Everolimus oral 2mg, 2.5mg, 3mg, 5mg, 10mg
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations containing 2mg, 2.5 mg, 3mg, 5 mg or 10 mg of everolimus
Different strength preparations are available for other specific uses and the separate Monographs should be consulted for further information.
Drugs List
Therapeutic Indications
Uses
Advanced renal cell carcinoma progressing on/after VEGF-targeted therapy
Hormone receptor positive, advanced breast cancer in post-menopausal women
Refractory seizures associated with tuberous sclerosis complex (TSC)
Renal angiomyolipoma associated with tuberous sclerosis complex (TSC)
Subependymal giant cell astrocytoma with tuberous sclerosis complex
Unresectable or metastatic gastrointestinal neuroendocrine tumours
Unresectable or metastatic lung neuroendocrine tumours
Unresectable or metastatic pancreatic neuroendocrine tumours
Advanced renal cell carcinoma when the disease has progressed on or after treatment with VEGF-targeted therapy.
Unresectable or metastatic, well or moderately differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease.
Unresectable or metastatic, well differentiated (grade 1 or 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin in adults with progressive disease.
Hormone receptor-positive, HER2/neu negative advanced breast cancer in post menopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor.
Renal angiomyolipoma associated with tuberous sclerosis complex (TSC) who are at risk of complications but who do not require immediate surgery.
Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require intervention but are not amenable to surgery.
Refractory seizures associated with tuberous sclerosis complex (TSC) in patients over 2 years.
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Adults
Advanced renal cell carcinoma
The recommended dose is 10 mg once daily.
Neuroendocrine tumours of pancreatic origin
The recommended dose is 10 mg once daily.
Neuroendocrine tumours of gastrointestinal tract origin
The recommended dose is 10 mg once daily.
Neuroendocrine tumours of lung origin
The recommended dose is 10 mg once daily.
Advanced hormone receptor-positive breast cancer
The recommended dose is 10 mg once daily.
Renal angiomyolipoma associated with tuberous sclerosis complex (TSC)
The recommended dose is 10 mg once daily.
Blood trough concentrations are to be considered.
Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC)
Initial dose, 4.5 mg per metre squared given once daily (manufacturer indicates that BSA is to be calculated using the Dubois formula).
Blood trough concentrations are required.
Refractory seizures associated with tuberous sclerosis complex (TSC)
Initial dose, 5 mg per metre squared unless given with CYP3A4/PgP inducer when starting dose should be increased to 8 mg per metre squared.
Blood trough concentrations are required.
Elderly
(See Dosage; Adult)
Children
Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC)
Children aged 3 to 18 years:
Initial dose, 4.5 mg per metre squared given once daily (manufacturer indicates that BSA is to be calculated using the Dubois formula).
Children aged 1 to less than 3 years:
Initial dose, 7 mg per metre squared given once daily (manufacturer indicates that BSA is to be calculated using the Dubois formula).
Blood trough concentrations are required.
Refractory seizures associated with tuberous sclerosis complex (TSC)
Children 6 years and over:
Initial dose, 5 mg per metre squared unless given with CYP3A4/PgP inducer when starting dose should be increased to 8 mg per metre squared.
Children 2 to less than 6 years:
Initial dose, 6 mg per metre squared unless given with CYP3A4/PgP inducer when starting dose should be increased to 9 mg per metre squared.
Blood trough concentrations are required.
Patients with Hepatic Impairment
Children under 18 years with hepatic impairment: Not recommended.
Advanced renal cell carcinoma, neuroendocrine tumours of pancreatic origin/gastrointestinal tract origin/lung origin, advanced hormone receptor-positive breast cancer and renal angiomyolipoma associated with tuberous sclerosis complex (TSC)
Mild hepatic impairment (Child-Pugh A): Reduce dose to 7.5 mg once daily.
Moderate hepatic impairment (Child-Pugh B): Reduce dose to 5 mg once daily.
Severe hepatic impairment (Child-Pugh C): If benefit outweighs risk, then 2.5 mg once daily must not be exceeded.
Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC), Refractory seizures associated with tuberous sclerosis complex (TSC)
Mild hepatic impairment (Child-Pugh A): Reduce dose to 75% of the recommended starting dose (rounded to the nearest strength).
Moderate hepatic impairment (Child-Pugh B): Reduce dose to 25% of the recommended starting dose (rounded to the nearest strength).
Severe hepatic impairment (Child-Pugh C): Contraindicated.
Additional Dosage Information
Switching Pharmaceutical Forms
Tablets and dispersible tablets are NOT interchangeable and must be used consistently and not combined.
If switching forms is necessary the dose of the new form should be adjusted to the closest mg of the current dose and blood trough concentrations should be assessed 1 week later.
Use with CYP3A4 Inducers
Potent: Not recommended
See individual product literature for advise on dose adjustment and washout period.
Use with CYP3A4 Inhibitors
Potent: Not recommended
See individual product literature for advise on dose adjustment and washout period.
Use with PgP inhibitors
Potent: Not recommended
See individual product literature for advise on dose adjustment and washout period.
Dose Reductions due to adverse reactions For the indications of Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) and renal angiomyolipoma associated with tuberous sclerosis complex (TSC) the manufacturer recommends a dose reduction to approximately 50% of the previous daily dose. If dose reduction requires a dose below the strength of an available licensed product for either indication then an alternate day dosing schedule can be considered.
For all other indications the recommendation is a reduction to 5 mg (but no lower than 5 mg).
Non-Infectious pneumonitis
Grade 2: Consider interruption of therapy until symptoms improve to less than or equal to grade 1. Re-initiate treatment at a lower dose. Discontinue treatment if failure to recover within 4 weeks. Grade 3: Interrupt treatment until symptoms resolve to less than or equal to grade 1. Consider re-initiating everolimus at a lower dose. If toxicity recurs at grade 3, consider discontinuation. Grade 4: Discontinue treatment. Stomatitis
Grade 2: Interrupt treatment until symptoms resolve to less than or equal to grade 1. Re-initiate treatment at same dose. If toxicity recurs at grade 2, interrupt treatment until symptoms resolve to less than or equal to grade 1 and then re-initiate treatment at a lower dose. Grade 3: Interrupt treatment until symptoms resolve to less than or equal to grade 1. Re-initiate treatment at a lower dose. Grade 4: Discontinue treatment. Other non-haematological toxicities (excluding metabolic events)
Grade 2: If toxicity is tolerable, no dose adjustment required. If toxicity becomes intolerable, temporary dose interruption until recovery to less than or equal to grade 1. Re-initiate everolimus at same dose. If toxicity recurs at grade 2, interrupt everolimus until recovery to less than or equal grade 1. Re-initiate everolimus at lower dose. Grade 3: Temporary dose interruption until recovery to less than or equal to grade 1. Consider re-initiating everolimus at a lower dose. If toxicity recurs at grade 3, consider discontinuation. Grade 4: Discontinue treatment. Metabolic events (e.g. hyperglycaemia, dyslipidaemia)
Grade 3: Temporary dose interruption. Re-initiate treatment at lower dose. Grade 4: Discontinue treatment. Thrombocytopenia
Grade 2 (platelets 50 to 75 x 10 to the power of 9 per litre): Temporary dose interruption until recovery to grade less than or equal to grade 1 (below 75 x 10 to the power of 9 per litre). Re-initiate treatment at the same dose. Grade 3 and 4 (platelets less than 50 x 10 to the power of 9 per litre): Temporary dose interruption until recovery to grade less than or equal to grade 1. Re-initiate treatment at lower dose. Neutropenia
Grade 3 (neutrophils 0.5 to 1 x 10 to the power of 9 per litre): Temporary dose interruption until recovery to less than or equal to grade 2. Re-initiate treatment at the same dose. Grade 4 (neutrophils less than 0.5 x 10 to the power of 9 per litre): Temporary dose interruption until recovery to grade less than or equal to grade 2. Re-initiate treatment at lower dose. Febrile neutropenia
Grade 3: Temporary dose interruption until recovery to less than or equal to grade 2 (neutrophils equal to or greater than 1.25 x 10 to the power of 9 per litre) and no fever. Re-initiate treatment at lower dose. Grade 4: Discontinue treatment.
Administration
For oral use.
The Votubia tablet product indicates that it may be dispersed in approximately 30 ml of water by gently stirring (taking approximately 7 minutes to disintegrate), immediately before drinking. After the solution has been swallowed, any residue must be re-dispersed in the same volume of water and swallowed.
For Votubia dispersible tablet preparation instruction see product information.
Therapeutic Drug Monitoring
Once a stable dose is attained
Trough concentrations should be monitored:
- Every 3 to 6 months in patients with changing body surface area.
- Every 6 to 12 months in patients with a stable body surface area.
Renal angiomyolipoma associated with tuberous sclerosis complex (TSC)
Blood trough concentrations are to be considered for monitoring after the initiation or change in CYP 3A4 inhibitors or inducers or change in hepatic function. Dosing should be titrated to achieve a trough concentration of 5 to 15 nanograms per ml.
Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC)
Blood trough concentrations are required to be assessed at least 1 week after the initial dose, after any change in dose or formulation, after changes in hepatic function or initiation/change in co-administration of a CYP3A4 inhibitor. Blood trough concentrations to be assessed 2 to 4 weeks after initiation change in co-administration of CYP3A4 inducers. Dosing should be titrated to achieve a trough concentration of 5 to 15 nanograms per ml.
SEGA volume should be evaluated approximately 3 months after commencing therapy, with subsequent dose adjustments taking changes in SEGA volume, corresponding trough concentration, and tolerability into consideration.
Refractory seizures associated with tuberous sclerosis complex (TSC)
Blood trough concentrations are required to be assessed at least 1 week after the initial dose, after any change in dose or formulation, after changes in hepatic function or initiation/change in co-administration of a CYP3A4 inhibitor. Blood trough concentrations to be assessed 2 to 4 weeks after initiation change in co-administration of CYP3A4 inducers. Dosing should be titrated to achieve a trough concentration of 5 to 15 nanograms per ml. Dose increases of 1 to 4 mg should be used to achieve optimal clinical response.
Treatment should continue as long as benefit is observed or until unacceptable toxicity occurs.
Contraindications
Children under 1 year
Breastfeeding
Galactosaemia
Pregnancy
Precautions and Warnings
Children under 18 years
Females of childbearing potential
Peri-operative period
Predisposition to haemorrhage
Uncontrolled systemic infection
Coagulopathy
Diabetes mellitus
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of hepatitis B
Lactose intolerance
Administration of live vaccines is not recommended
Consider anti-infective prophylaxis in immunocompromised patients
Advise ability to drive/operate machinery may be affected by side effects
Not all presentations are licensed for all indications
Treat and control infections prior to commencing therapy
Treatment to be initiated and supervised by a specialist
Contains lactose
Different oral formulations are not interchangeable (not bioequivalent)
Consult local policy on the safe use of anti-cancer drugs
Blood counts should be performed before and periodically during treatment
Monitor fasting serum glucose prior to and periodically during treatment
Monitor for proteinuria before and periodically during treatment
Monitor renal function before treatment and regularly during treatment
Consider non-infectious pneumonitis in patients with respiratory symptoms
Monitor blood urea nitrogen (BUN)
Monitor serum lipids
Trough levels recommended in some indications
Advise patient to report any new or worsening respiratory symptoms
Advise patient to report any symptoms of interstitial lung disease
Advise patient to report symptoms of infection immediately
May reduce effectiveness of vaccinations during treatment
Risk of developing opportunistic infections
Treatment may adversely affect wound healing
Consider suspending treatment if grade 2 non-infectious pneumonitis occurs
Discontinue permanently if invasive systemic fungal infection occurs
Suspend and/or reduce dose in grade 3 neutropenia with fever/infection
Suspend therapy if platelet count falls below 75,000 per cubic mm
Suspend treatment and/or reduce dose in grade 3 non-haematological toxicity
Suspend treatment if grade 2 non-haematological toxicity occurs
Suspend treatment if grade 2 or greater stomatitis occurs
Suspend treatment if grade 3 non-infectious pneumonitis occurs
Suspend treatment if grade 3 or greater haematological toxicity
Suspend treatment and reduce dose if grade 3 metabolic toxicity occurs
Not licensed for all indications in all age groups
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
May cause impaired fertility
Female: Contraception required during and for 2 months after treatment
Advise patient of risk of bleeding
Opportunistic infections including pneumocystis jirovecii/ carinii pneumonia should be ruled out as a differential diagnosis of non-infectious pneumonitis. Prophylaxis for pneumocystis jirovecii/ carinii pneumonia should be considered when concomitant use of corticosteroids or other immunosuppressive agents.
Mouth ulcers, stomatitis and oral mucositis have been reported in patients treated with everolimus. In such cases topical treatments are recommended, but alcohol, peroxide, iodine or thymol containing mouthwashes should be avoided as they may exacerbate the condition.
Patients treated for subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require intervention but are not amenable to surgery should have their SEGA volume assessed approximately every 3 months after starting treatment.
In patients with non-functional gastrointestinal or lung neuroendocrine tumours and good prognostic baseline factors, e.g. ileum as primary tumour origin and normal chromogranin A values or without bone involvement, an individual benefit risk assessment should be performed prior to the start of everolimus therapy.
Pregnancy and Lactation
Pregnancy
Everolimus is contraindicated in pregnancy.
No reports have been found at the time of writing describing the use of everolimus in human pregnancy. Severe embryo toxicities, in the absence of maternal toxicity, were observed in one animal species at exposures much lower than those occurring in humans taking the recommended dose (Briggs, 2011).
The effect of concurrent therapies must also be considered.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Everolimus is contraindicated in breastfeeding.
No reports have been found at the time of writing describing the use of everolimus in breastfeeding. The molecular weight (about 958), moderate (about 74%) plasma protein binding and long (about 30 hours) elimination half-life suggest the drug will be excreted into breast milk.
The effect of concurrent therapies must also be considered.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Side Effects
Abdominal pain
Acneform changes
Acute respiratory distress syndrome
Ageusia
Aggression
Agitation
Alopecia
Alveolitis
Amenorrhoea
Anaemia
Angioedema
Anorexia
Arthralgia
Asthenia
Blood glucose disturbances
Chest pain
Congestive cardiac failure
Conjunctivitis
Constipation
Convulsions
Cough
Decrease in haemoglobin
Decreased appetite
Deep vein thrombosis (DVT)
Dehydration
Diabetes mellitus
Diarrhoea
Dry mouth
Dry skin
Dyspepsia
Dysphagia
Dyspnoea
Electrolyte disturbances
Epistaxis
Erythema
Eyelid oedema
Fatigue
Flatulence
Flushing
Gastritis
Gingivitis
Haemoptysis
Haemorrhage
Headache
Hypercholesterolaemia
Hyperlipidaemia
Hypersensitivity reactions
Hypertension
Hypocalcaemia
Hypokalaemia
Hypophosphataemia
Impaired fertility
Increase in creatinine
Increase in lactate dehydrogenase
Increase in plasma triglyceride concentration
Increase in serum ALT/AST
Increased susceptibility to infection
Increased urinary frequency
Insomnia
Interstitial lung disease
Irritability
Leucopenia
Lymphopenia
Menstrual disturbances
Mouth ulcers
Mucosal inflammation
Nail disorders
Nausea
Neutropenia
Onycholysis
Oral pain
Ovarian cysts
Palmar-Plantar Erythrodysaesthesia syndrome
Peripheral oedema
Pneumocystis jiroveci pneumonia
Pneumonitis
Proteinuria
Pruritus
Pulmonary embolism
Pulmonary haemorrhage
Pulmonary infiltration
Pulmonary toxicity
Pyrexia
Rash
Reactivation of hepatitis B
Red cell aplasia
Renal failure
Rhabdomyolysis
Skin exfoliation
Skin lesions
Stomatitis
Taste disturbances
Thrombocytopenia
Vomiting
Weight loss
Wound healing retarded
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review: March 2017
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Joint Formulary Committee. British National Formulary. 72nd ed. London: BMJ Group and Pharmaceutical Press; 2016.
Paediatric Formulary Committee. BNF for Children 2016-2017. London: BMJ Group, Pharmaceutical Press, and RCPCH Publications; 2016.
Summary of Product Characteristics: Afinitor tablets. Novartis Pharmaceuticals UK Ltd. May 2016.
Summary of Product Characteristics: Votubia tablets. Novartis Pharmaceuticals UK Ltd. January 2017.
Summary of Product Characteristics: Votubia Dispersible tablets. Novartis Pharmaceuticals UK Ltd. January 2017.
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Everolimus. Last revised: 26 April 2016
Last accessed: 17 March 2017
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