Desofal 250 mg Solution for injection

DESOFAL 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- estrogen.

Posology

Adult females (including the elderly): The recommended dose is 500 mg at intervals of 1 month with an additional 500 mg dose given two weeks after the initial dose.

Special populations

Patients with renal impairment: No dose adjustments are recommended for patients with a 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 impairment: No dose adjustments are recommended for patients with mild to moderate hepatic impairment. However, as fulvestrant exposure may be increased two fold, DESOFAL 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 population: 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.

Method of administration

DESOFAL should be administered as two consecutive 5 mL injections by slow intramuscular injection (1-2 minutes/injection), one in each buttock (gluteal area). Caution should be taken if injecting DESOFAL at the dorsogluteal site due to the proximity of the underlying sciatic nerve. For detailed instructions for assembly, handling and disposal, see section 6.6.

DESOFAL is contraindicated in:

• patients with a known hypersensitivity to the active substance fulvestrant, or any of the excipients listed in section 6.1.
• patients with severe hepatic impairment.
• pregnancy and women breastfeeding their infants.

Hypersensitivity reactions such as angioedema and urticaria have been commonly reported (incidence of 1 - 10 %) and may be serious (see section 4.8). DESOFAL should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.2, 4.3 and 5.2). Caution should be used before treating patients with 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. Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with DESOFAL injection. Caution should be taken while administering DESOFAL at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve (see section 4.2).

DESOFAL contains ethanol DESOFAL 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.

DESOFAL contains benzyl alcohol DESOFAL contains benzyl alcohol as an excipient which may cause allergic reactions.

Paediatric population DESOFAL is not recommended for use in children or adolescents, as safety and effectiveness have not been established in this age group.

Fulvestrant does not significantly inhibit any of the major cytochrome P450 (CYP) isoenzymes in vitro , and results from a clinical pharmacokinetic study 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 estradiol, fulvestrant as in DESOFAL may interfere with antibody-based estradiol assays and may result in falsely increased levels of estradiol.

Women of childbearing potential Patients of childbearing potential should use effective contraception during treatment with DESOFAL and for two years after the last dose.

Pregnancy DESOFAL is contraindicated in pregnancy (see section 4.3). DESOFAL 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. If pregnancy occurs while taking DESOFAL, the patient must be informed of the potential hazard to the foetus and potential risk for loss of pregnancy.

Breastfeeding Breastfeeding must be discontinued during treatment with DESOFAL . Fulvestrant as in DESOFAL 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, the use of DESOFAL during lactation is contraindicated (see section 4.3).

Fertility The effect of DESOFAL on fertility in humans has not been studied.

DESOFAL is unlikely to impair the ability of patients to drive or operate machinery. However, during treatment with DESOFAL, asthenia has been reported and caution should be observed by those patients who experience this symptom when driving or operating machinery.

a. Summary of the safety profile 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 Table 1: Summary of adverse reactions for DESOFAL

System organ class Frequency Adverse reaction

General disorders and administration site conditions Frequent Injection site reactions a , asthenia, neuropathy peripheral d , sciatica d Less frequent Injection site haemorrhage e , injection site haematoma e , neuralgia e

Hepatobiliary disorders Frequent Elevated liver enzymes (ALT, AST, ALP) b , elevated bilirubin b Less frequent Elevated gamma-GT Frequency unknown Hepatic failure, hepatitis

Gastrointestinal disorders Frequent Nausea, vomiting, diarrhoea

Immune system disorder Frequent Hypersensitivity reactions: angioedema and urticaria d Less frequent Anaphylactic reactions

Musculoskeletal and connective tissue disorders Frequent Joint and musculoskeletal pain c , back pain

Skin and subcutaneous tissue disorders Frequent Rash d

Vascular disorders Frequent Hot flushes d , venous thromboembolism

Nervous system disorders Frequent Headache

Blood and lymphatic system Frequent Reduced platelet count d

Metabolism and nutrition disorders Frequent Anorexia

Infections and infestations Frequent Urinary tract infections

Reproductive system and breast disorders Frequent Vaginal haemorrhage d Less frequent Vaginal moniliasis e , leukorrea e

a Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy.

b Based on any CT grade change from baseline.

c Includes: arthralgia, and less frequently musculoskeletal pain, back pain, myalgia and pain in extremity.

d Frequency category differs between pooled safety dataset and FALCON.

e ADR was not observed in the FALCON study that compared fulvestrant and anastrozole.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation 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 to SAHPRA via the u20186.04 Adverse Drug Reactions Reporting Formu2019, found under SAHPRAu2019s publications: https://www/sahpra.org.za/Publications/Index/8

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 as in DESOFAL. If overdose occurs, this should be managed symptomatically.