Afinitor

If you develop mouth sores or ulcers, avoid using mouthwashes or applying medicines that contain alcohol, peroxide, iodine, or thyme.

Do not receive a "live" vaccine while using Afinitor, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Grapefruit and grapefruit juice may interact with Afinitor and lead to unwanted side effects. Avoid the use of grapefruit products while taking Afinitor.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Do not receive a "live" vaccine while using Zortress, or you could develop a serious infection. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Zortress may increase your risk of developing skin cancer. Avoid exposure to sunlight or tanning beds. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Grapefruit and grapefruit juice may interact with Zortress and lead to unwanted side effects. Avoid the use of grapefruit products while taking Zortress.

Many drugs can interact with Afinitor. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• an antibiotic;
• antifungal medicine;
• heart or blood pressure medication;
• medicine to treat hepatitis C, or HIV/AIDS;
• seizure medicine;
• St. John's wort;
• tuberculosis medication; or
• drugs that weaken the immune system, such as cancer medicine, steroids, and medicines to prevent organ transplant rejection.

This list is not complete and many other drugs can interact with Afinitor. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Many drugs can interact with Zortress. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with Zortress, especially:

• aprepitant, conivaptan, cyclosporine, deferiprone, imatinib, natalizumab; or
• an antibiotic--clarithromycin, dalfopristin, erythromycin, telithromycin; an antidepressant--fluvoxamine, nefazodone; antifungal medication--fluconazole, itraconazole, ketoconazole; heart or blood pressure medication--diltiazem, verapamil; HIV/AIDS medication--atazanavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir.

This list is not complete and many other drugs can interact with Zortress. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Everolimus should be taken at the same time each day. You may take everolimus with or without food, but take it the same way each time.

Do not take an Afinitor regular tablet together with an Afinitor dispersible tablet. Use only one form of this medicine.

Take the Afinitor regular tablet with a full glass of water. Do not crush, chew, or break the tablet. Swallow the pill whole.

Do not swallow the dispersible tablet (Afinitor Disperz) whole. Place it into about 2 tablespoons of water and allow the tablet to disperse in the liquid for at least 3 minutes. Stir gently and drink this mixture right away. The dispersed tablet may also be taken with an oral syringe. Wear latex gloves while handling the Afinitor Disperz tablet.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Afinitor can lower blood cells that help your body fight infections and help your blood to clot. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often.

If you have ever had hepatitis B, Afinitor can cause this condition to come back or get worse. You will need frequent blood tests to check your liver function during treatment and for several months after you stop using this medicine.

If you need surgery, tell the surgeon ahead of time that you are using Afinitor. Your surgical incisions or other wounds may take longer to heal while you are taking this medicine.

Store at room temperature in the original container, away from moisture, heat, and light. Keep each tablet in its blister pack until you are ready to take it.

Zortress is usually taken twice daily (every 12 hours). Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take the medicine with or without food, but take it the same way each time. If you also take cyclosporine or tacrolimus, take both medications at the same time.

Do not stop taking Zortress or change your dose without first talking to your doctor.

Take this medication with a full glass (8 ounces) of water.

Do not crush or chew an everolimus tablet. Swallow the pill whole.

While using Zortress, you will need frequent blood and urine tests at your doctor's office.

Store at room temperature in the original container, away from moisture, heat, and light. Keep each tablet in its blister pack until you are ready to take it.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Take the missed dose as soon as you remember. If you are more than 6 hours late, skip the missed dose. Do not take extra medicine to make up the missed dose.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

If you develop mouth sores or ulcers, avoid using mouthwashes or applying medicines that contain alcohol, peroxide, iodine, or thyme.

Do not receive a "live" vaccine while using Afinitor, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Grapefruit and grapefruit juice may interact with Afinitor and lead to unwanted side effects. Avoid the use of grapefruit products while taking Afinitor.

General

Therapeutic Drug Monitoring in Patients with SEGA and TSC

• The manufacturer recommends routine monitoring of whole blood trough everolimus concentrations for all patients.1 Use the same assay and laboratory when possible.1

• Measure trough concentrations approximately 2 weeks after initiation of everolimus treatment, any change in everolimus dosage, any change in concomitant treatment with inducers or inhibitors of CYP3A4 and/or P-glycoprotein, a change in hepatic function, or a change in dosage form between everolimus tablets (Afinitor) and everolimus tablets for oral suspension (Afinitor Disperz).1

Therapeutic Drug Monitoring in Renal Allotransplantation Patients

• The manufacturer recommends monitoring of blood everolimus and cyclosporine concentrations for all patients.13 Standard dosages of cyclosporine in combination with everolimus are associated with an increased risk of nephrotoxicity and should not be used.(See Boxed Warning and also see Nephrotoxicity under Cautions).13

• Carefully monitor clinical signs and symptoms, tissue biopsies, and laboratory parameters.13

• Carefully monitor blood everolimus concentrations in patients with hepatic impairment, patients receiving concomitant inducers or inhibitors of CYP3A4, when switching cyclosporine formulations, and/or when cyclosporine dosages are reduced according to recommended target concentrations.13

Therapeutic Drug Monitoring in Hepatic Allotransplantation Patients

• The manufacturer recommends monitoring of blood everolimus and tacrolimus concentrations for all patients.13

• Carefully monitor clinical signs and symptoms, tissue biopsies, and laboratory parameters.13

• Carefully monitor blood everolimus concentrations in patients with hepatic impairment and/or in patients receiving concomitant inducers or inhibitors of CYP3A4.13

• Cyclosporine not used in combination with everolimus in patients with hepatic transplant.13

Administration

Oral Administration

Administer everolimus at the same time every day (or approximately 12 hours apart when given twice daily), either consistently with food or consistently without food.1 13

Available as tablets (Afinitor, Zortress) and as tablets for oral suspension (Afinitor Disperz).1 13 Afinitor Disperz is recommended only for treatment of SEGA with TSC.1 Do not combine everolimus tablets (Afinitor) and everolimus tablets for oral suspension (Afinitor Disperz) to achieve the desired dose; use only one dosage form.1

Tablets

Administer everolimus tablets (Afinitor, Zortress) orally once or twice daily.1 2 3 13

In patients with renal or hepatic allografts, administer twice daily at the same time as cyclosporine or tacrolimus, respectively.13

Swallow everolimus tablets whole with a glass of water; do not chew or crush.1 13

Tablets for Oral Suspension

Administer everolimus tablets for oral suspension (Afinitor Disperz) once daily.1

For administration using an oral syringe, place the prescribed dose (≤10 mg) in a 10-mL syringe; do not crush or break tablets.1 Draw approximately 5 mL of water and 4 mL of air into syringe; place syringe containing mixture in a container (tip up) for 3 minutes, until tablets are in suspension.1 Gently invert the syringe 5 times immediately prior to administration.1 Following administration, refill the syringe with 5 mL of water and 4 mL of air, swirl to suspend remaining particles, and administer entire contents of syringe.1 Prepare an additional syringe if a dose of >10 mg is required.1

For administration using a small drinking glass, place the prescribed dose (≤10 mg) in a glass (size ≤100 mL) containing approximately 25 mL of water; do not crush or break tablets.1 Allow mixture to suspend for 3 minutes.1 Gently stir the mixture with a spoon immediately prior to administration.1 Following administration, add 25 mL of water to the glass and stir with the same spoon to resuspend the remaining particles, and swallow entire contents of the glass.1 Prepare an additional glass if a dose of >10 mg is required.1

Dosage

Pediatric Patients

SEGA with TSC Initial Dosage Oral

4.5 mg/m2 once daily.1

Not studied in patients <1 year of age.1

Round dosage to the nearest strength of either everolimus tablets (Afinitor) or everolimus tablets for oral suspension (Afinitor Disperz).1 Subsequent dosing should be guided by therapeutic drug monitoring.1

Continue therapy until disease progression or unacceptable toxicity occurs.1 The optimal duration of therapy is not known.1

Therapeutic Drug Monitoring and Dosage Adjustments in SEGA with TSC Oral

Adjust dosage at 2-week intervals as needed to achieve and maintain trough blood everolimus concentrations of 5–15 ng/mL.1

Higher trough concentrations may be associated with larger reductions in SEGA volume; however, responses have been observed at trough concentrations as low as 5 ng/mL, and additional dosage increases may not be necessary once acceptable efficacy has been achieved.1

Patients with trough concentrations <5 ng/mL: Increase daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).1

Patients with trough concentrations >15 ng/mL: Reduce daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).1

If dosage reduction is required in patients receiving 2.5 mg (as Afinitor) or 2 mg (as Afinitor Disperz) daily, use alternate-day dosing.1

Once a stable dosage is attained, monitor trough concentrations every 3–6 months in patients with changing body surface area and every 6–12 months in patients with stable body surface area for the duration of treatment.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderate inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

Adults

Breast Cancer Oral

10 mg once daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

Neuroendocrine Tumors of Pancreatic Origin Oral

10 mg once daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

Renal Cell Carcinoma Oral

10 mg once daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

Renal Angiomyolipoma with TSC Oral

10 mg once daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

SEGA with TSC Initial Dosage Oral

4.5 mg/m2 once daily.1

Round dosage to the nearest strength of either everolimus tablets (Afinitor) or everolimus tablets for oral suspension (Afinitor Disperz).1 Subsequent dosing should be guided by therapeutic drug monitoring.1

Continue therapy until disease progression or unacceptable toxicity occurs.1 The optimal duration of therapy is not known.1

Therapeutic Drug Monitoring and Dosage Adjustments in SEGA with TSC Oral

Adjust dosage at 2-week intervals as needed to achieve and maintain trough blood everolimus concentrations of 5–15 ng/mL.1

Higher trough concentrations may be associated with larger reductions in SEGA volume; however, responses have been observed at trough concentrations as low as 5 ng/mL, and additional dosage increases may not be necessary once acceptable efficacy has been achieved.1

Patients with trough concentrations <5 ng/mL: Increase daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).1

Patients with trough concentrations >15 ng/mL: Reduce daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).1

If dosage reduction is required in patients receiving 2.5 mg (as Afinitor) or 2 mg (as Afinitor Disperz) daily, use alternate-day dosing.1

Once a stable dosage is attained, monitor trough concentrations every 3–6 months in patients with changing body surface area and every 6–12 months in patients with stable body surface area for the duration of treatment.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderate inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein. (See Specific Drugs and Foods under Interactions).1

Renal Allotransplantation Initial Dosage Oral

Initially, 0.75 mg twice daily, initiated as soon as possible following transplantation; used with basiliximab induction therapy and in combination with reduced-dosage cyclosporine and corticosteroids.13

Administer oral prednisone once oral medications are tolerated.13 May taper corticosteroid dosage on an individualized basis based on patient’s clinical status and allograft function.13

Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus in Renal Allotransplantation Oral

Adjust dosage based on trough blood everolimus concentrations, tolerability, individual response, change in concomitant drug therapy, and clinical situation.13 (See Interactions). May adjust maintenance dosage based on trough everolimus concentrations obtained 4–5 days after a previous dosage change in either everolimus or cyclosporine.13

Titrate dosage to attain therapeutic trough everolimus concentrations of 3–8 ng/mL.13 In clinical trials, whole blood trough concentrations ≥3 ng/mL were associated with a lower incidence of treated biopsy-proven acute rejection.13 Similar efficacy and more adverse effects observed in patients with trough everolimus concentrations of 6–12 ng/mL compared with patients with trough concentrations of 3–8 ng/mL.13

Recommended therapeutic range of 3–8 ng/mL is based on a liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay method.13 May measure concentrations by chromatographic or immunoassay methodologies; however, the measured concentrations depend on the type of assay used, and individual patient sample concentration values from different assay methodologies may not be interchangeable.13 Consider assay results with knowledge of the specific assay used.13 Maintaining communication with the laboratory performing the assay is essential.13

Therapeutic Drug Monitoring and Dosage Adjustment of Cyclosporine with Everolimus in Renal Allotransplantation Oral

Reduce cyclosporine dosage and target therapeutic range when used in combination with everolimus to minimize risk of nephrotoxicity. (See Nephrotoxicity under Cautions.)13

Adjust cyclosporine dosage based on whole blood trough concentrations.13 The recommended therapeutic ranges for cyclosporine are 100–200 ng/mL through month 1 posttransplant, 75–150 ng/mL at months 2 and 3, 50–100 ng/mL at month 4, and 25–50 ng/mL from month 6 through month 12.13

Administer cyclosporine (USP modified) as oral capsules twice daily unless administration of oral solution or IV cyclosporine cannot be avoided.13 Everolimus has not been evaluated in clinical trials with other formulations of cyclosporine.13

Initiate cyclosporine as soon as possible and no later than 48 hours after reperfusion of the graft, and adjust the dosage to target concentrations from day 5 onward.13 Adjust the treatment regimen if progressive impairment of renal function occurs.13

Data regarding everolimus dosages with reduced trough cyclosporine concentrations of 25–50 ng/mL after 12 months are limited.13

Prior to dosage reduction of cyclosporine, verify steady-state whole blood trough everolimus concentrations of ≥3 ng/mL.13 Everolimus concentrations may decrease if cyclosporine exposure is reduced.13

Hepatic Allotransplantation Initial Dosage Oral

Initially, 1 mg twice daily, initiated ≥30 days following transplantation; used in combination with reduced-dosage tacrolimus and corticosteroids.13

May taper corticosteroid dosage on an individualized basis based on patient’s clinical status and allograft function.13

Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus in Hepatic Allotransplantation Oral

Adjust dosage based on trough blood everolimus concentrations, tolerability, individual response, change in concomitant drug therapy, and clinical situation.13 (See Interactions.) May adjust maintenance dosage based on trough everolimus concentrations obtained 4–5 days after a previous dosage change.13

Titrate dosage to attain therapeutic trough everolimus concentrations of 3–8 ng/mL.13 In clinical trials, whole blood trough concentrations ≥3 ng/mL were associated with a lower incidence of treated biopsy-proven acute rejection.13 Similar efficacy and more adverse effects observed in patients with trough everolimus concentrations of 6–12 ng/mL compared with patients with trough concentrations of 3–8 ng/mL.13

Therapeutic Drug Monitoring and Dosage Adjustment of Tacrolimus with Everolimus in Hepatic Allotransplantation Oral

Reduce tacrolimus dosage and target therapeutic range when used in combination with everolimus to minimize risk of nephrotoxicity.13 (See Nephrotoxicity under Cautions.)

Adjust tacrolimus dosage based on whole blood trough concentrations.13 Recommended therapeutic range for tacrolimus is 3–5 ng/mL by 3 weeks after the first dose of everolimus (approximately month 2 posttransplant) through month 12 posttransplant.13

Administer tacrolimus as oral capsules twice daily unless administration of IV tacrolimus cannot be avoided.13

Data regarding everolimus dosages with reduced trough tacrolimus concentrations of 3–5 ng/mL after 12 months are limited.13 Prior to dosage reduction of tacrolimus, verify steady-state whole blood trough everolimus concentrations of ≥3 ng/mL.13

Tacrolimus does not affect everolimus concentrations.13

Dosage Modification for Toxicity

Adjustment of everolimus dosage and/or interruption of therapy may be required according to toxicity.1 The suggested dosage is approximately 50% lower than the previously administered daily dosage, if dosage reduction is required.1

Noninfectious Pneumonitis

In patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.

Table 1. Recommended Dosage Modifications for Noninfectious Pneumonitis with Everolimus1

Toxicity Grade	Number of Appearances	Comments
Grade 1 (asymptomatic, radiographic findings only)	Any appearance	No dosage adjustment necessary; monitor appropriately
Grade 2 (symptomatic, not interfering with activities of daily living)	1st appearance	Consider interrupting therapy until symptoms improve to grade 1 or less and initiating corticosteroids, then resume everolimus at lower daily dosage; discontinue therapy if failure to recover within 4 weeks
Grade 3 (symptomatic, interfering with activities of daily living, oxygen indicated)	1st appearance	Interrupt therapy until resolved to grade 1 or less, then may resume at lower daily dosage; rule out infection and consider initiating corticosteroids
	2nd appearance	Consider therapy discontinuance
Grade 4 (life-threatening, ventilatory support indicated)	1st appearance	Discontinue therapy permanently, rule out infection, and consider initiating corticosteroids

Stomatitis

In patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.

Table 2. Recommended Dosage Modifications for Stomatitis with Everolimus1

Toxicity Grade	Number of Appearances	Comments
Grade 1 (minimal symptoms, normal diet)	Any appearance	Continue therapy without dosage adjustment
Grade 2 (symptomatic, can eat and swallow modified diet)	1st appearance	Interrupt therapy until resolved to grade 0–1, then resume at original daily dosage
	2nd appearance	Interrupt therapy until resolved to grade 0–1, then resume at lower daily dosage
Grade 3 (symptomatic, unable to adequately aliment or hydrate orally)	1st appearance	Interrupt therapy until resolved to grade 0–1, then resume at lower daily dosage
Grade 4 (symptoms associated with life-threatening consequences)	1st appearance	Discontinue therapy permanently

Other Nonhematologic Toxicity

Excluding metabolic events; in patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.

Table 3. Recommended Dosage Modifications for Nonhematologic Toxicity with Everolimus1

Toxicity Grade	Number of Appearances	Comments
Grade 1 (mild symptoms)	Any appearance	If toxicity is tolerable, continue therapy without dosage adjustment
Grade 2 (moderate symptoms)	1st appearance	If toxicity is tolerable, continue therapy without dosage adjustment. If toxicity is intolerable, interrupt therapy until resolved to grade 0–1, then resume at original dosage
	2nd appearance	Interrupt therapy until resolved to grade 0–1, then resume at lower dosage
Grade 3 (severe symptoms)	1st appearance	Interrupt therapy until resolved to grade 0–1, then consider reinitiating therapy at lower dosage
	2nd appearance	Consider therapy discontinuance
Grade 4 (life-threatening symptoms)	1st appearance	Discontinue therapy permanently

Metabolic Events

Metabolic events include hyperglycemia and dyslipidemia; in patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.

Table 4. Recommended Dosage Modifications for Metabolic Events with Everolimus1

Toxicity Grade	Number of Appearances	Comments
Grade 1 (mild symptoms)	Any appearance	Continue therapy without dosage adjustment
Grade 2 (moderate symptoms)	Any appearance	Continue therapy without dosage adjustment
Grade 3 (severe symptoms)	1st appearance	Interrupt therapy temporarily, then resume at lower dosage
Grade 4 (life-threatening symptoms)	1st appearance	Discontinue therapy permanently

Special Populations

Hepatic Impairment

Breast Cancer, Neuroendocrine Tumors of Pancreatic Origin, Renal Cell Carcinoma, or Renal Angiomyolipoma with TSC Oral

Mild (Child-Pugh class A) hepatic impairment: 7.5 mg daily; may decrease dosage to 5 mg daily if not well tolerated.1

Moderate (Child-Pugh class B) hepatic impairment: 5 mg daily; may decrease dosage to 2.5 mg daily if not well tolerated.1

Severe (Child-Pugh class C) hepatic impairment: If potential benefit outweighs risk, may use maximum dosage of 2.5 mg daily.1

If hepatic status changes during treatment, adjust dosage accordingly.1

SEGA with TSC Oral

Mild or moderate (Child-Pugh class A or B) hepatic impairment: Adjustment of initial dosage may not be necessary; base subsequent dosage on therapeutic drug monitoring.1

Severe (Child-Pugh class C) hepatic impairment: Decrease initial dosage by approximately 50%; base subsequent dosage on therapeutic drug monitoring.1

Renal or Hepatic Allotransplantation Oral

Mild (Child-Pugh class A) hepatic impairment: Decrease initial dosage by approximately 33%; adjust subsequent dosage to attain trough concentrations of 3–8 ng/mL.13

Moderate or severe (Child-Pugh class B or C) hepatic impairment: Decrease initial dosage by approximately 50%; adjust subsequent dosage to attain trough concentrations of 3–8 ng/mL.13

Renal Impairment

Dosage adjustment not required.1 13

Geriatric Patients

Dosage adjustment not required.1 13 Close monitoring and appropriate dosage adjustments for adverse effects are recommended for Afinitor and Afinitor Disperz.1

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control while you are using this medicine and for at least 8 weeks after stopping treatment. If you think you have become pregnant while using the medicine, tell your doctor right away.

If you are planning to have children, talk with your doctor before using this medicine. This medicine may decrease fertility in men and women.

This medicine may cause a serious lung problem called noninfectious pneumonitis. Check with your doctor right away if you have chest pain, chills, a cough, a fever, shortness of breath, or trouble breathing.

Check with your doctor right away if you have agitation, confusion, decreased urine amount, dizziness, headache, irritability, muscle twitching, nausea, rapid weight gain, swelling of the face, ankles, or hands, or unusual tiredness or weakness. These may be symptoms of a serious kidney problem.

While you are being treated with everolimus, and after you stop treatment with it, do not have any immunizations (vaccines) without your doctor's approval. Everolimus may lower your body's resistance and the vaccine may not work as well or you might get the infection the vaccine is meant to prevent. In addition, you should not be around other persons living in your household who receive live virus vaccines because there is a chance they could pass the virus on to you. Some examples of live virus vaccines include measles, mumps, influenza (nasal flu vaccine), poliovirus (oral form), rotavirus, and rubella. Do not get close to them and do not stay in the same room with them for very long. If you have questions about this, talk to your doctor.

Everolimus can temporarily lower the number of white blood cells in your blood, which increases the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

This medicine may increase your risk for getting skin cancer. When you begin taking this medicine:

• Stay out of direct sunlight, especially between the hours of 10:00 AM and 3:00 PM, if possible.
• Wear protective clothing, including a hat and sunglasses.
• Apply a sunblock product that has a sun protection factor (SPF) of at least 15, or higher if you have a fair complexion.
• Apply a sunblock lipstick that has an SPF of at least 15 to protect your lips.
• Do not use sunlamps, tanning beds, or tanning booths.
• If you have any questions about this, check with your doctor.

Everolimus may cause a serious type of allergic reaction called angioedema. This may occur more often when it is used with certain heart and blood pressure medicines called ACE inhibitors (eg, captopril [Capoten®], enalapril [Vasotec®], fosinopril [Monopril®], quinapril [Accupril®], ramipril [Altace®]). Check with your doctor right away if you have a rash, itching, a large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs, trouble breathing, or chest tightness while you are using this medicine.

If you have a kidney transplant, this medicine may increase your risk for having a blood clot in the new kidney. This usually occurs within the first 30 days after the kidney transplant. Check with your doctor right away if you are making less urine, or if you have pain in your groin, lower back, side, or stomach, dark-colored urine, a fever, or nausea or vomiting.

This medicine may also prevent you from healing correctly after an injury. Call your doctor right away if you have blood, fluid, or pus in your incision, your incision opens up, or it is red, warm, painful, or swollen.

If you are taking this medicine after a kidney transplant, it may increase your risk for developing rare and serious virus infections, such as polyoma virus-associated nephropathy (PVAN), progressive multiple leukoencephalopathy (PML), and BK virus-associated nephropathy (BKVAN). The BK virus may affect how your kidneys work and cause a transplanted kidney to fail. Check with your doctor right away if you have bloody urine, a decreased frequency or amount of urine, increased thirst, loss of appetite, lower back or side pain, nausea, swelling of the face, fingers, or lower legs, trouble breathing, unusual tiredness or weakness, vomiting, or weight gain.

Everolimus may cause mouth ulcers and sores in some patients. Tell your doctor right away if you have pain, discomfort, or open sores in your mouth while you are using this medicine. You may use a special mouthwash or mouth gel to treat these ulcers. Ask your doctor what type of products to use.

This medicine may affect blood sugar levels. If you have diabetes, check with your doctor if you notice a change in your blood or urine sugar tests.

Tell your doctor if you are taking a corticosteroid or another medicine that may weaken your immune system. This may increase your risk for developing a serious infection.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's Wort) or vitamin supplements.

• Tell all of your health care providers that you take Afinitor. This includes your doctors, nurses, pharmacists, and dentists.
• You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
• Check your blood sugar as you have been told by your doctor.
• Tell your doctor if you have signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Avoid grapefruit and grapefruit juice.
• Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
• If you have mouth irritation or mouth sores, do not use mouth rinses that have alcohol, peroxide, iodine, or thyme in them. Talk with your doctor.
• This medicine may affect how wounds heal. Sometimes, people with wound healing problems have needed surgery. Call your doctor right away if you have a wound that is red, warm, painful, or swollen. Call your doctor right away if your wound opens up or if there is blood, fluid, or pus in a wound.
• Very bad and sometimes deadly lung problems have happened with Afinitor. Call your doctor right away if you have lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• This medicine may affect sperm in men. This may affect being able to father a child. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust during care and for 2 months after care ends.
• If you get pregnant while taking Afinitor or within 2 months after your last dose, call your doctor right away.
• Avoid being near anyone who has had a recent live vaccine. There are many types of live vaccines. Ask your doctor or pharmacist if you are not sure.
• This medicine may cause fertility problems. This may affect being able to have children. Talk with the doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Redness or irritation of the palms of hands or soles of feet.
• A burning, numbness, or tingling feeling that is not normal.
• Chest pain.
• Any unexplained bruising or bleeding.
• A fast heartbeat.
• A heartbeat that does not feel normal.
• Seizures.
• Very bad dizziness or passing out.
• Muscle pain or weakness.
• Period (menstrual) changes. These may include a missed period.
• Mood changes.
• Change in the way you act.
• Swelling.
• Very bad and sometimes deadly kidney problems have happened with this medicine. Call your doctor right away if you are unable to pass urine or if you have blood in the urine or a change in the amount of urine passed.

Afinitor is available in two dosage forms: tablets (Afinitor Tablets) and tablets for oral suspension (Afinitor DISPERZ).

• Afinitor Tablets may be used for all approved indications.
• Afinitor DISPERZ 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 NET, Advanced RCC, and Renal Angiomyolipoma with TSC

The recommended dose of Afinitor 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)]. Afinitor 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 NET, 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 Afinitor therapy) or discontinuation. If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered [see Warnings and Precautions (5)].

Table 1 summarizes recommendations for dose reduction, interruption or discontinuation of Afinitor 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.

Table 1: Afinitor Dose Adjustment and Management Recommendation for Adverse Reactions

a Severity grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms.
b If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously administered.
c Activities of daily living (ADL)
d Avoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as they may worsen mouth ulcers.
Adverse Reaction	Severitya	Afinitor Dose Adjustmentb and Management Recommendations
Non-infectious pneumonitis	Grade 1 Asymptomatic, radiographic findings only	No dose adjustment required. Initiate appropriate monitoring.
	Grade 2 Symptomatic, not interfering with ADLc	Consider interruption of therapy, rule out infection and consider treatment with corticosteroids until symptoms improve to ≤ Grade 1. Re-initiate Afinitor at a lower dose. Discontinue treatment if failure to recover within 4 weeks.
	Grade 3 Symptomatic, interfering with ADLc; O2 indicated	Interrupt Afinitor until symptoms resolve to ≤ Grade 1. Rule out infection, and consider treatment with corticosteroids. Consider re-initiating Afinitor at a lower dose. If toxicity recurs at Grade 3, consider discontinuation.
	Grade 4 Life-threatening, ventilatory support indicated	Discontinue Afinitor, rule out infection, and consider treatment with corticosteroids.
Stomatitis	Grade 1 Minimal symptoms, normal diet	No dose adjustment required. Manage with non-alcoholic or salt water (0.9%) mouthwash several times a day.
	Grade 2 Symptomatic but can eat and swallow modified diet	Temporary dose interruption until recovery to Grade ≤1. Re-initiate Afinitor at the same dose. If stomatitis recurs at Grade 2, interrupt dose until recovery to Grade ≤1. Re-initiate Afinitor at a lower dose. Manage with topical analgesic mouth treatments (e.g., benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without topical corticosteroids (i.e., triamcinolone oral paste).d
	Grade 3 Symptomatic and unable to adequately aliment or hydrate orally	Temporary dose interruption until recovery to Grade ≤1. Re-initiate Afinitor at a lower dose. Manage with topical analgesic mouth treatments (i.e., benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without topical corticosteroids (i.e., triamcinolone oral paste).d
	Grade 4 Symptoms associated with life-threatening consequences	Discontinue Afinitor and treat with appropriate medical therapy.
Other non-hematologic toxicities (excluding metabolic events)	Grade 1	If toxicity is tolerable, no dose adjustment required. Initiate appropriate medical therapy and monitor.
	Grade 2	If toxicity is tolerable, no dose adjustment required. Initiate appropriate medical therapy and monitor. If toxicity becomes intolerable, temporary dose interruption until recovery to Grade ≤1. Reinitiate Afinitor at the same dose. If toxicity recurs at Grade 2, interrupt Afinitor until recovery to Grade ≤1. Reinitiate Afinitor at a lower dose.
	Grade 3	Temporary dose interruption until recovery to Grade ≤1. Initiate appropriate medical therapy and monitor. Consider reinitiating Afinitor at a lower dose. If toxicity recurs at Grade 3, consider discontinuation.
	Grade 4	Discontinue Afinitor and treat with appropriate medical therapy.
Metabolic events (e.g. hyperglycemia, dyslipidemia)	Grade 1	No dose adjustment required. Initiate appropriate medical therapy and monitor.
	Grade 2	No dose adjustment required. Manage with appropriate medical therapy and monitor.
	Grade 3	Temporary dose interruption. Reinitiate Afinitor at a lower dose. Manage with appropriate medical therapy and monitor.
	Grade 4	Discontinue Afinitor and treat with appropriate medical therapy.

Hepatic Impairment

Hepatic impairment will increase the exposure to everolimus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.8)]. 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) [see Warnings and Precautions (5.9) and Drug Interactions (7.1)].

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 Afinitor dose to 2.5 mg daily. The reduced dose of Afinitor is predicted to adjust the area under the curve (AUC) to the range observed without inhibitors. An Afinitor 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 Afinitor dose is increased. If the moderate inhibitor is discontinued, the Afinitor 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 Afinitor using increments of 5 mg or less. This dose of Afinitor 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 Afinitor dose is returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer [see Warnings and Precautions (5.9) and Drug Interactions (7.2)].

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 [see Dosage and Administration (2.5)]. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is 9 mg/m2, once daily [see Dosage and Administration (2.5)]. Round dose to the nearest strength of either Afinitor Tablets or Afinitor DISPERZ.

Do not combine Afinitor Tablets and Afinitor DISPERZ to achieve the desired total dose.

Use therapeutic drug monitoring to guide subsequent dosing [see Dosage and Administration (2.4)]. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5 to 15 ng/mL [see Dosage and Administration (2.4, 2.5)].

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 Afinitor Tablets and Afinitor DISPERZ. 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 Afinitor Tablets) or 2 mg (in patients taking Afinitor DISPERZ).
• For trough concentrations greater than 15 ng/mL, reduce the daily dose by 2.5 mg (in patients taking Afinitor Tablets) or 2 mg (in patients taking Afinitor DISPERZ).
• 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 Afinitor Tablets or Afinitor DISPERZ for severe or intolerable adverse reactions. If dose reduction is required when reinitiating therapy, reduce the dose by approximately 50% [see Dosage and Administration (2.2) and Warnings and Precautions (5)]. If dose reduction is required for patients receiving the lowest available strength, administer every other day.

Hepatic Impairment

• Reduce the starting dose of Afinitor Tablets or Afinitor DISPERZ by approximately 50% in patients with SEGA who have severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.3)]. 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 [see Dosage and Administration (2.3, 2.4)].

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 Afinitor Tablets or Afinitor DISPERZ [see Warnings and Precautions (5.9) and Drug Interactions (7.1)].

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

• Reduce the Afinitor Tablets or Afinitor DISPERZ 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 [see Dosage and Administration (2.3, 2.4)].
• Assess everolimus trough concentrations approximately 2 weeks after dose reduction [see Dosage and Administration (2.3, 2.4)].
• 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 [see Dosage and Administration (2.3, 2.4)].

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 [see Warnings and Precautions (5.9) and Drug Interactions (7.2)]. For patients who require treatment with a strong CYP3A4/PgP inducer:

• Double the dose of Afinitor Tablets or Afinitor DISPERZ and assess tolerability [see Dosage and Administration (2.3)].
• 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 [see Dosage and Administration (2.3, 2.4)].
• Return the Afinitor Tablets or Afinitor DISPERZ 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 [see Dosage and Administration (2.3, 2.4)].

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 Afinitor Tablets in SEGA with TSC

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

Administer Afinitor Tablets orally once daily at the same time every day. Administer either consistently with food or consistently without food [see Clinical Pharmacology (12.3)].

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

     Administration and Preparation of Afinitor DISPERZ in SEGA with TSC

Wear gloves to avoid possible contact with everolimus when preparing suspensions of Afinitor DISPERZ for another person.

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

Administer Afinitor DISPERZ (everolimus tablets for oral suspension) as a suspension only.

Administer Afinitor DISPERZ orally once daily at the same time every day. Administer either consistently with food or consistently without food [see Clinical Pharmacology (12.3)].

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 Afinitor DISPERZ 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 Afinitor DISPERZ 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 Afinitor DISPERZ into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg of Afinitor DISPERZ 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.

     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 initiation 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 vivo studies.

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 Afinitor 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 Afinitor 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%.

In healthy subjects who received 9 mg of Afinitor DISPERZ, high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and Cmax by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and Cmax by 50%.

Relative bioavailability of Afinitor DISPERZ (everolimus tablets for oral suspension): The AUC0-∞ of Afinitor DISPERZ was equivalent to that of Afinitor Tablets; the Cmax of this dosage form was 20%-36% lower than that of Afinitor 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 Afinitor 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 [see Use in Specific Populations (8.7)].

Patients with Hepatic Impairment

The safety, tolerability and pharmacokinetics of Afinitor 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 NET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, Afinitor 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 [see Dosage and Administration (2.2)].

For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of Afinitor Tablets or Afinitor DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of Afinitor Tablets or Afinitor DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5)].

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 Afinitor (20 mg and 50 mg) and placebo. There is no indication of a QT/QTc prolonging effect of Afinitor in single doses up to 50 mg.

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.

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 [see Warnings and Precautions (5.1)].

Infections

Inform patients that they are more susceptible to infections while being treated with Afinitor and that cases of hepatitis B reactivation have been associated with Afinitor 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 [see Warnings and Precautions (5.2)].

Angioedema with Concomitant use of Angiotensin-Converting Enzyme (ACE) Inhibitors

Inform patients that they are more susceptible to angioedema if concomitantly taking angiotensin-converting enzyme (ACE) inhibitors. Patients should be aware of any signs or symptoms of angioedema and seek prompt medical attention [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.5)].

Impaired Wound Healing

Inform patients of the possibility of impaired wound healing or dehiscence while being treated with Afinitor [see Warnings and Precautions (5.6)].

Laboratory Tests and Monitoring

Inform patients of the need to monitor blood chemistry and hematology prior to the start of Afinitor therapy and periodically thereafter [see Warnings and Precautions (5.8)].

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 Afinitor treatment [see Dosage and Administration (2.2, 2.5), Warnings and Precautions (5.9), and Drug Interactions (7.1, 7.2)].

Vaccinations

Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines [see Warnings and Precautions (5.11)].

Embryo-Fetal Toxicity

Afinitor can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Afinitor, and for 8 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.12) and Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women that breastfeeding is not recommended during treatment with Afinitor and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)].

Safe Handling Practices for Afinitor DISPERZ

Advise patients and their caregivers to read and carefully follow the FDA approved Afinitor DISPERZ “Instructions for Use”.

Dosing Instructions

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

Inform patients to take Afinitor DISPERZ 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 Afinitor, 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 Afinitor at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

T2016-51
June 2016

This Patient Information has been approved by the U.S. Food and Drug Administration.	Revised: 6/2016
PATIENT INFORMATION
Afinitor® (a-fin-it-or) (everolimus) tablets	Afinitor® DISPERZ (a-fin-it-or dis-perz) (everolimus tablets for oral suspension)
Read this Patient Information leaflet that comes with Afinitor or Afinitor DISPERZ before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Afinitor and Afinitor DISPERZ? Afinitor and Afinitor DISPERZ 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. Possible increased risk for a type of allergic reaction called angioedema, in people who take an Angiotensin-Converting Enzyme (ACE) inhibitor medicine during treatment with Afinitor or Afinitor DISPERZ. Talk with your healthcare provider before taking Afinitor or Afinitor DISPERZ if you are not sure if you take an ACE inhibitor medicine. Get medical help right away if you have trouble breathing or develop swelling of your tongue, mouth, or throat during treatment with Afinitor.
4. 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 Afinitor or Afinitor DISPERZ.
If you have any of the serious side effects listed above, you may need to stop taking Afinitor or Afinitor DISPERZ for a while or use a lower dose. Follow your healthcare provider’s instructions.
What is Afinitor? Afinitor 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. adults with a type of cancer known as neuroendocrine tumor (NET) of the stomach and intestine (gastrointestinal), or lung that has progressed and cannot be treated with surgery. Afinitor 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 Afinitor DISPERZ? Afinitor DISPERZ 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 Afinitor or Afinitor DISPERZ? Do not take Afinitor or Afinitor DISPERZ if you are allergic to everolimus or to any of the ingredients in Afinitor or Afinitor DISPERZ. See the end of this leaflet for a complete list of ingredients in Afinitor and Afinitor DISPERZ. Talk to your healthcare provider before taking this medicine if you are allergic to:
sirolimus (Rapamune®) temsirolimus (Torisel®) Ask your healthcare provider if you do not know.
What should I tell my healthcare provider before taking Afinitor or Afinitor DISPERZ? Before taking Afinitor or Afinitor DISPERZ, 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 Afinitor or Afinitor DISPERZ. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. Are pregnant, or could become pregnant. Afinitor or Afinitor DISPERZ can cause harm to your unborn baby. If you are able to become pregnant you should use effective birth control during treatment and for 8 weeks after your last dose of Afinitor or Afinitor DISPERZ. Talk to your healthcare provider about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your healthcare provider right away. Are breastfeeding or plan to breastfeed. It is not known if Afinitor or Afinitor DISPERZ passes into your breast milk. Do not breastfeed during treatment and for 2 weeks after your last dose of Afinitor or Afinitor DISPERZ.
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Afinitor or Afinitor DISPERZ may affect the way other medicines work, and other medicines can affect how Afinitor or Afinitor DISPERZ work. Taking Afinitor or Afinitor DISPERZ 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 Afinitor or Afinitor DISPERZ may need to be changed. You should also tell your healthcare provider before you start taking any new medicine.
How should I take Afinitor or Afinitor DISPERZ?
Your healthcare provider will prescribe the dose of Afinitor or Afinitor DISPERZ that is right for you. Take Afinitor or Afinitor DISPERZ exactly as your healthcare provider tells you to. Your healthcare provider may change your dose of Afinitor or Afinitor DISPERZ or tell you to temporarily interrupt dosing, if needed. Take only Afinitor or Afinitor DISPERZ. Do not mix Afinitor and Afinitor DISPERZ together. Use scissors to open the blister pack.
Afinitor:
Swallow Afinitor tablets whole with a glass of water. Do not take any tablet that is broken or crushed.
Afinitor DISPERZ:
If your healthcare provider prescribes Afinitor DISPERZ 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 Afinitor DISPERZ must be prepared as a suspension before it is given. Afinitor DISPERZ 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. Wear gloves to avoid possible contact with everolimus when preparing suspensions of Afinitor DISPERZ for another person. Take Afinitor or Afinitor DISPERZ 1 time each day at about the same time. Take Afinitor or Afinitor DISPERZ the same way each time, either with food or without food. If you take too much Afinitor or Afinitor DISPERZ contact your healthcare provider or go to the nearest hospital emergency room right away. Take the pack of Afinitor or Afinitor DISPERZ with you. If you miss a dose of Afinitor or Afinitor DISPERZ, 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 Afinitor or Afinitor DISPERZ, skip the dose for that day. The next day, take Afinitor or Afinitor DISPERZ 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 Afinitor or Afinitor DISPERZ 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 Afinitor or Afinitor DISPERZ 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 Afinitor or Afinitor DISPERZ you need to take.
What should I avoid while taking Afinitor or Afinitor DISPERZ? You should not drink grapefruit juice or eat grapefruit during your treatment with Afinitor or Afinitor DISPERZ. It may make the amount of Afinitor in your blood increase to a harmful level.
What are the possible side effects of Afinitor or Afinitor DISPERZ? Afinitor and Afinitor DISPERZ can cause serious side effects.
See “What is the most important information I should know about Afinitor and Afinitor DISPERZ?” for more information. Delayed wound healing. Afinitor 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 Afinitor in people with advanced hormone receptor-positive, HER2-negative breast cancer, advanced neuroendocrine tumors of the pancreas, stomach and intestine (gastrointestinal) or lung, and advanced kidney cancer include
Mouth ulcers. Afinitor 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 Afinitor and Afinitor DISPERZ in people who have SEGA or renal angiomyolipoma with TSC include:
Mouth ulcers. Afinitor 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 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
Other side effects that may occur with Afinitor and Afinitor DISPERZ:
Absence of menstrual periods (menstruation). You may miss 1 or more menstrual periods. Tell your healthcare provider if this happens. Afinitor and Afinitor DISPERZ may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you. Afinitor and Afinitor DISPERZ may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you. 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 Afinitor and Afinitor DISPERZ. 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 at 1-800-FDA-1088.
How should I store Afinitor or Afinitor DISPERZ?
Store Afinitor or Afinitor DISPERZ at room temperature, between 68°F to 77°F (20°C to 25°C). Keep Afinitor or Afinitor DISPERZ in the pack it comes in. Open the blister pack just before taking Afinitor or Afinitor DISPERZ. Keep Afinitor or Afinitor DISPERZ dry and away from light. Do not use Afinitor or Afinitor DISPERZ that is out of date or no longer needed. Keep Afinitor or Afinitor DISPERZ and all medicines out of the reach of children.
General information about Afinitor and Afinitor DISPERZ
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Afinitor or Afinitor DISPERZ for a condition for which it was not prescribed. Do not give Afinitor or Afinitor DISPERZ to other people, even if they have the same problem you have. It may harm them. This leaflet summarizes the most important information about Afinitor and Afinitor DISPERZ. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information written for healthcare professionals. For more information call 1-888-423-4648 or go to www.Afinitor.com.
What are the ingredients in Afinitor?
Active ingredient: everolimus. Inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate.
What are the ingredients in Afinitor DISPERZ?
Active ingredient: everolimus. Inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose.
Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936
The brands listed are the trademarks or register marks of their respective owners and are not trademarks or register marks of Novartis.
© Novartis
T2016-52

Instructions For Use
Afinitor® (a-fin-it-or) DISPERZ™ (dis-perz)
(everolimus tablets for oral suspension)

Read these Instructions for Use for Afinitor DISPERZ before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

Important Information:

• Take Afinitor DISPERZ as a suspension only. Afinitor DISPERZ is prepared as a suspension of un-dissolved medicine that is mixed with water, and then it is taken by mouth. Do not chew, crush, or swallow Afinitor DISPERZ whole.
• Afinitor DISPERZ 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.
• Keep Afinitor DISPERZ and the prepared suspension out of the reach of children.
• Anyone who prepares suspensions of Afinitor DISPERZ for another person should wear gloves to avoid possible contact with the drug.
• Only use water with Afinitor DISPERZ to prepare the suspension. Do not prepare the suspension with juice or any other liquids.
• The suspension must be given right away. If you do not give the dose within 60 minutes after it has been prepared, throw away the dose and prepare a new dose of Afinitor DISPERZ.
• Before starting to prepare the suspension, collect all of the supplies that you will need to prepare and take the suspension. Do not use any of these supplies for purposes other than preparing and taking the Afinitor DISPERZ suspension.

Supplies needed to prepare the suspension in an oral syringe:

• Blister card with Afinitor DISPERZ
• Scissors to open the blister card
• Disposable gloves (for one time use)
• 2 clean drinking glasses
• Approximately 30 mL of water
• 10 mL oral syringe (for one time use) (see Figure A)
• Paper towels

Figure A

Supplies needed to prepare the suspension in a small drinking glass:

• Blister card with Afinitor DISPERZ
• Scissors to open the blister card
• Disposable gloves (for one time use)
• 30 mL dose cup for measuring water (you can ask your pharmacist for this)
• 1 clean drinking glass (maximum size 100 mL)
• Water to prepare the suspension
• Spoon for stirring
• Paper towels

Preparing a dose of Afinitor DISPERZ suspension using an oral syringe:

Step 1: Prepare a clean, flat work surface that is away from where you prepare and eat food. Place a clean paper towel on the work surface. Place the needed supplies on the paper towel.

Step 2: Wash and dry your hands well before preparing the medicine (see Figure B).

Figure B

Step 3: If preparing the Afinitor DISPERZ suspension for another person, put on disposable gloves (see Figure C).

Figure C

Step 4: Take a 10 mL oral syringe and pull back on the plunger. Remove the plunger from the barrel of the syringe (see Figure D).

Figure D

Step 5: Use scissors to open the blister card along the dotted line (see Figure E) and remove the prescribed number of Afinitor DISPERZ tablets for oral suspension from the blister card. Place them into the barrel of the oral syringe (see Figure F).

Figure E

Figure F

• Doses of up to 10 mg can be prepared with the oral syringe. If your total prescribed dose is more than 10 mg, you will need to split the dose. Follow steps 4 through 17 for the first half of the dose. Then repeat steps 4 through 17 for the second half of the dose. Do not prepare a dose of more than 10 mg in one syringe. Ask your pharmacist or healthcare provider if you are not sure what to do.

Step 6: Re-insert the plunger into the barrel of the oral syringe (see Figure G) and push the plunger in until it comes into contact with the Afinitor DISPERZ tablets for oral suspension (see Figure H).

Figure G

Figure H

Step 7: Fill a small drinking glass with about 30 mL of water. Insert the tip of the oral syringe into the water. Then slowly pull back on the plunger until the syringe is about half full of water and all the tablets are covered by water (see Figure I).

Figure I

Step 8: Hold the oral syringe with the tip pointing up. Pull back on the plunger to draw back about 4 mL of air (see Figure J).

Figure J

Step 9: Place the filled oral syringe in the clean, empty glass with the tip pointing up. Wait 3 minutes to allow Afinitor DISPERZ to break apart (see Figure K).

Figure K

Step 10: Slowly turn the oral syringe up and down five times just before giving the dose (see Figure L). Do not shake the syringe.

Figure L

Step 11: Hold the oral syringe in an upright position (with the tip up). Carefully remove most of the air by pushing up gently on the plunger (see Figure M).

Figure M

Step 12: Give the full contents of the oral syringe slowly and gently into the mouth right away, within 60 minutes of preparing it (see Figure N). Carefully remove the syringe from the mouth. Continue with steps 13 through 17 to make sure that the entire dose of medicine is given.

Figure N

Step 13: Insert the tip of the oral syringe into the drinking glass that is filled with water, and pull up about 5 mL of water by slowly pulling back on the plunger (see Figure O).

Figure O

Step 14: Hold the oral syringe with the tip pointing up and use the plunger to draw back about 4 mL of air (see Figure P).

Figure P

Step 15: With the tip of the syringe still pointing up, swirl the contents by gently rotating the syringe in a circular motion (see Figure Q).

Figure Q

Step 16: Hold the oral syringe in an upright position (with the tip up). Carefully remove most of the air by pushing up gently on the plunger (see Figure R).

Figure R

Step 17: Give the full contents of the oral syringe slowly and gently into the mouth by pushing on the plunger (see Figure S). Carefully remove the syringe from the mouth.

Figure S

If the total prescribed dose is more than 10 mg, repeat steps 4 through 17 to finish giving the dose.

Step 18: Throw away the oral syringe, paper towel, and used gloves in your household trash.

Step 19: Wash your hands.

Preparing a dose of Afinitor DISPERZ suspension using a small drinking glass:

Step 1: Prepare a clean, flat work surface that is away from where you prepare and eat food. Place a clean paper towel on the work surface. Place the needed supplies on the paper towel.

Step 2: Wash and dry your hands before preparing the medicine (See Figure T).

Figure T

Step 3: If preparing the Afinitor DISPERZ suspension for another person, put on disposable gloves (see Figure U).

Figure U

Step 4: Add about 25 mL of water to the 30 mL dose cup. The amount of water added does not need to be exact (see Figure V).

Figure V

Step 5: Pour the water from the dose cup into a small drinking glass (maximum size 100 mL) (see Figure W).

Figure W

• Doses up to 10 mg can be prepared in the small drinking glass. If your total prescribed dose is more than 10 mg you will need to split the dose. Follow steps 4 through 10 for the first half of the dose. Then repeat steps 4 through 10 for the second half of the dose. Ask your pharmacist or healthcare provider if you are not sure what to do.

Step 6: Use scissors to open the blister card along the dotted line (see Figure X) and remove the prescribed number of Afinitor DISPERZ tablets for oral suspension from the blister card.

Figure X

Step 7: Add the prescribed number of Afinitor DISPERZ tablets for oral suspension into the water (see Figure Y).

Figure Y

Step 8: Wait 3 minutes to allow Afinitor DISPERZ tablets for oral suspension to break apart (see Figure Z).

Figure Z

Step 9: Gently stir the contents of the glass with a spoon and place the spoon back on the paper towel (see Figure AA). Drink the full amount of the suspension right away, within 60 minutes of preparing it (see Figure BB).

Figure AA

Figure BB

Step 10: Refill the glass with the same amount of water (about 25 mL). Stir the contents with the same spoon and place the spoon back on the paper towel (see Figure CC). Drink the full amount right away so that you take any remaining medicine (see Figure DD).

Figure CC

Figure DD

If your total prescribed dose is more than 10 mg, repeat steps 4 through 10 to finish taking your dose.

Step 11: Wash the glass and the spoon thoroughly with water. Wipe the glass and spoon with a clean paper towel and store them in a dry and clean place until your next dose of Afinitor DISPERZ (see Figure EE).

Figure EE

Step 12: Throw away the used paper towel and gloves in your household trash.

Step 13: Wash your hands.

How should I store Afinitor DISPERZ?

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

Keep Afinitor DISPERZ and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by:
Novartis Pharma Stein AG
Stein, Switzerland

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

T2012-157
August 2012

PRINCIPAL DISPLAY PANEL

Package Label – 2.5 mg

Rx Only             NDC 0078-0594-51

Afinitor® (everolimus) Tablets

Each tablet contains

2.5 mg everolimus

28 Tablets

Carton contains 4 individual blister cards of 7 tablets.

PRINCIPAL DISPLAY PANEL

Package Label – 5 mg

Rx Only             NDC 0078-0566-51

Afinitor® (everolimus) Tablets

Each tablet contains

5 mg everolimus

28 Tablets

Carton contains 4 individual blister cards of 7 tablets.

PRINCIPAL DISPLAY PANEL

Package Label – 7.5 mg

Rx Only             NDC 0078-0620-51

Afinitor® (everolimus) Tablets

Each tablet contains

7.5 mg everolimus

28 Tablets

Carton contains 4 individual blister cards of 7 tablets.

PRINCIPAL DISPLAY PANEL

Package Label – 10 mg

Rx Only             NDC 0078-0567-51

Afinitor® (everolimus) Tablets

Each tablet contains

10 mg everolimus

28 Tablets

Carton contains 4 individual blister cards of 7 tablets.

PRINCIPAL DISPLAY PANEL

Package Label – 2 mg

Rx Only             NDC 0078-0626-51

Afinitor® DISPERZTM
(everolimus tablets for oral suspension)

TABLETS MUST BE DISPERSED IN WATER.

TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED OR CRUSHED.

28 Tablets for Oral Suspension

Carton contains 4 individual blister cards of 7 tablets.

PRINCIPAL DISPLAY PANEL

Package Label – 3 mg

Rx Only             NDC 0078-0627-51

Afinitor® DISPERZTM
(everolimus tablets for oral suspension)

TABLETS MUST BE DISPERSED IN WATER.

TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED OR CRUSHED.

28 Tablets for Oral Suspension

Carton contains 4 individual blister cards of 7 tablets.

PRINCIPAL DISPLAY PANEL

Package Label – 5 mg

Rx Only             NDC 0078-0628-51

Afinitor® DISPERZTM
(everolimus tablets for oral suspension)

TABLETS MUST BE DISPERSED IN WATER.

TABLETS MUST NOT BE SWALLOWED WHOLE, CHEWED OR CRUSHED.

28 Tablets for Oral Suspension

Carton contains 4 individual blister cards of 7 tablets.

Afinitor  everolimus tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0566 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EVEROLIMUS (EVEROLIMUS) EVEROLIMUS 5 mg

Inactive Ingredients Ingredient Name Strength BUTYLATED HYDROXYTOLUENE   CROSPOVIDONE   HYPROMELLOSES   ANHYDROUS LACTOSE   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color WHITE (White to slightly yellow) Score no score Shape OVAL (elongated with a bevelled edge) Size 12mm Flavor Imprint Code 5;NVR Contains

Packaging # Item Code Package Description 1 NDC:0078-0566-51 28 BLISTER PACK in 1 CARTON 1 NDC:0078-0566-61 1 TABLET in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022334 03/31/2009

Afinitor  everolimus tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0567 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EVEROLIMUS (EVEROLIMUS) EVEROLIMUS 10 mg

Inactive Ingredients Ingredient Name Strength BUTYLATED HYDROXYTOLUENE   CROSPOVIDONE   HYPROMELLOSES   ANHYDROUS LACTOSE   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color WHITE (White to slightly yellow) Score no score Shape OVAL (elongated with a bevelled edge) Size 15mm Flavor Imprint Code UHE;NVR Contains

Packaging # Item Code Package Description 1 NDC:0078-0567-51 28 BLISTER PACK in 1 CARTON 1 NDC:0078-0567-61 1 TABLET in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022334 03/31/2009

Afinitor  everolimus tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0594 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EVEROLIMUS (EVEROLIMUS) EVEROLIMUS 2.5 mg

Inactive Ingredients Ingredient Name Strength BUTYLATED HYDROXYTOLUENE   CROSPOVIDONE   HYPROMELLOSES   ANHYDROUS LACTOSE   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color WHITE (White to slightly yellow) Score no score Shape OVAL Size 10mm Flavor Imprint Code LCL;NVR Contains

Packaging # Item Code Package Description 1 NDC:0078-0594-51 28 BLISTER PACK in 1 CARTON 1 NDC:0078-0594-61 1 TABLET in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022334 07/09/2010

Afinitor  everolimus tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0620 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EVEROLIMUS (EVEROLIMUS) EVEROLIMUS 7.5 mg

Inactive Ingredients Ingredient Name Strength BUTYLATED HYDROXYTOLUENE   CROSPOVIDONE   HYPROMELLOSES   ANHYDROUS LACTOSE   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color WHITE (white to slightly yellow) Score no score Shape OVAL (elongated tablets with a bevelled edge) Size 15mm Flavor Imprint Code 7P5;NVR Contains

Packaging # Item Code Package Description 1 NDC:0078-0620-51 28 BLISTER PACK in 1 CARTON 1 NDC:0078-0620-61 1 TABLET in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022334 07/29/2011

Afinitor  DISPERZ everolimus tablet, for suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0626 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EVEROLIMUS (EVEROLIMUS) EVEROLIMUS 2 mg

Inactive Ingredients Ingredient Name Strength BUTYLATED HYDROXYTOLUENE   MAGNESIUM STEARATE   LACTOSE MONOHYDRATE   HYPROMELLOSES   CROSPOVIDONE   MANNITOL   CELLULOSE, MICROCRYSTALLINE   SILICON DIOXIDE

Product Characteristics Color WHITE (white to slightly yellowish) Score no score Shape ROUND Size 9mm Flavor Imprint Code D2;NVR Contains

Packaging # Item Code Package Description 1 NDC:0078-0626-51 28 BLISTER PACK in 1 CARTON 1 NDC:0078-0626-61 1 TABLET, FOR SUSPENSION in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA203985 08/29/2012

Afinitor  DISPERZ everolimus tablet, for suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0627 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EVEROLIMUS (EVEROLIMUS) EVEROLIMUS 3 mg

Inactive Ingredients Ingredient Name Strength BUTYLATED HYDROXYTOLUENE   MAGNESIUM STEARATE   LACTOSE MONOHYDRATE   HYPROMELLOSES   CROSPOVIDONE   MANNITOL   CELLULOSE, MICROCRYSTALLINE   SILICON DIOXIDE

Product Characteristics Color WHITE (white to slightly yellowish) Score no score Shape ROUND Size 10mm Flavor Imprint Code D3;NVR Contains

Packaging # Item Code Package Description 1 NDC:0078-0627-51 28 BLISTER PACK in 1 CARTON 1 NDC:0078-0627-61 1 TABLET, FOR SUSPENSION in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA203985 08/29/2012

Afinitor  DISPERZ everolimus tablet, for suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0628 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EVEROLIMUS (EVEROLIMUS) EVEROLIMUS 5 mg

Inactive Ingredients Ingredient Name Strength BUTYLATED HYDROXYTOLUENE   MAGNESIUM STEARATE   LACTOSE MONOHYDRATE   HYPROMELLOSES   CROSPOVIDONE   MANNITOL   CELLULOSE, MICROCRYSTALLINE   SILICON DIOXIDE

Product Characteristics Color WHITE Score no score Shape ROUND Size 12mm Flavor Imprint Code D5;NVR Contains

Packaging # Item Code Package Description 1 NDC:0078-0628-51 28 BLISTER PACK in 1 CARTON 1 NDC:0078-0628-61 1 TABLET, FOR SUSPENSION in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA203985 08/29/2012

Labeler - Novartis Pharmaceuticals Corporation (002147023)

Revised: 06/2016   Novartis Pharmaceuticals Corporation

>10%

Stomatitis (44%)

Constipation (38%)

Infections (37%)

Asthenia (33%)

Fatigue (31%)

Cough (30%)

Diarrhea (30%)

Rash (29%)

Anemia (26%)

Nausea (26%)

Anorexia (25%)

Edema, peripheral (25-45%)

Dyspnea (24%)

Pyrexia (20%)

Vomiting (20%)

Headache (19%)

Epistaxis (18%)

Decreased lymphocytes, Grade 3 (16%)

Increased glucose, Grade 3 (15%)

Pneumonitis (14%)

Pruritus (14%)

Dry skin (13%)

Decreased Hgb, Grade 3 (12%)

Menstrual irregularities (11%)

1-10% (selected)

Dysgeusia (10%)

Hypertension, including hypertensive crisis (4%)

Hemorrhage (3%)

Tachycardia (3%)

CHF (1%)

Postmarketing Reports

Angioedema

Pancreatitis

Cholelithiasis

Arterial thrombotic events

Reflex sympathetic dystrophy

Pulmonary embolism

Male infertility with mTOR inhibitors (including everolimus)

Gengivitis

Ovarian cyst

Renal angiomyolipoma with tuberous sclerosis complex

Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event

Hypotension

Deep vein thrombosis

Hypothyroidism

Abdominal hernia

Ascites

Gastritis

Bile duct stenosis

Cytomegalovirus

Increase in blood creatinine

Nocturia

Osteoarthritis

Hypokalemia

Hypomagnesemia

Phlebitis

Echymosis

Animal studies showed embryofetal and maternal toxicities at exposures lower than expected in humans at a dose of 10 mg daily. Toxicities included increased resorption, preimplantation and postimplantation loss, decreased number of live fetuses, malformation, and retarded skeletal development. There are no controlled data in human pregnancy. There are no controlled data in human pregnancy. It is not known whether this drug can cause fetal harm or adversely affect reproductive capacity in humans. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.

Use is not recommended. AU TGA pregnancy category: C US FDA pregnancy category: -Afinitor(R): Not assigned -Zortress(R): C Comments: Encourage use of adequate methods of contraception during treatment and for up to 8 weeks following the last dose. Risk Summary: Based on animal studies and the mechanism of action, this drug can cause fetal harm when administered to a pregnant woman.