Everolimus
Everolimus 5mg/10mg Tablets

What is the most important information I should know about Everolimus and Everolimus Dispersible?

Everolimus and Everolimus Dispersible can cause serious side effects. These serious side effects include:

1. You may develop lung or breathing problems. In some people lung or breathing problems may be severe, and can even lead to death. Tell your healthcare provider right away if you have any of these symptoms:
   
   
   • New or worsening cough
   • Shortness of breath
   • Chest pain
   • Difficulty breathing or wheezing
2. You may be more likely to develop an infection, such as pneumonia, or a bacterial, fungal or viral infection. Viral infections may include active hepatitis B in people who have had hepatitis B in the past (reactivation). In some people these infections may be severe, and can even lead to death. You may need to be treated as soon as possible.
   
   Tell your healthcare provider right away if you have a temperature of 100.5°F or above, chills, or do not feel well.
   
   Symptoms of hepatitis B or infection may include the following:
   
   
   • Fever
   • Chills
   • Skin rash
   • Joint pain and inflammation
   • Tiredness
   • Loss of appetite
   • Nausea
   • Pale stools or dark urine
   • Yellowing of the skin
   • Pain in the upper right side of the stomach
3. You may develop kidney failure. In some people this may be severe and can even lead to death. Your healthcare provider should do tests to check your kidney function before and during your treatment with Everolimus or Everolimus Dispersible .

If you have any of the serious side effects listed above, you may need to stop taking Everolimus or Everolimus Dispersible for a while or use a lower dose. Follow your healthcare provider’s instructions.

What is Everolimus?

Everolimus is a prescription medicine used to treat:

• advanced hormone receptor-positive, HER2-negative breast cancer, along with the medicine exemestane, in postmenopausal women who have already received certain other medicines for their cancer.
• adults with a type of pancreatic cancer known as pancreatic neuroendocrine tumor (PNET), that has progressed and cannot be treated with surgery. Everolimus is not for use in people with carcinoid tumors that actively produce hormones.
• adults with advanced kidney cancer (renal cell carcinoma or RCC) when certain other medicines have not worked.
• people with the following types of tumors that are seen with a genetic condition called tuberous sclerosis complex (TSC):
  • adults with a kidney tumor called angiomyolipoma, when their kidney tumor does not require surgery right away.
  • adults and children with a brain tumor called subependymal giant cell astrocytoma (SEGA) when the tumor cannot be removed completely by surgery.

What is Everolimus Dispersible?

Everolimus Dispersible is a prescription medicine used to treat:

• adults and children with a genetic condition called tuberous sclerosis complex (TSC) who have a brain tumor called subependymal giant cell astrocytoma (SEGA) when the tumor cannot be removed completely by surgery.

Who should not take Everolimus or Everolimus Dispersible?

Do not take Everolimus or Everolimus Dispersible if you are allergic to everolimus or to any of the ingredients in Everolimus or Everolimus Dispersible . See the end of this leaflet for a complete list of ingredients in Everolimus and Everolimus Dispersible .

Talk to your healthcare provider before taking this medicine if you are allergic to:

• sirolimus
• temsirolimus

Ask your healthcare provider if you do not know.

What should I tell my healthcare provider before taking Everolimus or Everolimus Dispersible?

Before taking Everolimus or Everolimus Dispersible, tell your healthcare provider about all of your medical conditions, including if you:

• Have or have had kidney problems
• Have or have had liver problems
• Have diabetes or high blood sugar
• Have high blood cholesterol levels
• Have any infections
• Previously had hepatitis B
• Are scheduled to receive any vaccinations. You should not receive a “live vaccine” or be around people who have recently received a “live vaccine” during your treatment with Everolimus or Everolimus Dispersible . If you are not sure about the type of immunization or vaccine, ask your healthcare provider.
• Have other medical conditions
• Are pregnant, or could become pregnant. Everolimus or Everolimus Dispersible can cause harm to your unborn baby. You should use effective birth control while using Everolimus or Everolimus Dispersible and for 8 weeks after stopping treatment. Talk to your healthcare provider about birth control options while taking Everolimus or Everolimus Dispersible .
• Are breastfeeding or plan to breastfeed. It is not known if Everolimus or Everolimus Dispersible passes into your breast milk. You and your healthcare provider should decide if you will take Everolimus or Everolimus Dispersible , or breastfeed. You should not do both.

Tell your healthcare provider about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Everolimus or Everolimus Dispersible may affect the way other medicines work, and other medicines can affect how Everolimus or Everolimus Dispersible work. Using Everolimus or Everolimus Dispersible with other medicines can cause serious side effects.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Especially tell your healthcare provider if you take:

• St. John’s Wort (Hypericum perforatum)
• Medicine for:
  • Fungal infections
  • Bacterial infections
  • Tuberculosis
  • Seizures
  • HIV-AIDS
  • Heart conditions or high blood pressure
• Medicines that weaken your immune system (your body’s ability to fight infections and other problems)

Ask your healthcare provider or pharmacist if you are not sure if your medicine is one of those taken for the conditions listed above. If you are taking any medicines for the conditions listed above, your healthcare provider might need to prescribe a different medicine or your dose of Everolimus or Everolimus Dispersible may need to be changed. You should also tell your healthcare provider before you start taking any new medicine.

How should I take Everolimus or Everolimus Dispersible?

• Your healthcare provider will prescribe the dose of Everolimus or Everolimus Dispersible that is right for you.
• Take Everolimus or Everolimus Dispersible exactly as your healthcare provider tells you to.
• Your healthcare provider may change your dose of Everolimus or Everolimus Dispersible or tell you to temporarily interrupt dosing, if needed.
• Use scissors to open the blister pack.

Everolimus:

• Swallow Everolimus tablets whole with a glass of water. Do not take any tablet that is broken or crushed.

Everolimus Dispersible:

• If your healthcare provider prescribes Everolimus Dispersible for you, see the “Instructions for Use” that come with your medicine for instructions on how to prepare and take your dose.
• Each dose of Everolimus Dispersible must be prepared as a suspension before it is given.
• Everolimus Dispersible can cause harm to an unborn baby. When possible, the suspension should be prepared by an adult who is not pregnant or planning to become pregnant.
• Anyone who prepares suspensions of Everolimus Dispersible for another person should wear gloves to avoid possible contact with the medicine.

• Take Everolimus or Everolimus Dispersible 1 time each day at about the same time.
• Take Everolimus or Everolimus Dispersible the same way each time, either with food or without food.
• If you take too much Everolimus or Everolimus Dispersible contact your healthcare provider or go to the nearest hospital emergency room right away. Take the pack of Everolimus or Everolimus Dispersible with you.
• If you miss a dose of Everolimus or Everolimus Dispersible , you may still take it up to 6 hours after the time you normally take it. If it is more than 6 hours after you normally take your Everolimus or Everolimus Dispersible , skip the dose for that day. The next day, take Everolimus or Everolimus Dispersible at your usual time. Do not take 2 doses to make up for a missed dose. If you are not sure about what to do, call your healthcare provider.
• You should have blood tests before you start Everolimus or Everolimus Dispersible and as needed during your treatment. These will include tests to check your blood cell count, kidney and liver function, cholesterol, and blood sugar levels.
• If you take Everolimus or Everolimus Dispersible to treat SEGA, you will also need to have blood tests regularly to measure how much medicine is in your blood. This will help your healthcare provider decide how much Everolimus or Everolimus Dispersible you need to take.

What should I avoid while taking Everolimus or Everolimus Dispersible?

You should not drink grapefruit juice or eat grapefruit during your treatment with Everolimus or Everolimus Dispersible . It may make the amount of Everolimus in your blood increase to a harmful level.

What are the possible side effects of Everolimus or Everolimus Dispersible?

Everolimus and Everolimus Dispersible can cause serious side effects.

• See “What is the most important information I should know about Everolimus and Everolimus Dispersible ?” for more information.
• Delayed wound healing. Everolimus can cause incisions to heal slowly or not heal well. Call your healthcare provider right away if you have any of the following symptoms:
  • your incision is red, warm or painful
  • blood, fluid, or pus in your incision
  • your incision opens up
  • swelling of your incision

Common side effects of Everolimus in people with advanced hormone receptor-positive, HER 2-negative breast cancer, advanced pancreatic neuroendocrine tumors, and advanced kidney cancer include:

• Mouth ulcers. Everolimus can cause mouth ulcers and sores. Tell your healthcare provider if you have pain, discomfort, or open sores in your mouth. Your healthcare provider may tell you to use a special mouthwash or mouth gel that does not contain alcohol, peroxide, iodine, or thyme.
• Infections
• Feeling weak or tired
• Cough, shortness of breath
• Diarrhea and constipation
• Rash, dry skin, and itching
• Nausea and vomiting
• Fever
• Loss of appetite, weight loss
• Swelling of arms, hands, feet, ankles, face or other parts of the body
• Abnormal taste
• Dry mouth
• Inflammation of lining of the digestive system
• Headache
• Nose bleeds
• Pain in arms and legs, mouth and throat, back or joints
• High blood glucose
• High blood pressure
• Difficulty sleeping
• Hair loss
• Muscle spasms
• Feeling dizzy
• Nail disorders

Common side effects of Everolimus and Everolimus Dispersible in people who have SEGA or renal angiomyolipoma with TSC include:

• Mouth ulcers. Everolimus can cause mouth ulcers and sores. Tell your healthcare provider if you have pain, discomfort, or open sores in your mouth. Your healthcare provider may tell you to use a special mouthwash or mouth gel that does not contain alcohol, peroxide iodine, or thyme.
• Infections
• Nausea and vomiting
• Diarrhea and constipation
• Swelling of your hands, arms, legs, and feet
• Joint pain
• Cough
• Skin problems (such as rash, acne, or dry skin)
• Fever
• Feeling tired
• Anxiety, aggression, and other abnormal behaviors
• Absence of menstrual periods (menstruation). You may miss 1 or more menstrual periods. Tell your healthcare provider if this happens.
• Low red blood cells, white blood cells or platelets
• Increased blood cholesterol level and certain other blood tests
• Increased blood sugar levels
• Decreased blood phosphate levels

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all the possible side effects of Everolimus and Everolimus Dispersible. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA.

How should I store Everolimus or Everolimus Dispersible?

• Store Everolimus or Everolimus Dispersible at room temperature, between 68°F to 77°F (20°C to 25°C).
• Keep Everolimus or Everolimus Dispersible in the pack it comes in.
• Open the blister pack just before taking Everolimus or Everolimus Dispersible.
• Keep Everolimus or Everolimus Dispersible dry and away from light.
• Do not use Everolimus or Everolimus Dispersible that is out of date or no longer needed.

Keep Everolimus or Everolimus Dispersible and all medicines out of the reach of children.

What are the ingredients in Everolimus?

Active ingredient: everolimus.
Inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate.

What are the ingredients in Everolimus Dispersible?

Active ingredient: everolimus.
Inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose.

Everolimus
Everolimus 5mg/10mg Tablets

INDICATIONS AND USAGE

Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC)
Everolimus is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

Advanced Neuroendocrine Tumors of Pancreatic Origin (PNET)
Everolimus is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.

Everolimus is not indicated for the treatment of patients with functional carcinoid tumors.

Advanced Renal Cell Carcinoma (RCC)
Everolimus is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.

Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC)
Everolimus is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

The effectiveness of Everolimus in the treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes.

Subependymal Giant Cell Astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC)
Everolimus Tablets and Everolimus Dispersible are indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

The effectiveness of Everolimus Tablets and Everolimus Dispersible is based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in patients with SEGA and TSC have not been demonstrated.

DOSAGE AND ADMINISTRATION

Everolimus is available in two dosage forms: tablets (Everolimus Tablets) and tablets for oral suspension (Everolimus Dispersible)

• Everolimus Tablets may be used for all approved indications.
• Everolimus Dispersible is approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC).

Recommended Dose in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced PNET, Advanced RCC, and Renal Angiomyolipoma with TSC
The recommended dose of Everolimus Tablets is 10 mg, to be taken once daily at the same time every day. Administer either consistently with food or consistently without food [see Clinical Pharmacology (12.3)]. Everolimus Tablets should be swallowed whole with a glass of water. Do not break or crush tablets.

Continue treatment until disease progression or unacceptable toxicity occurs.

Dose Modifications in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced PNET, Advanced RCC, and Renal Angiomyolipoma with TSC
Adverse Reactions
Management of severe or intolerable adverse reactions may require temporary dose interruption (with or without a dose reduction of Everolimus therapy) or discontinuation. If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered.

Table 1 summarizes recommendations for dose reduction, interruption or discontinuation of Everolimus in the management of adverse reactions. General management recommendations are also provided as applicable. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Hepatic Impairment
Hepatic impairment will increase the exposure to everolimus. Dose adjustments are recommended:

• Mild hepatic impairment (Child-Pugh class A) – The recommended dose is 7.5 mg daily; the dose may be decreased to 5 mg if not well tolerated.
• Moderate hepatic impairment (Child-Pugh class B) – The recommended dose is 5 mg daily; the dose may be decreased to 2.5 mg if not well tolerated.
• Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily may be used but must not be exceeded.

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

CYP3A4/P-glycoprotein (PgP) Inhibitors
Avoid the use of strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole).

Use caution when co-administered with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4/PgP inhibitor, reduce the Everolimus dose to 2.5 mg daily. The reduced dose of Everolimus is predicted to adjust the area under the curve (AUC) to the range observed without inhibitors. An Everolimus dose increase from 2.5 mg to 5 mg may be considered based on patient tolerance. If the moderate inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the Everolimus dose is increased. If the moderate inhibitor is discontinued, the Everolimus dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor.

Grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment.

Strong CYP3A4/PgP Inducers 
Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). If patients require co-administration of a strong CYP3A4/PgP inducer, consider doubling the daily dose of Everolimus using increments of 5 mg or less. This dose of Everolimus is predicted, based on pharmacokinetic data, to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4/PgP inducers. If the strong inducer is discontinued, consider a washout period of 3 to 5 days, before the Everolimus dose is returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer.

St. John’s Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided.

Recommended Dose in SEGA with TSC
The recommended starting dose is 4.5 mg/m2, once daily. The recommended starting dose for patients with severe hepatic impairment (Child-Pugh class C) or requiring moderate CYP3A4/PgP inhibitors is 2.5 mg/m2, once daily. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is 9 mg/m2, once daily. Round dose to the nearest strength of either Everolimus Tablets or Everolimus Dispersible.

Do not combine Everolimus Tablets and Everolimus Dispersible to achieve the desired total dose.

Use therapeutic drug monitoring to guide subsequent dosing. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5 to 15 ng/mL.

Continue treatment until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown.

Therapeutic Drug Monitoring in SEGA with TSC
Monitor everolimus whole blood trough levels routinely in all patients. When possible, use the same assay and laboratory for therapeutic drug monitoring throughout treatment.

Assess trough concentrations approximately 2 weeks after initiation of treatment, a change in dose, a change in co-administration of CYP3A4/PgP inducers and/or inhibitors, a change in hepatic function, or a change in dosage form between Everolimus Tablets and Everolimus Dispersible. Once a stable dose is attained, monitor trough concentrations every 3 to 6 months in patients with changing body surface area or every 6 to 12 months in patients with stable body surface area for the duration of treatment.

Titrate the dose to attain trough concentrations of 5 to 15 ng/mL.

• For trough concentrations less than 5 ng/mL, increase the daily dose by 2.5 mg (in patients taking Everolimus Tablets) or 2 mg (in patients taking Everolimus Dispersible).
• For trough concentrations greater than 15 ng/mL, reduce the daily dose by 2.5 mg (in patients taking Everolimus Tablets) or 2 mg (in patients taking Everolimus Dispersible).
• If dose reduction is required for patients receiving the lowest available strength, administer every other day.

Dose Modifications in SEGA with TSC
Adverse Reactions
Temporarily interrupt or permanently discontinue Everolimus Tablets or Everolimus Dispersible for severe or intolerable adverse reactions. If dose reduction is required when reinitiating therapy, reduce the dose by approximately 50%. If dose reduction is required for patients receiving the lowest available strength, administer every other day.

Hepatic Impairment

• Reduce the starting dose of Everolimus Tablets or Everolimus Dispersible by approximately 50% in patients with SEGA who have severe hepatic impairment (Child-Pugh class C). Adjustment to the starting dose for patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment may not be needed. Subsequent dosing should be based on therapeutic drug monitoring.
• Assess everolimus trough concentrations approximately 2 weeks after commencing treatment, a change in dose, or any change in hepatic function.

CYP3A4/P-glycoprotein (PgP) Inhibitors
Avoid the use of concomitant strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving Everolimus Tablets or Everolimus Dispersible.

For patients who require treatment with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem):

• Reduce the Everolimus Tablets or Everolimus Dispersible dose by approximately 50%. Administer every other day if dose reduction is required for patients receiving the lowest available strength and maintain trough concentrations of 5 to 15 ng/mL.
• Assess everolimus trough concentrations approximately 2 weeks after dose reduction.
• Resume the dose that was used prior to initiating the CYP3A4/PgP inhibitor 2 to 3 days after discontinuation of a moderate inhibitor. Assess the everolimus trough concentration approximately 2 weeks later.

Do not ingest foods or nutritional supplements (e.g., grapefruit, grapefruit juice) that are known to inhibit cytochrome P450 or PgP activity.

Strong CYP3A4/PgP Inducers
Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. For patients who require treatment with a strong CYP3A4/PgP inducer:

• Double the dose of Everolimus Tablets or Everolimus Dispersible and assess tolerability.
• Assess the everolimus trough concentration 2 weeks after doubling the dose and adjust the dose if necessary to maintain a trough concentration of 5 to 15 ng/mL.
• Return the Everolimus Tablets or Everolimus Dispersible dose to that used prior to initiating the strong CYP3A4/PgP inducer if the strong inducer is discontinued, and assess the everolimus trough concentrations approximately 2 weeks later.

Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity.

Administration of Everolimus Tablets in SEGA with TSC
Do not combine the 2 dosage forms (Everolimus Tablets and Everolimus Dispersible) to achieve the desired total dose. Use one dosage form or the other.

Administer Everolimus Tablets orally once daily at the same time every day. Administer either consistently with food or consistently without food.

Everolimus Tablets should be swallowed whole with a glass of water. Do not break or crush tablets.

Administration and Preparation of Everolimus Dispersible in SEGA with TSC
Wear gloves to avoid possible contact with everolimus when preparing suspensions of Everolimus Dispersible for another person.

Do not combine the 2 dosage forms (Everolimus Tablets and Everolimus Dispersible) to achieve the desired total dose. Use one dosage form or the other.

Administer Everolimus Dispersible (everolimus tablets for oral suspension) as a suspension only.

Administer Everolimus Dispersible orally once daily at the same time every day. Administer either consistently with food or consistently without food.

Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation.

Prepare suspension in water only.

Using an oral syringe:

• Place the prescribed dose of Everolimus Dispersible into a 10-mL syringe. Do not exceed a total of 10 mg per syringe. If higher doses are required, prepare an additional syringe. Do not break or crush tablets.
• Draw approximately 5 mL of water and 4 mL of air into the syringe.
• Place the filled syringe into a container (tip up) for 3 minutes, until the Everolimus Dispersible tablets are in suspension.
• Gently invert the syringe 5 times immediately prior to administration.
• After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles. Administer the entire contents of the syringe.

Using a small drinking glass:

• Place the prescribed dose of Everolimus Dispersible into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg of Everolimus Dispersible per glass. If higher doses are required, prepare an additional glass. Do not break or crush tablets.
• Allow 3 minutes for suspension to occur.
• Stir the contents gently with a spoon, immediately prior to drinking.
• After administration of the prepared suspension, add 25 mL of water and stir with the same spoon to re-suspend remaining particles. Administer the entire contents of the glass.

DOSAGE FORMS AND STRENGTHS

Everolimus (everolimus) Tablets

2.5 mg tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other.

5 mg tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other.

7.5 mg tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “7P5” on one side and “NVR” on the other.

10 mg tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other.

Everolimus Dispersible (everolimus tablets for oral suspension)

2 mg tablet for oral suspension
White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D2” on one side and “NVR” on the other.

3 mg tablet for oral suspension
White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D3” on one side and “NVR” on the other.

5 mg tablet for oral suspension
White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D5” on one side and “NVR” on the other.

CONTRAINDICATIONS

Everolimus is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

WARNINGS AND PRECAUTIONS

Non-infectious Pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Everolimus. Non-infectious pneumonitis was reported in up to 19% of patients treated with Everolimus in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue Everolimus therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis.

If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. Everolimus may be reintroduced at a daily dose approximately 50% lower than the dose previously administered.

For cases of Grade 3 non-infectious pneumonitis interrupt Everolimus until resolution to less than or equal to Grade 1. Everolimus may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances. If toxicity recurs at Grade 3, consider discontinuation of Everolimus. For cases of Grade 4 non-infectious pneumonitis, discontinue Everolimus. Corticosteroids may be indicated until clinical symptoms resolve. The development of pneumonitis has been reported even at a reduced dose.

Infections
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking Everolimus. Some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with Everolimus. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with Everolimus. While taking Everolimus, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Everolimus. If a diagnosis of invasive systemic fungal infection is made, discontinue Everolimus and treat with appropriate antifungal therapy.

Oral Ulceration
Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with Everolimus at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of patients. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme- containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed.

Renal Failure
Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Everolimus.

Impaired Wound Healing
Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of Everolimus in the peri-surgical period.

Geriatric Patients
In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last Everolimus dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended.

Laboratory Tests and Monitoring

Renal Function
Elevations of serum creatinine and proteinuria have been reported in patients taking Everolimu. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of Everolimus therapy and periodically thereafter. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.

Blood Glucose and Lipids
Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking Everolimus. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of Everolimus therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when Everolimus is co-administered with other drugs that may induce hyperglycemia. When possible, optimal glucose and lipid control should be achieved before starting a patient on Everolimus.

Hematologic Parameters
Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients taking Everolimus. Monitoring of complete blood count is recommended prior to the start of Everolimus therapy and periodically thereafter.

Drug-drug Interactions
Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4/PgP inhibitors should be avoided.

A reduction of the Everolimus dose is recommended when co-administered with a moderate CYP3A4/PgP inhibitor.

An increase in the Everolimus dose is recommended when co-administered with a strong CYP3A4/PgP inducer.

Hepatic Impairment
Exposure to everolimus was increased in patients with hepatic impairment.

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), Everolimus may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended.

For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of Everolimus Tablets or Everolimus Dispersible based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of Everolimus Tablets or Everolimus Dispersible by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring.

Vaccinations
During Everolimus treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

Embryo-fetal Toxicity
Based on the mechanism of action, Everolimus can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using Everolimus and for up to 8 weeks after ending treatment.

ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in another section of the label:

• Non-infectious pneumonitis.
• Infections.
• Oral ulceration
• Renal failure
• Impaired wound healing

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Clinical Study Experience in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer
The efficacy and safety of Everolimus (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93 years), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred more frequently in patients who received Everolimus plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the Everolimus plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the Everolimus plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%).

Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving Everolimus 10 mg daily versus placebo.

Key observed laboratory abnormalities are presented in Table 3.

Clinical Study Experience in Advanced Pancreatic Neuroendocrine Tumors
In a randomized, controlled trial of Everolimus (n=204) versus placebo (n=203) in patients with advanced PNET the median age of patients was 58 years (range 20-87), 79% were Caucasian, and 55% were male. Patients on the placebo arm could cross over to open-label Everolimus upon disease progression. 

The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were decreased hemoglobin, hyperglycemia, alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST). The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia.  Deaths during double-blind treatment where an adverse event was the primary cause occurred in seven patients on Everolimus and one patient on placebo. Causes of death on the Everolimus arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. There was one death due to pulmonary embolism on the placebo arm. After cross-over to open-label Everolimus, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rates of treatment-emergent adverse events resulting in permanent discontinuation were 20% and 6% for the Everolimus and placebo treatment groups, respectively. Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. Grade 3-4 renal failure occurred in six patients in the everolimus arm and three patients in the placebo arm. Thrombotic events included five patients with pulmonary embolus in the everolimus arm and one in the placebo arm as well as three patients with thrombosis in the everolimus arm and two in the placebo arm.

Table 4 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus 10 mg daily versus placebo. 

In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) Everolimus-treated females and none of the 33 females in the placebo group.

Key observed laboratory abnormalities are presented in Table 5. 

Clinical Study Experience in Advanced Renal Cell Carcinoma
The data described below reflect exposure to Everolimus (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving Everolimus and 60 days (range 21-295 days) for those receiving placebo.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Everolimus arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the Everolimus and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during Everolimus treatment were for infections, anemia, and stomatitis.

Table 6 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Other notable adverse reactions occurring more frequently with Everolimus than with placebo, but with an incidence of < 10% include:

• Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)
• General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%)
• Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)
• Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%)
• Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%)
• Psychiatric disorders: Insomnia (9%)
• Nervous system disorders: Dizziness (7%), paresthesia (5%)
• Eye disorders: Eyelid edema (4%), conjunctivitis (2%)
• Vascular disorders: Hypertension (4%), deep vein thrombosis (< 1%)
• Renal and urinary disorders: Renal failure (3%)
• Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%)
• Musculoskeletal and connective tissue disorders: Jaw pain (3%)
• Hematologic disorders: Hemorrhage (3%)

Key laboratory abnormalities are presented in Table 7.

Clinical Study Experience in Renal Angiomyolipoma with Tuberous Sclerosis Complex
The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial of Everolimus in 118 patients with renal angiomyolipoma as a feature of TSC (n=113) or sporadic lymphangioleiomyomatosis (n=5). The median age of patients was 31 years (range 18 to 61 years), 89% were Caucasian, and 34% were male. The median duration of blinded study treatment was 48 weeks (range 2 to 115 weeks) for patients receiving Everolimus and 45 weeks (range 9 to 115 weeks) for those receiving placebo.

The most common adverse reaction reported for Everolimus (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia.

The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the Everolimus-treated patients. Adverse reactions leading to permanent discontinuation in the Everolimus arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of Everolimus-treated patients. The most common adverse reaction leading to Everolimus dose adjustment was stomatitis.

Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus and occurring more frequently with Everolimus than with placebo. Laboratory abnormalities are described separately in Table 9.

Amenorrhea occurred in 15% of Everolimus-treated females (8 of 52) and 4% (1 of 26) of females in the placebo group. Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%).

The following additional adverse reactions occurred in less than 10% of Everolimus-treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), and pneumonitis (1%).

Clinical Study Experience in Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis Complex
The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (Study 1) of Everolimus in 117 patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). The median age of patients was 9.5 years (range 0.8 to 26 years), 93% were Caucasian, and 57% were male. The median duration of blinded study treatment was 52 weeks (range 24 to 89 weeks) for patients receiving Everolimus and 47 weeks (range 14 to 88 weeks) for those receiving placebo.

The most common adverse reactions reported for Everolimus (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common key laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was neutropenia.

There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of Everolimus-treated patients. The most common adverse reaction leading to Everolimus dose adjustment was stomatitis.

Table 10 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus and occurring more frequently with Everolimus than with placebo. Laboratory abnormalities are described separately in Table 11.

Amenorrhea occurred in 17% of Everolimus-treated females aged 10 to 55 years (3 of 18) and none of the females in the placebo group. For this same group of Everolimus-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%).

The following additional adverse reactions occurred in less than 10% of Everolimus-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%) and pneumonitis (1%).

Longer-term follow-up of 34.2 months (range 4.7 to 47.1 months) from a non-randomized, open-label, 28-patient trial resulted in the following additional notable adverse reactions and key laboratory abnormalities: cellulitis (29%), hyperglycemia (25%), and elevated creatinine (14%).

Postmarketing Experience
The following adverse reactions have been identified during post approval use of Everolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: acute pancreatitis.

DRUG INTERACTIONS

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Agents That May Increase Everolimus Blood Concentrations

CYP3A4 Inhibitors and PgP Inhibitors
In healthy subjects, compared to Everolimus treatment alone there were significant increases in everolimus exposure when Everolimus was coadministered with:

• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.
  
• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively.
  
• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively.

Concomitant strong inhibitors of CYP3A4/PgP should not be used.

Use caution when Everolimus is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the Everolimus dose.

Agents That May Decrease Everolimus Blood Concentrations

CYP3A4/PgP Inducers
In healthy subjects, co-administration of Everolimus with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of Everolimus when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided.

Drugs That May Have Their Plasma Concentrations Altered by Everolimus
Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between Everolimus and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of Everolimus.

A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf).

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category D 

Risk Summary
Based on the mechanism of action, Everolimus can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus.

Animal Data
In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Nursing Mothers
It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use
Pediatric use of Everolimus Tablets and Everolimus Dispersible is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of Everolimus Tablets and Everolimus Dispersible have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA.

The effectiveness of Everolimus in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of Everolimus on growth and pubertal development are unknown.

Study 1 was a randomized, double-blind, multicenter trial comparing Everolimus (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued Everolimus due to infection. Subgroup analyses showed reduction in SEGA volume with Everolimus treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of Everolimus (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar. Subgroup analyses showed reductions in SEGA volume with Everolimus treatment in all pediatric age subgroups.

Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA.The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA.

Geriatric Use
In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of Everolimus-treated patients were ≥ 65 years of age, while 15% were 75 years and over. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last Everolimus dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age.

In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of Everolimus treated patients were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of Everolimus-treated patients were ≥ 65 years of age, while 7% were 75 years and over.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended.

Females and Males of Reproductive Potential
Contraception
Females
Everolimus can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving Everolimus and for up to 8 weeks after ending treatment.

Infertility
Females
Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking Everolimus. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with Everolimus.

Males
Everolimus treatment may impair fertility in male patients based on animal findings.

Renal Impairment
No clinical studies were conducted with Everolimus in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment.

Hepatic Impairment
The safety, tolerability and pharmacokinetics of Everolimus were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment.

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, Everolimus may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended.

For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of Everolimus Tablets or Everolimus Dispersible by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring.

OVERDOSAGE

In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

DESCRIPTION

Everolimus (everolimus), an inhibitor of mammalian target of rapamycin (mTOR), is an antineoplastic agent.

The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone.

The molecular formula is C53H83NO14 and the molecular weight is 958.2. The structural formula is:

Everolimus Tablets are supplied for oral administration and contain 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus. The tablets also contain anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate as inactive ingredients.

Everolimus Dispersible (everolimus tablets for oral suspension) is supplied for oral administration and contains 2 mg, 3 mg, or 5 mg of everolimus. The tablets for oral suspension also contain butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose as inactive ingredients.

CLINICAL PHARMACOLOGY

Mechanism of Action
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivostudies.

Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner.

Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body.

Pharmacodynamics
Exposure Response Relationships
Markers of protein synthesis show that inhibition of mTOR is complete after a 10 mg daily dose.

In patients with SEGA, higher everolimus trough concentrations appear to be associated with larger reductions in SEGA volume. However, as responses have been observed at trough concentrations as low as 5 ng/mL, once acceptable efficacy has been achieved, additional dose increase may not be necessary.

Pharmacokinetics
Absorption
After administration of Everolimus tablets in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.

Dose Proportionality in Patients with SEGA and TSC: In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.

Food effect: In healthy subjects, high-fat meals reduced systemic exposure to Everolimus 10 mg tablet (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light-fat meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post absorption phase concentration-time profile.

Relative bioavailability of Everolimus Dispersible (everolimus tablets for oral suspension): The AUC0-∞ of Everolimus Dispersible was equivalent to that of Everolimus Tablets; the Cmax of this dosage form was 20%-36% lower than that of Everolimus Tablets. The predicted trough concentrations at steady-state were similar after daily administration.

Distribution
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given Everolimus 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.

Metabolism
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.

In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan.

Elimination
No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours.

Patients with Renal Impairment
Approximately 5% of total radioactivity was excreted in the urine following a 3 mg dose of [14C]-labeled everolimus. In a population pharmacokinetic analysis which included 170 patients with advanced cancer, no significant influence of creatinine clearance (25–178 mL/min) was detected on oral clearance (CL/F) of everolimus.

Patients with Hepatic Impairment
The safety, tolerability and pharmacokinetics of Everolimus were evaluated in a single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Compared to normal subjects (N=13), there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in exposure (i.e. AUC) for subjects with mild (Child-Pugh class A, n=6), moderate (Child-Pugh class B, n=9), and severe (Child-Pugh class C, n=6) hepatic impairment, respectively. In another study, the average AUC of everolimus in eight subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in eight subjects with normal hepatic function.

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, Everolimus may be used at a reduced dose if the desired benefit outweighs the risk. For patients with moderate or mild hepatic impairment, a dose reduction is recommended.

For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of Everolimus Tablets or Everolimus Dispersible based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of Everolimus Tablets or Everolimus Dispersible by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring.

Effects of Age and Gender
In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent between oral clearance and patient age or gender.

In patients with SEGA, the geometric mean Cmin values normalized to mg/m2 dose in patients aged < 10 years and 10 to 18 years were lower by 54% and 40%, respectively, than those observed in adults (> 18 years of age), suggesting that everolimus clearance normalized to body surface area was higher in pediatric patients as compared to adults.

Ethnicity
Based on a cross-study comparison, Japanese patients (n=6) had on average exposures that were higher than non-Japanese patients receiving the same dose.

Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% higher in black patients than in Caucasians.

The significance of these differences on the safety and efficacy of everolimus in Japanese or black patients has not been established.

QT/QTc Prolongation Potential
In a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of Everolimus (20 mg and 50 mg) and placebo. There is no indication of a QT/QTc prolonging effect of Everolimus in single doses up to 50 mg.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility
Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding respectively to 3.9 and 0.2 times the estimated clinical exposure (AUC0-24h) at the 10 mg daily human dose.

Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m2/day, approximately 255-fold the 10 mg daily human dose, and 103-fold the maximum dose administered to patients with SEGA, based on the body surface area), administered as 2 doses, 24 hours apart.

Based on non-clinical findings, male fertility may be compromised by treatment with Everolimus. In a 13-week male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. These doses result in exposures which are within the range of therapeutic exposure (52 ng•hr/mL and 414 ng•hr/mL respectively compared to 560 ng•hr/mL human exposure at 10 mg/day), and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at the AUC0-24h values below that of therapeutic exposure (approximately 10%-81% of the AUC0-24h in patients receiving the 10 mg daily dose). After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60% (12/20 mated females were pregnant).

Oral doses of everolimus in female rats at ≥0.1 mg/kg (approximately 4% the AUC0-24h in patients receiving the 10 mg daily dose) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.

Animal Toxicology and/or Pharmacology
In juvenile rat toxicity studies, dose-related delayed attainment of developmental landmarks including delayed eye-opening, delayed reproductive development in males and females and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day.

CLINICAL STUDIES

Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer
A randomized, double-blind, multicenter study of Everolimus plus exemestane versus placebo plus exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER 2/neu-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomization was stratified by documented sensitivity to prior hormonal therapy (yes versus no) and by the presence of visceral metastasis (yes versus no). Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. Patients were permitted to have received 0-1 prior lines of chemotherapy for advanced disease.

The primary endpoint for the trial was progression-free survival (PFS) evaluated by Response Evaluation Criteria In Solid Tumors (RECIST), based on investigator (local radiology) assessment. Other endpoints included overall survival (OS), objective response rate (ORR), and safety.

Patients were randomly allocated in a 2:1 ratio to Everolimus 10 mg/day plus exemestane 25 mg/day (n = 485) or to placebo plus exemestane 25 mg/day (n = 239). The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics. Patients were not permitted to cross over to Everolimus at the time of disease progression.

The median progression-free survival by investigator assessment at the time of the final PFS analysis was 7.8 and 3.2 months in the Everolimus and placebo arms, respectively [HR = 0.45 (95% CI: 0.38, 0.54), one-sided log-rank p < 0.0001] (see Table 12 and Figure 1). The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment. PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy.

Objective response rate was 12.6% (95% CI: 9.8, 15.9) in the Everolimus plus exemestane arm versus 1.7% (95% CI: 0.5, 4.2) in the placebo plus exemestane arm. There were 3 complete responses (0.6%) and 58 partial responses (12.0%) in the Everolimus plus exemestane arm. There were no complete responses and 4 partial responses (1.7%) in the placebo plus exemestane arm.

The overall survival results were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted [HR=0.77 (95% CI: 0.57, 1.04)].

Figure 1: Kaplan-Meier Progression-free Survival Curves (Investigator Radiological Review)

Advanced Neuroendocrine Tumors
Locally Advanced or Metastatic Advanced Pancreatic Neuroendocrine Tumors (PNET)
A randomized, double-blind, multi-center trial of Everolimus plus best supportive care (BSC) versus placebo plus BSC was conducted in patients with locally advanced or metastatic advanced pancreatic neuroendocrine tumors (PNET) and disease progression within the prior 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes versus no) and by WHO performance status (0 versus 1 and 2). Treatment with somatostatin analogs was allowed as part of BSC. The primary endpoint for the trial was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). After documented radiological progression, patients could be unblinded by the investigator; those randomized to placebo were then able to receive open-label Everolimus. Other endpoints included safety, objective response rate [ORR (complete response (CR) or partial response (PR)], response duration, and overall survival.

Patients were randomized 1:1 to receive either Everolimus 10 mg/day (n=207) or placebo (n=203). Demographics were well balanced (median age 58 years, 55% male, 79% Caucasian). Cross-over from placebo to open-label Everolimus occurred in 73% (148/203) of patients.

The trial demonstrated a statistically significant improvement in PFS (median 11.0 months versus 4.6 months), resulting in a 65% risk reduction in investigator-determined PFS (HR 0.35; 95%CI: 0.27 to 0.45; p<0.001) (see Table 13 and Figure 2). PFS improvement was observed across all patient subgroups, irrespective of prior somatostatin analog use. The PFS results by investigator radiological review, central radiological review and adjudicated radiological review are shown below in Table 13.

Figure 2: Kaplan-Meier Investigator-Determined Progression-free Survival Curves

Investigator-determined response rate was low (4.8%) in the Everolimus arm and there were no complete responses. The overall survival results are not yet mature and no statistically significant treatment-related difference in OS was noted [HR=1.05 (95% CI: 0.71 to 1.55)]. 

Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors
The safety and effectiveness of Everolimus in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated. In a randomized (1:1), double-blind, multi-center trial in 429 patients with carcinoid tumors, Everolimus plus depot octreotide (Sandostatin LAR) was compared to placebo plus depot octreotide. After documented radiological progression, patients on the placebo arm could receive Everolimus; of those randomized to placebo, 143 (67%) patients received open-label Everolimus plus depot octreotide. The study did not meet its primary efficacy endpoint of a statistically significant improvement in PFS and the final analysis of OS favored the placebo plus depot octreotide arm.

Advanced Renal Cell Carcinoma
An international, multi-center, randomized, double-blind trial comparing Everolimus 10 mg daily and placebo, both in conjunction with best supportive care, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interleukin 2, or interferon-α was also permitted. Randomization was stratified according to prognostic score1 and prior anticancer therapy.

Progression-free survival (PFS), documented using Response Evaluation Criteria in Solid Tumors (RECIST) was assessed via a blinded, independent, central radiologic review. After documented radiological progression, patients could be unblinded by the investigator: those randomized to placebo were then able to receive open-label Everolimus 10 mg daily. 

In total, 416 patients were randomized 2:1 to receive Everolimus (n=277) or placebo (n=139). Demographics were well balanced between the 2 arms (median age 61 years; 77% male, 88% Caucasian, 74% received prior sunitinib or sorafenib, and 26% received both sequentially).

Everolimus was superior to placebo for PFS (see Table 14 and Figure 3). The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib. Final overall survival (OS) results yield a hazard ratio of 0.90 (95% CI: 0.71 to 1.14), with no statistically significant difference between the 2 treatment groups. Planned cross-over from placebo due to disease progression to open label Everolimus occurred in 111 of the 139 patients (79.9%) and may have confounded the OS benefit.

Figure 3: Kaplan-Meier Progression-free Survival Curves

Renal Angiomyolipoma with Tuberous Sclerosis Complex
A randomized (2:1), double-blind, placebo-controlled trial of Everolimus was conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n=113) or sporadic lymphangioleiomyomatosis (n=5).

The key eligibility requirements for this trial were at least one angiomyolipoma of ≥ 3 cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age ≥ 18 years. Patients received daily oral Everolimus 10 mg or matching placebo until disease progression or unacceptable toxicity. CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation. The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as a ≥ 50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion ≥ 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma related bleeding of ≥ Grade 2. Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate. Analyses of efficacy outcome measures were limited to the blinded treatment period which ended 6 months after the last patient was randomized. The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes versus no).

Of the 118 patients enrolled, 79 were randomized to Everolimus and 39 to placebo. The median age was 31 years (range 18 to 61 years), 34% were male, and 89% were Caucasian. At baseline, 17% of patients were receiving EIAEDs. On central radiology review at baseline, 92% of patients had at least 1 angiomyolipoma of ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions. The median values for the sum of all target renal angiomyolipoma lesions at baseline were 85 cm3 (range 9 to 1612 cm3) and 120 cm3 (range 3 to 4520 cm3) in the Everolimus and placebo arms respectively. Forty-six (39%) patients had prior renal embolization or nephrectomy. The median duration of follow-up was 8.3 months (range 0.7 to 24.8 months).

The renal angiomyolipoma response rate was statistically significantly higher in Everolimus-treated patients; there were 33 (41.8%) patients with angiomyolipoma responses in the Everolimus arm as compared to none in the placebo arm. Results are displayed in Table 15. The median response duration was 5.3+ months (range 2.3+ to 19.6+ months).

There were 3 patients in the Everolimus arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review. The time to angiomyolipoma progression was statistically significantly longer in the Everolimus arm (HR 0.08 [95% CI: 0.02, 0.37]; p <0.0001).

Skin lesion response rates were assessed by local investigators in 77 patients in the Everolimus arm and 37 patients in the placebo arm with skin lesions at study entry. The skin lesion response rate was statistically significantly higher in the Everolimus arm (26% versus 0, p=0.0011); all skin lesion responses were partial responses, defined as visual improvement in 50%-99% skin lesions, considering all skin lesions, durable for at least 8 weeks (Physician's Global Assessment of Clinical Condition).

Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis Complex
Study 1 was a randomized (2:1), double-blind, placebo-controlled trial of Everolimus Tablets conducted in 117 pediatric and adult patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). Eligible patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥ 1 cm in longest diameter, or new or worsening hydrocephalus. Patients randomized to the treatment arm received Everolimus Tablets at a starting dose of 4.5 mg/m2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/mL as tolerated. Everolimus/matched placebo treatment continued until disease progression or unacceptable toxicity. MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks, and annually thereafter.

The main efficacy outcome measure was SEGA response rate based on independent central radiology review. SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, and new or worsening hydrocephalus. Analysis of SEGA response rate was limited to the blinded treatment period which ended 6 months after the last patient was randomized. The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes versus no).

Of the 117 patients enrolled, 78 were randomized to Everolimus and 39 to placebo. The median age was 9.5 years (range 0.8 to 26 years; 69% were 3 to < 18 years at enrollment; 17% were < 3 years at enrollment), 57% were male, and 93% were Caucasian. At baseline, 18% of patients were receiving EIAEDs. Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥ 2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle, and 7% had radiographic evidence of hydrocephalus. The median values for the sum of all target SEGA lesions at baseline were 1.63 cm3 (range 0.18 to 25.15 cm3) and 1.30 cm3 (range 0.32 to 9.75 cm3) in the Everolimus and placebo arms respectively. Eight (7%) patients had prior SEGA-related surgery. The median duration of follow-up was 8.4 months (range 4.6 to 17.2 months).

The SEGA response rate was statistically significantly higher in Everolimus-treated patients. There were 27 (35%) patients with SEGA responses in the Everolimus arm and no SEGA responses in the placebo arm. Results are displayed in Table 16. At the time of the final analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (range 2.1 to 8.4 months). No patient in either treatment arm required surgical intervention during the course of Study 1.

With a median follow-up of 8.4 months, SEGA progression was detected in 6 of 39 (15.4%) patients randomized to receive placebo and none of the 78 patients randomized to receive Everolimus.

Study 2 was an open-label, single-arm trial conducted to evaluate the safety and efficacy of Everolimus in patients with SEGA and TSC. Serial radiological evidence of SEGA growth was required for entry. Change in SEGA volume at the end of the core 6-month treatment phase was assessed via independent central radiology review. In total, 28 patients received treatment with Everolimus; median age was 11 years (range 3-34), 61% male, 86% Caucasian. Four patients had surgical resection of their SEGA lesions with subsequent re-growth prior to receiving Everolimus treatment. After the core treatment phase, patients could continue to receive Everolimus treatment as part of an extension treatment phase where SEGA volume was assessed every 6 months. The median duration of treatment was 34.2 months (range 4.7-47.1 months).

At 6 months, nine of 28 patients (32%, 95% CI: 16% to 52%) had a ≥ 50% reduction in the tumor volume of their largest SEGA lesion. The median duration of response for these nine patients was 11.8 months (range 3.2 to 39.1 months). Seven of these nine patients had an ongoing volumetric reduction of ≥ 50% at the data cutoff.

Three of four patients who had prior surgery experienced a ≥ 50% reduction in the tumor volume of their largest SEGA lesion. One of these three patients responded by month 6. No patient developed new lesions.

REFERENCES

1. Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell cancer. J Clin Oncol (2004) 22:454-63.
   
2. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

HOW SUPPLIED/STORAGE AND HANDLING

Everolimus (everolimus) Tablets

2.5mg tablets

White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other; available in:

Blisters of 28 tablets

Each carton contains 4 blister cards of 7 tablets each

5mg tablets
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other; available in:

Blisters of 28 tablets

Each carton contains 4 blister cards of 7 tablets each

7.5 mg tablets
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “7P5” on one side and “NVR” on the other; available in:

Blisters of 28 tablets

Each carton contains 4 blister cards of 7 tablets each

10mg tablets
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other; available in:

Blisters of 28 tablets

Each carton contains 4 blister cards of 7 tablets each

Everolimus Dispersible (everolimus tablets for oral suspension)

2 mg tablets for oral suspension
White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D2” on one side and “NVR” on the other; available in:

Blisters of 28 tablets

Each carton contains 4 blister cards of 7 tablets each

3 mg tablets for oral suspension
White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D3” on one side and “NVR” on the other; available in:

Blisters of 28 tablets

Each carton contains 4 blister cards of 7 tablets each

5 mg tablets for oral suspension
White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D5” on one side and “NVR” on the other; available in:

Blisters of 28 tablets

Each carton contains 4 blister cards of 7 tablets each

Store Everolimus (everolimus) Tablets and Everolimus Dispersible (everolimus tablets for oral suspension) at 25°C (77°F); excursions permitted between 15°–30°C (59°–86°F). See USP Controlled Room Temperature. Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children.

Follow special handling and disposal procedures for anticancer pharmaceuticals.2

Everolimus Tablets and Everolimus Dispersible should not be crushed. Do not take tablets which are crushed or broken.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Non-infectious Pneumonitis
Warn patients of the possibility of developing non-infectious pneumonitis. In clinical studies, some non-infectious pneumonitis cases have been severe and occasionally fatal. Advise patients to report promptly any new or worsening respiratory symptoms.

Infections
Inform patients that they are more susceptible to infections while being treated with Everolimus and that cases of hepatitis B reactivation have been associated with Everolimus treatment. In clinical studies, some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) and occasionally fatal. Patients should be aware of the signs and symptoms of infection and should report any such signs or symptoms promptly to their physician.

Oral Ulceration
Inform patients of the possibility of developing mouth ulcers, stomatitis, and oral mucositis. In such cases, mouthwashes and/or topical treatments are recommended, but these should not contain alcohol, peroxide, iodine, or thyme.

Renal Failure
Inform patients of the possibility of developing kidney failure. In some cases kidney failure has been severe and occasionally fatal. Inform patients of the need for the healthcare provider to monitor kidney function, especially in patients with risk factors that may impair kidney function.

Impaired Wound Healing
Inform patients of the possibility of impaired wound healing or dehiscence while being treated with Everolimus.

Laboratory Tests and Monitoring
Inform patients of the need to monitor blood chemistry and hematology prior to the start of Everolimus therapy and periodically thereafter.

Drug-drug Interactions
Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements. Inform the patients to avoid concomitant administration of strong CYP3A4/PgP inhibitors or inducers while on Everolimus treatment .

Vaccinations
Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines.

Embryo-fetal Toxicity
Advise female patients of childbearing potential that Everolimus may cause fetal harm and that a highly effective method of contraception should be used during therapy with Everolimus and for up to 8 weeks after ending treatment.

Safe Handling Practices for Everolimus Dispersible
Advise patients and their caregivers to read and carefully follow the FDA approved Everolimus Dispersible “Instructions for Use”.

Dosing Instructions
Inform patients to take Everolimus Tablets orally once daily at the same time every day, either consistently with food or consistently without food. Inform patients that Everolimus Tablets should be swallowed whole with a glass of water.

Inform patients to take Everolimus Dispersible orally once daily at the same time every day as a suspension. Refer patients to the “Instructions for Use” pamphlet for additional information regarding these procedures.

Instruct patients that if they miss a dose of Everolimus, they may still take it up to 6 hours after the time they would normally take it. If more than 6 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take Everolimus at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.