Prigauro 150 mg injectable suspension

u2022 Endometriosis

u2022 Contraception (ovulation suppression)

u2022 Endometrial Cancer: As adjunctive and/or palliative therapy in inoperable, recurrent or metastatic endometrial carcinoma.

u2022 Renal Cancer: As adjunctive and/or palliative therapy in recurrent and/or metastatic adenocarcinoma of the kidney.

Posology

Endometriosis: The recommended dose of PRIGAURO 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 PRIGAURO 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 PRIGAURO.

Switching from other methods of contraception: When switching from other contraceptive methods, PRIGAURO 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 PRIGAURO within 7 days after taking their last active pill).

Endometrial and renal carcinoma: Doses of 400 mg to 1000 mg of PRIGAURO 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 PRIGAURO. However, PRIGAURO 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 PRIGAURO. However, since PRIGAURO is almost exclusively eliminated by hepatic metabolism, no dosage adjustment should be necessary in women with renal insufficiency.

Paediatric population: PRIGAURO 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 PRIGAURO are expected to be the same for post-menarcheal adolescent and adult females.

Method of administration: PRIGAURO is administered intramuscularly. The sterile aqueous suspension of PRIGAURO should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension of PRIGAURO.

u2022 Known sensitivity to medroxyprogesterone acetate or any of the other ingredients of PRIGAURO (listed in section 6.1).

u2022 Undiagnosed vaginal bleeding.

u2022 Undiagnosed urinary tract bleeding.

u2022 Undiagnosed breast pathology.

u2022 Thrombophlebitis, or a history of thrombophlebitis.

u2022 Severe impairment of liver function.

u2022 Known or suspected pregnancy (see section 4.6).

u2022 Known or suspected malignancy of the breast (excluding use in oncology indications).

u2022 Depression not well controlled with treatment.

u2022 A history of depression with the use of hormonal contraceptives.

Contraception and endometriosis

Loss of Bone Mineral Density (BMD): Use of medroxyprogesterone acetate as in PRIGAURO 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 PRIGAURO 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 medroxyprogesterone acetate as in PRIGAURO 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 PRIGAURO 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 PRIGAURO 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 PRIGAURO in women with osteoporotic risk factors. PRIGAURO 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 medroxyprogesterone acetate as in PRIGAURO 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 u20132,86 %, -4,11 %, -4,89 %, -4,93 % and u20135,38 % 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 medroxyprogesterone acetate as in PRIGAURO, 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 PRIGAURO 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 PRIGAURO. Decreases in serum estrogen due to PRIGAURO 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 PRIGAURO should have her status and need for treatment carefully assessed before continuing therapy.

Ocular disorders: In any patient who develops an acute impairment of vision, proptosis, diplopia, or migraine headache, PRIGAURO 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 medroxyprogesterone acetate as in PRIGAURO.

Bleeding irregularities: Most women receiving medroxyprogesterone acetate as in PRIGAURO for contraception experience disruption of menstrual bleeding patterns. It is recommended that medical practitioners or others directly responsible for patients using PRIGAURO 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 PRIGAURO continues, without other therapy being required. Restoration of normal menstrual cycling may take from 5 to 28 months after the last injection of PRIGAURO. In cases of abnormal bleeding, appropriate investigation should first be instituted to rule out the possibility of organic pathology before continuing treatment with PRIGAURO. 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 PRIGAURO 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, PRIGAURO is not recommended for treatment of secondary amenorrhoea or dysfunctional uterine bleeding.

Central nervous system disorders: Mood changes and depression are side effects reported with the use of hormonal contraceptives including PRIGAURO (see section 4.8). There is some evidence that hormonal contraceptive use may be associated with severe depression and a higher risk of suicidal thoughts/behaviour (e.g. talking about suicide, withdrawing from social contact, having mood swings, being preoccupied with death or violence, feeling hopeless about a situation, increasing use of alcohol/drugs, doing self-destructive things, personality changes) and suicide. Prescribers should inform their patients to contact their doctor for advice if they experience mood changes and depression whilst on treatment with PRIGAURO. Patients who have a history of mental depression should be carefully observed and PRIGAURO discontinued if the depression recurs to a serious degree. Some patients may complain of premenstrual-like depression while on PRIGAURO therapy.

Carbohydrate metabolism: A decrease in glucose tolerance has been observed in patients on progestogens including medroxyprogesterone acetate as in PRIGAURO. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving PRIGAURO therapy.

Liver function: Certain endocrine and possibly liver function tests may be affected by treatment with PRIGAURO. Therefore, if such tests are abnormal in a patient taking PRIGAURO, it is recommended that they be repeated after the medicine has been withdrawn. If jaundice develops, consideration should be given to not re-administer PRIGAURO.

Weight changes: Weight gain may be associated with use of PRIGAURO.

Effects on laboratory tests: The pathologist should be advised of PRIGAURO therapy when relevant specimens are submitted. The following laboratory tests may be affected by the use of PRIGAURO: u2022 Gonadotropin levels u2022 Plasma progesterone levels u2022 Urinary pregnanediol levels u2022 Plasma testosterone levels (in the male) u2022 Plasma estrogen levels (in the female) u2022 Plasma cortisol levels u2022 Glucose tolerance test u2022 Metyrapone test - The medical practitioner/laboratory should be informed that, in addition to the endocrine biomarkers listed above, the use of PRIGAURO 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 PRIGAURO 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 PRIGAURO may exhibit suppressed adrenal function. PRIGAURO may decrease ACTH and hydrocortisone blood levels. The high dose of PRIGAURO 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 medroxyprogesterone acetate as in PRIGAURO 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 PRIGAURO does not protect against sexually transmitted infections (STIs) including HIV infection (AIDS) or other sexually transmitted diseases but equally, PRIGAURO 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.

Paediatric population: BMD changes in adolescent females (12 u2013 18 years) An open-label clinical study of medroxyprogesterone acetate as in PRIGAURO (150 mg IM every 12 weeks for 240 weeks) in adolescent females (12 u2013 18 years) for contraception showed that medroxyprogesterone acetate as in PRIGAURO was associated with a significant decline in BMD from baseline. 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. In adolescent females, the decrease in BMD appears to be fully reversible after medroxyprogesterone acetate as in PRIGAURO 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.

Aminoglutethimide administered concomitantly with PRIGAURO may significantly depress the bioavailability of PRIGAURO. Medroxyprogesterone acetate as in PRIGAURO 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 PRIGAURO have not been conducted.

Pregnancy: PRIGAURO is contraindicated in pregnancy (see section 4.3). PRIGAURO should not be used as a diagnostic test for pregnancy. Some reports suggest an association between intra-uterine exposure to progestational medicines, including medroxyprogesterone acetate as in PRIGAURO, 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 medroxyprogesterone acetate as in PRIGAURO 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 PRIGAURO are uncommon. If the patient becomes pregnant while using PRIGAURO, the patient should be apprised of the potential hazard to the foetus.

Breastfeeding: PRIGAURO 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 PRIGAURO on the ability to drive and use machinery has not been systematically evaluated.

Tabulated list of adverse drug reactions

System Organ Class Frequency Undesirable effects

Immune system disorders Less frequent Medicine hypersensitivity Anaphylactic reaction, anaphylactoid reaction, angioedema

Endocrine disorders Less frequent Prolonged anovulation

Psychiatric disorders Frequent Nervousness Decreased libido, anorgasmia, depression, insomnia

Nervous system disorders Frequent Headache Dizziness Less frequent Seizure, somnolence

Vascular disorders Frequent Hot flushes Less frequent Thromboembolic disorders (thrombosis, embolism, thrombophlebitis and pulmonary embolism)

Gastrointestinal disorders Frequent Abdominal pain, abdominal discomfort Abdominal distension, nausea Less frequent Diarrhoea

Hepato-biliary disorders Less frequent Jaundice, liver disorder

Skin and subcutaneous tissue disorders Frequent Rash, acne, alopecia Less frequent Hirsutism, pruritis, urticaria

Musculoskeletal and connective tissue disorders Frequent Back pain, leg cramps Less frequent Muscle cramps, arthralgia, muscle spasms

Reproductive system and breast disorders Frequent Dysfunctional uterine bleeding (irregular, increase, decrease, spotting), amenorrhoea Vaginal discharge, breast pain, breast tenderness, dysmenorrhoea, pelvic pain, vaginitis Less frequent Galactorrhoea Cervix changes in erosion and secretion, virilisation, feminisation

General disorders and administration site conditions Frequent Fluid retention Asthenia, fatigue Less frequent Pyrexia Injection-site reactions (pain, residual lumps and change in skin colour at site of injection)

Investigations Frequent Weight change Less frequent 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:

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

Skin and subcutaneous tissue disorders Frequency unknown Acquired lipodystrophy

Musculoskeletal and connective tissue disorders Frequency unknown Osteoporosis including osteoporotic fractures

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

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