ml.
Uses
Actions
Medroxyprogesterone acetate (17 α-hydroxy-6 α-methylprogesterone acetate) is a progestogen and a derivative of progesterone.
Medroxyprogesterone acetate induces responses in laboratory animals comparable to those caused by progesterone. It is more potent than progesterone and when injected as a suspension, has a long duration of action. Medroxyprogesterone acetate induces glandular development in the endometrium, maintains pregnancy, delays parturition, inhibits ovulation and suppresses oestrous cycles. It is devoid of androgenic and oestrogenic activity. In selected animal tests it has some adrenal corticoid-like activity and in dogs increases serum growth hormone levels.
Depo-Provera has prolonged progestational effects when administered by intramuscular injection.
Depo-Provera suppresses the secretion of pituitary gonadotropins which, in turn, prevents follicular maturation producing long-term anovulation in the reproductive-aged woman. Depo-Provera suppresses the Leydig cell function in the male. i.e. suppresses endogenous testosterone product.
A single dose of 50mg of parenteral medroxyprogesterone acetate has the equivalent effect of 20mg of oral progesterone given daily for 10 days in producing an optimal secretory change in an oestrogen-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 count in the maturation index of the vaginal epithelium.
Anti-cancer activity of Depo-Provera at pharmacologic doses may be dependent on its effect on the hypopituitary/gonadal axis oestrogen receptors and the metabolism of steroids at the tissue level.
Like progesterone parenteral medroxyprogesterone acetate is thermogenic. Clinically suppression of adrenocortical function has not been observed at the dose levels employed for ovulation suppression. However, at the very high dosage levels used in the treatment of certain cancers (500mg daily or more) corticoid-like activity may manifest.
In chronic toxicity studies in rats and mice no significant differences between controls and treated groups in relation to clinical signs, mortality rates, development of neoplasms or the development of any other gross or histologic lesions developed. No teratogenic effects were observed in mice and rats. In rabbits Depo-Provera exhibited a corticoid-like effect on foetal development.
In long-term toxicology studies in monkeys two of the monkeys receiving intramuscular doses of 150mg/kg every 90 days developed undifferentiated carcinoma of the uterus. No uterine malignancies were found in monkeys receiving 30mg/kg, 3mg/kg or placebo every 90 days.
The occurrence of the lesions in these two monkeys does not signify that Depo-Provera is carcinogenic in women. The incidence of endometrial carcinoma reported with women on Depo-Provera is considerably less than the random incidence in the general population. This may be an artifact but it suggests no causal relationship between endometrial cancer and the usage of Depo-Provera. Depo-Provera is used successfully as palliative treatment in endometrial and breast cancer.
Pharmacokinetics
Parenteral medroxyprogesterone acetate is a long acting progestational steroid. The 150mg/ml formulation reaches half its initial concentration in about 27 days. Its long duration of action results from its slow absorption from the injection site.
The principal metabolic of medroxyprogesterone acetate that has been identified is a 6alpha-methyl-6beta 17alpha, 21-trihydroxy-4-pregnene-3, 20-dione-17-acetate which is excreted in the urine.
Indications
Depo-Provera is indicated for:
- Ovulation suppression
- The treatment of endometriosis
- Adjunctive and/or palliative treatment of recurrent and/or metastatic endometrial or renal carcinoma
- The treatment of hormonally-dependant recurrent breast cancer in post-menopausal women
Dosage and Administration
Ovulation Suppression
The recommended dose is 150mg of Depo-Provera every three months administered by deep, intramuscular injection. To increase assurance that the patient is not pregnant at the time of the first administration, it is recommended that this injection be given during the first 5 days after the onset of a normal menstrual period or before the sixth week post-partum.
Depo-Provera does not interfere with lactation. Although medroxyprogesterone acetate is secreted in the mother's milk, the amounts are very low. To date no adverse effects on infant development have been observed. Clinical studies are continuing to monitor the possible occurrence of any such effects.
It is recommended that physicians or others directly responsible for these patients advise them at the beginning of treatment that their menstrual cycle may be disrupted, that irregular and unpredictable bleeding or spotting are produced, but that this usually decreases to the point of amenorrhoea as treatment with Depo-Provera continues without other therapy being required.
Pharmacia do not recommend routine or long-term cyclic use of supplemental oestrogens with Depo-Provera. Excessive or prolonged bleeding which becomes troublesome to the patient can usually be controlled by the administration of oral or parenteral oestrogens in the equivalent of 0.05 to 0.1 mg ethinyl oestradiol daily for 7 to 21 days. This therapy can be continued for 1 to 2 cycles, but should not be considered for long-term administration.
Based on limited experience, some investigators favour the use of a second injection of Depo-Provera before 90 days to control troublesome bleeding. The third and subsequent injections should be administered at separate 90 day intervals.
If abnormal bleeding persists, appropriate investigation should be instituted to rule out the possibility of organic pathology. Uterine curettage may be required on rare occasions.
Endometriosis
The recommended dose of Depo-Provera in this condition is 50mg weekly or 100mg every 2 weeks intramuscularly for at least 6 months. It should be noted that return of ovulation might be delayed following this therapy due the depot properties of the drug. (See Warnings)
Pharmacia do not recommend routine or long-term cyclic use of supplemental oestrogens with Depo-Provera.
Endometrial and Renal Carcinoma
Doses of 500mg to 1000mg of Depo-Provera intramuscularly per week are recommended initially. If improvement is noted within a few weeks or months and the disease appears stabilised, it may be possible to maintain improvement with 500mg per week or less. Depo-Provera is not recommended as primary therapy, but as adjunctive and palliative treatment in advanced inoperable cases including those with recurrent or metastatic disease.
Breast Cancer
The recommended dosage schedule is Depo-Provera 500mg/day intramuscularly for 28 days. The patient should then be placed on a maintenance schedule of 500mg twice weekly as long as she is responding to treatment. Response to hormonal therapy (Depo-Provera) for breast cancer may not be evident until 8 to 10 weeks of therapy. Treatment with Depo-Provera should be terminated should rapid progression of disease occur at any time during therapy.
Contraindications
Depo-Provera should not be used in patients who have a known or suspected pregnancy.
Depo-Provera should not be used in patients who have undiagnosed vaginal bleeding.
Depo-Provera should not be used in patients with known or suspected malignancy of the breast.
Depo-Provera should not be used in patients with active thrombophlebitis, or current or past history of thromboembolic disorders or cerebral vascular disease. The physician should be alert to the earliest manifestation of thrombotic disorders (thrombophlebitis, pulmonary embolism, cerebrovascular disorders, and retinal thrombosis).
Depo-Provera should not be used in patients with liver dysfunction or disease.
Depo-Provera should not be used in patients who are known to be hypersensitive to medroxyprogesterone acetate or any of its other ingredients.
Warnings and Precautions
Most women using Depo-Provera experience disruption of menstrual bleeding patterns. Altered menstrual patterns include irregular or unpredictable bleeding or spotting, or rarely, heavy or continuous bleeding. As women continue using Depo-Provera, fewer experience irregular bleeding and more experience amenorrhea.
Use of Depo-Provera may be considered among the risk factors for development of osteoporosis.
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.
An increased relative risk (RR) of 2.19 (95% CI 1.23 to 3.89) of breast cancer has been associated with 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 [CI = Confidence Interval]. However, the overall RR for ever-users of Depo-Provera was only 1.2 (95% CI 0.96 to 1.52).
Other recent analyses have shown similar findings on the RR of breast cancer associated with the use of Depo-Provera.
Ocular Disorders. Medication should not be readministered pending examination if there is a 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 not be readministered.
The pretreatment and annual history and physical examination should include special reference to breast and pelvic organs.
Progestational drugs may cause some degree of fluid retention, therefore, caution should be exercised in treating any patient with a pre-existing medical condition that might be adversely affected by weight gain or fluid retention.
There is a tendency for women to gain weight while on therapy with Depo-Provera.
Depo-Provera has a prolonged contraceptive effect. The median time to conception for those who do conceive is 10 months following the last injection with a range of 4 to 31 months, and is unrelated to the duration of use.
Patients who have a history of psychic depression should be carefully observed and the drug should not be readministered if the depression recurs.
Some patients receiving Depo-Provera may exhibit a decreased glucose tolerance. For this reason, diabetic patients should be carefully observed while receiving such therapy.
If jaundice develops, consideration should be given to not readminister the drug.
Patients should be counselled that Depo-Provera does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
Any patient who develops signs and/or symptoms consistent with a thromboembolic disorder should be re-evaluated before continuing treatment with Depo-Provera.
The pathologist (laboratory) should be informed of the patient's use of Depo-Provera if endometrial or endocervical tissue is submitted for examination.
The use of progestational agents during pregnancy is not recommended. Progestational agents are also not recommended as a diagnostic test for pregnancy.
Following repeated injections, amenorrhoea and anovulation may persist for periods up to 18 months and, in rare instances, for longer periods.
Anaphylactic and anaphylactoid reactions have occasionally been reported in patients treated with Depo-Provera. Clinical suppression of adrenocortical function has not been observed at the dose levels employed for ovulation suppression. However, at the very high doses (500mg daily or more) used in the treatment of certain cancers, corticoid-like activity has been reported and in some cases may produce Cushingoid symptoms eg. moon faces, fluid retention, glucose intolerance and blood pressure elevation.
In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, organic causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated. Pharmacia & Upjohn does not recommend routine or long-term cyclic use of supplemental oestrogen to control excessive or prolonged bleeding when Depo-Provera is used for endometriosis. (See Dosage and Administration.)
The use of Depo-Provera may mask the onset of the climacteric.
Certain endocrine and possibly liver function tests may be affected by treatment with Depo-Provera. Therefore, if such tests are abnormal in a patient taking Depo-Provera, it is recommended that they be repeated after the drug has been withdrawn for 4-6 months.
Because of the prolonged action and the resulting difficulty in predicting the time of withdrawal bleeding following injection, Depo-Provera is not recommended for treatment of secondary amenorrhoea or dysfunctional uterine bleeding. In these conditions oral therapy is recommended.
Pregnancy
To ensure that Depo-Provera is not administered inadvertently to a pregnant woman, it is important that no longer than 90 days elapse between each successive administration and that the first injection in a course be given:
- during the first five days after onset of a normal menstrual period
- within five days post-partum if not breast feeding; or
- if breast feeding, at the sixth week post-partum, after having excluded pregnancy
Teratogenicity and mutagenicity
Cases of birth defects have occurred where the mother was exposed to Depo-Provera during pregnancy. Studies in animals have shown that progestogens, including medroxyprogesterone acetate, may have an adverse effect on the developing foetus, including teratogenicity and fetotoxicity. Several reports suggest an association between intrauterine exposure to progestational medicines in the first trimester of pregnancy and genital abnormalities in male and female foetuses.
Infants from accidental pregnancies that occur 1-2 months after injection of Depo-Provera may be at increased risk of low birth weight, which in turn may be associated with an increased risk of neonatal death. The attributable risk is low because such pregnancies are uncommon.
A significant increase in polysyndactyly and chromosomal anomalies was observed among infants of Depo-Provera users, 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 casual association unlikely.
Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female foetuses. The risk of hypospadias (5 to 8 per 1000 male births in the general population) may be approximately doubled with exposure to these drugs. There are insufficient data to quantify the risks to female foetuses, but because some of these drugs induce mild virilisation of the external genitalia of the female foetus and because of the increased association of hypospadias in the male foetus, it is prudent to avoid use of these drugs during the first trimester of pregnancy.
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.
Adverse Effects
The following medical events have been reported by 1% or more of subjects in clinical trials:
Genitourinary
Menstrual irregularity (bleeding and amenorrhoea or both), decreased libido or anorgasmia, leukorrhea, vaginitis, hot flashes, pelvic pain.
Central Nervous System
Headache, nervousness, dizziness, depression, insomnia.
Gastrointestinal
Abdominal pain or discomfort, nausea, bloating.
Skin and mucous membranes
Acne, no hair growth or alopecia, rash.
Musculoskeletal
Asthenia, leg cramps, backache, arthralgia.
Breasts
Breast discomfort
Miscellaneous
Weight change
Voluntary reports of the following reactions with the use of Depo-Provera have been received:
- Anaphylaxis and anaphylactoid reactions
- Convulsions
Association with drug use or pre-existing conditions is not clear.
Interactions
Drug interaction - Aminoglutethimide administered concomitantly with Depo-Provera may significantly depress the serum concentrations 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.
The pathologist (laboratory) should be informed of the patient's use of Depo-Provera if endometrial or endocervical tissue is submitted for examination.
The following tests may be affected by progestins including Depo-Provera:
- Plasma and urinary steroid levels are decreased (eg, progesterone, oestradiol, pregnanediol, testosterone, cortisol)
- Gonadotrophin levels are decreased
- Sex-hormone-binding-globulin concentrations are decreased
- Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase
- Liver function test values may be increased
Overdosage
Nil
Pharmaceutical Precautions
Syringe: Store at or below 25°C (77°F).
Vial: Store below 30°C (86°F).
Package Quantities
150mg/ml - 1ml disposable syringe
150mg/ml - 1ml vial
Further Information
Depo-Provera is a registered trademark.
Lowest Expected and Typical Failure Rates*
Expressed as % of Women Experiencing an Accidental Pregnancy in the First Year of Continuous Use
Method | Lowest Expected | Typical |
| Injectable progestogen Depo-Provera | 0.3 | 0.3 |
| Implants Norplant (6 capsules) | 0.2 | 0.2 |
| Female sterilisation | 0.2 | 0.4 |
| Male sterilisation | 0.1 | 0.15 |
Pill
Combined
Progestin only |
0.1
0.5 | 3 |
IUD
Progestasert
Copper T 380A |
2.0
0.8 | 3 |
| Condom | 2 | 12 |
| Diaphragm | 6 | 18 |
| Cap | 6 | 18 |
| Spermicides | 3 | 21 |
Sponge
Parous women
Nulliparous women |
9
6 |
28
18 |
| Periodic abstinence | 1-9 | 20 |
| Withdrawal | 4 | 18 |
| No method | 85 | 85 |
Source: Trussell et al
* Lowest expected - when used exactly as directed.
Typical - includes those not following directions exactly.
