Depo-Provera_ 150 mg Suspension for injection

• Endometriosis
• Contraception (ovulation suppression)
• Endometrial cancer: As adjunctive and/or palliative therapy in inoperable, recurrent or metastatic endometrial carcinoma
• Renal cancer: As adjunctive and/or palliative therapy in recurrent and/or metastatic adenocarcinoma of the kidney

Posology

Endometriosis

The recommended dose of DEPO-PROVERA in this condition is 50 mg weekly or 100 mg every 2 weeks intramuscularly for at least 6 months. It should be noted that return of ovulation may be delayed following this therapy due to the depot properties of the medicine (see section 4.4).

Contraception

The recommended dose is 150 mg 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, within 5 days postpartum if not breastfeeding, or, if exclusively breastfeeding, at or after the sixth week postpartum. If the period between injections is greater than 14 weeks, the medical practitioner should determine that the patient is not pregnant before administering DEPO-PROVERA.

Switching from other methods of contraception

When switching from other contraceptive methods, DEPO-PROVERA 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 DEPO-PROVERA within 7 days after taking their last active pill).

Endometrial and renal carcinoma

Doses of 400 mg to 1000 mg 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 as little as 400 mg per month.

Special populations

Hepatic insufficiency

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

Renal insufficiency

No clinical studies have evaluated the effect of renal disease on the pharmacokinetics of DEPO-PROVERA. However, since DEPO-PROVERA is almost exclusively eliminated by hepatic metabolism, no dosage adjustment should be necessary in women with renal insufficiency.

Paediatric population

DEPO-PROVERA is not indicated before menarche. Data are available in adolescent females (12 to 18 years) (see section 4.4). Other than concerns about loss of bone mineral density (BMD), the safety and effectiveness of DEPO-PROVERA are expected to be the same for post-menarcheal adolescent and adult females.

Method of administration

For intramuscular injection. The sterile aqueous suspension of DEPO-PROVERA should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension of DEPO-PROVERA.

• Known hypersensitivity to medroxyprogesterone acetate or to any of the excipients of DEPO-PROVERA (listed in section 6.1)
• Undiagnosed vaginal bleeding
• Undiagnosed urinary tract bleeding
• Undiagnosed breast pathology
• Thrombophlebitis, or a history of thrombophlebitis
• Severe impairment of liver function
• Known or suspected pregnancy (see section 4.6)
• Known or suspected malignancy of the breast (excluding use in oncology indications)
• Depression not well controlled with treatment
• A history of depression with the use of hormonal contraceptives

Contraception and endometriosis

Loss of bone mineral density (BMD)

Use of DEPO-PROVERA reduces serum estrogen levels and is associated with 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 both adult and adolescent females, the decrease in BMD appears to be at least partially reversible after DEPO-PROVERA is discontinued and ovarian estrogen production increases.

Medical examinations

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 medicine. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include a measurement of blood pressure and, if judged appropriate by the medical practitioner, breast, abdominal and pelvic examination including cervical cytology.

Other birth control methods should be considered when DEPO-PROVERA injection is required as a long-term birth control method (e.g., longer than 2 years). 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.

Other birth control methods or endometrial treatments should be considered in the risk/benefit analysis for the use of DEPO-PROVERA in woman with osteoporotic risk factors. DEPO-PROVERA can pose an additional risk in patients with risk factors for osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use, low body mass index or eating disorder, e.g. anorexia nervosa or bulimia, strong family history of osteoporosis or chronic use of medicines that can reduce bone mass such as anticonvulsants or corticosteroids). It is recommended that all patients have adequate calcium and vitamin D intake.

BMD changes in adult women

In a controlled, clinical study, adult woman using DEPO-PROVERA for up to 5 years for contraception showed spine and hip mean BMD decreases of 5 - 6 %, compared to no significant change in BMD in the control group. The decline in BMD was more pronounced during the first two years of use, with smaller declines in subsequent years. Mean changes in lumbar spine BMD of u2013 2,86 %, -4,11 %, -4,89 %, -4,93 % and u2013 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. After stopping use of DEPO-PROVERA, there was partial recovery of BMD toward baseline values during the 2-year post-therapy period. BMD increased but deficits at the total hip, femoral neck and lumbar spine remained. A longer duration of treatment was associated with a slower rate of BMD recovery. Since loss of BMD may occur in pre-menopausal women who use DEPO-PROVERA long-term, a risk/benefit assessment which also takes into consideration the decrease in BMD that occurs during pregnancy and/or lactation, should be considered.

Endometrial and renal carcinoma (high dose parenteral formulations)

Decrease in bone mineral density

There are no studies on the BMD effects of high doses of DEPO-PROVERA. Decreases in serum estrogen due to DEPO-PROVERA may result in a decrease in BMD in a pre-menopausal woman and may increase her risk for developing osteoporosis later in life.

Thromboembolic disorders

Any patient who develops signs and/or symptoms consistent with a thromboembolic disorder while undergoing therapy with DEPO-PROVERA should have her status and need for treatment carefully assessed before continuing therapy.

Meningioma

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

Ocular disorders

In any patient who develops an acute impairment of vision, proptosis, diplopia, or migraine headache, DEPO-PROVERA should be discontinued and the patient carefully evaluated ophthalmologically to exclude the presence of papilloedema or retinal vascular lesions before continuing treatment.

Anaphylactic and anaphylactoid reactions

Anaphylactic and anaphylactoid reactions have occasionally been reported in patients treated with DEPO-PROVERA.

Bleeding irregularities

Most women receiving DEPO-PROVERA for contraception experience disruption of menstrual bleeding patterns. It is recommended that medical practitioners or others directly responsible for patients using DEPO-PROVERA advise them at the beginning of treatment that their menstrual cycle may be disrupted, that irregular and unpredictable bleeding, spotting or heavy or continuous bleeding may occur, but that this usually decreases to the point of amenorrhoea as treatment with DEPO-PROVERA continues, without other therapy being required. Restoration of normal menstrual cycling may take from 5 to 28 months after the last injection of DEPO-PROVERA.

In cases of abnormal bleeding, appropriate investigation should first be instituted to rule out the possibility of organic pathology before continuing treatment with DEPO-PROVERA. In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, organic causes should be excluded. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated. Following repeated injections, amenorrhoea and anovulation may persist for periods up to 18 months and, in rare instances, for longer periods. The use of DEPO-PROVERA may mask the onset of the climacteric. 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.

Central nervous system disorders

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use and preparations containing estrogen and/or progesterone/progestogen (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 medical practitioner in case of mood changes and depressive symptoms, including shortly after initiating the treatment. Patients who have a history of mental depression should be carefully observed and DEPO-PROVERA discontinued if the depression recurs to a serious degree. Some patients may complain of premenstrual-like depression while on DEPO-PROVERA therapy.

Carbohydrate metabolism

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

Liver function

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 medicine has been withdrawn. If jaundice develops, consideration should be given to not re-administer DEPO-PROVERA.

Weight changes

Weight gain may be associated with use of DEPO-PROVERA.

Effects on laboratory tests

The pathologist should be advised of DEPO-PROVERA therapy when relevant specimens are submitted. The following laboratory tests may be affected by the use of DEPO-PROVERA:

• gonadotropin 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 medical practitioner/laboratory should be informed that, in addition to the endocrine biomarkers listed above, the use of DEPO-PROVERA in oncology indications (endometrial and renal carcinoma) may also cause partial adrenal insufficiency (decrease in pituitary-adrenal axis response) during metyrapone testing. Thus, the ability of adrenal cortex to respond to adrenocorticotropic hormone (ACTH) should be demonstrated before metyrapone is administered.

Fluid retention

Because DEPO-PROVERA may cause fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation.

Adrenocortical effects

Clinical suppression of adrenocortical function has not been observed at the dose levels employed for contraception. However, at very high doses (500 mg daily or more) used in the treatment of certain cancers, corticoid-like activity has been reported. Some patients receiving DEPO-PROVERA may exhibit suppressed adrenal function. DEPO-PROVERA may decrease ACTH and hydrocortisone blood levels. The high dose of DEPO-PROVERA used in the treatment of cancer patients may, in some cases produce Cushingoid symptoms, e.g. moon faces, fluid retention, glucose intolerance, and blood pressure elevation.

Cancer risks

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.

Sexually transmitted infections

Patients should be counselled that DEPO-PROVERA does not protect against sexually transmitted infections (STIs) including HIV infection (AIDS) or other sexually transmitted diseases but equally, DEPO-PROVERA 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.

Aminoglutethimide administered concomitantly with DEPO-PROVERA may significantly depress the bioavailability of DEPO-PROVERA. DEPO-PROVERA is metabolised in vitro primarily by hydroxylation via cytochrome P450 3A4. Specific interaction studies evaluating the clinical effects of cytochrome P450 3A4 inhibitors or inducers on DEPO-PROVERA have not been conducted.

Pregnancy

The use of DEPO-PROVERA during pregnancy is contraindicated (see section 4.3). DEPO-PROVERA should not be used as a diagnostic test for pregnancy. Some reports suggest an association between intra-uterine exposure to progestational medicines, including DEPO-PROVERA, in the first trimester of pregnancy and genital abnormalities in male and female foetuses.

Infants from unintentional pregnancies that occur 1 to 2 months after injection with 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 pregnancies while on DEPO-PROVERA are uncommon. If the patient becomes pregnant while using DEPO-PROVERA, the patient should be apprised of the potential hazard to the foetus.

Breastfeeding

DEPO-PROVERA and its metabolites are excreted in breast milk but there is no evidence to suggest that this presents any hazard to the nursing child.

The effect of DEPO-PROVERA on the ability to drive and use machinery has not been systematically evaluated.

Tabulated summary of adverse reactions

Adverse events have been categorised as follows: Very common ( uf0b3 1/10); common ( uf0b3 1/100 to < 1/10); uncommon ( uf0b3 1/1 000 to < 1/100); rare ( uf0b3 1/10 000 to < 1/1 000); very rare: ( < 1/10 000); not known (cannot be estimated from the available data).

Contraception

A clinical trial conducted using DEPO-PROVERA for contraception in women who were treated for up to 7 years reported the adverse reactions in the table below. The following adverse reactions were reported by more than 5 % of patients: abdominal pain or discomfort, dizziness, weight fluctuation, nervousness and headache.

System Organ Class Frequency Undesirable effects

Immune system disorders Uncommon Medicine hypersensitivity

Rare Anaphylactic reaction, anaphylactoid reaction, angioedema

Endocrine disorders Rare Prolonged anovulation

Psychiatric disorders Very common Nervousness

Common Decreased libido, anorgasmia, depression, insomnia

Nervous system disorders Very common Headache

Common Dizziness

Uncommon Seizure, somnolence

Vascular disorders Common Hot flushes

Rare Thromboembolic disorders (thrombosis, embolism, thrombophlebitis and pulmonary embolism)

Gastrointestinal disorders Very common Abdominal pain, abdominal discomfort

Common Abdominal distension, nausea

Uncommon Diarrhoea

Hepato-biliary disorders Uncommon Jaundice, liver disorder

Skin and subcutaneous tissue disorders Common Rash, acne, alopecia

Uncommon Hirsutism, pruritis, urticaria

Musculoskeletal and connective tissue disorders Common Back pain, leg cramps

Rare Muscle cramps, arthralgia, muscle spasms

Reproductive system and breast disorders Very common Dysfunctional uterine bleeding (irregular, increase, decrease, spotting), amenorrhoea

Common Vaginal discharge, breast pain, breast tenderness, dysmenorrhoea, pelvic pain, vaginitis

Uncommon Galactorrhoea

Rare Cervix changes in erosion and secretion, virilisation, feminisation

Very common Fluid retention

General disorders and administration site conditions Common Asthenia, fatigue

Rare Pyrexia

Very rare Injection-site reactions (pain, residual lumps and change in skin colour at site of injection)

Investigations Very common Weight change

Rare Decreased glucose tolerance, loss of bone mineral density

Contraception post-marketing reported side effects

The following side effects have been reported with the post-marketing use of hormonal contraceptives:

System Organ Class Undesirable effects

Psychiatric disorders Severe depression with a higher risk of suicidal thoughts/behaviour and suicide

Skin and subcutaneous tissue disorders Acquired lipodystrophy

Musculoskeletal and connective tissue disorders Osteoporosis including osteoporotic fractures

General disorders and administration site conditions Injection site nodule/lump, injection site persistent atrophy/indentation/dimpling, injection site reaction, injection site pain/tenderness

Oncology

System Organ Class Frequency Undesirable effects

Endocrine disorders Uncommon Moon face

Metabolism and nutrition disorders Common Weight increase

Nervous system disorders Common Tremor

Vascular disorders Uncommon Thrombophlebitis

Skin and subcutaneous tissue disorders Common Hyperhidrosis

Musculoskeletal and connective tissue disorders Not known Osteoporosis including osteoporotic fractures

Reproductive system and breast disorders Uncommon Dysfunctional vaginal bleeding (irregular, increased, decreased, spotting)

General disorders and administration site conditions Common Oedema/fluid retention

Rare Pyrexia

Investigations Not known Abnormal liver values

Oncology post-marketing reported side effects

System Organ Class Undesirable effects

Psychiatric disorders Severe depression with a higher risk of suicidal thoughts/behaviour and suicide

Skin and subcutaneous tissue disorders Acquired lipodystrophy

General disorders and administration site conditions Injection site reaction, injection site pain/tenderness, injection site persistent atrophy/indentation/dimpling, injection site nodule/lump

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Nausea, vomiting, somnolence, lower abdominal discomfort, insomnia, fullness and tenderness of the breasts and headache have been attributed to therapeutic doses. Treatment should be symptomatic and supportive.