Everolimus

Large decrease in exposure expected. Preparations containing St John’s Wort should not be used during treatment with everolimus.

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells.

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by decreasing metabolism or the efflux of everolimus from intestinal cells.

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

Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients treated with everolimus. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein or serum creatinine, is recommended prior to the start of Votubia therapy and periodically thereafter.

Increased exposure expected (the effect varies widely). Combination should be avoided.

Large increase in everolimus concentration is expected. Concomitant treatment of everolimus and potent inhibitors is not recommended.

Use caution when co-administration of moderate CYP3A4 inhibitors or PgP inhibitors cannot be avoided.

For patients with renal angiomyolipoma associated with TSC:

If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, dose reduction to 5 mg or 2.5 mg daily may be considered. However, there are no clinical data with this dose adjustment.

Avoid the use of concomitant potent CYP3A4 inducers.

For patients with renal angiomyolipoma associated with TSC:

If patients require co-administration of a potent CYP3A4 inducer, a everolimus dose increase from 10 mg daily up to 20 mg daily should be considered using 5 mg increments or less applied on Day 4 and 8 following start of the inducer. This dose of everolimus is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment. If treatment with the inducer is discontinued, consider a washout period of at least 3 to 5 days (reasonable time for significant enzyme de-induction) before the everolimus dose is returned to the dose used prior to initiation of the co-administration.

For patients with SEGA associated with TSC:

Patients receiving concomitant potent CYP3A4 inducers may require an increased everolimus dose to achieve the same exposure as patients not taking potent inducers. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. If concentrations are below 5 ng/ml, the daily dose may be increased by 2.5 mg every 2 weeks, checking the trough level and assessing tolerability before increasing the dose. The addition of another concomitant strong CYP3A4 inducer may not require additional dose adjustment.

Assess the everolimus trough level 2 weeks after initiating the additional inducer. Adjust the dose by increments of 2.5 mg as necessary to maintain the target trough concentration. Discontinuation of one of multiple strong CYP3A4 inducers may not require additional dose adjustment. Assess the everolimus trough level 2 weeks after discontinuation of one of multiple strong CYP3A4 inducers. If all potent inducers are discontinued, consider a washout period of at least 3 to 5 days (reasonable time for significant enzyme de-induction) before the everolimus dose is returned to the dose used prior to initiation of the co-administration. The everolimus trough concentrations should be assessed 2 to 4 weeks later since the natural degradation time of the induced enzymes has to be taken into account.

75% of the recommended starting dose calculated based on BSA (rounded to the nearest strength).

50% of the recommended starting dose calculated based on BSA (rounded to the nearest strength).

Everolimus is only recommended if the desired benefit outweighs the risk. In this case, 25% of the dose calculated based on BSA (rounded to the nearest strength) must not be exceeded.

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema.

The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with everolimus. The use of live vaccines should be avoided during treatment with everolimus. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines.

The potential for everolimus to cause infertility in male and female patients is unknown, however secondary amenorrhoea and associated luteinising hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients. Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus.

In EXIST-3 (Study CRAD001M2304), everolimus increased pre-dose concentrations of the antiepileptics carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about 10%. The increase in the pre-dose concentrations of these antiepileptics may not be clinically significant but dose adjustments for antiepileptics with a narrow therapeutic index, e.g carbamazepine, may be considered. Everolimus had no impact on pre-dose concentrations of antiepileptics that are substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide).

AUC↑ 15.3-fold in everolimus AUC/C_max (range 11.2-22.5).

Geometric mean ratio (observed range): C_max↑ 4.1-fold (range 2.6-7.0).

Concomitant treatment of everolimus and potent inhibitors is not recommended.

Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut cannot be excluded. An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A substrate probe, with everolimus resulted in a 25% increase in midazolam C_max and a 30% increase in midazolam AUC_(0-inf). The effect is likely to be due to inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability of orally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure of systemically administered CYP3A4 substrates is not expected.

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. Non-infectious pneumonitis (including interstitial lung disease) was described very commonly in patients taking everolimus in the advanced renal cell carcinoma (RCC) setting. Some cases were 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 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 pneumonitis and have few or no symptoms may continue everolimus therapy without dose adjustments. If symptoms are moderate, consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Everolimus may be reinitiated at a daily dose approximately 50% lower than the dose previously administered.

For cases where symptoms of non-infectious pneumonitis are severe, everolimus therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. everolimus may be reinitiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances.

For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) may be considered.

Serious cases of haemorrhage, some with a fatal outcome, have been reported in patients treated with everolimus in the oncology setting. No serious cases of renal haemorrhage were reported in the TSC setting.

Caution is advised in patients taking everolimus, particularly during concomitant use with active substances known to affect platelet function or that can increase the risk of haemorrhage as well as in patients with a history of bleeding disorders. Healthcare professionals and patients should be vigilant for signs and symptoms of bleeding throughout the treatment period, especially if risk factors for haemorrhage are combined.

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

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

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoal infections, including infections with opportunistic pathogens. Localised and systemic infections, including pneumonia, other bacterial infections, 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 everolimus. Some of these infections have been severe (e.g. leading to sepsis [including septic shock], respiratory or hepatic failure) and occasionally fatal in adult and paediatric patients.

Physicians and patients should be aware of the increased risk of infection with everolimus. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with everolimus. While taking everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of everolimus.

If a diagnosis of invasive systemic fungal infection is made, everolimus treatment should be promptly and permanently discontinued and the patient treated 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 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 everolimus.

Hyperglycaemia has been reported in patients taking everolimus. Monitoring of fasting serum glucose is recommended prior to the start of everolimus therapy and periodically thereafter. More frequent monitoring is recommended when everolimus is co-administered with other medicinal products that may induce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting a patient on everolimus.

Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported adverse reaction in patients treated with everolimus. Stomatitis mostly occurs within the first 8 weeks of treatment. A single-arm study in postmenopausal breast cancer patients treated with everolimus plus exemestane suggested that an alcohol-free corticosteroid oral solution, administered as a mouthwash during the initial 8 weeks of treatment, may decrease the incidence and severity of stomatitis. Management of stomatitis may therefore include prophylactic (in adults) and/or therapeutic use of topical treatments, such as an alcohol-free corticosteroid oral solution as a mouthwash. However products containing alcohol, hydrogen peroxide, iodine and thyme derivatives should be avoided as they may exacerbate the condition. Monitoring for and treatment of fungal infection is recommended, especially in patients being treated with steroid-based medicinal products. Antifungal agents should not be used unless fungal infection has been diagnosed.

There are no adequate data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity. The potential risk for humans is unknown.

Everolimus is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is not known whether everolimus is excreted in human breast milk. However, in rats, everolimus and/or its metabolites readily pass into the milk. Therefore, women taking everolimus should not breast-feed during treatment and for 2 weeks after the last dose.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential must use a highly effective method of contraception (e.g. oral, injected, or implanted non-oestrogen-containing hormonal method of birth control, progesterone-based contraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device [IUD], and/or female/male sterilisation) while receiving everolimus, and for up to 8 weeks after ending treatment.

Male patients should not be prohibited from attempting to father children.

Fertility

The potential for everolimus to cause infertility in male and female patients is unknown, however secondary amenorrhoea and associated luteinising hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients. Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus.

Everolimus may have a minor or moderate influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with everolimus.