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14 references

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33. Li SY, Rong M, Grieu F, Iacopetta B. PIK3CA mutations in breast cancer are associated with poor outcome. *Breast cancer research and treatment.* 2006;96(1):91-95.  
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by the rictor-mTOR complex. *Science.* 2005;307(5712):1098-1101.  
38. Pollack IF, Hamilton RL, Burger PC, et al. Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the Children's Oncology Group. J Neurooncol. 2010;99(2):155-163.  
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40. Cho YJ, Tsherniak A, Tamayo P, et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. *J Clin Oncol.* 2011;29(11):1424-1430.  
41. Northcott PA, Shih DJ, Peacock J, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. *Nature.* 2012;488(7409):49-56.  
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43. Hartmann W, Digon-Sontgerath B, Koch A, et al. Phosphatidylinositol 3'-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN.  
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44. Johnson RA, Wright KD, Poppleton H, et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. *Nature.* 2010;466(7306):632-636.  
45. D'Cunja J, Shalaby T, Rivera P, et al. Antisense treatment of IGF-IR induces apoptosis and enhances chemosensitivity in central nervous system atypical teratoid/rhabdoid tumours cells. Eur J Cancer. 2007;43(10):1581-1589.  
46. Darr J, Klochendler A, Isaac S, Eden A. Loss of IGFBP7 expression and persistent AKT activation contribute to SMARCB1/Snf5-mediated tumorigenesis. *Oncogene.* 2014;33(23):3024-3032.  
47. Tamura K, Hashimoto K, Suzuki K, Yoshie M, Kutsukake M, Sakurai T. Insulin-like growth factor binding protein-7 (IGFBP7) blocks vascular endothelial cell growth factor (VEGF)-induced angiogenesis in human vascular endothelial cells. *European journal of pharmacology.* 2009;610(1-3):61-67.  
48. LEE011 (Ribociclib) Investigator's Brochure. *Novartis*. 9 edMar 2016. 49. Patel Y. PDTB-12. CNS PENETRATION OF THE CDK4/6 INHIBITOR RIBOCICLIB
(LEE011) IN NON-TUMOR BEARING MICE AND MICE BEARING ORTHOTOPIC
PEDIATRIC BRAIN TUMORS. *Neuro-oncology.* 2016;18(suppl 6):vi152-vi152.  
50. LEE011 (Ribociclib) Investigator's Brochure. *Novartis*. 7 ed2014. 51. LEE011 (Ribociclib) Investigator's Brochure. *Novartis* 10 edOct 2016. 52. Kovarik JM, Hartmann S, Figueiredo J, et al. Effect of food on everolimus absorption:
quantification in healthy subjects and a confirmatory screening in patients with renal transplants. Pharmacotherapy. 2002;22(2):154-159.  
53. Urva S, Bouillaud E, Delaney R, Jappe A, Cheung W. A phase I study evaluating the effect of everolimus on the pharmacokinetics of midazolam in healthy subjects. *Journal of clinical* pharmacology. 2013;53(4):444-450.  
54. Geoerger B, Bourdeaut F, DuBois SG, et al. 455PPHASE I STUDY OF LEE011 (CDK4/6 INHIBITOR) IN PATIENTS WITH MALIGNANT RHABDOID TUMORS, NEUROBLASTOMA, AND CYCLIN D–CDK4/6 PATHWAY-ACTIVATED TUMORS. Annals of Oncology. 2014;25(suppl 4):iv151-iv152.  
55. Houghton PJ. Everolimus. *Clinical Cancer Research.* 2010;16(5):1368-1372. 56. Houghton PJ, Morton CL, Kolb EA, et al. Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. *Pediatr Blood Cancer.* 2008;50(4):799-805.  
57. Zeng Z, Sarbassov dos D, Samudio IJ, et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. *Blood.* 2007;109(8):3509-3512.  
58. Treeck O, Wackwitz B, Haus U, Ortmann O. Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells. *Gynecologic* oncology. 2006;102(2):292-299.  
59. Haritunians T, Mori A, O'kelly J, Luong Q, Giles F, Koeffler H. Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia. 2007;21(2):333-339.  
60. Dilling MB, Dias P, Shapiro DN, Germain GS, Johnson RK, Houghton PJ. Rapamycin selectively inhibits the growth of childhood rhabdomyosarcoma cells through inhibition of signaling via the type I insulin-like growth factor receptor. *Cancer research.* 1994;54(4):903-907.  
61. Hosoi H, Dilling MB, Liu LN, et al. Studies on the mechanism of resistance to rapamycin in human cancer cells. *Molecular pharmacology.* 1998;54(5):815-824.  
62. Houghton PJ, Morton CL, Gorlick R, et al. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. *Molecular cancer therapeutics.*
2010;9(1):101-112.  
63. Geoerger B, Kerr K, Tang C-B, et al. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. *Cancer research.* 2001;61(4):1527-1532.  
64. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. *The Lancet.* 2013;381(9861):125-132.  
65. Franz DN, Belousova E, Sparagana S, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. *The lancet oncology.* 2014;15(13):1513-1520.  
66. Everolimus Investigator's Brochure. *Novartis*. 15 edApr 2016. 67. Fouladi M, Laningham F, Wu J, et al. Phase I study of everolimus in pediatric patients with refractory solid tumors. *J Clin Oncol.* 2007;25(30):4806-4812.  
68. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. *New England Journal of Medicine.* 2010;363(19):1801-1811.  
69. Kieran MW, Yao X, Macy M, et al. Final results of a prospective multi-institutional phase II study of everolimus (RAD001), an mTOR inhibitor, in pediatric patients with recurrent or progressive low-grade glioma. A POETIC consortium trial. *Neuro-oncology.* 2014;16(suppl 3):iii27-iii27.  
70. Geoerger B, Kieran MW, Grupp S, et al. Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma. *Eur J Cancer.* 2012;48(2):253-262.  
71. Wagner LM, Fouladi M, Ahmed A, et al. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: a report from the Children's Oncology Group. *Pediatr Blood Cancer.* 2015;62(3):440-444.  
72. Yalon M, Rood B, MacDonald TJ, et al. A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric low‐grade glioma (LGG). Pediatric blood & *cancer.* 2013;60(1):71-76.  
73. Becher OJ, Gilheeney SW, Khakoo Y, et al. A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors. *Pediatr Blood Cancer.* 2016.  
74. Divers J OSJ. Stomatitis associated with use of mTOR inhibitors: Implications for patients with invasive breast cancer. *Clinical Journal of Oncology Nursing.* 2015;19(4):468-474.  
75. Pilotte AP HM, Polson, KMO, Huftalen TM, Treister N. Managing stomatitis in patients treated with mammalian target of rapamycin inhibitors. *Clinical Journal of Oncology Nursing.* 2011;15(5):E83-E89.  
76. Rugo HS, Hortobagyi GN, Yao J, et al. Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy. *Annals of Oncology.* 2016;27(3):519-525.  
77. Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. *The lancet oncology.* 2017;18(5):654-662.  
78. Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. *Pediatrics.* 2017;140(3).  
79. Goldhoff P, Clarke J, Smirnov I, et al. Clinical stratification of glioblastoma based on alterations in retinoblastoma tumor suppressor protein (RB1) and association with the proneural subtype.  
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81. Onar-Thomas A, Xiong Z. A simulation-based comparison of the traditional method, Rolling-6 design and a frequentist version of the continual reassessment method with special attention to trial duration in pediatric Phase I oncology trials. *Contemp Clin Trials.* 2010;31(3):259-270. Updated Date: September 26, 2018
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15 appendices 15.1 performance status

MODIFIED LANSKY SCORE (Score as 0 - 100) A. Normal Range 100 = Fully active 90 = Minor restrictions in physically strenuous play 80 = Restricted in strenuous play, tires more easily, otherwise active B. Mild to moderate restriction 70 = Both greater restrictions of and less time spent in active play 60 = Ambulatory up to 50% of time, limited active play with assistance/supervision 50 = Considerable assistance required for any active play; full able to engage in quiet play C. Moderate to severe restriction 40 = Able to initiate quiet activities 30 = Needs considerable assistance for quiet activity 20 = Limited to very passive activity initiated by others e.g. TV) 10 = Completely disabled, not even passive play 0 = Unresponsive, coma
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karnofsky scale

100 = Normal; no complaints 90 = Able to carry on normal activities; minor signs or symptoms of disease 80 = Normal activity with effort 70 = Cares for self. Unable to carry on normal activity or to do active work 60 = Requires occasional assistance but able to care for most of his/her needs 50 = Requires considerable assistance and frequent medical care 40 = Disabled; requires special care and assistance 30 = Severely disabled; hospitalization indicated though death not imminent 20 = Very sick. Hospitalization necessary. Active support treatment necessary. 10 = Moribund 0 = Dead Updated Date: September 26, 2018  
| 15.2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Prohibited medications - Ribociclib alone or Ribociclib and Everolimus                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Category                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Drug Name                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| Strong CYP3A4/5 inhibitors                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan,  danoprevir /ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice,  idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole,  lopinavir/ritonavir, mibefradil, nefazodone,  nelfinavir,ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK),  posaconazole, ritonavir, saquinavir/ritonavir, telaprevir, telithromycin,  tipranavir/ritonavir, troleandomycinvoriconazole                                                                                                                          |
| Strong CYP3A4/5 inducers                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | carbamazepine3 , enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin3 ,  rifabutin, rifampin (rifampicin)3 , St. John's wort (hypericum perforatum)2,3                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| CYP3A4/5 substrates with                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Alfentanil, astemizole, cisapride, cyclosporine, diergotamine                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| NTI1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | (dihydroergotamine), ergotamine, fentanyl, pimozide, quinidine, sirolimus,  tacrolimus Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin,                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| Medications with a known  risk for QT prolongation4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram,  clarithromycin, disopyramide, dofetilide, domperidone, donepezil, dronedarone,  droperidol, erythromycin, escitalopram, flecainide, fluconazole, gatifloxacine,  grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin,  levomepromazine, levosulpiride, methadone, moxifloxacin, ondansetron,  oxaliplatin, papaverine HCl (intra-coronary), pentamidine, pimozide,  procainamide, propofol, quinidine, roxithromycin, sevoflurane, sotalol,  sulpiride, sultopride, terlipressin, terodiline, thioridazine, vandetanib |
| Herbal preparations/                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Herbal preparations/medications known as strong inducers or inhibitors of                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| medications                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | CYP3A4/5 or those with a known risk of QT prolongation are prohibited  throughout the study. These herbal medications include, but are not limited to:  St. John's wort, Kava, ephedra (ma huang), gingko biloba,  dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients  should stop using these herbal medications 7 days prior to first dose of study  drug.                                                                                                                                                                                                                                |
| Other investigational and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Other investigational therapies must not be used while the patient is on the                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| antineoplastic therapies                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | study. Anticancer therapy (chemotherapy, all SERMS (including raloxifene),  biologic or radiation therapy, and surgery) other than the study treatments must  not be given to patients while the patient is on the study medication. If such  agents are required for a patient then the patient must be discontinued study  drug.                                                                                                                                                                                                                                                                                   |
| 1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure levels  by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes) or  drugs which have <2-fold difference in the minimum toxic concentrations and minimum effective concentrations  in the blood. 2 Herbal product 3 P-gp inducer 4 The list provided is as of January 2018.Check https www crediblemeds.org/healthcare-providers/drug-list for the  most updated list.  As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the potential to  increase the risk of drug-related QT prolongation (e.g., via a potential DDI that increases the exposure of  ribociclib or the exposure of the QT prolonging drug). A definitive list of drugs with a known risk, possible risk,  or conditional risk of QT prolongation and/or Torsades de Pointes (TdP) is available online at qtdrugs.org. Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations  for Novartis Clinical Trials (January 2018), which is compiled from Indiana University "Clinically Relevant"  Flockhart Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug  Interactions: Table of Substrates, Inhibitors and Inducers. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |  
Updated Date: September 26, 2018  
| alone or Ribociclib and Everolimus                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                |                                                  |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------|--------------------------------------------------|
| Category                                                                                                                                                                                                                                                                                                                                                                                                                                              | Drug Name Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida) cimetidine, crizotinib,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                |                                                  |
| Moderate CYP3A4/5                                                                                                                                                                                                                                                                                                                                                                                                                                     | diltiazem, faldaprevir,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | imatinib,                                      | isavuconazole, netupitant, nilotinib, tofisopam, |
| inhibitors                                                                                                                                                                                                                                                                                                                                                                                                                                            | Schisandra sphenanthera (nan wu wei zi), verapamil                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                |                                                  |
| Moderate CYP3A4/5 inducers                                                                                                                                                                                                                                                                                                                                                                                                                            | Bosentan, dabrafenib, efavirenz, etravirine, genistein,lopinavir5 , modafinil, nafcillin,  telotristat                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                |                                                  |
| Sensitive CYP3A4/5                                                                                                                                                                                                                                                                                                                                                                                                                                    | Alpha-dihydroergocryptine, aprepitant, atorvastatin, avanafil, bosutinib,brotizolam,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                |                                                  |
| substrates1                                                                                                                                                                                                                                                                                                                                                                                                                                           | budesonide, buspirone, cobimetinib,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | darifenacin, dasatininb, ebastine, eletriptan, |                                                  |
| eplerenone, everolimus, felodipine, fluticasone, grazoprevir, ibrutnib, isavuconazole,  ivabradine, ivacaftor, , levomethadyl (LAAM), lomitapide, lovastatin, lumefantrine,  lurasidone, maraviroc, midazolam, midostaurin, naloxegol, neratinib, nisoldipine,  perospirone, quetiapine, ridaforolimus, sildenafil, simeprevir, simvastatin, ticagrelor,  tilidine, tolvaptan, triazolam, ulipristal, vardenafil, venetoclax, vicriviroc, voclosporin |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                |                                                  |
| BSEP inhibitors                                                                                                                                                                                                                                                                                                                                                                                                                                       | Alectinib, atorvastatin, bromocriptine, candesartan, clobetasol, clofaziminie,  dabigatran, dipyridamole, glyburide, grazoprevir, ledipasvir,  mifepristone,pioglitazone, reserpine, rifamycin, simeprevir, telmisartan,timcodar,  troglitazone, valinomycin, velpatasvir                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                |                                                  |
| Medications that carry a  possible risk for QT  prolongation2                                                                                                                                                                                                                                                                                                                                                                                         | Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , asenapine, , atomoxetine, bedaquiline, bendamustine, bortezomib, bosutinib, buprenorphine,  cabozantinib, capecitabine, ceritinib, clomipramine, crizotinib,clozapine,  cyamemazine (cyamepromazine), dabrafenib, dasatinib, degarilix, delamanid,  desipramine, dexmedetomidine, dolasetron, efavirenz, eliglustat, epirubicin, eribulin  mesylate, ezogabine(retigabine), famotidine, felbamate, fingolimod, flupentixol,  gemifloxacin, granisetron, hydrocodone-ER, iloperidone, imipramine (melipramine),  isradipine, ketanserin, lapatinib, lenvatinib, leuprolide, lithium, melperone,  midostaurin, mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, necitumumab,  nicardipine, nilotinib, norfloxacin, nortriptyline, nusinersen, ofloxacin, osimertinib,  oxytocin, paliperidone, palonosetron, panabinostat, pasireotide, pazopanib, perflutren  lipid microspheres, perphenazine, pilsicainide, pimavanserin, pipamperone, promethazine, prothipendyl, rilpivirine, risperidone, romidepsin, sertindole, sorafenib,  sunitinib, tamoxifen, tipiracil/trifluridine, tizanidine, tolterodine,  toremifene,trimipramine, tropisetron, vardenafil, vemurafenib, venlafaxine, vorinostat, ziprasidone |                                                |                                                  |
| MATE1/2 substrates3                                                                                                                                                                                                                                                                                                                                                                                                                                   | Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium,  metformin, pindolol, plisicainide, ranitidine, topotecan, varenicline                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                |                                                  |
| OCT1/2 substrates4                                                                                                                                                                                                                                                                                                                                                                                                                                    | Amantadine, 6-beta-hydroxycortisol, carboplatin, cisplatin, cephalexin, cephradine, ,  , , ipratropium, lamivudine, linagliptin, metformin, , oxyplatin, oxybutynin,  phenformin, picoplatin, pilsicainide, pindolol, , ranitidine, sorafenib, tropisetron,  trospium, umeclidinium,, , and zidovudine                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                |                                                  |
| BCRP substrates                                                                                                                                                                                                                                                                                                                                                                                                                                       | Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib, methotrexate,  mitoxantrone, pitavastatin, rosuvastatin, irinotecan, ethinyl estradiol, simvastatin,  sulfasalazine, sofosbuvir, tenofovir, topotecan, venetoclax                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                |                                                  |
| 1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when coadministered with a potent inhibitor.2 The list provided is as of January 2018. Check https www  crediblemeds.org/healthcare-providers/drug-list for the most updated list. 3 MATE1 and MATE2 share considerable substrate specificity.  4 OCT1 and OCT2 share considerable substrate specificity. 5 Lopinavir is prohibited when combined with ritonavir (see Table 14-1) Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for  Novartis Clinical Trials (January 2018), which is compiled from Indiana University "Clinically Relevant" Flockhart  Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and Inducers.                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                |                                                  |  
Updated Date: September 26, 2018
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15.4 list of prohibited medications

| Category                                                                                                                                                                                                                                                                                                                                            | Drug Name                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                      |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------|
| Strong PgP Inihibitors                                                                                                                                                                                                                                                                                                                              | alogliptin, canaglifozin, cremophor RH40, curcumin, ketoconazole,  lapatinib, lopinavir/ritonavir, mirabegron, propafenone, simepravir, valspodar, vandetanib, voclosporin                                                                                                                                                                                                                                                                                                                            |                                                                      |
| Strong PgP/CYP3A4 dual                                                                                                                                                                                                                                                                                                                              | amiodarone, azithromycin, captopril, carvedilol, clarithromycin,                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                      |
| inhibitors                                                                                                                                                                                                                                                                                                                                          | conivaptan, diltiazem, dronedarone, elacridar, erythromycin, felodipine, , fluvoxamine, ginkgo (Ginkgo biloba),  indinavir, indinavir/ritonavir, itraconazole, mibefradil, milk thistle (Silybum marianum), nelfinavir, nifedipine,  nitrendipine, paroxetine, quercetin, quinidine, ranolazine, rifampin, ritonavir, saquinavir/ritonavir, Schisandra  chinensis, St John's wort (Hypericum perforatum), talinolol, telaprevir, telmisartan, ticagrelor, tipranavir/ritonavir,  tolvaptan, verapamil |                                                                      |
| Herbal                                                                                                                                                                                                                                                                                                                                              | preparations/                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Herbal preparations/medications are prohibited throughout the study. |
| medications                                                                                                                                                                                                                                                                                                                                         | These herbal medications include, but are not limited to: St. John's wort,  Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone  (DHEA), yohimbe, saw palmetto, and ginseng. Patients should stop using  these herbal medications 7 days prior to first dose of study drug.                                                                                                                                                                                                               |                                                                      |
| Other investigational and                                                                                                                                                                                                                                                                                                                           | Other investigational therapies must not be used while the patient is on the                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                      |
| antineoplastic therapies                                                                                                                                                                                                                                                                                                                            | study. Anticancer therapy (chemotherapy, biologic or radiation therapy,  and surgery) other than the study treatments must not be given to patients  while the patient is on the study medication. If such agents are required  for a patient then the patient must be discontinued study drug.                                                                                                                                                                                                       |                                                                      |
| Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated April-2015  which summarizes DDI data from three sources including the FDA's "Guidance for Industry, Drug  Interaction Studies", the University of Washington's Drug Interaction Database, and Indiana University School of  Medicine's Drug Interaction Table. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                      |
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15.5 dosing tables for ribociclib

Surgical Study
- Based on 50mg and 200mg Capsules, round to the nearest 50mg. Patients allergic to peanut and soy are not permitted to take the film-coated tablet formulation.  
- Ribociclib liquid formulation is 30 mg/ mL. **If a 1 mL syringe is used, each 0.1 mL is equivalent**
to 3 mg.  
| BSA Range                      | Liquid            | Liquid total   |        |    |      |     |
|--------------------------------|-------------------|----------------|--------|----|------|-----|
| (m2 )                          | Capsules Required | Formulation    | dose   |    |      |     |
| low                            | high              | 50 mg          | 200 mg | ml | mg   |     |
| 150                            | 0.50              | 0.62           | 3      | 0  | 5    | 150 |
| 200                            | 0.63              | 0.80           | 0      | 1  | 6.6  | 198 |
| 250                            | 0.81              | 0.98           | 1      | 1  | 8.3  | 249 |
| 300                            | 0.99              | 1.16           | 2      | 1  | 10   | 300 |
| 350                            | 1.17              | 1.33           | 3      | 1  | 11.6 | 348 |
| 400                            | 1.34              | 1.51           | 0      | 2  | 13.3 | 399 |
| 450                            | 1.52              | 1.69           | 1      | 2  | 15   | 450 |
| 500                            | 1.70              | 1.87           | 2      | 2  | 16.6 | 498 |
| 550                            | 1.88              | 2.05           | 3      | 2  | 18.3 | 549 |
| 600                            | 2.06              | 2.23           | 0      | 3  | 20   | 600 |
| 650                            | 2.24              | 2.41           | 1      | 3  | 21.6 | 648 |
| 700                            | 2.42              | 2.50           | 2      | 3  | 23.3 | 699 |
| Total Daily  Dose (mg)         |                   |                |        |    |      |     |
| Ribociclib Dose Level 280 mg/m |                   |                |        |    |      |     |
| 2/day                          |                   |                |        |    |      |     |  
| BSA Range                 | Liquid            | Liquid total   |        |    |      |     |
|---------------------------|-------------------|----------------|--------|----|------|-----|
| (m2 )                     | Capsules Required | Formulation    | dose   |    |      |     |
| low                       | high              | 50 mg          | 200 mg | ml | mg   |     |
| 200                       | 0.50              | 0.62           | 0      | 1  | 6.6  | 198 |
| 250                       | 0.63              | 0.78           | 1      | 1  | 8.3  | 249 |
| 300                       | 0.79              | 0.92           | 2      | 1  | 10   | 300 |
| 350                       | 0.93              | 1.07           | 3      | 1  | 11.6 | 348 |
| 400                       | 1.08              | 1.21           | 0      | 2  | 13.3 | 399 |
| 450                       | 1.22              | 1.35           | 1      | 2  | 15   | 450 |
| 500                       | 1.36              | 1.50           | 2      | 2  | 16.6 | 498 |
| 550                       | 1.51              | 1.64           | 3      | 2  | 18.3 | 549 |
| 600                       | 1.65              | 1.79           | 0      | 3  | 20   | 600 |
| 650                       | 1.80              | 1.92           | 1      | 3  | 21.6 | 648 |
| 700                       | 1.93              | 2.08           | 2      | 3  | 23.3 | 699 |
| 750                       | 2.09              | 2.21           | 3      | 3  | 25   | 750 |
| 800                       | 2.22              | 2.35           | 0      | 4  | 26.6 | 798 |
| 850                       | 2.36              | 2.49           | 1      | 4  | 28.3 | 849 |
| 900                       | 2.50              | 2.50           | 2      | 4  | 30   | 900 |
| Total Daily  Dose (mg)    |                   |                |        |    |      |     |
| Ribociclib Dose Level 350 |                   |                |        |    |      |     |
| mg/m                      |                   |                |        |    |      |     |
| 2/day                     |                   |                |        |    |      |     |
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phase i study

- Based on 50 mg and 200 mg Capsules, round to the nearest 50 mg. Patients allergic to peanut and soy are not permitted to take the film-coated tablet formulation.  
- Ribociclib liquid formulation is 30 mg/ mL. **If a 1 mL syringe is used, each 0.1 mL is equivalent**
to 3 mg.  
| Liquid                             | Liquid          |                   |        |         |        |        |
|------------------------------------|-----------------|-------------------|--------|---------|--------|--------|
| Formulation                        | dose            |                   |        |         |        |        |
| calculation                        |                 |                   |        |         |        |        |
| low                                | high            | 50 mg             | 200 mg | 30mg/ml | total  |        |
| 50                                 | 0.55            | 1.02              | 1      | 0       | 1.6 ml | 48 mg  |
| 100                                | 1.03            | 1.66              | 2      | 0       | 3.3 ml | 99 mg  |
| 150                                | 1.67            | 2.33              | 3      | 0       | 5 ml   | 150 mg |
| 200                                | 2.34            | 2.50              | 0      | 1       | 6.6 ml | 198 mg |
| Ribociclib Dose Level 75 mg/m2/day | BSA Range (m2 ) | Capsules Required |        |         |        |        |
| Total Daily Dose  (mg)             |                 |                   |        |         |        |        |  
  
| Liquid                              | Liquid          |                   |        |         |        |        |
|-------------------------------------|-----------------|-------------------|--------|---------|--------|--------|
| formulation                         | dose            |                   |        |         |        |        |
| calculation                         |                 |                   |        |         |        |        |
| low                                 | high            | 50 mg             | 200 mg | 30mg/ml | total  |        |
| 100                                 | 0.75            | 1.02              | 2      | 0       | 3.3 ml | 99 mg  |
| 150                                 | 1.03            | 1.45              | 3      | 0       | 5 ml   | 150 mg |
| 200                                 | 1.46            | 1.87              | 0      | 1       | 6.6 ml | 198 mg |
| 250                                 | 1.88            | 2.29              | 1      | 1       | 8.3 ml | 249 mg |
| 300                                 | 2.30            | 2.50              | 2      | 1       | 10 ml  | 300 mg |
| Ribociclib Dose Level 120 mg/m2/day | BSA Range (m2 ) | Capsules Required |        |         |        |        |
| Total Daily Dose  (mg)              |                 |                   |        |         |        |        |  
  
Total Daily Dose  
(mg)  
BSA Range (m2) **Capsules Required**  
| Total Daily Dose  (mg)              |
|-------------------------------------|
| Ribociclib Dose Level 170 mg/m2/day |  
  
Liquid  
formulation  
Liquid  
dose  
calculation  
low high 50 mg 200 mg 30mg/ml **total**  
100 0.45 0.73 2 0 3.3 ml 99 mg  
150 0.74 1.02 3 0 5 ml 150 mg  
200 1.03 1.32 0 1 6.6 ml 198 mg  
250 1.33 1.61 1 1 8.3 ml 249 mg  
300 1.62 1.91 2 1 10 ml 300 mg  
350 1.92 2.20 3 1 11.6 ml 348 mg  
400 2.21 2.50 0 2 13.3 ml 399 mg
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15.6 patient drug information handout

Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible Interactions with Other Drugs and Herbal Supplements The patient ____________________________ is enrolled on a clinical trial using the experimental study drugs, ribociclib (LEE011) and everolimus (RAD001). This form is addressed to the patient, but includes important information for others who care for this patient. These are the things that you as a healthcare provider **need to know:**
Ribociclib and everolimus interact with many drugs that are processed by your liver* and have an effect on the heart's electrical activity (QTc prolongation)**.  
*The enzyme(s) in question are CYP3A4, FMO3, CYP2D6, and p-glycoprotein. *Ribociclib and* everolimus are broken down by these enzymes and may be affected by other drugs that inhibit or induce these *enzymes.*
**The heart's electrical activity may be affected by *ribociclib.* The study doctor may be concerned about QTc prolongation and any other medicine that is associated with greater risk for having QTc prolongation.  
To the patient: Take **this paper with you to your medical appointments and keep the attached**
information card in your wallet.  
Ribociclib and everolimus may interact with other drugs which can cause side effects. For this reason, it is very important to tell your study doctors of any medicines you are taking before you enroll onto this clinical trial. It is also very important to tell your doctors if you stop taking any regular medicines, or if you start taking a new medicine while you take part in this study. When you talk about your current medications with your doctors, include medicine you buy without a prescription (over-the-counter remedy), or any herbal supplements such as St. John's Wort. It is helpful to bring your medication bottles or an updated medication list with you. Many health care providers can write prescriptions. You must tell all of your health care providers
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.
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these are the things that

Ribociclib and everolimus must be used very carefully with other medicines that use certain liver enzymes or transport proteins to be effective or to be cleared from your system or that may affect your heart's electrical activity. Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to review any medicines and herbal supplements that are considered *strong* inducers/inhibitors or substrates of CYP3A4, FMO3, p-glycoprotein, or any medicine associated with greater risk for having QTc prolongation.  
- Please be very careful! Over-the-counter drugs (including herbal supplements) may contain ingredients that could interact with your study drug. Speak to your doctors or pharmacist to determine if there could be any side effects. Updated Date: September 26, 2018
- Patients must avoid consumption of grapefruit, Seville oranges or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medication, due to potential CYP3A4 interaction with the study medications. Orange juice is allowed.  
Your regular health care provider should check a frequently updated medical reference or call your study doctor before prescribing any new medicine or discontinuing any medicine. Your study doctor's name is __________________________ and he or she can be contacted at _____________________________________.  
| STUDY DRUG INFORMATION WALLET CARD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| You are enrolled on a clinical trial using the experimental study  drug Ribociclib and Everolimus. Ribociclib and Everolimus may interact  with drugs that are processed by your liver, or use certain transport  proteins in your body or affects the electrical activity of your heart.  Because of this, it is very important to: ➢ Tell your doctors if you stop taking any medicines or if you start taking  any new medicines. ➢ Tell all of your health care providers (doctors, physician assistants,  nurse practitioners, or pharmacists) that you are taking part in a clinical  trial. ➢ Check with your doctor or pharmacist whenever you need to use an  over-the-counter medicine or herbal supplement. | Ribociclib and everolimus interacts with a specific liver enzyme called  CYP3A4, FMO3, CYP2D6, and p-glycoprotein,, transport protein, heart's  electrical activity (QTc prolongation, and must be used very carefully  with other medicines that interact with this enzyme, transporter, or  agent.  Before you enroll onto the clinical trial, your study doctor will work with  your regular health care providers to review any medicines and herbal  supplements that are considered strong inducers/inhibitors or  substrates of CYP3A4, FMO3, CYP2D6, and p-glycoprotein, or  transporter; or affect the heart's electrical activity  Before prescribing new medicines, your regular health care providers  should go to a frequently-updated medical reference for a list of drugs  to avoid, or contact your study doctor.  ➢ Your study doctor's name is _____________________________ and can be contacted at _________________________________. |
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15.7 caregiver and patient instructions

Please read this information before preparing and taking your study drug. **Please check with your study**
doctor or study team if you have any questions. The everolimus dispersible tablets are made to be dissolved in water creating an oral suspension of the study drug. The oral suspension can be mixed in either a cup or syringe. If drug gets into eyes, flush with large amount of water while holding eyelids open for at least 15 minutes. Call your doctor or nurse immediately (insert phone \#) and/or the Poison Control Center at (insert phone \#). If you spilled the drug on your skin, remove contaminated clothing. Wash the area with soap and a large amount of water. Get medical attention if irritation develops or persists by calling the numbers listed above.
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what do you need

- Everolimus dispersible tablets - Dosing cup or syringe - Drinking water or bottled water. Do not use seltzer (sparkling) water or juice.  
| HOW TO PREPARE THE EVEROLIMUS ORAL SUSPENSION - DOSING CUP Step 1: Wash and dry your hands before preparing the medication. Step 2: Add 5 mL of water into the dosing cup.  Step 3:  Remove the required number of dispersible tablets ( ) from  tablet cards  Step 4: Allow the dispersible tablets 3 minutes to disintegrate. Make sure to  proceed further only when the 3 minutes are over and when the  dispersible tablets have completely suspended. Step 5: Mix the content in the dosing cup by gentle swirling of the cup. The suspension is stable for up to one hour if cannot be given  immediately.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Step 6: Drink the full amount of liquid in the cup. Step 7: Refill the drinking glass with the same amount of water  ___________mL stir it again with the same spoon to suspend  remaining particles and drink the full amount to ensure the entire  dose is administered. Step 8: Rinse the dosing cup thoroughly with water. Wipe the dosing cup  with a clean paper towel and store it in a dry and clean place until  next dosing. Step 9: Wash your hands.   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
TABLET STORAGE The everolimus tablets should be stored at room temperature. Store the drug away from food and out of reach of children and pets.
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return of study drug

All left over everolimus tablets need to be brought back to the study doctor at every clinic visit with the completed patient diary. Updated Date: September 26, 2018
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15.8 caregiver and patient instructions

Please read this information before preparing and taking your study drug. **Please check with your study**
doctor or study team if you have any questions. The everolimus dispersible tablets are made to be dissolved in water creating an oral suspension of the study drug. The oral suspension can be mixed in either a cup or syringe. If drug gets into your eyes, flush with large amount of water while holding eyelids open for at least 15 minutes. Call your doctor or nurse immediately (insert phone \#) and/or the Poison Control Center at (insert phone \#). If you spilled the drug on your skin, remove contaminated clothing. Wash the area with soap and a large amount of water. Get medical attention if irritation develops or persists by calling the numbers listed above.
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what do you need

- Everolimus dispersible tablets - Dosing cup or syringe - Drinking water or bottled water. Do not use seltzer (sparkling) water or juice.  
| HOW TO PREPARE THE EVEROLIMUS ORAL SUSPENSION - SYRINGE Step 1: Wash and dry your hands before preparing the  medication. Step 2: Take a ______ml oral syringe and remove the plunger. Step 3: Remove the required number of dispersible tablets  ( ) from tablet cards  Step 4: Re-insert the plunger into the syringe and push it inward to  make contact with the dispersible tablets.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Step 5: Fill drinking glass with water and fill 5 mL of the water into  the oral syringe by slowly pulling the plunger up. Turn the  syringe upside-down so the tip points up. Then pull some  additional _______ mL air. Place the filled syringe tip up in a  glass. Step 6: Allow the dispersible tablets 3 minutes to disintegrate. Make  sure to proceed further only when the 3 minutes are over and  when the dispersible tablets have completely suspended. Step 7: Carefully turn the oral syringe upside down five times. Do not shake the oral syringe to avoid suspension leaking from  the tip. Step 8: While holding the oral syringe in an upright position, carefully  remove the excess air. Expel/dispose ________mLs of the solution in the oral syringe  before giving to patient.  Step 9: Dispense immediately the full content of the oral syringe  slowly and gently into the mouth of the patient. Carefully  remove the syringe from patient's mouth when empty The suspension is stable for up to one hour of cannot be given  immediately.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
  
Step 10: Fill the oral syringe once more with the water by slowly pulling the plunger up. Turn the syringe so the tip is pointing up, and draw some additional mL air. Swirl the contents to suspend any remaining particles of the medication. While holding the syringe in an upright position, carefully remove the excess air. Then dispense the full contents of the oral syringe slowly and gently into the mouth of the patient.  
| Step 11: Take apart the oral syringe and rinse all parts thoroughly with  water. Store them in a dry and clean place until next dosing. Step 12: Wash your hands.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
TABLET STORAGE The everolimus tablets should be stored at room temperature. Store the drug away from food and out of reach of children and pets. RETURN OF STUDY DRUG All left over everolimus tablets need to be brought back to the study doctor at every clinic visit with the completed patient diary.