Afinitor 5mg & 10 mg Tablet

AFINITOR is indicated for

• The palliative treatment of patients with advanced renal cell carcinoma, who failed prior treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFTR-TKI) therapy.
• In combination with exemestane for palliative treatment of postmenopausal women with oestrogen receptor positive, HER2/neu negative advanced breast cancer with recurrence or progression after prior treatment with a non-steroidal aromatase inhibitor.
• Treatment of advanced neuroendocrine tumours of gastrointestinal, lung or pancreatic origin.
• Patients with tuberous sclerosis complex (TSC) who have renal angiomyolipoma not requiring immediate surgery.

Treatment with AFINITOR should be initiated by a medical practitioner experienced in the use of anticancer therapies.

Posology

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

General target population:

Adults

Dosing in advanced neuroendocrine tumours of gastrointestinal, lung or pancreatic origin, advanced renal cell carcinoma, advanced breast cancer and tuberous sclerosis complex (TSC) with renal angiomyolipoma. The recommended dose of AFINITOR is 10 mg, to be taken once daily.

Management of severe and/or intolerable suspected adverse reactions may require temporary dose reduction and/or interruption of AFINITOR therapy. If dose reduction is required, the suggested dose is 5 mg daily (see section 4.4).

Moderate CYP3A4 or PgP inhibitors: Use caution when administered in combination with moderate CYP3A4 inhibitors or PgP inhibitors. If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, the dose should be reduced to 5 mg daily. Further dose reduction to 5 mg every other day may be required to manage adverse reactions (see sections 4.4 and 4.5).

If the moderate inhibitor is discontinued, consider a washout period of at least 2 to 3 days (average for most commonly used moderate inhibitors) should be allowed before the AFINITOR dose is increased. The AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor (see sections 4.4 and 4.5).

Strong CYP3A4 inducers: Avoid the use of concomitant strong CYP3A4 inducers. If patients require co-administration of a strong CYP3A4 inducer, consider doubling the daily dose of AFINITOR (based on pharmacokinetic data), using 5 mg increments. This dose of AFINITOR is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued, consider a washout period of at least 3 to 5 days (reasonable time for significant enzyme de-induction), before AFINITOR dose is resumed to the dose used prior to initiation of the strong CYP3A4 inducer (see sections 4.4 and 4.5).

Clinical judgment of the treating medical practitioner should guide the management plan of each patient based on individual benefit/risk assessment.

Hypersensitivity to everolimus, to other rapamycin derivatives or to any of the excipients of AFINITOR (see section 4.4).

Concomitant use of live vaccines.

Pregnancy and lactation (see section 4.6).

Non-infectious interstitial pneumonitis

Non-infectious interstitial pneumonitis is a class effect of rapamycin derivatives, including everolimus. Cases of non-infectious interstitial pneumonitis (including interstitial lung disease) have been described in patients taking AFINITOR (see section 4.8). Some of these have been severe and fatalities have occurred.

A diagnosis of non-infectious interstitial pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnoea, and in whom infectious, neoplastic, and other non-medicinal causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jirovecii (carinii) pneumonia (PJP/PCP) should be ruled out in the differential diagnosis of non-infectious pneumonitis Patients should be advised to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious interstitial pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50 % lower than the dose previously administered.

For cases of grade 3 non-infectious interstitial pneumonitis, interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-initiated at a reduced dose of approximately 50 % lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. For cases of grade 4 non-infectious interstitial pneumonitis, AFINITOR therapy should be discontinued. Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for pneumocystis jirovecii (carinii) pneumonia (PJP/PCP) may be considered. The development of pneumonitis has been reported at a reduced dose.

Infections

AFINITOR has immunosuppressive properties and may predispose patients to infections; especially infections with opportunistic pathogens (see section 4.8). Localised and systemic infections, including pneumonia, other bacterial infections, and invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jirovecii (carinii) pneumonia (PJP/PCP) and viral infections including reactivation of hepatitis B virus have been described in patients taking AFINITOR. Some of these infections have been severe (e.g. leading to sepsis [including septic shock] or respiratory failure) and occasionally have had a fatal outcome. Medical practitioners and patients should be aware of the increased risk of infection with AFINITOR, be vigilant for symptoms and signs of infection, and institute appropriate treatment promptly.

Pre-existing invasive fungal infections should be treated prior to starting treatment with AFINITOR. If a diagnosis of invasive systemic fungal infection is made, AFINITOR should be discontinued and treat with appropriate antifungal therapy.

Cases of pneumocystis jirovecii (carinii) pneumonia (PJP/PCP), some with fatal outcome, have been reported in patients who received everolimus. PJP/PCP may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP/PCP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.

Hypersensitivity reactions

Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with AFINITOR (see section 4.3).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Angioedema with concomitant use of angiotensin-converting enzyme (ACE) inhibitors 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, including mouth ulceration and oral mucositis is the most commonly reported adverse drug reaction in patients treated with AFINITOR (see section 4.8). Stomatitis mostly occurs within the first 8 weeks of treatment. If stomatitis occurs, topical treatments are recommended, but alcohol-, iodine-, thyme- or hydrogen peroxide-containing products should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed (see section 4.5).

In a single arm study in 92 postmenopausal breast cancer patients, a topical alcohol-free corticosteroid oral solution was administered as a mouthwash during the initial 8 weeks of starting treatment with AFINITOR plus exemestane. In this study, a clinically meaningful reduction in the incidence and severity of stomatitis was observed.

Renal failure events

Cases of renal failure (including acute renal failure), some with fatal outcome, have been observed in patients treated with AFINITOR (see section 4.8). Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function (see sections 4.4 and 4.8).

Laboratory tests monitoring

Renal function

Elevation of serum creatinine, usually mild and proteinurea have been reported in patients taking AFINITOR (see section 4.8). Monitoring of renal function, including measurement of blood urea, urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Blood glucose

Hyperglycaemia has been reported in patients taking AFINITOR (see sections 4.8). Monitoring of fasting serum glucose is recommended prior to the start of AFINITOR therapy and periodically thereafter. More frequent monitoring is recommended when AFINITOR is co-administered with other medicines that may induce hyperglycaemia. Optimal glycaemia control should be achieved before starting a patient on AFINITOR.

Blood lipids

Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) has been reported in patients taking AFINITOR. Monitoring of blood cholesterol and triglycerides prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy is recommended.

Haematological parameters

Decreased haemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients treated with AFINITOR (see section 4.8). Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Vaccinations

Immunosuppressants may affect the response to vaccination and vaccination during treatment with AFINITOR may therefore be less effective. The use of live vaccines is contraindicated during treatment with AFINITOR (see sections 4.3 and 4.4). Examples of live vaccines are intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines (see section 4.4).

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multi-medicine efflux pump P-glycoprotein (PgP). Therefore, absorption and subsequent elimination of everolimus may be influenced by medicines that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Medicines that may increase everolimus blood concentrations:

Everolimus blood concentrations may be increased by medicines that inhibit CYP3A4 activity and thus decrease everolimus metabolism. Everolimus blood concentrations may be increased by inhibitors of PgP that may decrease the efflux of everolimus from intestinal cells. Concurrent treatment with AFINITOR and strong inhibitors of CYP3A4 or PgP (including but not limited to ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin) should be avoided.

There was a significant increase in exposure to everolimus (Cmax and AUC increased by 3.9- and 15.0-fold, respectively) in healthy subjects when everolimus was co-administered with ketoconazole (a strong CYP3A4 inhibitor and PgP inhibitor).

Concomitant treatment with moderate inhibitors of CYP3A4 including but not limited to erythromycin, verapamil, ciclosporin, fluconazole, diltiazem, amprenavir, fosamprenavir, or aprepitant) and PgP inhibitors requires caution. Reduce the AFINITOR dose if co-administered with moderate CYP3A4/PgP inhibitors (see sections 4.2 and 4.4).

There was an increase in exposure to everolimus in healthy subjects when everolimus was co-administered with:

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor; Cmax and AUC increased by 2.0- and 4.4-fold, respectively)
• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor; Cmax and AUC increased by 2.3- and 3.5-fold, respectively)
• ciclosporin (a CYP3A4 substrate and a PgP inhibitor; Cmax and AUC increased by 1.8- and 2.7-fold, respectively)
• cannabidiol (PgP inhibitor; Cmax and AUC increased by 2.5- and 2.5-fold, respectively)

Other moderate inhibitors of CYP3A4 and PgP that may increase everolimus blood concentrations include certain antifungal medicines (e.g. fluconazole) and calcium channel blockers (e.g. diltiazem). Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should be avoided during treatment with AFINITOR.

No difference in everolimus Cmin was apparent when administered in the presence or absence of substrates of CYP3A4 and/or PgP following treatment with the 10 mg or 5 mg daily dose. Co-administration of weak inhibitors of CYP3A4 with or without PgP inhibitors had no apparent impact on everolimus Cmin following treatment with 10 mg or 5 mg daily dose regimen.

Medicines that may decrease everolimus blood concentrations:

Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells. Concurrent treatment with strong inducers of CYP3A4 or PgP should be avoided. If AFINITOR must be co-administered with a strong CYP3A4 or PgP inducer (e.g. rifampicin and rifabutin), it may be necessary to adjust the dose (see sections 4.2 and 4.4).

Pre-treatment of healthy subjects with multiple doses of rifampicin (a CYP3A4 and PgP inducer) 600 mg daily for 8 days followed by a single dose of everolimus, increased everolimus oral-dose clearance nearly 3-fold and decreased Cmax by 58 % and AUC by 63 %.

Other inducers of CYP3A4 that may increase the metabolism of everolimus and decrease everolimus blood levels include St. Johnu2019s Wort (Hypericum perforatum), anticonvulsants (e.g. carbamazepine, phenobarbitone, phenytoin,) and anti-HIV medicines (e.g. efavirenz, nevirapine). Concomitant treatment with moderate inducers of CYP3A4 or PgP requires caution.

Medicines of which the plasma concentration may be altered by AFINITOR:

Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. In vitro, everolimus competitively inhibited the metabolism of the CYP3A4 substrate ciclosporin and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. The mean steady-state of everolimus Cmax with an oral dose of 10 mg daily or 70 mg weekly is more than 12- to 36-fold below the Ki-values of the in vitro inhibition. An effect of everolimus on the metabolism of CYP3A4 and CYP2D6 substrates is therefore unlikely. Co-administration of weak inhibitors of CYP3A4 with or without PgP inhibitors had no apparent impact on everolimus Cmin following treatment with 10 mg or 5 mg daily dose regimen.

Co-administration of AFINITOR and exemestane increased exemestane Cmin and C2h by 45 % and 71 % respectively. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on safety or efficacy.

Co-administration of an oral dose of midazolam with AFINITOR resulted in a 25 % increase in midazolam Cmax and a 30 % increase in midazolam AUC0-int, whereas the metabolic AUC0-int ratio (1-hydroxy-midazolam/midazolam) and the terminal t1/2 of midazolam were not affected. This suggests that increased exposure to midazolam is due to effects of AFINITOR in the gastrointestinal system when both medicines are taken at the same time. Therefore, AFINITOR may affect the bioavailability of orally administered medicines which are CYP3A4 substrate medicines which are administered by non-oral routes such as intravenous, subcutaneous, and transdermal administrations (see section 4.4).

AFINITOR increased pre-dose concentrations of the antiepileptic medicines (AEMs) carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about 10 %. The increase in the pre-dose concentrations of these AEMs may not be clinically significant and dose adjustments for AEMs with a narrow therapeutic index, e.g. carbamazepine, may be considered. AFINITOR had no impact on pre-dose concentrations of AEMs that are substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide). AFINITOR had no impact on the pre-dose concentration of other AEMs, including valproic acid, topiramate, oxcarbazepine, phenobarbital, phenytoin, and primidone. Co-administration of AFINITOR containing everolimus and depot octreotide increased octreotide Cmin with a geometric mean ratio (everolimus /placebo) of 1.47 (90 % CI: 1.32 to 1.64) which was unlikely to have clinically significant effects on the efficacy response to everolimus in patients with advanced neuroendocrine tumours.

Pregnancy

AFINITOR should not be given to pregnant women (see section 4.3). AFINITOR is contraindicated in pregnancy. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity. The potential risk for humans is unknown.

Breastfeeding

There are no reported cases of exposure to everolimus during breast-feeding in humans. However, in animal studies everolimus and/or its metabolites readily passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Women taking AFINITOR should therefore not breastfeed their infants during treatment and for 2 weeks after the last dose (see section 4.3).

Women of childbearing potential

Women of childbearing potential should be advised that animal studies have been performed showing AFINITOR to be harmful to the developing foetus. Sexually active women of childbearing potential should use highly effective contraception (one that results in an annual pregnancy rate <1% when used correctly) while receiving AFINITOR, and for up to 8 weeks after ending treatment.

Fertility

Both male and female fertility may be compromised by treatment with AFINITOR.

Caution is advised when driving and using machines, until the effect of AFINITOR on the individual patient has been established.

Oncology - Summary of the safety profile

Adverse drug reaction (ADR, suspected to be related to treatment by the investigator) information is based on pooled safety data in patients receiving AFINITOR (N=2672) in clinical studies including randomised, double-blind, placebo- or active comparator-controlled phase III trials and phase-II related to the approved indications in oncology (see section 4.1). The most common ADRs (incidence > 1/10 and suspected to be related to treatment by the investigator) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anaemia, dysgeusia, pneumonitis, peripheral oedema, hyperglycaemia asthenia, pruritus, decreased weight hypercholesterolaemia, epistaxis cough, headache. The most common grade 3-4 ADRs (incidence > 1/100 to < 1/10 and suspected to be related to treatment by the investigator) were stomatitis, anaemia, hyperglycaemia, fatigue, infections, pneumonitis, diarrhoea, aesthaenia, thrombocytopenia, neutropenia, dyspnoea, lymphopenia, proteinuria, haemorrhage, hypophosphataemia, rash, hypertension, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), pneumonia and diabetes mellitus.

Tabulated summary of adverse drug reactions from clinical trials in Oncology

Table 2 presents the frequency category of ADRs reported in the pooled, safety analysis. ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse reaction: very common (u2265 1 /10); common (u2265 1/100 to <1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1000); very rare (< 1/10 000).

General symptomatic and supportive measures should be initiated in case of overdose.