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Important Safety Information

AFINITOR®

Important note: Before prescribing, consult the full prescribing information.

Presentation: ♦ Tablets containing 2.5 mg, 5 mg or 10 mg of everolimus. ♦ Dispersible Tablets containing 2 mg, 3 mg or 5 mg of everolimus.

Indications:


♦ Tablets:
postmenopausal women with hormone receptor-positive advanced breast cancer (BC) in combination with an aromatase inhibitor after prior endocrine therapy; patients with advanced neuroendocrine tumors (NET) of gastrointestinal, lung or pancreatic origin; patients with advanced renal cell carcinoma (RCC); patients with tuberous sclerosis complex (TSC) who have renal angiomyolipoma not requiring immediate surgery. ♦ Tablets and Dispersible Tablets: patients with TSC who have subependymal giant cell astrocytoma (SEGA) not requiring immediate surgery. ♦ Dispersible Tablets: adjunctive treatment of patients 2 years and older with TSC and refractory seizures.

Dosage and administration:

♦ BC, NET, RCC, TSC with renal angiomyolipoma: 10 mg once daily.

♦ TSC with SEGA: starting daily dose is 4.5 mg/m2 according to body surface area (BSA) rounded to the nearest milligram strength of AFINITOR Tablets or AFINITOR Dispersible Tablets. Everolimus whole blood trough concentrations should be assessed approximately 1 to 2 weeks after the initial dose, after any change in dosage, after initiation of or change in co-administration of CYP3A4/PgP inhibitors, or after any change in hepatic (Child-Pugh) status. Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after initiation of or change in co-administration of CYP3A4/PgP inducers. Therapeutic drug monitoring is required and dosing should be titrated to attain everolimus trough concentrations of 3 to 15 ng/mL.

♦ TSC with refractory seizures: starting daily dose without co-administration of CYP3A4/PgP inducer for patients <6 years of age is 6 mg/m2 and for patients ≥6 years of age is 5 mg/m2. Starting daily dose with co-administration of CYP3A4/PgP inducer for patients <6 years of age is 9 mg/m2 and for patients ≥6 years of age is 8 mg/m2. Starting dose should be rounded to the nearest strength of AFINITOR Dispersible Tablets. Everolimus whole blood trough concentrations should be assessed approximately 1 to 2 weeks after the initial dose, after any change in dosage, after initiation of or change in co-administration of CYP3A4/PgP inhibitors, or after any change in hepatic (Child-Pugh) status. Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after initiation of or change in co-administration of CYP3A4/PgP inducers. Therapeutic drug monitoring is required and dosing should be titrated to attain everolimus trough concentrations of 5 to 15 ng/mL.

The daily dose should be taken orally at the same time every day, either consistently with or consistently without food. Dispersible Tablets are to be taken as a suspension only and should not be swallowed whole, chewed, or crushed.

♦ Dose modification: Dose interruption (with or without dose reduction) or discontinuation may be required to manage adverse drug reactions (ADRs). Dose modification may be required with concomitant use of moderate CYP3A4/PgP inhibitors or strong CYP3A4 inducers, hepatic impairment, or change in dosage form in patients being treated for TSC with SEGA. ♦ Pediatric patients: BC, NET, RCC, TSC with renal angiomyolipoma: not recommended for use in children or adolescents. TSC with SEGA: can be used in children and adolescents with normal hepatic function; has not been studied in patients <1 year of age. TSC with refractory seizures: can be used in children and adolescents with normal hepatic function; has not been studied in patients <2 years of age. ♦ Patients with hepatic impairment: BC, NET, RCC, TSC with renal angiomyolipoma: recommended dose is 7.5 mg daily in patients with mild hepatic impairment (Child-Pugh A); 5 mg daily in patients with moderate hepatic impairment (Child-Pugh B); not recommended in patients with severe hepatic impairment (Child-Pugh C), unless the benefit outweighs the risk. In the latter case, a dose of 2.5 mg daily must not be exceeded. TSC with SEGA and TSC with refractory seizures: patients <18 years of age: not recommended; patients ≥18 years of age: recommended dose is 75% of the dose calculated based on BSA in patients with mild hepatic impairment (Child-Pugh A); 50% of the dose calculated based on BSA in patients with moderate hepatic impairment (Child-Pugh B); not recommended in patients with severe hepatic impairment (Child-Pugh C) unless the benefit outweighs the risk. In the latter case, the recommended dose is 25% of the dose calculated based on BSA. Dose adjustment should be made if a patient’s hepatic (Child-Pugh) status changes during the treatment.

♦ Missed Dose: AFINITOR can still be taken up to 6 hours after the time it is normally taken. After more than 6 hours, the dose should be skipped for that day. The next day, AFINITOR should be taken at its usual time. Double doses should not be taken to make up for the one that was missed.

Contraindications: Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients.

Warnings and precautions:

♦ Non-infectious pneumonitis: Cases have been described in patients taking AFINITOR, some of these have been severe and on rare occasions, a fatal outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnea, and in whom infectious, neoplastic, and other non-medicinal causes have been excluded. Opportunistic infections such as pneumocystis jirovecii pneumonia (PJP) should be ruled out in the differential diagnosis of non-infectious pneumonitis. In some cases, management of pneumonitis may require interruption or discontinuation of treatment. The use of corticosteroids may be indicated. For patients who require use of corticosteroids for the treatment of non-infectious pneumonitis, prophylaxis for PJP may be considered. AFINITOR may be reinitiated at a lower dose.

♦ Infections: AFINITOR has immunosuppressive properties. Localized and systemic bacterial, fungal, viral, or protozoal infections (e.g. pneumonia, aspergillosis, candidiasis, or PJP and hepatitis B reactivation) have been described in patients taking AFINITOR; some of these have been severe and occasionally fatal in adult and pediatric patients. Pre-existing infections should be resolved prior to starting treatment with AFINITOR. Be vigilant for symptoms or signs of infection during treatment with AFINITOR. In case of emergent infections, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Prophylaxis for PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.

♦ Hypersensitivity reactions have been observed with everolimus.

♦ Angioedema: Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).

♦ Stomatitis: Stomatitis is the most commonly reported ADR in patients treated with AFINITOR and mostly occurs within the first 8 weeks of treatment. Management may require temporary dose interruption, dose reduction or discontinuation. Topical treatments are recommended, but alcohol-, hydrogen peroxide, iodine-, or thyme containing mouthwashes should be avoided.

♦ Renal failure events: Cases of renal failure (including acute renal failure), some fatal, have been observed in patients treated with AFINITOR. Renal function should be monitored particularly where patients have additional risk factors that may further impair their renal function.

♦ Laboratory tests and monitoring: Monitoring of renal function, blood glucose, blood lipids, and complete blood counts is recommended prior to initiation of and periodically during treatment.

♦ Interactions: Co-administration with strong CYP3A4/PgP inhibitors should be avoided. Use caution when co-administering with moderate CYP3A4/PgP inhibitors; monitor for adverse effects and consider a dose reduction. Co-administration with strong CYP3A4/PgP inducers should be avoided. If AFINITOR has to be co-administered with a strong CYP3A4/PgP inducer monitor for clinical response and consider a dose increase. Exercise caution when co-administering with oral CYP3A4 substrates with a narrow therapeutic index; monitor for adverse effects.

♦ Hepatic impairment: BC, NET, RCC, TSC with renal angiomyolipoma: Not recommended in patients with severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk. TSC with SEGA and TSC with refractory seizures: Not recommended in patients <18 years with hepatic impairment (Child-Pugh A, B, or C) or in patients ≥18 years with severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk.

♦ Vaccination: Avoid use of live vaccines and close contact with people who have received live vaccines. For pediatric patients with TSC with SEGA or with refractory seizures that do not require immediate treatment, consider completing the recommended childhood series of live virus vaccination prior to the start of the AFINITOR therapy, according to local treatment guidelines.

♦ Wound healing complications have been observed in patients taking AFINITOR. Caution should be exercised in the peri-surgical period.

Pregnancy, lactation, females and males of reproductive potential:

♦ Pregnancy: AFINITOR should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus. Male patients taking AFINITOR should not be prohibited from attempting to father children.

♦ Lactation: Women taking AFINITOR should not breast-feed during treatment and for 2 weeks after the last dose.

Females and males of reproductive potential:

♦ Contraception: Use highly effective contraception methods while receiving AFINITOR and for up to 8 weeks after ending treatment.

♦ Infertility:
Male and female fertility may be compromised by treatment with AFINITOR.

Interactions: See “Interactions” subsection of Warnings and precautions.

Adverse drug reactions:

BC, NET, RCC:

♦ Very common (≥10%): Infections, anaemia, decreased appetite, hyperglycaemia, hypercholesterolaemia, dysgeusia, headache, pneumonitis, epistaxis, cough, stomatitis, diarrhoea, nausea, rash, pruritus, fatigue, oedema peripheral, asthenia, weight decreased.

♦ Common (≥1 to <10%): Thrombocytopenia, neutropenia, leukopenia, lymphopenia, hypertriglyceridaemia, hyperlipidaemia, hypophosphataemia, diabetes mellitus, hypokalaemia, dehydration, insomnia, hypertension, haemorrhage, dyspnoea, vomiting, dry mouth, abdominal pain, oral pain, dyspepsia, dysphagia, dry skin, nail disorder, erythema, acne, hand-foot syndrome, arthralgia, renal failure, proteinuria, menstruation irregular, pyrexia, mucosal inflammation, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, blood creatinine increased.

♦ Uncommon (≥0.1 to <1%): Pancytopenia, hypersensitivity, ageusia, congestive cardiac failure, deep vein thrombosis, haemoptysis, pulmonary embolism, increased daytime urination, acute renal failure, amenorrhoea, non-cardiac chest pain, impaired wound healing.

♦ Rare (<0.1%): Pure red cell aplasia, acute respiratory distress syndrome, angioedema.

TSC:

♦ Very common (≥10%): Nasopharyngitis, upper respiratory tract infection, pneumonia, sinusitis, urinary tract infection, pharyngitis, hypercholesterolaemia, decreased appetite, headache, hypertension, cough, stomatitis, diarrhoea, vomiting, acne, rash, amenorrhoea, menstruation irregular, pyrexia, fatigue.

♦ Common (≥1 to <10%): Otitis media, cellulitis, pharyngitis streptococcal, gastroenteritis viral, gingivitis, anaemia, neutropenia, leukopenia, thrombocytopenia, lymphopenia, hypersensitivity, hypertriglyceridaemia, hyperlipidaemia,  hypophosphataemia, hyperglycaemia, insomnia, aggression, irritability, lymphoedema, epistaxis, pneumonitis, constipation, nausea, abdominal pain, flatulence, oral pain, gastritis, dry skin, dermatitis acneiform, proteinuria, menorrhagia, vaginal haemorrhage, ovarian cyst, blood lactate dehydrogenase increased, blood luteinizing hormone increased.

Uncommon (≥0.1 to <1%): Herpes zoster, sepsis, bronchitis viral, dysgeusia, angioedema, menstruation delayed, blood follicle stimulating hormone increased.

Laboratory abnormalities:

BC, NET, RCC:

♦ Very common (≥10%): Haematology: haemoglobin decreased, lymphocytes decreased, white blood cells decreased, platelet count decreased, neutrophils decreased (or collectively as pancytopenia). Clinical chemistry: glucose (fasting) increased, cholesterol increased, triglycerides increased, AST increased, phosphate decreased, ALT increased, creatinine increased, potassium decreased, albumin decreased.

TSC:

♦ Very common (≥10%); Haematology: partial thromboplastin time increased, neutrophils decreased, haemoglobin decreased, white blood cells decreased, platelet count decreased, lymphocytes decreased. Clinical chemistry: cholesterol increased, triglycerides increased, AST increased, ALT increased, phosphate decreased, alkaline phosphatase increased, glucose (fasting) increased.

Pediatric patients with TSC:

Infections were reported at a higher frequency and severity in patients below the age of 6 years and two fatal cases due to infection were reported in patients <18 years receiving everolimus.

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