Frexivo 250mg SOLUTION FOR INJECTION

FREXIVO 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.

In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products.

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. It is recommended that the injection be administered slowly (1-2 minutes/injection).

Caution should be taken if injecting FREXIVO at the dorsogluteal site due to the proximity of the underlying sciatic nerve. Refer to the end of this leaflet for detailed instructions for assembly, handling and disposal of the syringe and safety needle.

Children: Not recommended for use in children or adolescents, as safety and effectiveness have not been established in this age group.

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

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

FREXIVO is contraindicated in:

• patients with a known hypersensitivity to any of its ingredients
• patients with severe hepatic impairment
• pregnancy and women breastfeeding their infants

FREXIVO 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 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 FREXIVO injection. Caution should be taken while administering FREXIVO at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve (see section 4.2 and 4.8).

There is 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.

Special Precautions

Hypersensitivity Reactions: Hypersensitivity reactions including angioedema and urticaria have been commonly reported (incidence of u2265 10 %) and may be serious (see section 4.8).

Ethanol: FREXIVO contains 10 %w/v ethanol (alcohol) as excipient, i.e up to 500 mg per injection. This may be harmful for those suffering from alcohol dependency and should be taken into account in high risk groups such as patients with liver disease and epilepsy.

Benzyl alcohol: FREXIVO contains benzyl alcohol as an excipient which may cause allergic reactions.

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 oestradiol, fulvestrant may interfere with antibody-based oestradiol assays and may result in falsely increased levels of oestradiol.

Studies in animals have shown reproductive toxicity. Fulvestrant is found in ratsu2019 milk at levels significantly higher than those in rat plasma. The potential risk for humans is unknown. Therefore use of FREXIVO should be avoided in pregnant or women breastfeeding their infants. Patients of childbearing potential should use effective contraception during treatment with FREXIVO and for 2 years after the last dose.

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

Table 1: Summary of adverse reactions seen in clinical studies for FREXIVO 500 mg.

Frequency descriptor

System organ class Adverse reaction

Very common (u226510 %)

• General disorders and administration site conditions: Injection site reactions, asthenia
• Hepatobiliary disorders: Elevated liver enzymes (ALT, AST, ALP)
• Gastrointestinal disorders: Nausea
• Immune system disorders: Hypersensitivity reactions: angioedema and urticaria
• Musculoskeletal and connective tissue disorders: Joint and musculoskeletal pain
• Skin and subcutaneous tissue disorders: Rash
• Vascular disorders: Hot flushes

Common (u2265 1 - < 10 %)

• Nervous system disorders: Headache
• Hepatobiliary disorders: Elevated bilirubin
• Blood and lymphatic system: Reduced platelet count
• Gastrointestinal disorders: Vomiting, diarrhoea
• Metabolism and nutrition disorders: Anorexia
• Infections and infestations: Urinary tract infections

Uncommon (< 1 %)

• Hepatobiliary disorders: Elevated gamma-GT

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.

Post-marketing side effects: Hepatobiliary disorders: Hepatic failure and hepatitis.

Reporting of 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

In the event of overdose, side effects may be exacerbated (see 4.8). There is no specific antidote. Treatment of overdose is symptomatic and supportive.