Fulvestrant Mylan 250 mg Solution for injection.

FULVESTRANT MYLAN is indicated for the treatment of oestrogen receptor positive, locally advanced or metastatic breast cancer in postmenopausal women:

• not previously treated with endocrine therapy, or
• with disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression with an anti-oestrogen.

Posology:

Adult females (including the elderly): The recommended dose is 500 mg to be administered intramuscularly as two 5 ml injections, one in each buttock (gluteal area), at intervals of 1 month with an additional 500 mg dose given 2 weeks after the initial dose.

Special Population

Patients with renal insufficiency: No dose adjustments are recommended for patients with creatinine clearance greater than 30 ml/min. Safety and efficacy have not been further evaluated in patients with creatinine clearance less than 30 ml/min (see section 4.4).

Patients with hepatic insufficiency: No dose adjustments are recommended for patients with mild to moderate hepatic impairment. However, as fulvestrant exposure may be increased two-fold, FULVESTRANT MYLAN should be used with caution in these patients. Safety and efficacy have not been evaluated in patients with severe hepatic impairment (see section 4.3).

Elderly: No dose adjustment is required for elderly patients.

Paediatric population: Not recommended for use in children or adolescents, as safety and effectiveness have not been established in this age group (see section 5.1).

Interactions requiring dose adjustments: There are no known interactions requiring dose adjustment.

Method of Administration

It is recommended that the injection be administered slowly (1 u2013 2 minutes/injection). Caution should be taken if injecting FULVESTRANT MYLAN at the dorsogluteal site due to the proximity of the underlying sciatic nerve. Refer to section 6.6 for detailed instructions on administration.

FULVESTRANT MYLAN is contraindicated in:

• patients with known hypersensitivity to fulvestrant or any of the excipients (see section 6.1).
• patients with severe hepatic impairment.
• pregnancy and breastfeeding (see section 4.6).

FULVESTRANT MYLAN should be used with caution in patients with mild to moderate hepatic impairment (see section 5.2 and 4.2). Caution should be used before treating patients with severe renal impairment (creatinine clearance less than 30 ml/min). See section 4.2. Caution should be used before treating patients with bleeding diatheses or thrombocytopenia or patients on anticoagulants due to the route of administration. Thromboembolic events are observed in women with advanced breast cancer and have been observed in clinical trials with fulvestrant, as in FULVESTRANT MYLAN. This should be taken into consideration when prescribing FULVESTRANT MYLAN to patients at risk. There are no long-term data on the effect of fulvestrant on bone. Due to the mechanism of action of fulvestrant, there is a potential risk of osteoporosis.

Hypersensitivity Reactions

Hypersensitivity reactions such as angioedema and urticaria have been commonly reported (incidence of 1-10 %) and may be serious (see section 4.8). Injection site related events including sciatica, neuralgia, neuropathic pain and peripheral neuropathy have been reported with fulvestrant. Caution should be taken while administering FULVESTRANT MYLAN at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve (see sections 4.2 and 4.8).

The efficacy and safety of fulvestrant have not been studied in patients with critical visceral disease.

Interference with estradiol antibody assays

Due to the structural similarity of fulvestrant and estradiol, fulvestrant may interfere with antibody based-estradiol assays and may result in falsely increased levels of estradiol (see section 4.5).

Ethanol

FULVESTRANT MYLAN contains 10 % w/v ethanol (alcohol) as an excipient, i.e. up to 500 mg per injection, equivalent to 10 ml beer or 4 ml wine. This may be harmful for those suffering from alcoholism and should be taken into account in high risk groups such as patients with liver disease and epilepsy.

Benzyl alcohol

FULVESTRANT MYLAN contains benzyl alcohol as an excipient which may cause allergic reactions. Benzoate salt may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

Paediatric population

FULVESTRANT MYLAN is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see section 5.1).

Fulvestrant does not significantly inhibit any of the major cytochrome P450 (CYP) isoenzymes in vitro, and results from a clinical pharmacokinetic trial involving co-administration of fulvestrant with midazolam also suggest that therapeutic doses of fulvestrant will have no inhibitory effects on CYP3A4. In addition, although fulvestrant can be metabolised by CYP3A4 in vitro, a clinical study with rifampicin showed no change in fulvestrant clearance as a result of the induction of CYP3A4, and indirectly suggests that fulvestrant clearance would not be affected by CYP3A4 inhibitors. Results from a clinical study with ketoconazole, a potent inhibitor of CYP3A4, also indicated that there is no clinically relevant change in fulvestrant clearance. Dosage adjustment is not necessary in patients co-prescribed CYP3A4 inhibitors or inducers. Due to the structural similarity of fulvestrant and oestradiol, fulvestrant may interfere with antibody-based oestradiol assays and may result in falsely increased levels of oestradiol (see section 4.4).

Women of childbearing potential

Patients of childbearing potential should be advised to use effective contraception while on treatment and for two years after last dose.

Pregnancy

FULVESTRANT MYLAN is contraindicated in pregnancy (see section 4.3). Fulvestrant has been shown to cross the placenta after single intramuscular doses in rat and rabbit. Studies in animals have shown reproductive toxicity including an increased incidence of foetal abnormalities and deaths (see section 5.3). If pregnancy occurs while taking FULVESTRANT MYLAN, the patient must be informed of the potential hazard to the foetus and potential risk for loss of pregnancy.

Breast-feeding

Breast-feeding must be discontinued during treatment with FULVESTRANT MYLAN. Fulvestrant is excreted in milk in lactating rats. It is not known whether fulvestrant is excreted in human milk. Considering the potential for serious adverse reactions due to fulvestrant in breast-fed infants, use during lactation is contraindicated (see section 4.3).

Fertility

The effects of fulvestrant on fertility in humans have not been studied.

Fulvestrant has no or negligible influence on the ability to drive or use machines. However, since asthenia has been reported frequently with fulvestrant, caution should be observed by those patients who experience this adverse reaction when driving or operating machinery (see section 4.8).

a) Summary of the safety profile

This section provides information based on all adverse reactions from clinical studies, post-marketing studies or spontaneous reports. In the pooled dataset of fulvestrant monotherapy, the most frequently reported adverse reactions were injection site reactions, asthenia, nausea, and increased hepatic enzymes (ALT, AST, ALP).

b) Tabulated list of adverse reactions

Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency groupings are defined as Frequent, Less frequent and Frequency unknown. Within each frequency grouping adverse reactions are reported in order of decreasing seriousness.

MedDRA system organ class

Frequency

Adverse reactions

Infections and infestations

Frequent

Urinary tract infections

Blood and lymphatic system disorders

Frequent

Reduced platelet count

Immune system disorders

Frequent

Hypersensitivity reactions, (angioedema, uticaria)

Less frequent

Anaphylactic reactions

Metabolism and nutrition disorders

Frequent

Anorexia

Nervous system disorders

Frequent

Headache

Vascular disorders

Frequent

Hot flushes

Venous thromboembolism

Gastrointestinal disorders

Frequent

Nausea

Vomiting, diarrhoea

Hepato-biliary disorders

Frequent

Elevated hepatic enzymes (ALT, AST, ALP)

Elevated bilirubin

Less frequent

Hepatic failure, hepatitis, elevated gamma-GT

Skin and subcutaneous tissue disorders

Frequent

Rash

Musculoskeletal and connective tissue disorders

Frequent

Joint and musculoskeletal pain (e.g. arthralgia, myalgia)

Back pain

Reproductive system and breast disorders

Frequent

Vaginal haemorrhage

Less frequent

Vaginal moniliasis, leukorrhea

General disorders and administration site conditions

Frequent

Asthenia, injection site reactions

Neuropathy peripheral, sciatica

Less frequent

Injection site haemorrhage, injection site haematoma, neuralgia

c. Description of selected adverse reactions

Joint and musculoskeletal pain

In the FALCON study, of the 65 patients in the fulvestrant arm who reported joint and musculoskeletal pain, 40 % (26/65) of patients reported this within the first month of treatment, and 66,2 % (43/65) of patients within the first 3 months of treatment. No patients reported events that were CTCAE Grade u2265 3 or that required a dose reduction, dose interruption, or discontinued treatment due to these adverse reactions.

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 on the SAHPRA website at: https://medsafety.sahpra.org.za/#download1, via email at: [email protected] or via telephone at: 0125010311

There is no human experience of overdosage. Animal studies suggest that no effects other than those related directly or indirectly to anti-oestrogenic activity were evident with higher doses of fulvestrant. If overdose occurs, this should be managed symptomatically.