Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
everolimus
Everolimus is an inhibitor of mTORC1 (mammalian target of rapamycin complex 1). mTORC1 plays an essential role in protein synthesis downstream of the PI3K/AKT pathway, which is dysregulated in the many human cancers, and may also activate the estrogen receptor. Everolimus has been shown to reduce cell proliferation, glycolysis and angiogenesis in solid tumours in vivo. It also possesses immunosuppressive activity.
Peak concentrations are reached 1-2 hours; steady state achieved within 2 weeks with daily dosing. Cmax and exposure are dose-proportional within dose ranging from 5 to 10 mg daily. Although light to high fat meals reduced everolimus exposure, food had no apparent effect on the elimination phase concentration-time profile.
20% confined to plasma; mainly distributed to heart, lung, liver, kidney, spleen, thyroid, and adrenal gland.
| Cross blood brain barrier? | yes |
| PPB | 74% |
Mainly metabolized by CYP3A4. Substrate of CYP3A4 and P-glycoprotein (Pgp), moderate inhibitor of Pgp.
| Active metabolites | no |
| Inactive metabolites | yes |
Mainly biliary/fecal excretion. Black patients have higher clearance, and Japanese patients have higher exposure compared to Caucasian patients; significance is unknown. Children have higher clearance compared to adults.
| Half-life | 30 hours |
| Clearance | 15 L/h |
| Feces | 80% as metabolites, over 10 days |
| Urine | 5% as metabolites, over 10 days |
- metastatic renal cell carcinoma (MRCC, clear cell morphology), after failure of initial treatment with either sunitinib or sorafenib
- treatment of well- or moderately differentiated neuroendocrine tumours of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease that has progressed within the last 12 months
- postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer in combination with exemestane after recurrence or progression following treatment with letrozole or anastrozole
- treatment of unresectable, locally advanced or metastatic, well-differentiated, non-functional neuroendocrine tumours (NET) of GI or lung origin in adults with progressive disease
Refer to the everolimus product monograph for details of non-oncologic indications.
Note:
- The everolimus oral tablets and the DISPERZTM tablets (for oral suspension) are NOT interchangeable. Only everolimus oral tablets are indicated for use in metastatic RCC, breast cancer and advanced NET indications.
- Oncology indications are based on a benefit in progression-free suvival (PFS); improvements in overall survival (OS) or quality of life (QOL) have not been demonstrated.
- Everolimus is NOT indicated in functional NET, nor in combination with somatostatin - randomized studies demonstrated worse outcomes compared to somatostatin alone.
Emetogenic Potential:
The following adverse effects were reported in randomized trials of mRCC where the incidence was at least 2% higher than placebo; selected severe adverse effects from other sources may also be included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Cardiotoxicity (1%) | E D | |||
| Hypertension (4%) (may be severe) | E | ||||
| Venous thromboembolism (<1%) | E | ||||
| Dermatological | Hand-foot syndrome (5%) | E | |||
| Nail disorder (5%) | E | ||||
| Rash (29%) | E | ||||
| Gastrointestinal | Abdominal pain (9%) | E | |||
| Anorexia, weight loss (25%) | E | ||||
| Diarrhea (30%) | E | ||||
| GI obstruction (rare) | E | ||||
| Mucositis (44%) | E | ||||
| Nausea, vomiting (26%) | I | ||||
| General | Delayed wound healing (<1%) | E | |||
| Fatigue (33%) | E | ||||
| Fluid retention (25%) (including edema effusions) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (grade 3-4: 13%; includes opportunistic infections and viral reactivation) | E | |||
| Pure red cell aplasia (rare) | D | ||||
| Hepatobiliary | ↑ LFTs (25%) (rarely severe) | E | |||
| Hypersensitivity | Angioedema (3%) (if concomitant ACE inhibitor) | I | |||
| Hypersensitivity (rare) | I | ||||
| Metabolic / Endocrine | Hyperglycemia (16%) (grade 3 or 4) | E | |||
| Hyperlipidemia (4%) (grade 3 or 4) | E D | ||||
| Musculoskeletal | Musculoskeletal pain (10%) | E | |||
| Rhabdomyolysis (rare) | E | ||||
| Nervous System | Dizziness (7%) | E | |||
| Dysgeusia (10%) | I E | ||||
| Headache (19%) | E | ||||
| Insomnia (9%) | E | ||||
| Paresthesia (5%) | E | ||||
| Ophthalmic | Conjunctivitis (2%) | E | |||
| Renal | Renal failure (3%) | E | |||
| Reproductive and breast disorders | Other (Secondary amenorrhea - rare) | E | |||
| Respiratory | Cough, dyspnea (30%) | E | |||
| Pneumonitis (14%) | E D | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for everolimus include mucositis, fatigue, cough, dyspnea, diarrhea, rash, nausea, vomiting, ↑ lfts, anorexia, weight loss, fluid retention and headache.
Everolimus has immunosuppressant properties and may increase the risk of severe or fatal bacterial, protozoal or viral infections (including opportunistic, viral reactivation, pneumocystis jirovecii pneumonia (PJP)). Consider the use of PJP prophylaxis when concomitant use of corticosteroids or other immunosuppressants are required.
Rhabdomyolysis has been described.
Non-infective pneumonitis, including severe and fatal cases, is a class effect of rapamycin derivatives, and has been reported even at reduced doses. Opportunistic infection (e.g. PJP) should be ruled out. Symptoms include hypoxia, pleural effusion, cough or dyspnea.
Stomatitis mainly occurs within the first 8 weeks of treatment and should be managed with non-irritant oral rinses. Antifungal agents should not be used unless an oral infection has been diagnosed. The incidence and severity may be reduced by using an alcohol-free corticosteroid mouthwash during the first 8 weeks of treatment (uncontrolled study).
Hyperglycemia, hyperlipidemia and hypertriglyceridemia have been reported in clinical trials.
Angioedema has been reported and is more common (3% vs <1%) in patients taking ACE inhibitors.
Refer to protocol by which patient is being treated. Do not use for the treatment of functional carcinoid/NET tumours or in combination with somatostatin. Patients in whom drug-drug interactions are likely (and who cannot discontinue the concomitant medication) may require dose modification (refer to section H for details). Optimal glycemic/lipidemic control must be obtained prior to starting therapy.
Note: Everolimus oral tablets and the DISPERZTM tablets (for oral suspension) are NOT interchangeable. Only everolimus oral tablets are indicated for use in oncology indications.
Prophylaxis for PJP should be considered when concurrent use of corticosteroids or other immunosuppressive agents are required. Consider a corticosteroid mouthwash during the first 8 weeks of treatment to reduce the risk and severity of stomatitis.
Metastatic RCC, Breast Cancer and Advanced PNET/NET:
Oral: 10mg daily
|
Toxicity
|
Grade 1
|
Grade 2
|
Grade 3
|
Grade 4
|
| Thrombocytopenia | No dosage adjustment required. | Hold until ≤ grade 1. Restart treatment at the same dose. | Hold until ≤ grade 1. Restart treatment at a lower dose. | Hold until ≤ grade 1. Restart treatment at a lower dose. |
| Neutropenia | No dosage adjustment required. | No dosage adjustment required. | Hold until ≤ grade 2. Restart treatment at the same dose. | Hold until ≤ grade 2. Restart treatment at a lower dose. |
| Febrile neutropenia | n/a | n/a | Hold until recovery of ANC to ≥ 1.25 x 109/L and afebrile. Restart treatment at a lower dose. | Discontinue and treat patient appropriately. |
|
Non-infectious pneumonitis
|
If asymptomatic, maintain same dose. Monitor and treat patient appropriately. |
Consider hold until ≤ grade 1. Rule out infection and then consider corticosteroids.
Restart with 1 dose level ↓ . Discontinue if no recovery within 4 weeks.
|
Hold until ≤ grade 1. Rule out infection and then consider corticosteroids. Restart with 1 dose level ↓.
Discontinue if grade 3 recurs. |
Discontinue, investigate and treat patient appropriately. |
|
Stomatitis
|
As above and manage with non-alcoholic mouthwash several times daily. |
Hold until ≤ grade 1 and restart at same dose.
If recurs, hold until ≤ grade 1 and restart with 1 dose level ↓.
Manage with topical analgesic mouth treatments with or without topical corticosteroids.
|
Hold until ≤ grade 1 and restart with 1 dose level ↓.
Manage with topical analgesic mouth treatments with or without topical corticosteroids.
|
As above. |
|
Metabolic events (e.g. hyperglycemia, hyperlipidemia)*
|
Maintain same dose. Monitor and start appropriate therapy. |
Maintain same dose. Monitor and start appropriate therapy. |
Hold until ≤ grade 1 and restart with 1 dose level ↓.
Monitor and start appropriate therapy.
|
As above. |
|
Other related non-hematologic toxicities
|
If tolerable, maintain same dose and treat appropriately. |
Maintain same dose if tolerable.
If intolerable, hold until ≤ grade 1 and restart at same dose.
If recurs, hold until ≤ grade 1 and restart with 1 dose level ↓.
|
Hold until ≤ grade 1 and restart with 1 dose level ↓.
Consider discontinuing if recurs.
|
As above. |
|
* consider urgent therapy if hypertriglyceridemia due to risk of pancreatitis |
||||
Exposure is increased in patients with hepatic impairment. Do not use in pediatric patients with hepatic impairment. (Continued on next page)
MRCC, Breast Cancer, PNET/NET:
|
Hepatic impairment (baseline and during treatment) |
Everolimus dose for adults (see product monograph for pediatric indications)
|
|
Mild (Child-Pugh class A)
|
7.5mg once daily. ↓ to 5mg daily if not well tolerated |
|
Moderate (Child-Pugh class B)
|
5mg daily. ↓ to 2.5 mg daily if not well tolerated |
|
Severe (Child-Pugh class C)
|
Use only when benefits outweigh risks, at 2.5 mg daily |
No dose adjustment required.
No dose adjustment required; monitor patients carefully. In the advanced breast cancer study, higher incidences of adverse events leading to treatment discontinuation and deaths due to any cause (within 28 days of last dose) were observed in elderly patients.
In the advanced GI/Lung NET study, there were no overall differences in efficacy observed. Patients ≥ 65 reported a 1.5 fold increased incidence of cardiac failure, lower respiratory tract infections, cough, and decreased appetite.
Clinical data suggest risks of delayed development and reproductive landmarks in patients taking everolimus. See the product monograph for dosing, including for organ impairment in this population.
- Give dose at the same time each day, preferably in the morning, either consistently with food or consistently without food.
- Give everolimus on an empty stomach or after a light fat-free meal.
- Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
- Swallow whole with a glass of water; do not crush or chew.
- Note: Everolimus oral tablets and the DISPERZTM tablets (for oral suspension) are non-interchangeable. Only everolimus oral tablets are indicated for use in metastatic RCC, breast cancer and advanced PNET.
- If a dose is missed, it may be taken up to 6 hours after the time it is normally taken. Otherwise, skip this and take the next dose on the following day at its usual scheduled time.
- Store in original package at room temperature; protect from light.
- Contraindicated in patients with hypersensitivity to everolimus, other rapamycin derivatives, or to any excipients.
- Do not use in patients with severe COPD or pulmonary fibrosis.
- Use with caution in patients with significant lung disease and/or DLCO <20%, the elderly or patients at risk of bleeding (e.g. taking anti-platelet agents).
- Contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption
- Prior to starting everolimus, existing infections should be fully resolved and optimal glycemic and lipid control should be achieved.
- Avoid co-administration with strong CYP3A4 or PgP inhibitors and inducers; use with caution with moderate inhibitors/inducers.
- Use of everolimus for carcinoid tumours is not recommended outside of a clinical trial.
- Since everolimus use may affect wound healing, exercise caution in the peri-surgical period.
- Use with caution in patients with hepatitis B - consider prevention to reduce chance of reactivation
- Avoid the use of live vaccines. For children, if treatment can be delayed, complete vaccinations prior to starting therapy.
Other Drug Properties:
-
Carcinogenicity:
No
-
Immunosuppressive:
Yes
-
Mutagenicity:
No
-
Clastogenicity:
No
-
Crosses placental barrier:
Yes
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
Use in pregnancy is not recommended. Adequate contraception should be used by both sexes during treatment, and for 8 weeks after the last dose. -
Excretion into breast milk:
Yes
Breastfeeding is not recommended during treatment and for 2 weeks after the last dose.
-
Fertility effects:
Yes
CYP3A4 is the major enzyme involved in everolimus metabolism. Everolimus is a moderate PgP inhibitor. Based on in vitro studies, an effect of everolimus on the metabolism of CYP2D6 substrates is unlikely.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Strong CYP3A4 or P-glycoprotein (Pgp) inhibitors (i.e. ketoconazole, nefazodone, ritonavir, clarithromycin, grapefruit juice) | ↑ everolimus concentrations and risk of toxicity | ↓ everolimus metabolism or efflux | Avoid |
| Moderate CYP3A4 and/or Pgp inhibitors (i.e. erythromycin, verapamil, cyclosporine, fluconazole, diltiazem, amprenavir, aprepitant) | ↑ everolimus concentrations and risk of toxicity | ↓ everolimus metabolism or efflux | Avoid; if must co-administer, reduce everolimus dose by 50%; further dose reductions may be needed to manage adverse effects. |
| Strong CYP3A4 or Pgp inducers (i.e. rifampin, St. John's wort, corticosteroids, phenobarbital, carbamazepine, phenytoin, efavirenz, nevirapine | ↓ everolimus concentrations and efficacy | ↑ everolimus metabolism or efflux | Avoid. If must co-administer, monitor patient response; everolimus dose ↑ may be required (limited clinical data). |
| CYP3A4 substrates (oral) with a narrow therapeutic range | ↑ substrate exposure and possible ↑ in toxicity | ↑ concentrations of CYP3A4 substrates | Caution (non-oral CYP3A4 substrates have not been studied) |
| Depot octreotide | ↑ octreotide Cmin when used in combination with everolimus | Unknown | Caution |
| Exemestane | ↑ exemestane Cmin in combination as compared to exemestane alone, with similar estradiol levels at steady state | Both drugs metabolized by CYP3A4 | Used as combination treatment |
| Statins metabolized by CYP3A4 (e.g. atorvastatin, simvastatin, lovastatin) | ↑ risk of rhabdomyolysis | Inhibition of CYP3A4 by everolimus | Caution |
| Drugs that can affect platelet function; anticoagulants | ↑ risk of bleeding | Possibly additive | Caution; monitor patient closely |
| ACE inhibitors | ↑ risk of angioedema | Unknown | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline and at each visit |
Renal function tests, electrolytes (including Ca, Mg and PO4), urinalysis |
Baseline and at each visit |
| Fasting blood glucose and lipids | Baseline and periodic (more frequent with concomitant use of drugs that can cause hyperglycemia) |
CBC |
Baseline and at each visit |
Clinical assessment of mucositis, fatigue, fluid retention, pulmonary toxicity, infection, rash, diarrhea, bleeding, thromboembolism, rhabdomyolysis |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Pulmonary function tests in patients with significant lung disease |
Baseline and as clinically indicated |
Exceptional Access Program (EAP Website)
- everolimus - In combination with exemestane, for the treatment of hormone-receptor positive, HER2 negative advanced breast cancer, in postmenopausal women with ECOG performance status less than or equal to 2 after recurrence or progression following a non-steroidal aromatase inhibitor (NSAI)
- everolimus - Treatment of metastatic renal cell carcinoma (mRCC) as second or third line therapy in patients previously treated for mRCC with a funded tyrosine kinase inhibitor (TKI), with specific criteria
- everolimus - For patients who have progressive, unresectable, well or moderately differentiated, locally advanced or metastatic pancreatic neuroendocrine tumors (PNET), with specific criteria
- everolimus - Treatment of unresectable, locally advanced or metastatic, well-differentiated non-functional neuroendocrine tumours (NETs) of GI or lung origin, according to clinical criteria
- everolimus - Treatment of renal angiomyolipoma (AML) associated with tuberous sclerosis complex (TSC), with specific criteria
- everolimus - Treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex for whom surgical resection cannot be considered, with specific criteria
Prescribing information: Afinitor® (everolimus). Novartis Pharmaceuticals (US), May 2016.
Product monograph: Afinitor® (everolimus). Novartis Pharmaceuticals, November 2017.
Garnock-Jones KP, Keating GM. Everolimus: in advanced renal cell carcinoma. Drugs 2009;69(15):2115-24.
Porta C, Osanto S, Ravaud A, et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer 2011;47(9):1287-98.
Summary of Product Characteristics: Afinitor® (everolimus). Novartis Europharm Limited, August 3, 2009.
June 2019 Updated emetic risk category
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.