4.1. Therapeutic indications

Renal angiomyolipoma associated with tuberous sclerosis complex (TSC)

Votubia is indicated for the treatment of adult patients with renal angiomyolipoma associated with TSC who are at risk of complications (based on factors such as tumour size or presence of aneurysm, or presence of multiple or bilateral tumours) but who do not require immediate surgery.

The evidence is based on analysis of change in sum of angiomyolipoma volume.

Subependymal giant cell astrocytoma (SEGA) associated with TSC

Votubia is indicated for the treatment of adult and paediatric patients with SEGA associated with TSC who require therapeutic intervention but are not amenable to surgery.

The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.

4.2. Posology and method of administration

Treatment with Votubia should be initiated by a physician experienced in the treatment of patients with TSC and therapeutic drug monitoring.

Posology

Renal angiomyolipoma associated with TSC

The recommended dose is 10 mg of everolimus once daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose.

SEGA associated with TSC

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 (see section 4.5).

Dosing is individualised based on Body Surface Area (BSA) using the Dubois formula, where weight (W) is in kilograms and height (H) is in centimetres:

BSA = (W0.425 x H0.725) x 0.007184

The recommended starting dose for Votubia for the treatment of patients with SEGA is 4.5 mg/m2. A higher starting dose of 7 mg/m2 is recommended for patients 1 to less than 3 years of age based on pharmacokinetic simulations (see section 5.2). Different strengths of Votubia tablets can be combined to attain the desired dose.

Everolimus whole blood trough concentrations should be assessed at least 1 week after commencing treatment. 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.

Individualised dosing should be titrated by increasing the dose by increments of 2.5 mg to attain the target trough concentration for optimal clinical response. Efficacy, safety, concomitant therapy, and the current trough concentration should be considered when planning for dose titration. Individualised dose titration can be based on simple proportion:

New everolimus dose = current dose x (target concentration / current concentration)

For example, a patient's current dose based on BSA is 2.5 mg with a steady state concentration of 4 ng/ml. In order to achieve a target concentration above the lower Cmin limit of 5 ng/ml, e.g. 8 ng/ml, the new everolimus dose would be 5 mg (an increase of 2.5 mg from the current daily dose). In cases where the revised dose is not a multiple of 2.5 mg, it should be rounded to the next available tablet strength.

Dosing recommendations for paediatric patients with SEGA are consistent with those for the adult SEGA population, except for patients in the range from 1 year to less than 3 years of age, and those with hepatic impairment (see section “Hepatic impairment” below and section 5.2).

SEGA volume should be evaluated approximately 3 months after commencing Votubia therapy, with subsequent dose adjustments taking changes in SEGA volume, corresponding trough concentration, and tolerability into consideration.

Once a stable dose is attained, trough concentrations should be monitored every 3 to 6 months in patients with changing BSA, or every 6 to 12 months in patients with stable BSA, for the duration of treatment.

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose.

Dose adjustments due to adverse reactions

Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of Votubia therapy. For adverse reactions of Grade 1, dose adjustment is usually not required. If dose reduction is required, the recommended dose is approximately 50% lower than the daily dose previously administered. For dose reductions below the lowest available strength, alternate day dosing should be considered.

Table 1 summarises dose adjustment recommendations for specific adverse reactions (see also section 4.4).

Table 1 Votubia dose adjustment recommendations

Adverse reaction

Severity1

Votubia dose adjustment

Non-infectious pneumonitis

Grade 2

Consider interruption of therapy until symptoms improve to Grade ≤1.

Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.

Discontinue treatment if failure to recover within 4 weeks.

Grade 3

Interrupt Votubia until symptoms resolve to Grade ≤1.

Consider re-initiating Votubia at approximately 50% lower than the daily dose previously administered. If toxicity recurs at Grade 3, consider discontinuation.

Grade 4

Discontinue Votubia.

Stomatitis

Grade 2

Temporary dose interruption until recovery to Grade ≤1.

Re-initiate Votubia at same dose.

If stomatitis recurs at Grade 2, interrupt dose until recovery to Grade ≤1. Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.

Grade 3

Temporary dose interruption until recovery to Grade ≤1.

Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.

Grade 4

Discontinue Votubia.

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 Grade ≤1. Re-initiate Votubia at same dose.

If toxicity recurs at Grade 2, interrupt Votubia until recovery to Grade ≤1. Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.

Grade 3

Temporary dose interruption until recovery to Grade ≤1.

Consider re-initiating Votubia at approximately 50% lower than the daily dose previously administered. If toxicity recurs at Grade 3, consider discontinuation.

Grade 4

Discontinue Votubia.

Metabolic events

(e.g. hyperglycaemia, dyslipidaemia)

Grade 2

No dose adjustment required.

Grade 3

Temporary dose interruption.

Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.

Grade 4

Discontinue Votubia.

Thrombocytopenia

Grade 2

(<75, ≥50x109/l)

Temporary dose interruption until recovery to Grade ≤1 (≥75x109/l). Re-initiate Votubia at same dose.

Grade 3 & 4

(<50x109/l)

Temporary dose interruption until recovery to Grade ≤1 (≥75x109/l). Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.

Neutropenia

Grade 2

(≥1x109/l)

No dose adjustment required.

Grade 3

(<1, ≥0.5x109/l)

Temporary dose interruption until recovery to Grade ≤2 (≥1x109/l). Re-initiate Votubia at same dose.

Grade 4

(<0.5x109/l)

Temporary dose interruption until recovery to Grade ≤2 (≥1x109/l). Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.

Febrile neutropenia

Grade 3

Temporary dose interruption until recovery to Grade ≤2 (≥1.25x109/l) and no fever.

Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.

Grade 4

Discontinue Votubia.

1 Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0

Therapeutic drug monitoring

Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is required for patients treated for SEGA. Trough concentrations should be assessed at least 1 week after the initial dose, after any change in dose or pharmaceutical form, after initiation of or change in co-administration of CYP3A4 inhibitors (see sections 4.4 and 4.5) or after any change in hepatic status (Child-Pugh) (see section “Hepatic impairment” below and section 5.2). Trough concentrations should be assessed 2 to 4 weeks after initiation of or change in co-administration of CYP3A4 inducers (see sections 4.4 and 4.5) since the natural degradation time of the induced enzymes has to be taken into account.

Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is an option to be considered for patients treated for renal angiomyolipoma associated with TSC (see section 5.1) after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see sections 4.4 and 4.5) or after any change in hepatic status (Child-Pugh) (see section “Hepatic impairment” below and section 5.2).

When possible, the same assay and laboratory for therapeutic drug monitoring should be used throughout the treatment.

Switching pharmaceutical forms

Votubia is available in two pharmaceutical forms: tablets and dispersible tablets. Votubia tablets and Votubia dispersible tablets are not to be used interchangeably. The two pharmaceutical forms must not be combined to achieve the desired dose. The same pharmaceutical form must be used consistently, as appropriate for the indication being treated.

When switching pharmaceutical forms, the dose should be adjusted to the closest milligram strength of the new pharmaceutical form and the everolimus trough concentration should be assessed at least 1 week later (see section “Therapeutic drug monitoring” above).

Special populations

Elderly

No dose adjustment is required (see section 5.2).

Renal impairment

No dose adjustment is required (see section 5.2).

Hepatic impairment

Patients with renal angiomyolipoma associated with TSC:

• 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.

• Severe hepatic impairment (Child-Pugh C): Votubia is only recommended if the desired benefit outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded (see sections 4.4 and 5.2).

Dose adjustments should be made if a patient's hepatic (Child-Pugh) status changes during treatment.

Patients with SEGA associated with TSC:

Patients <18 years of age:

Votubia is not recommended for patients <18 years of age with SEGA and hepatic impairment.

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

• Severe hepatic impairment (Child-Pugh C): Votubia 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.

Everolimus whole blood trough concentrations should be assessed at least 1 week after any change in hepatic status (Child-Pugh).

Paediatric population

The safety and efficacy of Votubia in children aged 0 to 18 years with renal angiomyolipoma associated with TSC in the absence of SEGA have not been established. No data are available.

The safety, efficacy and pharmacokinetic profile of Votubia in children below the age of 1 year with TSC who have SEGA have not been established. No data are available (see sections 5.1 and 5.2).

Clinical study results did not show an impact of Votubia on growth and pubertal development.

Method of administration

Votubia must be administered orally once daily at the same time every day, consistently either with or without food (see section 5.2). Votubia tablets are to be swallowed whole with a glass of water. The tablets must not be chewed or crushed. For patients with TSC who have SEGA and are unable to swallow tablets, Votubia tablet(s) can be dispersed completely in a glass with approximately 30 ml of water by gently stirring until the tablet(s) is(are) fully disintegrated (approximately 7 minutes), immediately prior to drinking. After the dispersion has been swallowed, any residue must be re-dispersed in the same volume of water and swallowed (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Non-infectious pneumonitis

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 (see section 4.8). 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 (see section “Infections” below). 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 Votubia 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. Votubia 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, Votubia therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Votubia 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.

Infections

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoal infections, including infections with opportunistic pathogens (see section 4.8). 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 (see section 4.8).

Physicians and patients should be aware of the increased risk of infection with Votubia. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Votubia. While taking Votubia, 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 Votubia.

If a diagnosis of invasive systemic fungal infection is made, Votubia 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

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 (see section 4.3).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5).

Stomatitis

Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported adverse reaction in patients treated with Votubia (see section 4.8). Stomatitis mostly occurs within the first 8 weeks of treatment. A single-arm study in postmenopausal breast cancer patients treated with Afinitor (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 (see section 5.1). 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 (see section 4.5).

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 Votubia, 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 Votubia (see section 4.8). Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.

Laboratory tests and monitoring

Renal function

Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients treated with Votubia (see section 4.8). 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.

Blood glucose

Hyperglycaemia has been reported in patients taking Votubia (see section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Votubia therapy and periodically thereafter. More frequent monitoring is recommended when Votubia is co-administered with other medicinal products that may induce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting a patient on Votubia.

Blood lipids

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

Haematological parameters

Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported in patients treated with Votubia (see section 4.8). Monitoring of complete blood count is recommended prior to the start of Votubia therapy and periodically thereafter.

Interactions

Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP) should be avoided. If co-administration of a moderate CYP3A4 and/or PgP inhibitor or inducer cannot be avoided, the clinical condition of the patient should be monitored closely. Monitoring of everolimus through concentrations and dose adjustments of Votubia may be required (see section 4.5).

Concomitant treatment with potent CYP3A4/PgP inhibitors result in dramatically increased blood concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Votubia and potent inhibitors is not recommended.

Caution should be exercised when Votubia is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Votubia is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine, ergot alkaloid derivatives or carbamazepine), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see section 4.5).

Hepatic impairment

Votubia is not recommended for use in patients:

• ≥18 years of age and concomitant severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk (see sections 4.2 and 5.2).

• <18 years of age with SEGA and concomitant hepatic impairment (Child-Pugh A, B and C) (see sections 4.2 and 5.2).

Vaccinations

The use of live vaccines should be avoided during treatment with Votubia (see section 4.5). For paediatric patients with SEGA who do not require immediate treatment, completion of the recommended childhood series of live virus vaccinations is advised prior to the start of therapy according to local treatment guidelines.

Wound healing complications

Impaired wound healing is a class effect of rapamycin derivatives, including Votubia. Caution should therefore be exercised with the use of Votubia in the peri-surgical period.

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Radiation therapy complications

Serious and severe radiation reactions (such as radiation oesophagitis, radiation pneumonitis and radiation skin injury), including fatal cases, have been reported when everolimus was taken during, or shortly after, radiation therapy. Caution should therefore be exercised for the potentiation of radiotherapy toxicity in patients taking everolimus in close temporal relationship with radiation therapy.

Additionally, radiation recall syndrome (RRS) has been reported in patients taking everolimus who had received radiation therapy in the past. In the event of RRS, interrupting or stopping everolimus treatment should be considered.

4.5. Interaction with other medicinal products and other forms of interaction

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.

Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are listed in Table 2 below.

CYP3A4 and PgP inhibitors increasing everolimus concentrations

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

CYP3A4 and PgP inducers decreasing everolimus 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.

Table 2 Effects of other active substances on everolimus

Active substance by interaction

Interaction – Change in Everolimus AUC/Cmax

Geometric mean ratio (observed range)

Recommendations concerning co-administration

Potent CYP3A4/PgP inhibitors

Ketoconazole

AUC ↑15.3-fold

(range 11.2-22.5)

Cmax ↑4.1-fold

(range 2.6-7.0)

Concomitant treatment of Votubia and potent inhibitors is not recommended.

Itraconazole, posaconazole, voriconazole

Not studied. Large increase in everolimus concentration is expected.

Telithromycin, clarithromycin

Nefazodone

Ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir

Moderate CYP3A4/PgP inhibitors

Erythromycin

AUC ↑4.4-fold

(range 2.0-12.6)

Cmax ↑2.0-fold

(range 0.9-3.5)

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. Due to between subject variability the recommended dose adjustments may not be optimal in all individuals, therefore close monitoring of side effects is recommended. If the moderate inhibitor is discontinued, consider a washout period of at least 2 to 3 days (average elimination time for most commonly used moderate inhibitors) before the Votubia dose is returned to the dose used prior to initiation of the co-administration (see also Therapeutic drug monitoring in section 4.2).

For patients with SEGA associated with TSC:

If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, reduce the daily dose by approximately 50%. Further dose reduction may be required to manage adverse reactions (see sections 4.2 and 4.4). Everolimus trough concentrations should be assessed at least 1 week after the addition of a moderate CYP3A4 or PgP inhibitor. If the moderate inhibitor is discontinued, consider a washout period of at least 2 to 3 days (average elimination time for most commonly used moderate inhibitors) before the Votubia dose is returned to the dose used prior to initiation of the co-administration. The everolimus trough concentration should be assessed at least 1 week later (see sections 4.2 and 4.4).

Imatinib

AUC ↑ 3.7-fold

Cmax ↑ 2.2-fold

Verapamil

AUC ↑3.5-fold

(range 2.2-6.3)

Cmax ↑2.3-fold

(range1.3-3.8)

Ciclosporin oral

AUC ↑2.7-fold

(range 1.5-4.7)

Cmax ↑1.8-fold

(range 1.3-2.6)

Cannabidiol (PgP inhibitor)

AUC ↑2.5 fold

Cmax ↑2.5 fold

Fluconazole

Not studied. Increased exposure expected.

Diltiazem

Dronedarone

Not studied. Increased exposure expected.

Amprenavir, fosamprenavir

Not studied. Increased exposure expected.

Grapefruit juice or other food affecting CYP3A4/PgP

Not studied. Increased exposure expected (the effect varies widely).

Combination should be avoided.

Potent and moderate CYP3A4 inducers

Rifampicin

AUC ↓63%

(range 0-80%)

Cmax ↓58%

(range 10-70%)

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 Votubia 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 Votubia 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 Votubia dose is returned to the dose used prior to initiation of the co-administration (see also Therapeutic drug monitoring in section 4.2).

For patients with SEGA associated with TSC:

Patients receiving concomitant potent CYP3A4 inducers may require an increased Votubia 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 Votubia 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 (see sections 4.2 and 4.4).

Dexamethasone

Not studied. Decreased exposure expected.

Antiepileptics (e.g. carbamazepine, phenobarbital, phenytoin)

Not studied. Decreased exposure expected.

Efavirenz, nevirapine

Not studied. Decreased exposure expected.

St John's Wort (Hypericum perforatum)

Not studied. Large decrease in exposure expected.

Preparations containing St John's Wort should not be used during treatment with everolimus

Agents whose plasma concentration may be altered by everolimus

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 Cmax 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 (see section 4.4).

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).

Concomitant use of ACE inhibitors

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (see section 4.4).

Vaccinations

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

Radiation treatment

Potentiation of radiation treatment toxicity has been reported in patients receiving everolimus (see sections 4.4 and 4.8).

4.6. Fertility, pregnancy and lactation

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.

Pregnancy

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 (see section 5.3). The potential risk for humans is unknown.

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

Breast-feeding

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 (see section 5.3). Therefore, women taking everolimus should not breast-feed during treatment and for 2 weeks after the last dose.

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 (see also section 5.3 for preclinical observations on the male and female reproductive systems). Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus (see section 5.3).

4.7. Effects on ability to drive and use machines

Votubia has 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 Votubia.

4.8. Undesirable effects

Summary of the safety profile

Three randomised, double-blind, placebo-controlled pivotal phase III studies, including double-blind and open label treatment periods, and a non-randomised, open-label, single-arm phase II study contribute to the safety profile of Votubia (n=612, including 409 patients <18 years of age; median duration of exposure 36.8 months [range 0.5 to 83.2]).

• EXIST-3 (CRAD001M2304): This was a randomised, double-blind, controlled, phase III trial comparing adjunctive treatment of low and high everolimus exposure (low trough [LT] range of 3-7 ng/ml [n=117] and high trough [HT] range of 9-15 ng/ml [n=130]) versus placebo (n=119), in patients with TSC and refractory partial-onset seizures receiving 1 to 3 antiepileptics. The median duration of the double-blind period was 18 weeks. The cumulative median duration exposure to Votubia (361 patients who took at least one dose of everolimus) was 30.4 months (range 0.5 to 48.8).

• EXIST-2 (CRAD001M2302): This was a randomised, double-blind, controlled, phase III trial of everolimus (n=79) versus placebo (n=39) in patients with either TSC plus renal angiomyolipoma (n=113) or sporadic lymphangioleiomyomatosis (LAM) plus renal angiomyolipoma (n=5). The median duration of blinded study treatment was 48.1 weeks (range 2 to 115) for patients receiving Votubia and 45.0 weeks (range 9 to 115) for those receiving placebo. The cumulative median duration of exposure to Votubia (112 patients who took at least one dose of everolimus) was 46.9 months (range 0.5 to 63.9).

• EXIST-1 (CRAD001M2301): This was a randomised, double-blind, controlled, phase III trial of everolimus (n=78) versus placebo (n=39) in patients with TSC who have SEGA, irrespective of age. The median duration of blinded study treatment was 52.2 weeks (range 24 to 89) for patients receiving Votubia and 46.6 weeks (range 14 to 88) for those receiving placebo. The cumulative median duration of exposure to Votubia (111 patients who took at least one dose of everolimus) was 47.1 months (range 1.9 to 58.3).

• CRAD001C2485: This was a prospective, open-label, single-arm phase II study of everolimus in patients with SEGA (n=28). The median duration of exposure was 67.8 months (range 4.7 to 83.2).

The adverse events considered to be associated with the use of Votubia (adverse reactions), based upon the review and medical assessment of all adverse events reported in the above studies, are described below.

The most frequent adverse reactions (incidence ≥1/10) from the pooled safety data are (in decreasing order): stomatitis, pyrexia, nasopharyngitis, diarrhoea, upper respiratory tract infection, vomiting, cough, rash, headache, amenorrhoea, acne, pneumonia, urinary tract infection, sinusitis, menstruation irregular, pharyngitis, decreased appetite, fatigue, hypercholesterolaemia, and hypertension.

The most frequent grade 3-4 adverse reactions (incidence ≥1%) were pneumonia, stomatitis, amenorrhoea, neutropenia, pyrexia, menstruation irregular, hypophosphataemia, diarrhoea, and cellulitis. The grades follow CTCAE Version 3.0 and 4.03.

Tabulated list of adverse reactions

Table 3 shows the incidence of adverse reactions based on pooled data of patients receiving everolimus in the three TSC studies (including both the double-blind and open-label extension phase, where applicable). Adverse reactions are listed according to MedDRA system organ class. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3 Adverse reactions reported in TSC studies

Infections and infestations

Very common

Nasopharyngitis, upper respiratory tract infection, pneumonia a, urinary tract infection, sinusitis, pharyngitis

Common

Otitis media, cellulitis, pharyngitis streptococcal, gastroenteritis viral, gingivitis

Uncommon

Herpes zoster, sepsis, bronchitis viral

Blood and lymphatic system disorders

Common

Anaemia, neutropenia, leucopenia, thrombocytopenia, lymphopenia

Immune system disorders

Common

Hypersensitivity

Metabolism and nutrition disorders

Very common

Decreased appetite, hypercholesterolaemia

Common

Hypertriglyceridaemia, hyperlipidaemia, hypophosphataemia, hyperglycaemia

Psychiatric disorders

Common

Insomnia, aggression, irritability

Nervous system disorders

Very common

Headache

Uncommon

Dysgeusia

Vascular disorders

Very common

Hypertension

Common

Lymphoedema

Respiratory, thoracic and mediastinal disorders

Very common

Cough

Common

Epistaxis, pneumonitis

Gastrointestinal disorders

Very common

Stomatitis b, diarrhoea, vomiting

Common

Constipation, nausea, abdominal pain, flatulence, oral pain, gastritis

Skin and subcutaneous tissue disorders

Very common

Rash c, acne

Common

Dry skin, acneiform dermatitis, pruritus, alopecia

Uncommon

Angioedema

Musculoskeletal and connective tissue disorders

Uncommon

Rhabdomyolysis

Renal and urinary disorders

Common

Proteinuria

Reproductive system and breast disorders

Very common

Amenorrhoea d, menstruation irregular d

Common

Menorrhagia, ovarian cyst, vaginal haemorrhage

Uncommon

Menstruation delayed d

General disorders and administration site conditions

Very common

Pyrexia, fatigue

Investigations

Common

Blood lactate dehydrogenase increased, blood luteinising hormone increased, weight decreased

Uncommon

Blood follicle stimulating hormone increased

Injury, poisoning and procedural complications

Not knowne

Radiation recall syndrome, potentiation of radiation reaction

a Includes pneumocystis jirovecii (carinii) pneumonia (PJP, PCP)

b Includes (very common) stomatitis, mouth ulceration, aphthous ulcer; (common) tongue ulceration, lip ulceration and (uncommon) gingival pain, glossitis

c Includes (very common) rash; (common) rash erythematous, erythema and (uncommon) rash generalised, rash maculo-papular, rash macular

d Frequency based upon number of women from 10 to 55 years of age while on treatment in the pooled data

e Adverse reaction identified in the post-marketing setting.

Description of selected adverse reactions

In clinical studies, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an expected reaction during periods of immunosuppression.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome), proteinuria and increased serum creatinine. Monitoring of renal function is recommended (see section 4.4).

In clinical studies, everolimus has been associated with haemorrhage events. On rare occasions, fatal outcomes were observed in the oncology setting (see section 4.4). No serious cases of renal haemorrhage were reported in the TSC setting.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome (see section 4.4).

Additional adverse reactions of relevance observed in oncology clinical studies and post-marketing spontaneous reports, were cardiac failure, pulmonary embolism, deep vein thrombosis, impaired wound healing and hyperglycaemia.

In clinical studies and post-marketing spontaneous reports, angioedema has been reported with and without concomitant use of ACE inhibitors (see section 4.4).

Paediatric population

In the pivotal phase II study, 22 of the 28 SEGA patients studied were below the age of 18 years and in the pivotal phase III study, 101 of the 117 SEGA patients studied were below the age of 18 years. In the pivotal phase III study in patients with TSC and refractory seizures, 299 of the 366 patients studied were below the age of 18 years. The overall type, frequency and severity of adverse reactions observed in children and adolescents have been generally consistent with those observed in adults, with the exception of infections which were reported at a higher frequency and severity in children below the age of 6 years. A total of 49 out of 137 patients (36%) aged <6 years had Grade 3/4 infections, compared to 53 out of 272 patients (19%) aged 6 to <18 years and 27 out of 203 patients (13%) aged ≥18 years. Two fatal cases due to infection were reported in 409 patients aged <18 years receiving everolimus.

Elderly

In the oncology safety pooling, 37% of the patients treated with everolimus were ≥65 years of age. The number of oncology patients with an adverse reaction leading to discontinuation of everolimus was higher in patients ≥65 years of age (20% versus 13%). The most common adverse reactions leading to discontinuation were pneumonitis (including interstitial lung disease), fatigue, dyspnoea, and stomatitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been given with acceptable acute tolerability in the adult population.

It is essential to assess everolimus blood levels in cases of suspected overdose. General supportive measures should be initiated in all cases of overdose. Everolimus is not considered dialysable to any relevant degree (less than 10% was removed within 6 hours of haemodialysis).

Paediatric population

A limited number of paediatric patients have been exposed to doses higher than 10 mg/m2/day. No signs of acute toxicity have been reported in these cases.