Afinitor

/ Novartis

Treatment with this drug should be initiated and supervised by a physician experienced in the use of anticancer therapies or in the treatment of patients with TSC. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
General target population:
Dosing in hormone receptor-positive advanced breast cancer, advanced neuroendocrine tumors of pancreatic origin, advanced renal cell carcinoma and TSC with renal angiomyolipoma: The recommended dose of the drug is 10 mg, to be taken once daily. Careful titration may be required to obtain the optimal therapeutic effect. Doses that will be tolerated and effective vary between patients. Concomitant antiepileptic therapy may affect the metabolism of everolimus and may contribute to this variance.
Dosing in TSC with SEGA: Individualize dosing based on body surface area (BSA, in m2) using the Dubois formula, where weight (W) is in kilograms and height (H) is in centimeters: BSA = (W0.425 x H0.725) x 0.007184. The recommended starting daily dose for Everolimus for the treatment of patients with TSC who have SEGA is 4.5 mg/m2, rounded to the nearest strength of Everolimus Tablets. Different strengths of Everolimus tablets can be combined to attain the desired dose. Everolimus whole blood trough concentrations should be assessed at least 1 week after commencing treatment for patients <3 years of age and approximately 2 weeks after commencing treatment for patients ≥3 years of age. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. The dose may be increased to attain a higher trough concentration within the target range to obtain optimal efficacy, subject to tolerability. Once a stable dose is attained, monitor trough concentrations every 3 to 6 months in patients with changing body surface area or every 6 to 12 months in patients with stable body surface area for the duration of treatment.
Dose Modifications:
Adverse drug reactions: Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose interruption (with or without dose reduction) or discontinuation of therapy with the drug. If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered.
See prescribing information for full details.
CYP3A4/PgP inhibitors: Avoid the use of strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole).
Moderate CYP3A4 or PgP inhibitors: Use caution when administered in combination with moderate CYP3A4/ PgP inhibitors. If patients require co-administration of a moderate CYP3A4/ PgP inhibitor, reduce the drug’s dose by approximately 50%. For dose reductions below the lowest available strength, alternate day dosing should be considered.
Hormone receptor-positive advanced breast cancer, advanced neuroendocrine tumors of pancreatic origin, advanced renal cell carcinoma and TSC with renal angiomyolipoma: If the moderate CYP3A4/PgP inhibitor is discontinued, consider a washout period of approximately 2 to 3 days should be allowed before the drug’s dose is increased. The drug’s dose should be returned to the dose used prior to initiation of the moderate CYP3A4 -/- PgP inhibitor.
TSC with SEGA: Everolimus trough concentrations should be assessed approximately 2 weeks after the addition of a moderate CYP3A4/PgP inhibitor. If the inhibitor is discontinued the drug’s dose should be returned to the dose used prior to initiation of the inhibitor and the everolimus trough concentration should be re-assessed approximately 2 weeks later.
Strong CYP3A4/PgP inducers: Avoid the use of concomitant strong CYP3A4/ PgP inducers.
Hormone receptor-positive advanced breast cancer, advanced neuroendocrine tumors of pancreatic origin ,advanced renal cell carcinoma and TSC with renal angiomyolipoma: If patients require co-administration of a strong CYP3A4/ PgP inducer, consider doubling the daily dose of the drug (based on pharmacokinetic data), using increments of 5 mg or less. This dose of the drug 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 3 to 5 days, before the drug’s dose is returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer.
TSC with SEGA: Patients receiving concomitant strong CYP3A4 inducers (e.g., the enzyme inducing antiepileptic drugs carbamazepine, phenobarbital, and phenytoin) may require an increased dose to attain trough concentrations of 3 to 15 ng/mL. If concentrations are below 3 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. If the strong inducer is discontinued, the dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer and the everolimus trough concentrations should be assessed approximately 2 weeks later.
Pediatric population: The drug is not recommended for use in pediatric cancer patients. The safety and efficacy of the drug in pediatric patients with renal angiomyolipoma associated with TSC in the absence of SEGA have not been established. No data are available. The safety and efficacy of the drug in children below the age of 1 year with TSC who have SEGA have not been established. No data are available. Dosing recommendations for pediatric patients with TSC who have SEGA are consistent with those for the corresponding adult population with the exception of those patients with hepatic impairment. The drug is not recommended for patients <18 years of age with TSC who have SEGA and hepatic impairment.
Geriatrics (≥ 65 years): No dosage adjustment is required.
Renal impairment: No dosage adjustment is required.
Hepatic impairment
Hormone receptor-positive advanced breast cancer, advanced neuroendocrine tumors of pancreatic origin, advanced renal cell carcinoma and TSC with renal angiomyolipoma: Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily. Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 5 mg daily; the dose may be decreased to 2.5 mg if not well tolerated. Severe hepatic impairment (Child-Pugh C) – not recommended. If the desired benefit outweighs the risk, a dose of 2.5 mg daily must not be exceeded. Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment.
TSC with SEGA
Patients ≥18 years of age: Mild hepatic impairment (Child-Pugh A) – 75% of the recommended starting dose calculated based on BSA (rounded to the nearest strength). Moderate hepatic impairment (Child-Pugh B) – 25% of the recommended starting dose calculated based on BSA (rounded to the nearest strength). Severe hepatic impairment (Child-Pugh C) – not recommended. Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after commencing treatment or after any change in hepatic (Child-Pugh) status. Dosing should be titrated to attain trough concentrations of 3 to 15 ng/mL. Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment.
Patients <18 years of age: The drug is not recommended for patients <18 years of age with TSC who have SEGA and hepatic impairment.
For therapeutic drug monitoring for patients treated for TSC with SEGA: see prescribing information.

Treatment of patients with SEGA associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of the drug is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been demonstrated. Treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of the drug in the treatment of patients with carcinoid tumors have not been established. Treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. The effectiveness of the drug in treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes. Treatment of patients with advanced renal cell carcinoma whose disease has progressed on or after treatment with VEGF-targeted therapy. Treatment of unresectable, locally advanced or metastatic, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin in adults with progressive disease.

The drug is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients.         

Non-infectious pneumonitis: Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious pneumonitis (including interstitial lung disease) have also been described in patients taking this drug. 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 by means of appropriate investigations. Opportunistic infections such as pneumocystis jirovecii pneumonia (PJP) 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 therapy with this drug without dose alteration. If symptoms are moderate (grade 2), consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. The drug may be reintroduced at a daily dose approximately 50% lower than the dose previously administered. For cases of grade 3 non-infectious pneumonitis, interrupt the drug until resolution to less than or equal to grade 1. The drug may be reinitiated at a daily dose approximately 50% lower than the dose previously administered depending on individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of the drug. For cases of grade 4 non-infectious pneumonitis, therapy with this drug 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 pneumonia (PJP) may be considered. The development of pneumonitis has also been reported at a reduced dose.
Infections: This drug 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, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jirovecii pneumonia (PJP) and viral infections including reactivation of hepatitis B virus, have occurred in patients taking this drug. 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 this drug. Treat pre-existing infections prior to starting treatment with the drug. While taking this drug, 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 the drug. If a diagnosis of invasive systemic fungal infection is made, discontinue the drug and treat with appropriate antifungal therapy. Cases of pneumocystis jirovecii pneumonia (PJP), some with fatal outcome, have been reported in patients who received everolimus. PJP may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP 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, dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus.
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).
Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis have been seen in patients treated with this drug. In such cases topical treatments are recommended, but alcohol- hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed.
Haemorrhage: 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.
Renal failure events: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with this drug. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.
Impaired Wound Healing: Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of this drug in the peri-surgical period.
Geriatric Patients: In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended.
Laboratory tests and monitoring
Renal function: Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients taking this drug. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of therapy and periodically thereafter.
Blood glucose: Hyperglycaemia, has been reported in patients taking this drug. Monitoring of fasting serum glucose is recommended prior to the start of the therapy and periodically thereafter. More frequent monitoring is recommended when this drug is co-administered with other drugs that may induce hyperglycemia. Optimal glycaemic control should be achieved before starting a patient on this drug.
Blood lipids: Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in patients taking this drug. Monitoring of blood cholesterol and triglycerides prior to the start of therapy and periodically thereafter as well as management with appropriate medical therapy is recommended.
Hematological parameters: Decreased haemoglobin, lymphocytes, platelets and neutrophils have been reported in patients treated with this drug. Monitoring of complete blood count is recommended prior to the start of therapy and periodically thereafter.
Drug-drug interactions: Co-administration with strong CYP3A4/ PgP inhibitors should be avoided. Use caution when administered in combination with moderate CYP3A4/ PgP inhibitors. If the drug must be co-administered with a moderate CYP3A4/ PgP inhibitor, the patient should be carefully monitored for undesirable effects and the drug’s dose reduced if necessary. Concomitant treatment with potent CYP3A4 inhibitors result in dramatically increased blood concentrations of everolimus . There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Afinitor and potent inhibitors is not recommended. Co-administration with strong CYP3A4/PgP inducers should be avoided. If the drug must be co-administered with a strong CYP3A4/ PgP inducer, the patient should be carefully monitored for clinical response. Consider a dose increase of the drug when co-administered with strong CYP3A4/PgP inducers if alternative treatment is not possible. Exercise caution when the drug is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If the drug is taken with orally administered CYP3A4 substrates with a narrow therapeutic index, the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate.
Hepatic impairment: Exposure to everolimus was increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment. The drug is not recommended in patients with severe hepatic impairment (Child-Pugh C) for the treatment of hormone receptor-positive advanced breast cancer, advanced neuroendocrine tumors of pancreatic origin, advanced renal cell carcinoma, or TSC who have renal angiomyolipoma unless the potential benefit outweighs the risk. The drug is not recommended for use in patients< 18 years of age with TSC who have SEGA and concomitant hepatic impairment (Child-Pugh A, B or C) or in patients ≥ 18 years of age with severe hepatic impairment (Child-Pugh C).
Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with the drug. For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations prior to the start of therapy according to local treatment guidelines.
Lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Wound healing complications: Impaired wound healing is a class effect of rapamycin derivatives, including this drug. Caution should therefore be exercised with the use of this drug in the peri-surgical period.
See prescribing information for full details.

Oncology: 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, diarrhea, infections, nausea, decreased appetite, anemia, dysgeusia, pneumonitis, hyperglycemia, weight decreased, pruritus, asthenia, peripheral edema, asthenia, hypercholesterolemia, epistaxis, and 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, anemia, hyperglycemia, fatigue, infections, pneumonitis diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, lymphopenia, proteinuria, hemorrhage, hypophosphatemia, rash, hypertension, aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, and pneumonia.
See prescribing information for full details.
Clinically relevant laboratory abnormalities: In the pooled double-blind phase III safety database, the following new or worsening clinically relevant laboratory abnormalities were reported with an incidence of ≥1/10 (very common, listed in decreasing frequency): Hematology: hemoglobin decreased, lymphocytes decreased, white blood cells decreased. platelets decreased, and neutrophils decreased (or collectively as pancytopenia); Clinical chemistry: glucose (fasting) increased, cholesterol increased, triglycerides increased, AST increased, phosphate decreased. ALT increased, creatinine increased and potassium decreased. Most of the observed abnormalities (≥1/100) were mild (grade 1) or moderate (grade 2). Grade 3/4 hematology and chemistry abnormalities include: Hematology: lymphocytes decreased, hemoglobin decreased (very common); neutrophils decreased, platelet count decreased, white blood cells decreased (all common). Clinical chemistry: glucose (fasting) increased (very common), phosphate decreased, potassium decreased, AST increased, ALT increased, creatinine increased cholesterol (total) increased; triglycerides increased (all common).
Tuberous sclerosis complex (TSC): The most frequent ADRs (incidence ≥1/10 and suspected to be related to treatment by the investigator) from the pooled safety database are (in decreasing order): stomatitis, amenorrhea, upper respiratory tract infections, hypercholesterolemia, nasopharyngitis, acne, menstruation irregular, sinusitis, and pneumonia. The most frequent grade 3/4 adverse reactions (incidence ≥1/100 to <1/10 and suspected to be related to treatment by the investigator) were stomatitis, amenorrhea, pneumonia, neutropenia, pyrexia and gastroenteritis viral.
See prescribing information for full details.

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump 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.
Agents that may increase everolimus blood concentrations: Everolimus blood concentrations may be increased by substances 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 strong CYP3A4/PgP inhibitors (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 drug’s dose if co-administered with moderate CYP3A4/PgP inhibitors. 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). Grapefruit, grapefruit juice, star fruit, seville oranges and other foods that are known to affect cytochrome P450 and PgP activity should be avoided during treatment. 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 the 10-mg or 5-mg daily dose regimen.
Agents 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 CYP3A4/PgP inducers should be avoided. If the drug must be co-administered with a strong CYP3A4/ PgP inducer (e.g. rifampicin and rifabutin), it may be necessary to adjust the dose. Pre-treatment of healthy subjects with multiple doses of rifampicin (a strong 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 strong inducers of CYP3A4 and/or PgP that may increase the metabolism of everolimus and decrease everolimus blood levels include St. John’s wort (Hypericum perforatum), corticosteroids (e.g. dexamethasone, prednisone, prednisolone), anticonvulsants (e.g. carbamazepine, phenobarbital, phenytoin,) and anti HIV agents (e.g. efavirenz, nevirapine).
Agents whose plasma concentration may be altered by everolimus: Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between the drug 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 the drug. 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 was therefore considered to be unlikely. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC (0-inf), whereas the metabolic AUC(0-inf) 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 everolimus in the gastrointestinal system when both drugs are taken at the same time. Therefore, everolimus may affect the bioavailability of orally co-administered drugs which are CYP3A4 substrates. Everolimus is unlikely to affect the exposure of other CYP3A4 substrate drugs which are administered by non-oral routes such as intravenous, subcutaneous, and transdermal administrations. Coadministration of 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 tumors. Co-administration of everolimus 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 efficacy or safety.
Vaccinations: Immunosuppressants may affect the response to vaccination and vaccination during treatment with the drug may therefore be less effective. The use of live vaccines should be avoided during treatment with the drug. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.         

Pregnancy: There are no adequate data from the use of the drug in pregnant women. Studies in animals have shown reproductive toxicity effects including embryo-toxicity and feto-toxicity. The potential risk for humans is unknown. The drug should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus. Male patients taking the drug should not be prohibited from attempting to father children.
Lactation: It is not known whether everolimus is excreted in breast milk. However, in animal studies everolimus and/or its metabolites readily passed into the milk of lactating rats. Women taking this drug should therefore not breast-feed during treatment and for 2 weeks after the last dose.
See prescribing information for full details.

In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2,000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been given with acceptable acute tolerability. General supportive measures should be initiated in all cases of overdose.

Methode of administration: The drug’s tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed. For patients with TSC who have SEGA and are unable to swallow tablets whole, the tablet(s) can be dispersed completely in a glass of water (containing approximately 30 mL) by gently stirring until the tablet(s) is fully disintegrated (approximately 7 minutes), immediately prior to drinking.
Storage: Do not store above 25ºC.
Lactose: Contains lactose.