VOTUBIA 2.5mg tablets medication leaflet

Votubia 2.5 mg tablets

Votubia 5 mg tablets

Votubia 10 mg tablets

Votubia 2.5 mg tablets

Each tablet contains 2.5 mg everolimus.

Each tablet contains 74 mg lactose.

Votubia 5 mg tablets

Each tablet contains 5 mg everolimus.

Each tablet contains 149 mg lactose.

Votubia 10 mg tablets

Each tablet contains 10 mg everolimus.

Each tablet contains 297 mg lactose.

For the full list of excipients, see section 6.1.

Tablet.

Votubia 2.5 mg tablets

White to slightly yellow, elongated tablets of approximately 10.1 mm in length and 4.1 mm in width,with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other.

Votubia 5 mg tablets

White to slightly yellow, elongated tablets of approximately 12.1 mm in length and 4.9 mm in width,with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other.

Votubia 10 mg tablets

White to slightly yellow, elongated tablets of approximately 15.1 mm in length and 6.0 mm in width,with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other.

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 TSCwho require therapeutic intervention but are not amenable to surgery.

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

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

Renal angiomyolipoma associated with TSC

The recommended dose is 10 mg of everolimus once daily. Treatment should continue as long asclinical 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 nextdose.

SEGA associated with TSC

Careful titration may be required to obtain the optimal therapeutic effect. Doses that will be toleratedand effective vary between patients. Concomitant antiepileptic therapy may affect the metabolism ofeverolimus 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. Ahigher starting dose of 7 mg/m2 is recommended for patients 1 to less than 3 years of age based onpharmacokinetic simulations (see section 5.2). Different strengths of Votubia tablets can be combinedto attain the desired dose.

Everolimus whole blood trough concentrations should be assessed at least 1 week after commencingtreatment. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. The dose may beincreased 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 thetarget trough concentration for optimal clinical response. Efficacy, safety, concomitant therapy, andthe current trough concentration should be considered when planning for dose titration. Individualiseddose 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 of4 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 caseswhere the revised dose is not a multiple of 2.5 mg, it should be rounded to the next available tabletstrength.

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 thosewith hepatic impairment (see section “Hepatic impairment” below and section 5.2).

SEGA volume should be evaluated approximately 3 months after commencing Votubia therapy, withsubsequent 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 inpatients with changing BSA, or every 6 to 12 months in patients with stable BSA, for the duration oftreatment.

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 nextdose.

Dose adjustments due to adverse reactions

Management of severe and/or intolerable suspected adverse reactions may require dose reductionand/or temporary interruption of Votubia therapy. For adverse reactions of Grade 1, dose adjustment isusually not required. If dose reduction is required, the recommended dose is approximately 50% lowerthan 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 alsosection 4.4).

Table 1 Votubia dose adjustment recommendations

Adverse reaction Severity1 Votubia dose adjustment

Non-infectious Grade 2 Consider interruption of therapy until symptoms improve topneumonitis Grade 1.

Re-initiate Votubia at approximately 50% lower than thedaily 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% lowerthan the daily dose previously administered. If toxicityrecurs 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 recoveryto 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 thedaily dose previously administered.

Grade 4 Discontinue Votubia.

Other Grade 2 If toxicity is tolerable, no dose adjustment required.

non-haematological If toxicity becomes intolerable, temporary dose interruptiontoxicities until recovery to Grade 1. Re-initiate Votubia at same dose.(excluding metabolic If toxicity recurs at Grade 2, interrupt Votubia until recoveryevents) 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% lowerthan the daily dose previously administered. If toxicityrecurs at Grade 3, consider discontinuation.

Grade 4 Discontinue Votubia.

Metabolic events Grade 2 No dose adjustment required.

(e.g.

hyperglycaemia,dyslipidaemia)

Grade 3 Temporary dose interruption.

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

Grade 4 Discontinue Votubia.

Thrombocytopenia Grade 2 Temporary dose interruption until recovery to Grade 1(<75, ≥50x109/l) (≥75x109/l). Re-initiate Votubia at same dose.

Grade 3 & 4 Temporary dose interruption until recovery to Grade 1(<50x109/l) (≥75x109/l). Re-initiate Votubia at approximately 50% lowerthan the daily dose previously administered.

Neutropenia Grade 2 No dose adjustment required.

(≥1x109/l)

Grade 3 Temporary dose interruption until recovery to Grade 2(<1, ≥0.5x109/l) (≥1x109/l). Re-initiate Votubia at same dose.

Grade 4 Temporary dose interruption until recovery to Grade 2(<0.5x109/l) (≥1x109/l). Re-initiate Votubia at approximately 50% lowerthan 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 thedaily 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 requiredfor patients treated for SEGA. Trough concentrations should be assessed at least 1 week after theinitial dose, after any change in dose or pharmaceutical form, after initiation of or change inco-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 shouldbe assessed 2 to 4 weeks after initiation of or change in co-administration of CYP3A4 inducers (seesections 4.4 and 4.5) since the natural degradation time of the induced enzymes has to be taken intoaccount.

Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is an optionto 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 4.4and 4.5) or after any change in hepatic status (Child-Pugh) (see section “Hepatic impairment” belowand section 5.2).

When possible, the same assay and laboratory for therapeutic drug monitoring should be usedthroughout 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 notbe combined to achieve the desired dose. The same pharmaceutical form must be used consistently, asappropriate for the indication being treated.

When switching pharmaceutical forms, the dose should be adjusted to the closest milligram strength ofthe new pharmaceutical form and the everolimus trough concentration should be assessed at least1 week later (see section “Therapeutic drug monitoring” above).

No dose adjustment is required (see section 5.2).

No dose adjustment is required (see section 5.2).

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 benefitoutweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded (see sections 4.4and 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 calculatedbased on BSA (rounded to the nearest strength)

* Moderate hepatic impairment (Child-Pugh B): 50% of the recommended starting dosecalculated based on BSA (rounded to the nearest strength)

* Severe hepatic impairment (Child-Pugh C): Votubia is only recommended if the desired benefitoutweighs the risk. In this case, 25% of the dose calculated based on BSA (rounded to thenearest strength) must not be exceeded.

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

The safety and efficacy of Votubia in children aged 0 to 18 years with renal angiomyolipomaassociated 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.

Votubia must be administered orally once daily at the same time every day, consistently either with orwithout food (see section 5.2). Votubia tablets are to be swallowed whole with a glass of water. Thetablets must not be chewed or crushed. For patients with TSC who have SEGA and are unable toswallow tablets, Votubia tablet(s) can be dispersed completely in a glass with approximately 30 ml ofwater 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 bere-dispersed in the same volume of water and swallowed (see section 5.2).

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

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 inpatients taking everolimus in the advanced renal cell carcinoma (RCC) setting (see section 4.8). Somecases were severe and on rare occasions, a fatal outcome was observed. A diagnosis of non-infectiouspneumonitis should be considered in patients presenting with non-specific respiratory signs andsymptoms such as hypoxia, pleural effusion, cough or dyspnoea, and in whom infectious, neoplasticand other non-medicinal causes have been excluded by means of appropriate investigations.

Opportunistic infections such as pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) should beruled 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 orno 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 ofcorticosteroids may be indicated. Votubia may be reinitiated at a daily dose approximately 50% lowerthan the dose previously administered.

For cases where symptoms of non-infectious pneumonitis are severe, Votubia therapy should bediscontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Votubiamay be reinitiated at a daily dose approximately 50% lower than the dose previously administereddepending 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.

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viralor protozoal infections, including infections with opportunistic pathogens (see section 4.8). Localisedand systemic infections, including pneumonia, other bacterial infections, invasive fungal infectionssuch as aspergillosis, candidiasis or pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) and viralinfections including reactivation of hepatitis B virus, have been described in patients takingeverolimus. 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-existinginfections should be treated appropriately and should have resolved fully before starting treatmentwith Votubia. While taking Votubia, be vigilant for symptoms and signs of infection; if a diagnosis ofinfection is made, institute appropriate treatment promptly and consider interruption or discontinuationof Votubia.

If a diagnosis of invasive systemic fungal infection is made, Votubia treatment should be promptly andpermanently discontinued and the patient treated with appropriate antifungal therapy.

Cases of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome, have beenreported in patients who received everolimus. PJP/PCP may be associated with concomitant use ofcorticosteroids or other immunosuppressive agents. Prophylaxis for PJP/PCP should be consideredwhen concomitant use of corticosteroids or other immunosuppressive agents are required.

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 withoutrespiratory 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 forangioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (seesection 4.5).

Stomatitis

Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported adversereaction in patients treated with Votubia (see section 4.8). Stomatitis mostly occurs within the first8 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 andseverity 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 oralsolution as a mouthwash. However products containing alcohol, hydrogen peroxide, iodine and thymederivatives should be avoided as they may exacerbate the condition. Monitoring for and treatment offungal infection is recommended, especially in patients being treated with steroid-based medicinalproducts. Antifungal agents should not be used unless fungal infection has been diagnosed (seesection 4.5).

Serious cases of haemorrhage, some with a fatal outcome, have been reported in patients treated witheverolimus in the oncology setting. No serious cases of renal haemorrhage were reported in the TSCsetting.

Caution is advised in patients taking Votubia, particularly during concomitant use with activesubstances known to affect platelet function or that can increase the risk of haemorrhage as well as inpatients with a history of bleeding disorders. Healthcare professionals and patients should be vigilantfor signs and symptoms of bleeding throughout the treatment period, especially if risk factors forhaemorrhage are combined.

Renal failure events

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed inpatients treated with Votubia (see section 4.8). Renal function of patients should be monitoredparticularly where patients have additional risk factors that may further impair renal function.

Laboratory tests and monitoring

Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients treatedwith Votubia (see section 4.8). Monitoring of renal function, including measurement of blood ureanitrogen (BUN), urinary protein or serum creatinine, is recommended prior to the start of Votubiatherapy and periodically thereafter.

Blood glucose

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

Blood lipids

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

Haematological parameters

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

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 PgPinhibitor or inducer cannot be avoided, the clinical condition of the patient should be monitoredclosely. Monitoring of everolimus through concentrations and dose adjustments of Votubia may berequired (see section 4.5).

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

Caution should be exercised when Votubia is taken in combination with orally administered CYP3A4substrates with a narrow therapeutic index due to the potential for drug interactions. If Votubia istaken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide,terfenadine, astemizole, cisapride, quinidine, ergot alkaloid derivatives or carbamazepine), the patientshould be monitored for undesirable effects described in the product information of the orallyadministered CYP3A4 substrate (see section 4.5).

Votubia is not recommended for use in patients:

* ≥18 years of age and concomitant severe hepatic impairment (Child-Pugh C) unless thepotential 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).

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

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

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

Radiation therapy complications

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

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

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 inhibitorof CYP2D6.

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

CYP3A4 and PgP inhibitors increasing everolimus concentrations

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

Table 2 Effects of other active substances on everolimus

Active substance by Interaction - Change in Recommendations concerninginteraction Everolimus AUC/Cmax co-administration

Geometric mean ratio(observed range)

Potent CYP3A4/PgP inhibitors

Ketoconazole AUC ↑15.3-fold Concomitant treatment of Votubia(range 11.2-22.5) and potent inhibitors is not

Cmax ↑4.1-fold recommended.

(range 2.6-7.0)

Itraconazole, posaconazole, Not studied. Large increase invoriconazole everolimus concentration is

Telithromycin, expected.

clarithromycin

Nefazodone

Ritonavir, atazanavir,saquinavir, darunavir,indinavir, nelfinavir

Moderate CYP3A4/PgP inhibitors

Erythromycin AUC ↑4.4-fold Use caution when co-administration(range 2.0-12.6) of moderate CYP3A4 inhibitors or

Cmax ↑2.0-fold PgP inhibitors cannot be avoided.

(range 0.9-3.5)

Imatinib AUC ↑ 3.7-fold For patients with renal

Cmax ↑ 2.2-fold angiomyolipoma associated with

Verapamil AUC ↑3.5-fold TSC:

(range 2.2-6.3) If patients require co-administration

Cmax ↑2.3-fold of a moderate CYP3A4 or PgP(range1.3-3.8) inhibitor, dose reduction to 5 mg or

Ciclosporin oral AUC ↑2.7-fold 2.5 mg daily may be considered.

(range 1.5-4.7) However, there are no clinical data

Cmax ↑1.8-fold with this dose adjustment. Due to(range 1.3-2.6) between subject variability the

Cannabidiol (PgP inhibitor) AUC ↑2.5-fold recommended dose adjustments may

C ↑2.5-fold not be optimal in all individuals,max

Fluconazole Not studied. Increased exposure therefore close monitoring of side

Diltiazem expected. effects is recommended. If the

Dronedarone Not studied. Increased exposure moderate inhibitor is discontinued,expected. consider a washout period of at least

Amprenavir, fosamprenavir Not studied. Increased exposure 2 to 3 days (average elimination timeexpected. for most commonly used moderateinhibitors) before the Votubia dose isreturned to the dose used prior toinitiation of the co-administration(see also Therapeutic drugmonitoring in section 4.2).

For patients with SEGA associatedwith TSC:

If patients require co-administrationof a moderate CYP3A4 or PgPinhibitor, reduce the daily dose byapproximately 50%. Further dosereduction may be required to manageadverse reactions (see sections 4.2and 4.4). Everolimus troughconcentrations should be assessed atleast 1 week after the addition of amoderate CYP3A4 or PgP inhibitor.

If the moderate inhibitor isdiscontinued, consider a washoutperiod of at least 2 to 3 days(average elimination time for mostcommonly used moderate inhibitors)before the Votubia dose is returnedto the dose used prior to initiation ofthe co-administration. Theeverolimus trough concentrationshould be assessed at least 1 weeklater (see sections 4.2 and 4.4).

Grapefruit juice or other Not studied. Increased exposure Combination should be avoided.

food affecting CYP3A4/PgP expected (the effect varieswidely).

Potent and moderate CYP3A4 inducers

Rifampicin AUC ↓63% Avoid the use of concomitant potent(range 0-80%) CYP3A4 inducers.

Cmax ↓58%(range 10-70%) For patients with renal

Dexamethasone Not studied. Decreased angiomyolipoma associated withexposure expected. TSC:

Antiepileptics (e.g. Not studied. Decreased If patients require co-administrationcarbamazepine, exposure expected. of a potent CYP3A4 inducer, aphenobarbital, phenytoin) Votubia dose increase from 10 mg

Efavirenz, nevirapine Not studied. Decreased daily up to 20 mg daily should beexposure expected. considered using 5 mg increments orless applied on Day 4 and 8following start of the inducer. Thisdose of Votubia is predicted to adjustthe AUC to the range observedwithout inducers. However, there areno clinical data with this doseadjustment. If treatment with theinducer is discontinued, consider awashout period of at least 3 to 5 days(reasonable time for significantenzyme de-induction) before the

Votubia dose is returned to the doseused prior to initiation of theco-administration (see also

Therapeutic drug monitoring insection 4.2).

For patients with SEGA associatedwith TSC:

Patients receiving concomitantpotent CYP3A4 inducers mayrequire an increased Votubia dose toachieve the same exposure aspatients not taking potent inducers.

Dosing should be titrated to attaintrough concentrations of 5 to15 ng/ml. If concentrations arebelow 5 ng/ml, the daily dose maybe increased by 2.5 mg every2 weeks, checking the trough leveland assessing tolerability beforeincreasing the dose.

The addition of another concomitantstrong CYP3A4 inducer may notrequire additional dose adjustment.

Assess the everolimus trough level2 weeks after initiating the additionalinducer. Adjust the dose byincrements of 2.5 mg as necessary tomaintain the target troughconcentration.

Discontinuation of one of multiplestrong CYP3A4 inducers may notrequire additional dose adjustment.

Assess the everolimus trough level2 weeks after discontinuation of oneof multiple strong CYP3A4inducers. If all potent inducers arediscontinued, consider a washoutperiod of at least 3 to 5 days(reasonable time for significantenzyme de-induction) before the

Votubia dose is returned to the doseused prior to initiation of theco-administration. The everolimustrough concentrations should beassessed 2 to 4 weeks later since thenatural degradation time of theinduced enzymes has to be taken intoaccount (see sections 4.2 and 4.4).

St John’s Wort (Hypericum Not studied. Large decrease in Preparations containing St John’sperforatum) exposure expected. Wort should not be used duringtreatment 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 makeinhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in thegut cannot be excluded. An interaction study in healthy subjects demonstrated that co-administrationof 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 dueto inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability oforally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure ofsystemically administered CYP3A4 substrates is not expected (see section 4.4).

In EXIST-3 (Study CRAD001M2304), everolimus increased pre-dose concentrations of theantiepileptics carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about10%. The increase in the pre-dose concentrations of these antiepileptics may not be clinicallysignificant 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 aresubstrates 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 forangioedema (see section 4.4).

The immune response to vaccination may be affected and, therefore, vaccination may be less effectiveduring 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 (seesections 4.4 and 4.8).

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-basedcontraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device[IUD], and/or female/male sterilisation) while receiving everolimus, and for up to 8 weeks afterending treatment.

Male patients should not be prohibited from attempting to father children.

There are no adequate data from the use of everolimus in pregnant women. Studies in animals haveshown reproductive toxicity effects including embryotoxicity and foetotoxicity (see section 5.3). Thepotential risk for humans is unknown.

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

It is not known whether everolimus is excreted in human breast milk. However, in rats, everolimusand/or its metabolites readily pass into the milk (see section 5.3). Therefore, women taking everolimusshould not breast-feed during treatment and for 2 weeks after the last dose.

The potential for everolimus to cause infertility in male and female patients is unknown, howeversecondary 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 onthe male and female reproductive systems). Based on non-clinical findings, male and female fertilitymay be compromised by treatment with everolimus (see section 5.3).

Votubia has minor or moderate influence on the ability to drive and use machines. Patients should beadvised to be cautious when driving or using machines if they experience fatigue during treatmentwith Votubia.

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

* EXIST-3 (CRAD001M2304): This was a randomised, double-blind, controlled, phase III trialcomparing adjunctive treatment of low and high everolimus exposure (low trough [LT] range of3-7 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. Themedian duration of the double-blind period was 18 weeks. The cumulative median durationexposure 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 ofeverolimus (n=79) versus placebo (n=39) in patients with either TSC plus renalangiomyolipoma (n=113) or sporadic lymphangioleiomyomatosis (LAM) plus renalangiomyolipoma (n=5). The median duration of blinded study treatment was 48.1 weeks (range2 to 115) for patients receiving Votubia and 45.0 weeks (range 9 to 115) for those receivingplacebo. The cumulative median duration of exposure to Votubia (112 patients who took at leastone 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 ofeverolimus (n=78) versus placebo (n=39) in patients with TSC who have SEGA, irrespective ofage. The median duration of blinded study treatment was 52.2 weeks (range 24 to 89) forpatients receiving Votubia and 46.6 weeks (range 14 to 88) for those receiving placebo. Thecumulative median duration of exposure to Votubia (111 patients who took at least one dose ofeverolimus) was 47.1 months (range 1.9 to 58.3).

* CRAD001C2485: This was a prospective, open-label, single-arm phase II study of everolimusin patients with SEGA (n=28). The median duration of exposure was 67.8 months (range 4.7 to83.2).

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

The most frequent adverse reactions (incidence ≥1/10) from the pooled safety data are (in decreasingorder): stomatitis, pyrexia, nasopharyngitis, diarrhoea, upper respiratory tract infection, vomiting,cough, rash, headache, amenorrhoea, acne, pneumonia, urinary tract infection, sinusitis, menstruationirregular, 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, andcellulitis. The grades follow CTCAE Version 3.0 and 4.03.

Table 3 shows the incidence of adverse reactions based on pooled data of patients receivingeverolimus 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. Frequencycategories 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); notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 3 Adverse reactions reported in TSC studies

Very common Nasopharyngitis, upper respiratory tract infection, pneumonia a, urinary tractinfection, sinusitis, pharyngitis

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

Uncommon Herpes zoster, sepsis, bronchitis viral

Common Anaemia, neutropenia, leucopenia, thrombocytopenia, lymphopenia

Common Hypersensitivity

Very common Decreased appetite, hypercholesterolaemia

Common Hypertriglyceridaemia, hyperlipidaemia, hypophosphataemia, hyperglycaemia

Common Insomnia, aggression, irritability

Very common Headache

Uncommon Dysgeusia

Very common Hypertension

Common Lymphoedema

Very common Cough

Common Epistaxis, pneumonitis

Very common Stomatitis b, diarrhoea, vomiting

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

Very common Rash c, acne

Common Dry skin, acneiform dermatitis, pruritus, alopecia

Uncommon Angioedema

Uncommon Rhabdomyolysis

Common Proteinuria

Very common Amenorrhoea d, menstruation irregular d

Common Menorrhagia, ovarian cyst, vaginal haemorrhage

Uncommon Menstruation delayed d

Very common Pyrexia, fatigue

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

Uncommon Blood follicle stimulating hormone increased

Not knowne Radiation recall syndrome, potentiation of radiation reactiona Includes pneumocystis jirovecii (carinii) pneumonia (PJP, PCP)b Includes (very common) stomatitis, mouth ulceration, aphthous ulcer; (common) tongueulceration, lip ulceration and (uncommon) gingival pain, glossitisc Includes (very common) rash; (common) rash erythematous, erythema and (uncommon) rashgeneralised, rash maculo-papular, rash maculard Frequency based upon number of women from 10 to 55 years of age while on treatment in thepooled datae Adverse reaction identified in the post-marketing setting.

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 ofimmunosuppression.

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

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

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with casesof 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-marketingspontaneous reports, were cardiac failure, pulmonary embolism, deep vein thrombosis, impairedwound healing and hyperglycaemia.

In clinical studies and post-marketing spontaneous reports, angioedema has been reported with andwithout concomitant use of ACE inhibitors (see section 4.4).

In the pivotal phase II study, 22 of the 28 SEGA patients studied were below the age of 18 years andin the pivotal phase III study, 101 of the 117 SEGA patients studied were below the age of 18 years. Inthe pivotal phase III study in patients with TSC and refractory seizures, 299 of the 366 patients studiedwere below the age of 18 years. The overall type, frequency and severity of adverse reactions observedin children and adolescents have been generally consistent with those observed in adults, with theexception of infections which were reported at a higher frequency and severity in children below theage 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 receivingeverolimus.

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 everolimuswas higher in patients ≥65 years of age (20% versus 13%). The most common adverse reactionsleading to discontinuation were pneumonitis (including interstitial lung disease), fatigue, dyspnoea,and stomatitis.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

A limited number of paediatric patients have been exposed to doses higher than 10 mg/m2/day. Nosigns of acute toxicity have been reported in these cases.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EG02

Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a keyserine-threonine kinase, the activity of which is known to be upregulated in a number of humancancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibitsmTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes withthe translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase(S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involvedin the cell cycle, angiogenesis and glycolysis. Everolimus can reduce levels of vascular endothelialgrowth factor (VEGF). In patients with TSC, treatment with everolimus increases VEGF-A anddecreases VEGF-D levels. Everolimus is a potent inhibitor of the growth and proliferation of tumourcells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has beenshown to reduce glycolysis in solid tumours in vitro and in vivo.

Two primary regulators of mTORC1 signalling are the oncogene suppressors tuberin-sclerosiscomplexes 1 & 2 (TSC1, TSC2). Loss of either TSC1 or TSC2 leads to elevated rheb-GTP levels, aras family GTPase, which interacts with the mTORC1 complex to cause its activation. mTORC1activation leads to a downstream kinase signalling cascade, including activation of the S6 kinases. In

TSC syndrome, inactivating mutations in the TSC1 or the TSC2 gene lead to hamartoma formationthroughout the body.

Renal angiomyolipoma associated with TSC

EXIST-2 (study CRAD001M2302), a randomised, controlled phase III study was conducted toevaluate the efficacy and safety of Votubia in patients with TSC plus renal angiomyolipoma. Presenceof at least one angiomyolipoma ≥3 cm in longest diameter using CT/MRI (based on local radiologyassessment) was required for entry.

The primary efficacy endpoint was angiomyolipoma response rate based on independent centralradiology review. The analysis was stratified by use of enzyme-inducing antiepileptics atrandomisation (yes/no).

Key secondary endpoints included time to angiomyolipoma progression and skin lesion response rate.

A total of 118 patients were randomised, 79 to Votubia 10 mg daily and 39 to placebo. Median agewas 31 years (range: 18 to 61 years; 46.6% were <30 years at enrolment), 33.9% were male, and89.0% were Caucasian. Of the enrolled patients, 83.1% had angiomyolipomas ≥4 cm (28.8% ≥8 cm),78.0% had bilateral angiomyolipomas, and 39.0% had undergone prior renalembolisation/nephrectomy; 96.6% had skin lesions at baseline and 44.1% had target SEGAs (at leastone SEGA ≥1 cm in longest diameter).

Results showed that the primary objective related to best overall angiomyolipoma response was metwith best overall response rates of 41.8% (95% CI: 30.8, 53.4) for the Votubia arm compared with 0%(95% CI: 0.0, 9.0) for the placebo arm (p<0.0001) (Table 4).

Patients initially treated with placebo were allowed to cross over to everolimus at the time ofangiomyolipoma progression and upon recognition that treatment with everolimus was superior totreatment with placebo. At the time of the final analysis (4 years following the last patientrandomisation), the median duration of exposure to everolimus was 204.1 weeks (range 2 to 278). Theangiomyolipoma best overall response rate had increased to 58.0% (95% CI: 48.3, 67.3), with a rate ofstable disease of 30.4% (Table 4).

Among patients treated with everolimus during the study, no cases of angiomyolipoma-relatednephrectomy and only one case of renal embolisation were reported.

Table 4 EXIST-2 - Angiomyolipoma response

Primary analysis3 Finalanalysis4

Votubia Placebo p-value Votubian=79 n=39 n=112

Angiomyolipoma response rate1,2 - % 41.8 0 <0.0001 58.095% CI 30.8, 53.4 0.0, 9.0 48.3, 67.3

Best overall angiomyolipoma response - %

Response 41.8 0 58.0

Stable disease 40.5 79.5 30.4

Progression 1.3 5.1 0.9

Not evaluable 16.5 15.4 10.71 According to independent central radiology review2 Angiomyolipoma responses were confirmed with a repeat scan. Response was defined as:

≥50% reduction in the sum of angiomyolipoma volume relative to baseline, plus absence ofnew angiomyolipoma ≥1.0 cm in longest diameter, plus no increase in renal volume >20%from nadir, plus absence of grade ≥2 angiomyolipoma-related bleeding.3 Primary analysis for double blind period4 Final analysis includes patients who crossed over from the placebo group; median duration ofexposure to everolimus of 204.1 weeks

Consistent treatment effects on angiomyolipoma response rate were observed across all subgroupsevaluated (i.e. enzyme-inducing antiepileptic use versus enzyme-inducing antiepileptic non-use, sex,age and race) at the primary efficacy analysis.

In the final analysis, reduction in angiomyolipoma volume improved with longer term treatment with

Votubia. At weeks 12, 96 and 192, ≥ 30% reductions in volume were observed in 75.0%, 80.6%, and85.2% of the treated patients, respectively. Similarly, at the same timepoints, ≥50% reductions involume were observed in 44.2%, 63.3%, and 68.9% of the treated patients, respectively.

Median time to angiomyolipoma progression was 11.4 months in the placebo arm and was not reachedin the everolimus arm (HR 0.08; 95% CI: 0.02, 0.37; p<0.0001). Progressions were observed in 3.8%of patients in the everolimus arm compared with 20.5% in the placebo arm. Estimated progression-freerates at 6 months were 98.4% for the everolimus arm and 83.4% for the placebo arm. At the finalanalysis, median time to angiomyolipoma progression was not reached. Angiomyolipoma progressionswere observed in 14.3% of the patients. The estimated angiomyolipoma progression-free rates at24 months and 48 months were 91.6% and 83.1%, respectively.

At the primary analysis, skin lesion response rates of 26.0% (95% CI: 16.6, 37.2) for the Votubia armand 0% (95% CI: 0.0, 9.5) for the placebo arm were observed (p=0.0002). At the final analysis, theskin lesion response rate had increased to 68.2% (95% CI: 58.5, 76.9), with one patient reporting aconfirmed complete clinical skin lesion response and no patients experiencing progressive disease astheir best response.

In an exploratory analysis of patients with TSC with angiomyolipoma who also had SEGA, the SEGAresponse rate (proportion of patients with ≥50% reduction from baseline in target lesion volumes inthe absence of progression) was 10.3% in the everolimus arm in the primary analysis (versus noresponses reported in the 13 patients randomised to placebo with a SEGA lesion at baseline) andincreased to 48.0% in the final analysis.

Post-hoc sub-group analysis of EXIST-2 (study CRAD001M2302) carried out at time of primaryanalysis demonstrated that angiomyolipoma response rate is reduced below the threshold of 5 ng/ml(Table 5).

Table 5 EXIST-2 - Angiomyolipoma response rates by time-averaged Cmin category, atprimary analysis

Time-averaged Cmin Number of Response rate 95% confidence intervalcategory patients≤5 ng/ml 20 0.300 0.099, 0.501>5 ng/ml 42 0.524 0.373, 0.675

Difference1 -0.224 -0.475, 0.0271 Difference is “≤5 ng/ml” minus “>5 ng/ml”

SEGA associated with TSC

Phase III study in SEGA patients

EXIST-1 (Study CRAD001M2301), a randomised, double-blind, multicentre phase III study of

Votubia versus placebo, was conducted in patients with SEGA, irrespective of age. Patients wererandomised in a 2:1 ratio to receive either Votubia or matching placebo. Presence of at least one

SEGA lesion ≥1.0 cm in longest diameter using MRI (based on local radiology assessment) wasrequired for entry. In addition, serial radiological evidence of SEGA growth, presence of a new SEGAlesion ≥1 cm in longest diameter, or new or worsening hydrocephalus was required for entry.

The primary efficacy endpoint was SEGA response rate based on independent central radiologyreview. The analysis was stratified by use of enzyme-inducing antiepileptics at randomisation(yes/no).

Key secondary endpoints in hierarchal order of testing included the absolute change in frequency oftotal seizure events per 24-hour EEG from baseline to week 24, time to SEGA progression, and skinlesion response rate.

A total of 117 patients were randomised, 78 to Votubia and 39 to placebo. The two treatment armswere generally well balanced with respect to demographic and baseline disease characteristics andhistory of prior anti-SEGA therapies. In the total population, 57.3% of patients were male and 93.2%were Caucasian. The median age for the total population was 9.5 years (age range for the Votubia arm:

1.0 to 23.9; age range for the placebo arm: 0.8 to 26.6), 69.2% of the patients were aged 3 to <18 yearsand 17.1% were <3 years at enrolment.

Of the enrolled patients, 79.5% had bilateral SEGAs, 42.7% had ≥2 target SEGA lesions, 25.6% hadinferior growth, 9.4% had evidence of deep parenchymal invasion, 6.8% had radiographic evidence ofhydrocephalus, and 6.8% had undergone prior SEGA-related surgery. 94.0% had skin lesions atbaseline and 37.6% had target renal angiomyolipoma lesions (at least one angiomyolipoma ≥1 cm inlongest diameter).

The median duration of blinded study treatment was 9.6 months (range: 5.5 to 18.1) for patientsreceiving Votubia and 8.3 months (range: 3.2 to 18.3) for those receiving placebo.

Results showed that Votubia was superior to placebo for the primary endpoint of best overall SEGAresponse (p<0.0001). Response rates were 34.6% (95% CI: 24.2, 46.2) for the Votubia arm comparedwith 0% (95% CI: 0.0, 9.0) for the placebo arm (Table 6). In addition, all 8 patients on the Votubiaarm who had radiographic evidence of hydrocephalus at baseline had a decrease in ventricular volume.

Patients initially treated with placebo were allowed to cross over to everolimus at the time of SEGAprogression and upon recognition that treatment with everolimus was superior to treatment withplacebo. All patients receiving at least one dose of everolimus were followed until medicinal productdiscontinuation or study completion. At the time of the final analysis, the median duration of exposureamong all such patients was 204.9 weeks (range: 8.1 to 253.7). The best overall SEGA response ratehad increased to 57.7% (95% CI: 47.9, 67.0) at the final analysis.

No patient required surgical intervention for SEGA during the entire course of the study.

Table 6 EXIST-1 - SEGA response

Primary analysis3 Final analysis4

Votubia Placebo p-value Votubia

N=78 N=39 N=111

SEGA response rate1,2 - (%) 34.6 0 <0.0001 57.795% CI 24.2, 46.2 0.0, 9.0 47.9, 67.0

Best overall SEGA response - (%)

Response 34.6 0 57.7

Stable disease 62.8 92.3 39.6

Progression 0 7.7 0

Not evaluable 2.6 0 2.71 according to independent central radiology review2 SEGA responses were confirmed with a repeat scan. Response was defined as: ≥50% reduction inthe sum of SEGA volume relative to baseline, plus no unequivocal worsening of non-target SEGAlesions, plus absence of new SEGA ≥1 cm in longest diameter, plus no new or worseninghydrocephalus3 Primary analysis for double blind period4 Final analysis includes patients who crossed over from the placebo group; median duration ofexposure to everolimus of 204.9 weeks

Consistent treatment effects were observed across all subgroups evaluated (i.e. enzyme-inducingantiepileptic use versus enzyme-inducing antiepileptic non-use, sex and age) at the primary analysis.

During the double-blind period, reduction of SEGA volume was evident within the initial 12 weeks of

Votubia treatment: 29.7% (22/74) of patients had ≥50% reductions in volume and 73.0% (54/74) had≥30% reductions in volume. Sustained reductions were evident at week 24, 41.9% (31/74) of patientshad ≥50% reductions and 78.4% (58/74) of patients had ≥30% reductions in SEGA volume.

In the everolimus treated population (N=111) of the study, including patients who crossed over fromthe placebo group, tumour response, starting as early as after 12 weeks on everolimus, was sustainedat later time points. The proportion of patients achieving at least 50% reductions in SEGA volume was45.9% (45/98) and 62.1% (41/66) at weeks 96 and 192 after start of everolimus treatment. Similarly,the proportion of patients achieving at least 30% reductions in SEGA volume was 71.4% (70/98) and77.3% (51/66) at weeks 96 and 192 after start of everolimus treatment.

Analysis of the first key secondary endpoint, change in seizure frequency, was inconclusive; thus,despite the fact that positive results were observed for the two subsequent secondary endpoints (timeto SEGA progression and skin lesion response rate), they could not be declared formally statisticallysignificant.

Median time to SEGA progression based on central radiology review was not reached in eithertreatment arm. Progressions were only observed in the placebo arm (15.4%; p=0.0002). Estimatedprogression-free rates at 6 months were 100% for the Votubia arm and 85.7% for the placebo arm. Thelong-term follow-up of patients randomised to everolimus and patients randomised to placebo whothereafter crossed over to everolimus demonstrated durable responses.

At the time of the primary analysis, Votubia demonstrated clinically meaningful improvements in skinlesion response (p=0.0004), with response rates of 41.7% (95% CI: 30.2, 53.9) for the Votubia armand 10.5% (95% CI: 2.9, 24.8) for the placebo arm. At the final analysis, the skin lesion response rateincreased to 58.1% (95% CI: 48.1, 67.7).

Phase II study in patients with SEGA

A prospective, open-label, single-arm phase II study (Study CRAD001C2485) was conducted toevaluate the safety and efficacy of Votubia in patients with SEGA. Radiological evidence of serial

SEGA growth was required for entry.

Change in SEGA volume during the core 6-month treatment phase, as assessed via an independentcentral radiology review, was the primary efficacy endpoint. After the core treatment phase, patientscould be enrolled into an extension phase where SEGA volume was assessed every 6 months.

In total, 28 patients received treatment with Votubia; median age was 11 years (range 3 to 34), 61%male, 86% Caucasian. Thirteen patients (46%) had a secondary smaller SEGA, including 12 in thecontralateral ventricle.

Primary SEGA volume was reduced at month 6 compared to baseline (p<0.001 [see Table 7]). Nopatient developed new lesions, worsening hydrocephalus or increased intracranial pressure, and nonerequired surgical resection or other therapy for SEGA.

Table 7 Change in primary SEGA volume over time

SEGA Independent central reviewvolume(cm3)

Baseline Month 6 Month 12 Month 24 Month 36 Month 48 Month 60n=28 n=27 n=26 n=24 n=23 n=24 n=23

Primary tumour volume

Mean 2.45 1.33 1.26 1.19 1.26 1.16 1.24(standard (2.813) (1.497) (1.526) (1.042) (1.298) (0.961) (0.959)deviation)

Median 1.74 0.93 0.84 0.94 1.12 1.02 1.17

Range 0.49 - 14. 0.31 - 7.9 0.29 - 8.1 0.20 - 4.6 0.22 - 6.5 0.18 - 4.1 0.21 - 4.323 8 8 3 2 9 9

Reduction from baseline

Mean 1.19 1.07 1.25 1.41 1.43 1.44(standard (1.433) (1.276) (1.994) (1.814) (2.267) (2.230)deviation)

Median 0.83 0.85 0.71 0.71 0.83 0.50

Range 0.06 - 6.2 0.02 - 6.0 -0.55 - 9.6 0.15 - 7.7 0.00 - 10. -0.74 - 9.85 5 0 1 96 4

Percentage reduction from baseline, n (%)≥50% 9 (33.3) 9 (34.6) 12 (50.0) 10 (43.5) 14 (58.3) 12 (52.2)≥30% 21 (77.8) 20 (76.9) 19 (79.2) 18 (78.3) 19 (79.2) 14 (60.9)>0% 27 26 23 23 23 21(100.0) (100.0) (95.8) (100.0) (95.8) (91.3)

No 0 0 0 0 1 (4.2) 0change

Increase 0 0 1 (4.2) 0 0 2 (8.7)

The robustness and consistency of the primary analysis were supported by the:

− change in primary SEGA volume as per local investigator assessment (p<0.001), with 75.0%and 39.3% of patients experiencing reductions of ≥30% and ≥50%, respectively− change in total SEGA volume as per independent central review (p<0.001) or local investigatorassessment (p<0.001).

One patient met the pre-specified criteria for treatment success (>75% reduction in SEGA volume)and was temporarily taken off trial therapy; however, SEGA re-growth was evident at the nextassessment at 4.5 months and treatment was restarted.

Long-term follow-up to a median duration of 67.8 months (range: 4.7 to 83.2) demonstrated sustainedefficacy.

Other studies

Stomatitis is the most commonly reported adverse reaction in patients treated with Votubia (seesections 4.4 and 4.8). In a post-marketing single-arm study in postmenopausal women with advancedbreast cancer (N=92), topical treatment with dexamethasone 0.5 mg/5 ml alcohol-free oralsolution was administered as a mouthwash (4 times daily for the initial 8 weeks of treatment) topatients at the time of initiating treatment with Afinitor (everolimus, 10 mg/day) plus exemestane(25 mg/day) to reduce the incidence and severity of stomatitis. The incidence of Grade ≥2stomatitis at 8 weeks was 2.4% (n=2/85 evaluable patients) which was lower than historicallyreported. The incidence of Grade 1 stomatitis was 18.8% (n=16/85) and no cases of Grade 3 or 4stomatitis were reported. The overall safety profile in this study was consistent with thatestablished for everolimus in the oncology and TSC settings, with the exception of a slightlyincreased frequency of oral candidiasis which was reported in 2.2% (n=2/92) of patients.

The European Medicines Agency has waived the obligation to submit the results of studies with

Votubia in all subsets of the paediatric population in angiomyolipoma (see section 4.2 for informationon paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with

Votubia in one or more subsets of the paediatric population in refractory epilepsy associated with TSC(see section 4.2 for information on paediatric use).

In patients with advanced solid tumours, peak everolimus concentrations (Cmax) are reached at amedian time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditionsor with a light fat-free snack. Cmax is dose-proportional between 5 and 10 mg. Everolimus is a substrateand moderate inhibitor of PgP.

In healthy subjects, high fat meals reduced systemic exposure to Votubia 10 mg tablets (as measuredby AUC) by 22% and the peak blood concentration Cmax by 54%. Light fat meals reduced AUC by32% and Cmax by 42%.

In healthy subjects taking a single 9 mg dose (3 x 3 mg) of Votubia dispersible tablets in suspension,high fat meals reduced AUC by 11.7% and the peak blood concentration Cmax by 59.8%. Light fatmeals reduced AUC by 29.5% and Cmax by 50.2%.

Food, however, had no apparent effect on the post absorption phase concentration-time profile24 hours post-dose of either dosage form.

Relative bioavailability/bioequivalence

In a relative bioavailability study, AUC0-inf of 5 x 1 mg everolimus tablets when administered assuspension in water was equivalent to 5 x 1 mg everolimus tablets administered as intact tablets, and

Cmax of 5 x 1 mg everolimus tablets in suspension was 72% of 5 x 1 mg intact everolimus tablets.

In a bioequivalence study, AUC0-inf of the 5 mg dispersible tablet when administered as suspension inwater was equivalent to 5 x 1 mg intact everolimus tablets, and Cmax of the 5 mg dispersible tablet insuspension was 64% of 5 x 1 mg intact everolimus tablets.

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood isconfined to plasma of cancer patients given Votubia 10 mg/day. Plasma protein binding isapproximately 74% both in healthy subjects and in patients with moderate hepatic impairment. Inpatients with advanced solid tumours, Vd was 191 l for the apparent central compartment and 517 l forthe apparent peripheral compartment.

Nonclinical studies in rats indicate:

* A rapid uptake of everolimus in the brain followed by a slow efflux.

* The radioactive metabolites of [3H]everolimus do not significantly cross the blood-brainbarrier.

* A dose-dependent brain penetration of everolimus, which is consistent with the hypothesis ofsaturation of an efflux pump present in the brain capillary endothelial cells.

* The co-administration of the PgP inhibitor, cyclosporine, enhances the exposure of everolimusin the brain cortex, which is consistent with the inhibition of PgP at the blood-brain barrier.

There are no clinical data on the distribution of everolimus in the human brain. Non-clinical studies inrats demonstrated distribution into the brain following administration by both the intravenous and oralroutes.

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the maincirculating component in human blood. Six main metabolites of everolimus have been detected inhuman blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products,and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animalspecies used in toxicity studies and showed approximately 100 times less activity than everolimusitself. Hence, everolimus is considered to contribute the majority of the overall pharmacologicalactivity.

Mean CL/F of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h.

The mean elimination half-life of everolimus is approximately 30 hours.

No specific excretion studies have been undertaken in cancer patients; however, data are availablefrom the studies in transplant patients. Following the administration of a single dose of radiolabelledeverolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces,while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.

Steady-state pharmacokinetics

After administration of everolimus in patients with advanced solid tumours, steady-state AUC0-τ wasdose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within 2 weeks.

Cmax is dose-proportional between 5 and 10 mg. tmax occurs at 1 to 2 hours post-dose. There was asignificant correlation between AUC0-τ and pre-dose trough concentration at steady-state.

The safety, tolerability and pharmacokinetics of Votubia were evaluated in two single oral dosestudies of Votubia tablets in 8 and 34 adult subjects with impaired hepatic function relative to subjectswith normal hepatic function.

In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment(Child-Pugh B) was twice that found in 8 subjects with normal hepatic function.

In the second study of 34 subjects with different impaired hepatic function compared to normalsubjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC0-inf) for subjectswith mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment,respectively.

Simulations of multiple dose pharmacokinetics support the dosing recommendations in subjects withhepatic impairment based on their Child-Pugh status.

Based on the results of the two studies, dose adjustment is recommended for patients with hepaticimpairment (see sections 4.2 and 4.4).

In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significantinfluence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplantrenal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics ofeverolimus in transplant patients.

In patients with SEGA, everolimus Cmin was approximately dose-proportional within the dose rangefrom 1.35 mg/m2 to 14.4 mg/m2.

In patients with SEGA, the geometric mean C values normalised to mg/m2min dose in patients aged<10 years and 10-18 years were lower by 54% and 40%, respectively, than those observed in adults(>18 years of age), suggesting that everolimus clearance was higher in younger patients. Limited datain patients <3 years of age (n=13) indicate that BSA-normalised clearance is about two-fold higher inpatients with low BSA (BSA of 0.556 m2) than in adults. Therefore it is assumed that steady-statecould be reached earlier in patients <3 years of age (see section 4.2 for dosing recommendations).

The pharmacokinetics of everolimus have not been studied in patients younger than 1 year of age. It isreported, however, that CYP3A4 activity is reduced at birth and increases during the first year of life,which could affect the clearance in this patient population.

A population pharmacokinetic analysis including 111 patients with SEGA who ranged from 1.0 to27.4 years (including 18 patients 1 to less than 3 years of age with BSA 0.42 m2 to 0.74 m2) showedthat BSA-normalised clearance is in general higher in younger patients. Population pharmacokineticmodel simulations showed that a starting dose of 7 mg/m2 would be necessary to attain Cmin within the5 to 15 ng/ml range in patients younger than 3 years of age. A higher starting dose of 7 mg/m2 istherefore recommended for patients 1 to less than 3 years of age with SEGA (see section 4.2).

In a population pharmacokinetic evaluation in cancer patients, no significant influence of age(27-85 years) on oral clearance of everolimus was detected.

Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liverfunctions. Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20%higher in black transplant patients.

The non-clinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys andrabbits. The major target organs were male and female reproductive systems (testicular tubulardegeneration, reduced sperm content in epididymides and uterine atrophy) in several species; lungs(increased alveolar macrophages) in rats and mice; pancreas (degranulation and vacuolation ofexocrine cells in monkeys and minipigs, respectively, and degeneration of islet cells in monkeys), andeyes (lenticular anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat(exacerbation of age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse(exacerbation of background lesions). There was no indication of kidney toxicity in monkeys orminipigs.

Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats,coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinaltract in minipigs, skin lesions in mice and monkeys). These findings were generally observed atsystemic exposure levels within the range of therapeutic exposure or above, with the exception of thefindings in rats, which occurred below therapeutic exposure due to a high tissue distribution.

In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and spermmotility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg, which iswithin the range of therapeutic exposure and which caused a reduction in male fertility. There wasevidence of reversibility.

In animal reproductive studies female fertility was not affected. However, oral doses of everolimus infemale rats at ≥ 0.1 mg/kg (approximately 4% of the AUC0-24h in patients receiving the 10 mg dailydose) resulted in increases in pre-implantation loss.

Everolimus crossed the placenta and was toxic to the foetus. In rats, everolimus causedembryo/foetotoxicity at systemic exposure below the therapeutic level. This was manifested asmortality and reduced foetal weight. The incidence of skeletal variations and malformations (e.g.

sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits, embryotoxicity was evident in an increasein late resorptions.

In juvenile rat toxicity studies, systemic toxicity included decreased body weight gain, foodconsumption, and delayed attainment of some developmental landmarks, with full or partial recoveryafter cessation of dosing. With the possible exception of the rat-specific lens finding (where younganimals appeared to be more susceptible), it appears that there is no significant difference in thesensitivity of juvenile animals to the adverse reactions of everolimus as compared to adult animals.

Toxicity study with juvenile monkeys did not show any relevant toxicity.

Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic ormutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenicpotential in mice and rats up to the highest doses, corresponding respectively to 4.3 and 0.2 times theestimated clinical exposure.

Butylated hydroxytoluene (E321)

Magnesium stearate

Lactose monohydrate

Hypromellose

Crospovidone type A

Lactose anhydrous

Not applicable.

3 years.

Do not store above 25°C.

Store in the original package in order to protect from light and moisture.

Aluminium/polyamide/aluminium/PVC perforated unit-dose blister containing 10 x 1 tablets.

Votubia 2.5 mg tablets

Packs containing 10 x 1, 30 x 1 or 100 x 1 tablets.

Votubia 5 mg tablets

Packs containing 30 x 1 or 100 x 1 tablets.

Votubia 10 mg tablets

Packs containing 10 x 1, 30 x 1 or 100 x 1 tablets.

Not all pack sizes may be marketed.

The extent of absorption of everolimus through topical exposure is not known. Therefore caregiversare advised to avoid contact with the suspension. Hands should be washed thoroughly before and afterpreparation of the suspension.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Votubia 2.5 mg tablets

EU/1/11/710/001-003

Votubia 5 mg tablets

EU/1/11/710/004-005

Votubia 10 mg tablets

EU/1/11/710/006-008

Date of first authorisation: 02 September 2011

Date of latest renewal: 23 July 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu