Consumer medicine information

Depo-Provera

Medroxyprogesterone acetate

BRAND INFORMATION

Brand name

Depo-Provera

Active ingredient

Medroxyprogesterone acetate

Schedule

What is in this leaflet

This leaflet answers some common questions about DEPO-PROVERA.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking DEPO-PROVERA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What DEPO-PROVERA is used for

The active ingredient of DEPO-PROVERA is a chemical similar to the natural hormone progesterone. Your ovaries produce progesterone during the second half of your monthly cycle.

There are several reasons why your doctor may have prescribed DEPO-PROVERA for you.

DEPO-PROVERA is used for the following reasons.

Contraception
DEPO-PROVERA is an injectable form of contraception. Each injection protects you from pregnancy for 3 months.

DEPO-PROVERA works by inhibiting the hormones that are needed for the release of eggs from your ovaries.

Endometriosis
Endometriosis is a condition in which cells from the lining of the uterus (womb) grow in places outside the uterus.

During your period, these cells may grow and break down in the same way as those in the lining of the uterus. This causes pain and discomfort. DEPO-PROVERA helps to stop the growth of cells outside the uterus.

Cancer
DEPO-PROVERA is also used in the treatment of certain types of cancer including cancer of the breast, kidney and endometrium (lining of the uterus). It works by inhibiting the growth of these types of cancer cells. DEPO-PROVERA is not a cure for cancer.

Your doctor may have prescribed DEPO-PROVERA for another purpose. Ask your doctor if you have any questions about why DEPO-PROVERA has been prescribed for you.

This medicine is available only with a doctor's prescription.

Before you are given DEPO-PROVERA

When you must not be given it

DEPO-PROVERA should not be used if you have or have had any of the following medical conditions:

swelling and redness along a vein (usually extremely tender when touched)
a stroke, blood clots
liver problems
unusual or irregular vaginal bleeding that has not been diagnosed
blood in your urine that has not been diagnosed
any lumps in your breast that have not been diagnosed
a missed miscarriage
any bleeding or discharge from your nipples
severe, uncontrolled, high blood pressure.

DEPO-PROVERA should not be used if you are pregnant or intend to become pregnant.

DEPO-PROVERA should not be used if you have an allergy to medroxyprogesterone acetate or any of the ingredients listed at the end of this leaflet.

DEPO-PROVERA should not be used after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering.

If you are not sure whether you should be treated with DEPO-PROVERA, talk to your doctor or pharmacist.

Before you are given it

DEPO-PROVERA does not protect against sexually transmitted infections (STIs) including HIV infection. Using DEPO-PROVERA as directed will not expose you to STIs, as it is a sterile injection product. Practising safe sex (ie. Using condoms) can lower the risk of STI transmission, including HIV through sexual contact.

You must tell your doctor if you have allergies to:

any other medicines
any other substances, such as foods, preservatives or dyes.

Tell your doctor if you are pregnant, suspect you may be pregnant or intend to become pregnant.

Tell your doctor if you are breastfeeding or plan to breastfeed.

Tell your doctor if you have or have had any medical conditions, especially the following:

blood clots in your legs
swollen red veins
stroke
breast cancer or a family history of breast cancer
any problems with your breasts
unusual or irregular vaginal bleeding or spotting
blood pressure problems
epilepsy
migraine
asthma
heart problems
kidney problems
liver problems
diabetes
depression
abnormal menstrual periods
bone disease or a family history of bone disease, such as brittle bones (osteoporosis)
eating disorders (anorexia).

If you have not told your doctor or pharmacist about any of the above, tell them before you are treated with DEPO-PROVERA.

DEPO-PROVERA is intended to prevent pregnancy. It will not protect you from sexually transmitted diseases such as AIDS (HIV), Hepatitis B and C, genital herpes, genital warts, syphilis or gonorrhoea. Talk to your doctor about how to avoid these diseases.

If you are under 35 years of age when you first start treatment with DEPO-PROVERA, you may have a slightly increased risk of developing breast cancer. This is similar to the risk with oral contraceptives (the Pill). If you have any concerns about this, please discuss them with your doctor.

The use of DEPO-PROVERA results in a decrease in the amount of calcium stored in your bones. This could increase your risk of developing brittle bones (osteoporosis), which can lead to bone breakages in later life. This affects women of all ages; however, it can be greater if you are under 18 years old. Your doctor will assess this risk before giving you DEPO-PROVERA and if you continue using DEPO-PROVERA for more than 2 years.

The amount of calcium in your bones will start to increase again once you stop treatment with DEPO-PROVERA. The time to recovery depends on duration of use. Some women may only partially recover the amount of calcium in their bone. Talk to your doctor if you have any concerns over the risk of developing osteoporosis.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may interfere with DEPO-PROVERA. These include aminoglutethimide, a medicine used to treat breast cancer. This medicine may affect how well DEPO-PROVERA works. You may need different amounts of your medicine or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist may have more information on medicines to be careful with or avoid while being treated with DEPO-PROVERA.

How DEPO-PROVERA is given

DEPO-PROVERA is given as an injection into the muscle of your buttock. Your doctor or a trained nurse will give you the injection.

The amount of DEPO-PROVERA and the number of injections that you receive will depend on the reason for the treatment.

The dose for contraception and for endometriosis is a lot less than for cancer.

How much is given

Contraception
The recommended dose of DEPO-PROVERA for effective contraception is 150 mg every three months. The contraceptive protection of DEPO-PROVERA starts as soon as you have the first injection.

It is very important that you make arrangements to return to your doctor every three months for your injections, to ensure that pregnancy is prevented.

If you are using DEPO-PROVERA as a contraceptive for the first time, your first injection should only be given during the first 5 days after the start of your normal monthly period.

If you are using DEPO-PROVERA as a form of contraception after the birth of your baby and if you are not breastfeeding, the first injection should be given within 5 days after the baby was born.

If you are breastfeeding, the first injection should be given 6 weeks after the baby was born and after your doctor has checked that you are not pregnant.

If you are switching from another form of contraception, then DEPO-PROVERA should be given in a way that ensures you have continuous contraceptive cover. For example, patients switching from the oral contraceptive pill should have their first DEPO-PROVERA injection within 7 days after taking the last active pill.

If the time between your injections is greater than 14 weeks, your doctor will need to check that you are not pregnant before they give you another injection.

Endometriosis
The usual dosage is either 50 mg weekly or 100 mg every two weeks.

Treatment for endometriosis is usually for at least 6 months.

Breast Cancer
The usual dosage for breast cancer is 500 mg every day for 4 weeks. After the first 4 weeks, DEPO-PROVERA is given as a weekly injection of 500 mg or 1000 mg.

Your doctor will determine how much you should receive and how long you should continue to receive these injections.

Other types of cancer
The initial dose range of DEPO-PROVERA is 600 mg to 1200 mg every week. This is followed by an injection of 450 mg to 600 mg every 1 to 4 weeks.

Your doctor will determine how much you will receive and how long you should continue to receive the injections.

If you are given too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) or go to Accident and Emergency at your nearest hospital if you think you or anyone else may have been treated with too much DEPO-PROVERA.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using DEPO-PROVERA

Things you must do

If you become pregnant while using DEPO-PROVERA, tell your doctor. (The chance of falling pregnant while using DEPO-PROVERA as a contraceptive is low).

If you have sudden partial or complete loss of vision or sudden onset of double vision or migraine while you are taking DEPO-PROVERA, tell your doctor immediately.

Tell all doctors, dentists, and pharmacists who are treating you that you have been treated with DEPO-PROVERA, particularly if you are about to have any pathology tests (e.g., blood or urine tests). DEPO-PROVERA may interfere with the results.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you have been treated with DEPO-PROVERA.

Things to be careful of

Be careful driving or operating machinery until you know how DEPO-PROVERA affects you. DEPO-PROVERA generally does not cause any problems with your ability to drive a car or operate machinery. However, DEPO-PROVERA may cause dizziness, drowsiness or fatigue in some people. Make sure you know how you react to DEPO-PROVERA before driving a car or operating machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well during or after treatment with DEPO-PROVERA.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. However, you may need medical treatment if you get some side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Most women using DEPO-PROVERA for contraception experience changes in their normal monthly period. This includes irregular or unpredictable bleeding or spotting or, rarely, heavy or continuous bleeding. If abnormal bleeding continues or is severe, see your doctor immediately.

With continued use of DEPO-PROVERA, it is usual for vaginal bleeding to decrease. Your periods may stop completely.

When you stop treatment with DEPO-PROVERA, your periods will return. However, this may take up to 18 months. Most women find that it takes 12 to 18 months after their last injection to become pregnant. The length of time that you use DEPO-PROVERA does not affect the time it takes for you to become pregnant. If you do not wish to become pregnant after you stop using DEPO-PROVERA, you or your partner should use another form of contraception.

A reduction in the amount of calcium stored in your bones leading to brittle bones (osteoporosis) or fractures may occur. Tell your doctor if this worries you.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

nervousness, confusion
euphoria
loss of concentration
trouble sleeping
fatigue, drowsiness or sleepiness
depression
dizziness, headache
hives, rash or itching
acne, darkening patches of skin on the cheeks
excessive hair growth or unusual hair loss or thinning
sweating
nausea, vomiting, diarrhoea or constipation
dry mouth, increased thirst
breast tenderness or secretions
frequently urinating
pain during sex
changes in vaginal secretions
irregular vaginal bleeding or spotting
lack of menstrual periods
weight increases or decreases
changes in appetite
high fever
abscess formation at the injection site
abdominal pain, bloating or discomfort
decreased libido or the inability to climax
backache, leg cramps, muscle spasms
joint pain
pain and inflammation of the vagina
increased heart rate
swelling or puffiness, fluid retention
hot flushes
vision problems
impotence (in men being treated for cancer)

Tell your doctor or pharmacist immediately if you notice any of the following:

sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
pressure or tightness in the chest, back or jaw pain, difficulty breathing, or coughing up blood
weakness or numbness in your arms or legs
fainting
severe pain or swelling in your calf
sudden onset of migraine
severe abdominal pain
changes in metabolism resulting in the loss of body fat in certain areas of your body such as your face.
hand tremors, sweating, cramps in calves at night
seizures, paralysis
yellowing of the skin and/or eyes.

These may be signs of a serious side effect. You may need urgent medical attention. Serious side effects are rare.

Other side effects not listed above may occur in some patients. These include side effects that can only be detected with a blood test. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After treatment with DEPO-PROVERA

Storage

Keep DEPO-PROVERA in a cool dry place where the temperature stays below 30°C. Normally you should take DEPO-PROVERA straight from the pharmacy to your doctor. Do not leave it in a car.

If for any reason you take your DEPO-PROVERA home, always ensure that it is stored in a place where children cannot reach it.

Do not store DEPO-PROVERA or any other medicine in the bathroom or near a sink.

Disposal

If the vial of DEPO-PROVERA has passed its expiry date, return it to your pharmacist.

Product description

What it looks like

DEPO-PROVERA is a white cloudy liquid.

Ingredients

Each vial of DEPO-PROVERA contains medroxyprogesterone acetate as an active ingredient.

In addition, each vial contains macrogol 3350, polysorbate 80, sodium chloride, methyl hydroxybenzoate, propyl hydroxybenzoate and Water for Injections.

DEPO-PROVERA does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Identification

DEPO-PROVERA vials can be identified by the Australian Register Number on the carton:
150 mg/1 mL: AUST R 12300.

Supplier

DEPO-PROVERA is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

This leaflet was revised in April 2020.

®Registered Trademark.

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Depo-Provera

Active ingredient

Medroxyprogesterone acetate

Schedule

1 Name of Medicine

Medroxyprogesterone acetate (MPA).

2 Qualitative and Quantitative Composition

Depo-Provera 150 mg/mL injection suspension contains 150 mg medroxyprogesterone acetate (MPA).

Excipient(s) with known effect.

Depo-Provera contains methyl hydroxybenzoate, propyl hydroxybenzoate and sodium.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Injection, suspension.

4 Clinical Particulars

4.1 Therapeutic Indications

Carcinoma.

Palliative treatment of recurrent and/or metastatic breast or renal cell cancer and of inoperable recurrent or metastatic endometrial carcinoma.

Endometriosis.

For use in the treatment of visually proven (laparoscopy) endometriosis where the required endpoint of treatment is pregnancy, or for the control of symptoms when surgery is contraindicated or has been unsuccessful.

Contraception (ovulation suppression).

For long-term prevention of pregnancy in women when administered at 3 month intervals.
Since loss of BMD may occur in premenopausal women who use MPA long-term (greater than 2 years), women should be assessed, before starting treatment for contraception or endometriosis, for the risk of osteoporosis. Women under the age of 18 years may be at risk of failing to achieve their predicted peak BMD (see Section 4.4 Special Warnings and Precautions for Use).

4.2 Dose and Method of Administration

Inoperable, recurrent, metastatic, endometrial and renal carcinoma.

Initially 600 mg to 1200 mg weekly, followed by 450 mg to 600 mg every 1 to 4 weeks for maintenance.

Breast carcinoma.

IM injection 500 mg daily for 4 weeks, then 500 mg to 1000 mg at weekly intervals for maintenance.

Endometriosis.

50 mg weekly or 100 mg every 2 weeks by IM injection for at least 6 months.

Contraception (ovulation suppression).

150 mg every 3 months by deep IM injection. To increase assurance that the patient is not pregnant at the time of the first administration it is recommended that this injection is given only during the first 5 days after the onset of normal menstrual period; within 5 days postpartum if not breastfeeding; or, if breastfeeding, at 6 weeks postpartum, after having excluded pregnancy.
If the period between injections is greater than 14 weeks, the physician should determine that the patient is not pregnant before administering the drug.
BMD should be evaluated when considering contraceptive or endometriotic treatment beyond 2 years. An evaluation of BMD may also be appropriate in some patients who use Depo-Provera long-term for oncology indications.
Gluteal infiltration and abscess formation may occur with IM administration. This complication appears to be particularly related to the volume administered and careful attention to injection technique should be observed. If large volumes are to be given, i.e. greater than 2.5 mL, then divided administration into several sites is recommended. It is also important that the suspension be shaken well before use and administered by deep IM injection into the gluteal muscle.
Routine or long-term cyclic use of supplemental estrogens with Depo-Provera is not recommended. Excessive or prolonged bleeding which becomes troublesome to the patient can usually be controlled by the administration of oral or parenteral estrogens in the equivalent of 0.05 mg to 0.1 mg ethinylestradiol 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.
If abnormal bleeding persists, appropriate investigation should be instituted to rule out the possibility of organic pathology.

4.3 Contraindications

Depo-Provera is contraindicated in patients with:
thrombophlebitis, thromboembolic disorders, cerebral apoplexy or patients with a past history of these conditions;
markedly impaired liver function;
undiagnosed vaginal bleeding;
undiagnosed urinary tract bleeding;
undiagnosed breast pathology;
missed abortion;
known sensitivity to MPA or any of the excipients in the injection (see Section 6.1 List of Excipients);
known or suspected pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy);
severe uncontrolled hypertension;
known or suspected malignancy of the breast (excluding use in oncology indications).

4.4 Special Warnings and Precautions for Use

Physical examination.

The pretreatment physical examination should include special reference to breast and pelvic organs as well as Papanicolaou smear.

Thromboembolic disorders.

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.

Meningioma.

Meningiomas have been reported following long-term administration of progestins, including MPA. MPA should be discontinued if a meningioma is diagnosed. Caution is advised when recommending medroxyprogesterone to patients with a history of meningioma.

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 papilloedema, or retinal vascular lesions, medication should be withdrawn.

Bleeding irregularities.

Most women receiving Depo-Provera for contraception experienced disruption of menstrual bleeding patterns. Altered bleeding patterns including irregular or unpredictable bleeding or spotting, or rarely, heavy or continuous bleeding. If abnormal bleeding persists or is severe, appropriate investigations should be instituted to rule out the possibility of organic pathology and appropriate treatment should be instituted when necessary.
As women continued to use Depo-Provera, fewer experienced intermenstrual bleeding and more experienced amenorrhoea. By month 12, amenorrhoea was reported by 57% of women, and by month 24, amenorrhoea was reported by 68% of women using Depo-Provera.
Infertility and anovulation with amenorrhoea and/or erratic menstrual patterns may persist for periods of up to 18 months and occasionally longer following either single or multiple injections of Depo-Provera.

Bone mineral density changes.

Contraception and endometriosis.

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 use of Depo-Provera by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life.
In adult females, BMD was observed for a period of 2 years after Depo-Provera injection was discontinued and mean BMD increased but deficits at the total hip, femoral neck and lumbar spine remain.
In adolescent females, the decrease in BMD appears to be fully reversible after Depo-Provera is discontinued and ovarian estrogen production increases. Full recovery took 1.2 years at the lumbar spine, 4.6 years at the total hip and 4.6 years at the femoral neck after discontinuation of treatment. Longer duration of treatment and smoking were associated with slower recovery (see Section 5.1 Pharmacodynamic Properties, Clinical trials, BMD changes in adolescent females (12 to 18 years)).
Depo-Provera should only be used as a long-term (e.g. longer than 2 years) contraceptive method or treatment for endometriosis if other contraceptive methods or endometriotic treatments are inadequate. BMD should be evaluated when a female needs to continue to use Depo-Provera long-term. In adolescent females, interpretation of BMD results should take into account patient age and skeletal maturity. Since loss of BMD may occur in premenopausal women who use Depo-Provera long-term (greater than 2 years), a risk/benefit assessment, which also takes into consideration the decrease in BMD that occurs during pregnancy and/or lactation, should be considered.
Other contraceptive methods or endometriotic treatments should be considered in the risk/benefit analysis for the use of Depo-Provera in women with osteoporotic risk factors such as:
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.
See Section 5.1 Pharmacodynamic Properties, Clinical trials.

Oncology.

There are no studies on the BMD effects of high doses of parenteral Depo-Provera for oncology use.
However, two clinical studies of adult women of childbearing potential and of adolescent females given Depo-Provera 150 mg IM every 3 months for contraception, demonstrated significant decreases in BMD (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Decreases in serum estrogen due to Depo-Provera may result in a decrease in BMD in a premenopausal woman and may increase her risk for developing osteoporosis later in life.
An evaluation of BMD may be appropriate in some patients who use Depo-Provera long-term.
It is recommended that all patients have adequate calcium and vitamin D intake.

Cancer risks.

Long-term case controlled surveillance of Depo-Provera use for contraception found slight or no increased overall risk of breast cancer and no increased overall risk of ovarian, liver or cervical cancer. There was a prolonged effect of reducing the risk of endometrial cancer in the population of users, with a relative risk (RR) of 0.21 (95% confidence interval [CI] of 0.06-0.79). This protective effect lasts for at least 8 years after the cessation of Depo-Provera use.
The overall RR of breast cancer associated with the use of Depo-Provera appears to be 1.2 (95% CI 0.96-1.52). However, an increased RR of 2.19 (95% CI 1.23-3.89) has been associated with use of Depo-Provera in women whose first exposure to the drug was within the previous 4 years and were under 35 years of age. The RR increases in women aged between 25 and 34 years of age (RR of 2 (95% CI 1.0-3.8) and rises to 4.6 (95% CI 1.4-15.1)) in women aged less than 25 years with more than 2 years exposure to Depo-Provera. The risk of breast cancer was comparable in similar groups of women who used either Depo-Provera or an oral contraceptive.
The Australian Institute of Health and Welfare report, between 1983 to 1985, an average incidence rate for breast cancer in Australian women, aged 30 to 34 years, of 20.97/100,000. A RR of 2.19, thus, increases the possible risk from 20.97 to 45.92 cases per 100,000 women. The attributable risk, therefore, is 24.95 per 100,000 women per year.
The overall, nonsignificant, relative rate of invasive squamous cell cervical cancer in women who ever used Depo-Provera was estimated at 1.11 (95% CI 0.95-1.28). 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 of 1.22 to 1.28, 95% CI 0.93-1.70). No trends in risk with duration of use or times since initial or most recent exposure were observed.

Accidental pregnancies.

Infants from accidental pregnancies that occur 1 to 2 months after injection of Depo-Provera may be at increased risk of low birthweight, 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 causal association unlikely.

Ectopic pregnancy.

As with all forms of hormonal contraception, healthcare providers should be alert to the possibility of an ectopic pregnancy among women using Depo-Provera who become pregnant or complain of severe abdominal pain.

Sexually transmitted infections.

Depo-Provera 150 mg/mL is intended to prevent pregnancy. Women should be counselled that DMPA injectable suspension does not protect against sexually transmitted infections (STIs) including HIV infection (AIDS) but equally, DMPA is a sterile injection and, used as directed, will not expose them to sexually transmitted infections. Safer sex practices including correct and consistent use of condoms reduce the transmission of STIs through sexual contact, including HIV.
In all situations where cessation of therapy is warranted, the physician should be aware of the slow elimination of the depot formulation.
Clinical suppression of adrenocorticoid function has not been observed at low dose levels, however, at the high doses used in the treatment of cancer, corticoid-like activity has been reported. MPA may decrease adrenocorticotrophic hormone and hydrocortisone blood levels. Animal studies show that MPA possesses adrenocorticoid activity.

Anaphylactic and anaphylactoid reactions.

Anaphylactic and anaphylactoid reactions have occasionally been reported in patients treated with IM MPA.

Fluid retention.

Because this drug may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, or cardiac or renal dysfunction, require careful observation.

Breakthrough bleeding.

Breakthrough bleeding is likely to occur in patients being treated for endometriosis. No other hormonal intervention is recommended for managing this bleeding. Nonfunctional causes should also be borne in mind and in cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.

Carbohydrate metabolism.

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

CNS disorders and convulsions.

Patients who have a history of mental depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

Weight changes.

There is a tendency for women to gain weight while on Depo-Provera therapy. From an initial average bodyweight of 61.8 kg women who completed 1 year of therapy with Depo-Provera gained an average of 2.45 kg. Women who completed 2 years of therapy gained an average of 3.68 kg. Women who completed 4 years gained an average of 6.3 kg. Women who completed 6 years gained an average of 7.5 kg. Two percent of women withdrew from a large scale clinical trial because of excessive weight gain.

Return of fertility.

Depo-Provera has a prolonged contraceptive effect. In a large US study of women who discontinued use of Depo-Provera to become pregnant, data are available for 61% of them. Based on Life-Table analysis of these data, it is expected that 65% of women who do become pregnant may conceive within 12 months. 83% may conceive within 15 months, and 93% may conceive within 18 months from the last injection. The median time 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. No data are available for 39% of the patients who discontinued Depo-Provera and were lost to follow-up or changed their mind.

Liver function.

Certain endocrine and possible 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. If jaundice develops, consideration should be given to not readminister Depo-Provera.

Patient age.

The age of the patient constitutes no absolute limiting factor although treatment with progestogens may mask the onset of the climacteric.

Pathology tests.

The pathologist should be advised of progestin therapy when relevant specimens are submitted.

IM administration.

Gluteal infiltration and abscess formation may occur with IM administration. The IM suspension is not formulated for subcutaneous injection (see Section 4.2 Dose and Method of Administration).

General.

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 for secondary amenorrhoea or dysfunctional uterine bleeding. In these conditions, oral therapy is recommended.
MPA used in the treatment of cancer patients may produce Cushingoid symptoms.

Use in hepatic impairment.

No clinical studies have evaluated the effect of hepatic disease on the pharmacokinetics of MPA. However, MPA is almost exclusively eliminated by hepatic metabolism and steroid hormones may be poorly metabolised in patients with severe liver insufficiency (see Section 4.3 Contraindications).

Use in renal impairment.

See Section 4.4 Special Warnings and Precautions for Use, Fluid retention.

Use in the elderly.

No data available.

Paediatric use.

Depo-Provera is not indicated before menarche. Data are available in adolescent females (12 to 18 years) (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Other than concerns about loss of BMD, the safety and effectiveness of Depo-Provera are expected to be the same for postmenarcheal adolescent and adult females.

Effects on laboratory tests.

The following laboratory tests may be affected by the use of Depo-Provera:
Gonadotrophin levels.
Plasma progesterone levels.
Urinary pregnanediol levels.
Plasma testosterone levels (in the male).
Plasma estrogen levels (in the female).
Plasma cortisol levels.
Glucose tolerance test.
Metyrapone test: the use of MPA in oncology indications may also cause partial adrenal insufficiency (decrease in pituitary adrenal axis response) during metyrapone testing. Thus the ability of the adrenal cortex to respond to adrenocorticotrophic hormone should be demonstrated before metyrapone is administered.
Sex hormone binding globulin concentrations are decreased.
Coagulation test values for prothrombin (factor II) and factors VII, VIII, IX and X may increase.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Aminoglutethimide administered concomitantly with Depo-Provera may significantly decrease the serum concentration of MPA. Depo-Provera users should be warned of the possibility of decreased efficacy with the use of this or any related drugs.
MPA is metabolised in vitro primarily by hydroxylation via the CYP3A4. While specific drug-drug interaction studies evaluating the clinical effect of CYP3A4 inhibitors or inducers on MPA have not been conducted or reported in the literature, physicians should consider that interactions could occur which may result in compromised efficacy. Coadministration with CYP3A4 inducers may result in decreased systemic levels of MPA whilst coadministration with CYP3A4 inhibitors may result in increased MPA levels.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 4.4 Special Warnings and Precautions for Use, Return of fertility.
(Category D)
Depo-Provera is not to be used as a test for pregnancy or where pregnancy is suspected.
Studies in animals have shown that progestogens, including MPA, may have an adverse effect on the developing fetus, including teratogenicity and fetotoxicity.
In addition, other animal studies have shown that high doses of progestogens can cause masculinisation of the female fetus.
Several reports suggest an association between intrauterine 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 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 fetuses, but because some of these drugs induce mild virilisation of the external genitalia of the female fetus and because of the increased association of hypospadias in the male fetus, it is prudent to avoid use of these drugs during the first trimester of pregnancy.
Children exposed to MPA in utero and followed to adolescence, showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development.
If Depo-Provera is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.
To ensure that Depo-Provera is not administered inadvertently to a pregnant woman, it is important that the first injection only be given during the first 5 days after the onset of a normal menstrual period; within 5 days postpartum if not breastfeeding; and, if breastfeeding, at the sixth week postpartum, after having excluded pregnancy.
When switching from other contraceptive methods, MPA IM should be given in a manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g. patients switching from oral contraceptives should have their first injection of MPA within 7 days after taking their last active pill).
See Section 4.2 Dose and Method of Administration. Also see Section 4.4 Special Warnings and Precautions for Use.
Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera. In mothers who are breastfeeding and who are treated with Depo-Provera, milk composition, quality and amount are not adversely affected. Infants exposed to medroxyprogesterone via breast milk have been studied for developmental and behavioural effects through puberty. No adverse effects have been noted.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The following events are associated with the use of progestogens including medroxyprogesterone.

Cardiac disorders.

Palpitations, myocardial infarction, congestive heart failure.

Endocrine disorders.

Prolonged anovulation, Cushingoid syndrome.

Eye disorders.

Retinal embolism and thrombosis, diabetic cataract, visual impairment.

Gastrointestinal.

Abdominal distension, nausea, constipation, diarrhoea, dry mouth.

General disorders and administrative site conditions.

Fatigue, injection site reactions, malaise, hyperpyrexia.

Hepatobiliary disorders.

Liver disorders, hepatic function abnormal (transient elevations of alkaline phosphatase and/or serum transaminase activities).

Immune system disorders.

Anaphylactic reactions, anaphylactoid reactions, angioedema.

Investigations.

Bone density decreased, blood pressure increased, weight increased, weight decreased, elevations of serum calcium and potassium levels, increases in white cell and platelet counts, decreased glucose tolerance.

Metabolic and nutritional disorders.

Exacerbation of diabetes mellitus, hypercalcaemia.

Musculoskeletal and connective tissue disorders.

Arthralgia, gluteal infiltration and abscess formation (this reaction appears to be related to the volume of agent administered and the highest frequency of this complication occurs with large volumes, i.e. greater than 2.5 mL), back pain, muscle spasm.

Nervous system disorders.

Cerebral infarction, somnolence, dizziness, headache, adrenergic-like effects (e.g. fine-hand tremors, sweating, cramps in calves at night), tremor.

Psychiatric disorders.

Depression, insomnia, nervousness.

Renal and urinary system disorders.

Glycosuria.

Reproductive and breast disorders.

Dysfunctional uterine bleeding (irregular, increase, decrease, spotting), breast pain, breast tenderness, galactorrhoea, vaginal discharge, changes in the position of the transformation zone, cervical discharge.

Respiratory, thoracic and mediastinal disorders.

Pulmonary embolism.

Skin and subcutaneous tissue disorders.

Urticaria, pruritus, rash, acne, hirsutism, alopecia, hyperhidrosis.

Vascular disorders.

Embolism and thrombosis, thrombophlebitis.
In a clinical trial conducted using Depo-Provera for contraception, over 3,900 women who were treated for up to 7 years reported the following adverse reactions, which may or may not be related to the use of Depo-Provera. The following adverse reactions were reported by more than 5% of subjects: menstrual irregularities (bleeding and/or amenorrhoea), abdominal pain or discomfort, dizziness, weight fluctuation, nervousness, headache, asthenia (weakness or fatigue).
Adverse reactions reported by 1% to 5% of subjects using Depo-Provera were: decreased libido or anorgasmia, vaginitis, backache, pelvic pain, leg cramps, breast pain, depression, no hair growth or alopecia, nausea, bloating, insomnia, rash, leukorrhoea, oedema/fluid retention, acne, hot flushes.
The following events were reported by fewer than 1% of subjects.

Blood and lymphatic system disorders.

Blood dyscrasia, anaemia.

Cardiac disorders.

Tachycardia, chest pain.

Gastrointestinal disorders.

Gastrointestinal disorders, vomiting, rectal bleeding.

General disorders and administrative site conditions.

Pyrexia, chills, excessive thirst, pain at injection site.

Hepatobiliary disorders.

Jaundice, jaundice cholestatic.

Immune systems disorders.

Drug hypersensitivity reactions.

Metabolism and nutrition disorders.

Changes in appetite.

Musculoskeletal and connective tissue disorders.

Scleroderma, osteoporosis.

Nervous system disorders.

Seizures, facial palsy, paralysis, somnolence, syncope.

Psychiatric disorders.

Confusion, euphoria, loss of concentration, changes in libido.

Renal and urinary disorders.

Genitourinary infections.

Respiratory, thoracic and mediastinal disorders.

Pulmonary embolism, dyspnoea, asthma, dysphonia.

Reproductive and breast disorder.

Galactorrhoea, dyspareunia, vaginal cysts, changes in breast size, breast lumps or nipple bleeding, axillary swelling, breast cancer, prevention of lactation, sensation of pregnancy, lack of return to fertility, accidental pregnancy, uterine cervical erosions, cervical cancer, dysmenorrhoea, uterine hyperplasia.

Skin and subcutaneous tissue disorders.

Chloasma, hirsutism, dry skin, hyperhidrosis, abnormal body odour.

Vascular disorders.

Thrombophlebitis, deep vein thrombosis, varicose veins.

Post-marketing experience.

In post-marketing experience, there have been reports of anaphylactic responses, thromboembolic events and rare cases of osteoporosis including osteoporotic fractures reported in patients taking Depo-Provera.
There have been post-marketing reports of lipodystrophy acquired.
There have been post-marketing reports of erectile dysfunction in association with use of MPA in oncology treatments.
Injection site nodule/lump, injection site persistent atrophy/indentation/dimpling, injection site reaction and injection site pain/tenderness were identified post-marketing.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

No serious medical effects have been reported in association with overdosage of Depo-Provera injection suspension.
Oral doses up to 3 g per day have been well tolerated. Patients receiving pharmacological doses of MPA for treatment of neoplasms (400 mg/day or greater) may occasionally exhibit effects resembling those of glucocorticoid excess.
As with the management of any overdosage, the physician should carefully observe the patient for the potential side effects. Overdose treatment is symptomatic and supportive.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Animal.

MPA 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. MPA induces glandular development in the endometrium, maintains pregnancy, delays parturition, inhibits ovulation and suppresses estrous cycles. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. In selected animal tests it has some adrenocorticoid-like activity and in dogs increases serum growth hormone levels.

Human.

Depo-Provera is a progestational agent with prolonged progestational effects when administered by intramuscular (IM) injection. When administered 3 monthly in recommended doses to women with adequate endogenous estrogen, it transforms proliferative into secretory endometrium. MPA inhibits gonadotrophin production, which in turn prevents follicular maturation and ovulation. These actions produce the contraceptive effect. In 5 Depo-Provera clinical studies, the 3 month failure rate for the group of women treated with Depo-Provera was zero (no pregnancies reported to 0.7 by Life-Table method). The effectiveness of Depo-Provera is dependent on the woman returning every 3 months for reinjection.
Women with lower bodyweights conceive sooner than women with higher bodyweights after discontinuation of Depo-Provera.

Clinical trials.

Bone mineral density changes in adult women.

In a controlled, clinical study adult women using Depo-Provera (150 mg IM) for up to 5 years for contraception showed spine and hip mean bone mineral density (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 -2.9%, -4.1%, -4.9%, -4.9% and -5.4% after 1, 2, 3, 4 and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar.
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 slower rate of BMD recovery. See Section 4.4 Special Warnings and Precautions for Use.

BMD changes in adolescent females (12 to 18 years).

An open-label non-randomised clinical study of Depo-Provera (150 mg IM every 12 weeks for up to 240 weeks (4.6 years) in adolescent females (12 to 18 years) for contraception also showed that Depo-Provera 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; mean decreases for the total hip and femoral neck were -6.4% and -5.4%, respectively. In contrast, most adolescent girls will significantly increase bone density during this period of growth following menarche.
Based on mean changes, post-treatment follow-up showed that lumbar spine BMD recovered to baseline levels approximately 1.2 years after treatment was discontinued and hip and femoral neck BMD recovered to baseline levels approximately 4.6 years after treatment was discontinued (see Section 4.4 Special Warnings and Precautions for Use).

5.2 Pharmacokinetic Properties

Absorption.

Parenteral MPA is a long acting progestational steroid. Its long duration of action results from its slow absorption from the injection site.
Following a single 150 mg IM dose of Depo-Provera, MPA levels increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 nanogram/mL. The levels then decrease exponentially until they become undetectable (< 100 picogram/mL) between 120 and 200 days following the injection. Considerable interindividual variability in serum levels occurs after administration of standard doses of IM MPA.

Metabolism.

MPA is metabolised and conjugated in the liver. Metabolic products are predominantly excreted in the urine, both as conjugated and free forms.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Macrogol 3350, sodium chloride, polysorbate 80, methyl hydroxybenzoate, propyl hydroxybenzoate, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Do not refrigerate or freeze.

6.5 Nature and Contents of Container

Depo-Provera 150 mg/mL injection suspension is supplied as:
1 x 1 mL vial, 1 x 1 mL pre-filled syringe.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

MPA is a progestogen and a derivative of progesterone. It is a white to off white, odourless crystalline powder, stable in air, melting between 200°C and 210°C. 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.

Chemical structure.

MPA is 6α-methyl-3,20-dioxopregn-4-en-17α-yl acetate, the molecular formula is C₂₄H₃₄O₄ and its molecular weight is 386.52. The structural formula is as follows:

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