Systemic Therapy Program
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Cancer Type

Document Type

Drug Monographs
Treatment Regimens
Scientific Name:
EVEROLIMUS
Brand Name(s):
Afinitor®

Drug Monograph

Pharmacology

Mechanism of Action

Everolimus is an mTORC1 inhibitor (mTOR complex 1 is the target of rapamycin).  When mTOR is inhibited, phosphorylation of p70S6k and S6 ribosomal protein are reduced, blocking downstream the P13 kinase/AKT pathway for nkey protein synthesis.  Everolimus has been shown to reduce cell proliferation, glycolysis and angiogenesis in solid tumours in vivo. It also possesses immunosuppressive activity.

Pharmacokinetics

Absorption:
 11% Peak concentrations in 1-2 hours
Steady state within 2 weeks with daily dosing.
Cmax and exposure are proportional to doses ranging from 5 to 10 mg daily.
High-fat meals reduce everolimus exposure and Cmax
Increased everolimus exposure was observed in Japanese patients
Distribution:
20% in plasma; no information on tissue distribution
PPB ~74%
cross blood brain barrier? Yes
Metabolism:
Metabolism by CYP450 3A4, and in the gut wall. Substrate of CYP3A4 and P-glycoprotein
metabolite(s): active- No; inactive- Yes
Excretion:
Primarily eliminated via feces and biliary excretion (85%) and 5% in urine, as metabolites.
Cl = 15 L/h; Black patients have higher clearance than Caucasian patients
t½  = 30 hours

Side Effects

EARLY ONSET  (days to weeks)
* lymphopenia (53%); infections (37%; Grade 3 or 4 10%)
   anemia (92%), thrombocytopenia (23%), neutropenia (14%)
   stomatitis (44%), diarrhea (30%), abdominal pain (9%), dry mouth (8%), dysphagia (4%)
* cough (30%), dyspnea (24%), pneumonitis (14%), fatal acute respiratory failure; pleural effusion  (7%)
   fatigue (31%), aesthenia (33%), dzziness (7%), paresthesia (5%)
   peripheral edema (25%)
   nausea (26%) and vomiting (20%)
   skin rash (29%), pruritis (14%), dry skin (13%); hand-foot syndrome (5%)
   insomnia (9%)
   hypertension (4%); tachycardia (3%), congestive cardiac failure (1%)
   jaw pain (3%)
* acute renal failure (3%)
* hemorrhage (3%)
   weight decreased (9%)
   impaired wound healing (<1%)
   Abnormal lab results: increased cholesterol (77%), increased triglycerides (73%), increased glucose (57%), increased creatinine (50%), increased liver enzymes (AST, ALT)

Therapeutics

Approved Indications

Advanced renal cell carcinoma (clear cell morphology), after failure of initial treatment with either of sunitinib or sorafenib.

Routes

Oral

Administration

• Take dose at the same time each day, preferably in the morning.
• Take everolimus on an empty stomach or after a light fat-free meal.
• Avoid grapefruit or grapefruit products.
• Swallow whole with a glass of water; do not crush or chew.
• Store in original package at room temperature; protect from light.

Dosing

10 mg PO daily

Dose Adjustment Criteria

Adverse Drug Reactions:
Reduce to 50% dose (5 mg po daily) 
Hepatic Impairment:
If moderate impairment, reduce to 50% dose (5 mg po daily)
If severe impairment, STOP treatment

Antiemetic Risk

INTERMEDIATE RISK (10-30% of patients)
• Use a  dopamine receptor antagonist PRN post-chemotherapy

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets and hemoglobin (CBC) before each treatment
• Monitor for signs of infection
• Monitor glucose and lipid profiles
• Monitor for symptoms or radiographic changes of pneumonitis and lung disease 

SUGGESTED CRITERIA
None

Significant Interactions

• Drugs that may increase everolimus plasma concentrations: CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin): consider dose reduction of everolimus to 5 mg if co-administered with a strong CYP3A4 inhibitor • Drugs that may decrease everolimus plasma concentrations: Strong CYP3A4 Inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John’s Wort): consider dose increase of everolimus to 50 mg if co-administered with a strong CYP3A4 inducer. *Avoid live vaccines and close contact with people who receive them (BCG, varicella, yellow fever, typhoid, mumps, measles, and rubella). • Anticoagulants (Anisindione, Ardeparin, Dalteparin, Dicoumarol, Enoxaparin, Heparin, Tinzaparin, Warfarin) - may increase risk of bleeding from Everolimus • Bisphosphonate agents (Alendronate, Etidronate, Ibandronate, Pamidronate, Risedronate, Zoledronic Acid)- may increase risk of osteonecrosis of the jaw from bisphosphonates • CYP 3A4 inducer medications (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John’s Wort): consider dose increase of Everolimus if co-administered with a strong CYP3A4 inducer (may decrease Everolimus plasma concentrations) • CYP 3A4 inhibitor medications (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin): consider dose reduction of Everolimus if co-administered with a strong CYP3A4 inhibitor (may increase Everolimus plasma concentrations) • Dabigatran- Increased levels of Dabigatrin in the blood • Denosumab- Increased risk of serious infections • Echinacea- Reduced Everolimus levels • Grapefruit or grapefruit juice- Increased Everolimus blood levels • Hepatotoxic drugs (Black Cohosh, Clofarabine, Interferon beta-1a, Interferon beta-1b, Leflunomide, Methotrexate, Naltrexone, Teriflunomide) - Increased risk of hepatotoxicity • PR prolongation- medications that cause a change in the heart rhythm • QT prolongation- medications that cause a change in the heart rhythm • Silodosin- Increased silodosin blood levels • Statins- Everolimus may inhibit metabolism, increased blood levels and higher risk of developing rhabdomylosis. • Sunitinib- concomitant use with is associated with dose-limiting toxicities (erythematous macropapular rash, gout, cellulitis) • Tacrolimus ointment- Increased risk of serious infections, lymphoma and skin cancers

Product Information

Commercial Product Description

Tablets with 2.5 mg, 5 mg, and 10 mg of Everolimus.

Pharmaceutical Considerations

Tablets:
tablets contain 2.5 mg, 5 mg and 10 mg of everolimus together with butylated hydroxytoluene, magnesium stearate, lactose monohydrate, hypromellose, crospovidone and lactose anhydrous as inactive ingredients
2.5 mg tablet- White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other.
5 mg tablet- White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other.
10 mg tablet- White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other.
Store at room temperature (20-25oC). 
Store in the original container, protect from light and moisture. Keep out of the reach of children.

Handling Risk Level

Pregnancy DKNOWN HAZARDOUS DRUG
FDA Pregnancy Risk Factor D

  • This drug must be handled using precuations outlined in CCNS Policies for Occupational Safety and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:

HAZARD RISK LEVEL 2
FDA Pregnancy Risk Factor D
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy and the CCNS Standard for Oral Systemic Therapy for Cancer
• Go to "Additional Information" tab (above) for links to CCNS Policies

GUIDELINES:

Treatment of Renal Cell Carcinoma
As a single agent for metastatic RCC patients with documented clear cell histology who have a Karnofsky performance status of 70% or higher after progression or intolerance to the multi-targeted tyrosine kinase inhibitors (TKIs), sunitinib and/or sorafenib

Pancreatic Neuroendocrine Tumours
pCODR Recommendation:  Patients with progressive, unresectable, well- or moderately differentiated, locally advanced or metastatic pancreatic neuroendocrine tumours with WHO performance status < 2.  August 30, 2012

Advanced Breast Cancer
pCODR Recommendation:  For the treatment of patients with hormone-receptor positive, HER2 negative advanced breast cancer, in postmenopausal women with ECOG performance  status < 2 after recurrence or progression following a non-steroidal aromatase inhibitor, if the treating oncologist would consider exemestane in combination with everolimus.  March 25, 2013

Neuroendocrine tumors (NET) of Gastrointestinal or Lung origin
pCODR Recommendations:  Under review as at 30 May 2016

Visit the Pan-Canadian Oncology Drug Review website (www.pcodr.ca) for the guidelines on Everolimus for pancreatic neuroendocrine tumours, advanced breast cancer.
• Go to "Additional Information" tab (above) for links to pCODR Reviews

Serious Warnings
Non-infectious pneumonitis: Monitor for clinical symptoms or radiological changes; fatal cases have occurred. Manage by dose reduction or discontinuation until symptoms resolve, and consider use of corticosteroids.

Visit the Nova Scotia Department of Health website (www.gov.ns.ca/health/cancer_drugs/) for the guideline on Everolimus for renal cell carcinoma
• Go to "Additional Information" tab (above) for links to DHW Cancer Drug Guidelines

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Oral- Take Home Prescription • Go to "Additional Information" tab (above) for the Provincial Formulary of Cancer Drugs • Pharmacare Formulary Status- Non-Formulary • NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety.

New Cancer Drug Fund Status (Nova Scotia)

Pharmacare funding approved for: • Treatment of renal cell cancer (when funding available)