Sayana 104 mg/0,65 mL Suspension for injection

• Contraception
• Management of endometriosis-associated pain

Posology

Contraception

The recommended dose is a pre-filled injection of 104 mg given subcutaneously, once every 3 months.

First injection

The first injection should be given during the first 5 days after the onset of a normal menstrual period; within 5 days postpartum if not breast feeding; or, if exclusively breastfeeding, at or after 6 weeks postpartum.

Second and subsequent injections

The second and subsequent injections should be given at 3-month intervals (12 u2013 14 weeks). If more than 14 weeks have elapsed since the last subcutaneous injection, pregnancy should be ruled out before administering the next subcutaneous injection.

Self-injection

When used for contraception, SAYANA Pre-filled injection (pre-filled single use injection system) may be administered by a health care provider or, when considered appropriate by the health care provider, self-injected by the patient, with medical follow up as necessary in accordance with local clinical guidance. The self-injection option is not recommended for the SAYANA Pre-filled syringe presentation or when SAYANA is used for management of endometriosis-associated pain.

Administration of SAYANA should be initiated under the supervision of a health care provider. After proper training in injection technique and schedule of administration, patients may self-inject with SAYANA Pre-filled injection if their health care provider determines that it is appropriate and with medical follow-up as necessary. See section 4.2 - Instructions for use, for full details on preparing and giving an injection.

Switching from other methods of contraception

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

Endometriosis

A pre-filled injection of 104 mg given subcutaneously by a health care provider every 3 months for at least 6 months.

Special populations

Hepatic insufficiency

The effect of hepatic disease on the pharmacokinetics of SAYANA is unknown. However, SAYANA 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

The effect of renal disease on the pharmacokinetics of SAYANA is unknown. However, since SAYANA is almost exclusively eliminated by hepatic metabolism, no dosage adjustment should be necessary in women with renal insufficiency.

Paediatric population

SAYANA is not indicated before menarche. Data in adolescent females (12-18 years) is available for intramuscular administration of medroxyprogesterone acetate (see section 4.4). Other than concerns about loss of bone mineral density (BMD), the safety and effectiveness of SAYANA is expected to be the same for adolescents after menarche and adult females.

Method of administration

For subcutaneous injection. SAYANA must be administered as a subcutaneous injection into the anterior thigh or abdomen. SAYANA subcutaneous suspension is not for intramuscular use. Dosage does not need to be adjusted for body weight.

The sterile aqueous suspension of SAYANA should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension. Once opened: use immediately, discard any unused portion.

• Known hypersensitivity to medroxyprogesterone acetate or to any of the excipients of SAYANA (listed in section 6.1)
• Known or suspected pregnancy and lactation (see section 4.6)
• Undiagnosed vaginal bleeding
• Severe liver dysfunction
• Known or suspected malignancy of the breast
• Thrombophlebitis or a history of thrombophlebitis
• In patients with meningioma or history of meningioma.

Loss of bone mineral density (BMD)

Use of SAYANA reduces serum oestrogen levels in premenopausal women and is associated with significant loss of BMD as bone metabolism accommodates to a lower oestrogen 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 SAYANA by younger women will reduce peak bone mass and increase the risk for osteoporotic fractures in later life.

Since loss of (BMD) may occur in pre-menopausal women who use SAYANA 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. SAYANA should be used as a long-term (e.g., longer than 2 years) birth control method or endometrial treatment only if other birth control methods or endometrial treatments are inadequate. BMD should be evaluated when a female needs to continue use of SAYANA long term.

Other contraceptive methods or endometrial treatments should be considered in the risk/benefit analysis for the use of SAYANA in woman with osteoporotic risk factors such as:

• chronic alcohol and/or tobacco use
• chronic use of medicines 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

It is recommended that all patients have adequate calcium and vitamin D intake.

BMD changes in adult women

A controlled, clinical study of adult women using medroxyprogesterone acetate intramuscular injectable suspension for up to 5 years 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 treatment, 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.

A study comparing changes in BMD in women using SAYANA 104 mg subcutaneously with women using medroxyprogesterone acetate intramuscular injectable suspension 150 mg showed no significant differences in BMD loss between the two groups after two years of treatment.

Bleeding irregularities

Most women using SAYANA experience disruption of menstrual bleeding patterns (e.g., irregular or unpredictable bleeding or spotting, heavy or continuous bleeding). Patients should be appropriately counselled concerning the likelihood of menstrual disturbance. As women continue using SAYANA, fewer experience irregular bleeding and more experience amenorrhoea. If abnormal bleeding associated with SAYANA persists or is severe, appropriate investigation and treatment should be instituted. Unexpected vaginal bleeding should be investigated.

Prolonged anovulation with amenorrhoea and/or erratic menstrual patterns may follow the administration of either a single or multiple injectable dose of SAYANA. Patients should be appropriately counselled concerning the likelihood of menstrual disturbance.

In cases of breakthrough bleeding, organic causes should be excluded. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.

The use of SAYANA may mask the onset of the climacteric.

Thromboembolic disorders

A patient who develops a thrombotic or thromboembolic event, e.g., pulmonary embolism, cerebrovascular disease, retinal thrombosis or deep venous thrombosis, while undergoing therapy with medroxyprogesterone containing medicines such as SAYANA should not be re-administered SAYANA. Women with a prior history of thromboembolic disorders should not receive SAYANA.

Meningioma

Meningiomas have been reported following long-term administration of progestins, including medroxyprogesterone acetate (MPA). SAYANA should be discontinued if a meningioma is diagnosed. SAYANA is contraindicated in patients with meningioma or a history of meningioma (see section 4.3)

Anaphylactic and anaphylactoid reactions

Anaphylactic and anaphylactoid reactions have been reported in patients treated with SAYANA.

Ocular disorders

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

Fluid retention

SAYANA may cause fluid retention; therefore, caution should be exercised in treating any patient with a pre-existing condition that might be adversely affected by fluid retention, such as epilepsy, migraine, asthma or cardiac or renal dysfunction.

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 with a history of treatment for mental depression should be carefully observed and SAYANA discontinued if the depression recurs to a serious degree. Some patients may complain of premenstrual-like depression while on SAYANA therapy.

Carbohydrate metabolism

Some patients receiving SAYANA may exhibit a decreased glucose tolerance. Diabetic patients should be carefully observed while receiving SAYANA.

Physical examination

The pre-treatment physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology.

Effects on laboratory tests

The pathologist (laboratory) should be informed of the patientu2019s use of SAYANA if endometrial or endocervical tissue is submitted for examination. The medical practitioner/laboratory should be informed that use of SAYANA may decrease the levels of the following endocrine biomarkers:

• Plasma/urinary steroids (e.g., cortisol, oestrogen, pregnanediol, progesterone, testosterone)
• Plasma/urinary gonadotrophins (e.g., LH and FSH)
• Sex-hormone-binding-globulin

Liver function

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

Weight changes

Weight gain may be associated with the use of SAYANA.

Cancer risks

Long-term case-controlled surveillance of users of medroxyprogesterone acetate intramuscular injectable suspension 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.

Sexually transmitted infections

Patients should be counselled that SAYANA does not protect against sexually transmitted infections (STIs) including HIV infection (AIDS) but equally, SAYANA 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) after long-term treatment for contraception

An open-label clinical study of medroxyprogesterone acetate injectable suspension (150 mg intramuscularly every 3 months for up to 240 weeks) in adolescent females (12 u2013 18 years) for contraception showed 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 general, adolescents increase bone density during the period of growth following menarche. Post-treatment follow-up showed that lumbar spine 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.

Preservative sensitivity

SAYANA contains the excipients methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm. If an anaphylactic reaction occurs appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.

No interaction studies have been performed with SAYANA. SAYANA is metabolised in vitro primarily by hydroxylation via cytochrome P450 3A4 (CYP3A4). Specific interaction studies evaluating the clinical effects of CYP3A4 inducers or inhibitors on SAYANA have not been conducted and therefore the clinical effects of CYP3A4 inducers or inhibitors are unknown. The possibility of interactions should be borne in mind in patients receiving concurrent treatment with other medicines.

The clearance of SAYANA is approximately equal to the rate of hepatic blood flow. Because of this fact, it is unlikely that medicines which induce hepatic enzymes will significantly affect kinetics of SAYANA. Therefore, no dose adjustment is recommended in patients receiving medicines known to affect hepatic metabolising enzymes. Aminoglutethimide administered concomitantly with SAYANA may significantly depress the bioavailability of SAYANA.

Pregnancy

SAYANA is contraindicated in women who are pregnant. Reports suggest an association between intra-uterine exposure to progestational medicines 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 SAYANA 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 SAYANA are uncommon. If the patient becomes pregnant while using SAYANA, the patient should be apprised of the potential hazard to the foetus.

Breastfeeding

Safety in breastfeeding has not been established. SAYANA and its metabolites are excreted in breast milk and mothers receiving SAYANA should not breastfeed their infants.

The effect of SAYANA on the ability to drive and use machinery has not been systematically evaluated. Dizziness is a potential side effect. Patients should be aware of how they might be affected by SAYANA before driving or operating machinery.

Tabulated summary of adverse reactions

Side effects reported during safety and efficacy studies have been classified 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

Adverse reactions reported by 5 % or more of all women in clinical trials of SAYANA for contraception included headache (9 %), metrorrhagia (7 %), increased weight (7 %), amenorrhea (6 %) and injection site reactions (6 %).

System organ class

Frequency

Adverse events

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Not known

Meningioma

Metabolism and nutrition disorders

Very common

Increased weight

Uncommon

Decreased weight, increased appetite, fluid retention, decreased appetite

Psychiatric disorders

Common

Depression, decreased libido, affective disorder, anxiety, insomnia, irritability

Uncommon

Anorgasmia, emotional disorder

Nervous system disorders

Common

Headache, dizziness, migraine

Ear and labyrinth disorders

Uncommon

Vertigo

Vascular disorders

Uncommon

Hot flushes, hypertension, varicose veins

Gastrointestinal disorders

Common

Abdominal pain, nausea

Uncommon

Abdominal distension

Skin and subcutaneous tissue disorders

Common

Acne, dermatitis

Uncommon

Hirsutism, chloasma, ecchymosis, rash, alopecia

Musculoskeletal and connective tissue disorders

Common

Back pain, pain in extremity

Uncommon

Muscle spasms

Reproductive system and breast disorders

Common

Amenorrhoea, breast pain, metrorrhagia, menometrorrhagia, menorrhagia, dysmenorrhoea, vaginitis

Uncommon

Breast tenderness, vaginal discharge, vulvovaginal dryness, breast enlargement, dyspareunia, ovarian cyst, pelvic pain, premenstrual syndrome

General disorders and administration site conditions

Common

Fatigue, injection site reaction

Investigations

Common

Abnormal smear cervix

Uncommon

Abnormal hepatic enzyme

Please note that in patients taking medroxyprogesterone acetate injection (150 mg intramuscular), there have been reports of anaphylactic responses, thromboembolic events and rare cases of osteoporosis including osteoporotic fractures.

Overdose treatment is symptomatic and supportive.