Afinitor Disperz

Name: Afinitor Disperz

Uses of Afinitor Disperz

Afinitor Disperz is a prescription medicine used to treat certain types of brain tumors seen with a genetic condition called tuberous sclerosis complex (TSC).

This medication may be prescribed for other uses.  Ask your doctor or pharmacist for more information.

Afinitor Disperz Precautions

Afinitor Disperz can cause serious side effects including: 

Lung or breathing problems that may be severe, and can even lead to death. Tell your doctor right away if you have any of these symptoms:

  • New or worsening cough
  • Shortness of breath
  • Chest pain
  • Difficulty breathing or wheezing

Increased risk of developing 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 doctor 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
  • Skin rash
  • Joint pain and inflammation
  • Tiredness
  • Loss of appetite
  • Nausea
  • Pale stool or dark urine
  • Yellowing of the skin
  • Pain in your upper right side

Kidney failure which may be severe and can even lead to death. Your doctor will likely do tests to check your kidney function before and during your treatment with Afinitor Disperz.

Swelling under your skin especially around your mouth, eyes and in your throat (angioedema). Your chance of having swelling under your skin is higher if you take Afinitor Disperz along with certain other medicines. Tell your doctor right away or go to the nearest emergency room if you have any of these symptoms of angioedema:

  • sudden swelling of your face, mouth, throat, tongue or hands
  • hives or welts
  • itchy or painful swollen skin
  • trouble breathing

Delayed wound healing. Afinitor Disperz can cause your incision to heal slowly or not heal well. Call your doctor 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

Do not take Afinitor Disperz if you are allergic to Afinitor Disperz or to any of its ingredients. Talk to your doctor before taking this medicine if you are allergic to:

  • sirolimus (Rapamune)
  • temsirolimus (Torisel)

What should I avoid while taking 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.

Proper Use of everolimus

This section provides information on the proper use of a number of products that contain everolimus. It may not be specific to Afinitor Disperz. Please read with care.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

If you have a kidney or liver transplant, you might have to take this medicine for the rest of your life to prevent rejection of the organ. Do not change your dose or stop taking this medicine without checking first with your doctor.

This medicine comes with a patient information leaflet. Read the information carefully and make sure you understand it before taking this medicine. If you have any questions, talk to your doctor.

Take this medicine the same way every day. Take it at the same time and take it consistently either with or without food.

Swallow the regular tablet whole with a glass of water. Do not crush, break, or chew it. If you accidentally break or crush the tablet, wash your hands with water right away.

Do not swallow the tablet for suspension. It must be dissolved in water before you take the medicine. If you are preparing the oral suspension for another person, wear disposable gloves.

  • To dissolve the tablet for suspension in a small glass:
    • Use a medicine cup to measure 25 milliliters (mL) of water. Pour the water into a small glass and put the tablet in the water without breaking or crushing it. Wait 3 minutes then gently stir the mixture to break up the tablets. Drink the mixture right away. After drinking, rinse the glass with the same amount of water and drink the liquid.
  • To dissolve the tablet for suspension in an oral syringe:
    • Use a syringe that measures 10 milliliters (mL). Pull out the plunger and put the tablet in the barrel of the syringe. Replace the plunger and push it until it touches the tablet. Fill a small glass with 30 mL (2 tablespoons) of water. Place the syringe tip in the water and draw up enough water to cover the tablet and to fill half of the syringe. Hold the syringe with the tip up and draw in 4 mL of air. Place the syringe in an empty glass with the tip up and wait 3 minutes. Slowly turn the syringe up and down 5 times but do not shake it. Hold the syringe with the tip up and push the plunger to remove most of the air. Place the syringe in the mouth and slowly give the dose. Fill the syringe with 5 mL of water from the small glass. Hold the tip up and add 4 mL of air. Swirl the water in the syringe to rinse any extra medicine from the sides. Hold the syringe with the tip up and push the plunger to remove most of the air. Place the syringe in the mouth and slowly give the liquid. Use a new syringe for each dose.

Do not use the regular tablet and the tablet for suspension together. Use only one dosage form of this medicine.

You should not eat grapefruit or drink grapefruit juice while you are taking this medicine. Grapefruit and grapefruit juice may cause higher levels of everolimus in the body. This could result in more unwanted effects.

If you have a kidney transplant, everolimus will be given together with another medicine called cyclosporine. Take both medicines at the same time.

If you have a liver transplant, everolimus will be given together with another medicine called tacrolimus. Take both medicines at the same time.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (tablets):
    • For advanced breast cancer:
      • Adults—10 milligrams (mg) once a day. Your doctor may adjust your dose if needed.
      • Children—Use and dose must be determined by your doctor.
    • For advanced kidney cancer:
      • Adults—10 milligrams (mg) once a day. Your doctor may adjust your dose if needed.
      • Children—Use and dose must be determined by your doctor.
    • For advanced neuroendocrine tumors:
      • Adults—10 milligrams (mg) once a day. Your doctor may adjust your dose if needed.
      • Children—Use and dose must be determined by your doctor.
    • For angiomyolipomas:
      • Adults—10 milligrams (mg) once a day. Your doctor may adjust your dose if needed.
      • Children—Use and dose must be determined by your doctor.
    • For brain tumors (SEGA):
      • Adults and children 1 year and older—Dose is based on body size and must be determined by your doctor. The starting dose is 4.5 milligrams (mg) per square meter (m(2)) of body size once a day. Your doctor may adjust your dose if needed.
      • Children younger than 1 year—Use is not recommended.
    • For kidney transplant rejection:
      • Adults—At first, 0.75 milligram (mg) two times per day, taken 12 hours apart. Your doctor may adjust your dose if needed.
      • Children—Use and dose must be determined by your doctor.
    • For liver transplant rejection:
      • Adults—At first, 1 milligram (mg) two times per day, taken 12 hours apart. Your doctor may adjust your dose if needed.
      • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (tablets for suspension):
    • For brain tumors (SEGA):
      • Adults and children 1 year and older—Dose is based on body size and must be determined by your doctor. The starting dose is 4.5 milligrams (mg) per square meter (m(2)) of body size once a day. Your doctor may adjust your dose if needed.
      • Children younger than 1 year—Use is not recommended.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

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 the dose. But if more than 6 hours have passed, skip the missed dose and go back to your regular dosing schedule.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep the medicine in the original package until you are ready to use it. The oral suspension must be used within 60 minutes after mixing. If it is not used during this time, throw it away and prepare another dose.

Afinitor Disperz Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Bloating or swelling of the face, arms, hands, lower legs, or feet
  • bloody nose
  • chest pain or tightness
  • cough or hoarseness
  • decreased weight
  • diarrhea
  • difficult or labored breathing
  • difficulty with swallowing
  • fever or chills
  • general feeling of discomfort or illness
  • lower back or side pain
  • painful or difficult urination
  • rapid weight gain
  • sores, ulcers, or white spots on the lips, tongue, or inside the mouth
  • tingling of the hands or feet
Less common
  • Bleeding gums
  • bloody urine
  • blurred vision
  • burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
  • coughing up blood
  • extreme fatigue
  • fast, pounding, or irregular heartbeat or pulse
  • increased thirst or urination
  • irregular breathing
  • loss of appetite
  • nausea or vomiting
  • nervousness
  • nosebleeds
  • prolonged bleeding from cuts
  • red or black, tarry stools
  • red or dark brown urine
  • slow heartbeat
  • stomachache
  • sweating
  • unusual tiredness or weakness
Incidence not known
  • Agitation
  • confusion
  • depression
  • dizziness
  • hostility or irritability
  • lethargy
  • muscle twitching
  • seizures
  • stupor

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Abdominal or stomach pain
  • change in taste
  • dry skin
  • itching skin or rash
  • lack or loss of strength
  • loss of taste
  • pain in the arms or legs
  • unable to sleep
Less common
  • Back pain
  • blistering, peeling, redness, or swelling of the palms, hands, or bottoms of the feet
  • bumps on the skin
  • burning, dry, or itching eyes
  • discoloration of the fingernails or toenails
  • flushing or redness of the skin
  • full feeling
  • jaw pain
  • numbness, pain, tingling, or unusual sensations in the palms of the hands or bottoms of the feet
  • passing gas
  • redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
  • sleepiness or unusual drowsiness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

For Healthcare Professionals

Applies to everolimus: oral tablet, oral tablet dispersible

General

The most common side effects included stomatitis, infection, rash, fatigue, diarrhea, edema, peripheral edema, anemia, nausea, hyperlipidemia, headache, abdominal pain, fever, asthenia, cough, constipation, hypertension, urinary tract infection, leukopenia, and decreased appetite.[Ref]

Metabolic

Very common (10% or more): Hypercholesterolemia (up to 85%), cholesterol increased (up to 77%), glucose increased (up to 75%), alkaline phosphatase increased (up to 74%), triglycerides increased (up to 73%), bicarbonate decreased (56%), hypertriglyceridemia (up to 52%), creatinine increased (up to 50%), hypophosphatemia (up to 49%), phosphate decreased (up to 40%), calcium decreased (37%), appetite decreased (up to 30%), potassium decreased (29%), weight decreased (up to 28%), anorexia (25%), hyperlipidemia (up to 21%), hyperkalemia (18%), sodium decreased (16%), dyslipidemia (15%), hyperglycemia (14%), hypomagnesemia (14%), hypokalemia (12%), diabetes mellitus (up to 10%)
Common (1% to 10%): Dehydration, blood urea increased, acidosis, gout, hypercalcemia, hyperuricemia, hypocalcemia, hypoglycemia, hyponatremia, iron deficiency, vitamin B12 deficiency, potassium increased[Ref]

Hematologic

Very common (10% or more): Decreased hemoglobin (up to 92%), elevated partial thromboplastin time (72%), anemia (up to 61%), WBC decreased (up to 58%), lymphocytes decreased (up to 54%), platelets decreased (up to 54%), neutropenia (up to 46%), leukopenia (up to 37%), albumin decreased (up to 33%), neutrophils decreased (up to 31%), lymphopenia (up to 20%), thrombocytopenia (up to 19%)
Common (1% to 10%): Hemorrhage, leukocytosis, lymphadenopathy, pancytopenia
Uncommon (0.1% to 1%): Pure red cell aplasia[Ref]

Gastrointestinal

Very common (10% or more): Stomatitis (up to 78%), diarrhea (Up to 50%), constipation (up to 38%), abdominal pain (up to 36%), nausea (up to 32%), vomiting (up to 29%), dry mouth (up to 11%), gastroenteritis (10%)
Common (1% to 10%): Abdominal distention, dyspepsia, dysphagia, epigastric discomfort, flatulence, gastritis, gastroesophageal reflux disease, gingival hypertrophy, hematemesis, hemorrhoids, ileus, mouth ulceration, oral candidiasis, oral pain, peritonitis[Ref]

Other

Very common (10% or more): Fatigue (up to 45%), peripheral edema (up to 45%), edema (39%), asthenia (up to 33%), pyrexia (up to 31%), mucosal inflammation (19%), incision site pain (16%), procedural pain (15%)
Common (1% to 10%): Mucosal inflammation, irritability, blood lactate dehydrogenase increased, non-cardiac chest pain, chills, incisional hernia, edema[Ref]

Dermatologic

Very common (10% or more): Rash (up to 59%), cellulitis (29%), nail disorders (22%), acne (up to 22%), pruritus (up to 21%), dry skin (13%), alopecia (10%)
Common (1% to 10%): Dermatitis acneiform, erythema, folliculitis, hand-foot syndrome, hirsutism, hyperhidrosis, hypertrichosis, night sweats, onychoclasis, onychomycosis, oral herpes skin exfoliation, skin lesion, tinea pedis
Uncommon (0.1% to 1%): Angioedema, Herpes zoster[Ref]

Respiratory

Very common (10% or more): Respiratory tract infection (up to 31%), cough (up to 30%), dyspnea (up to 24%), epistaxis (up to 22%), pneumonitis (up to 19%), oropharyngeal pain (up to 11%), streptococcal pharyngitis (10%)
Common (1% to 10%): Nasopharyngitis, pharyngitis, pneumonia, pulmonary embolism, bronchitis, sinusitis, pleural effusion, rhinorrhea, atelectasis, nasal congestion, pulmonary edema, sinus congestion, wheezing
Uncommon (0.1% to 1%): Hemoptysis, acute respiratory distress syndrome[Ref]

Genitourinary

Very common (10% or more): Amenorrhea (up to 17%), urinary tract infection (up to 16%), hematuria (12%), dysuria (11%), menorrhagia (up to 10%), menstrual irregularities (up to 10%)
Common (1% to 10%): Urethritis, bladder spasm, micturition urgency, pollakiuria, polyuria, pyuria, urinary retention, erectile dysfunction ovarian cyst, scrotal edema, blood luteinizing hormone increased, vaginal hemorrhage, blood follicle stimulating hormone increased, metrorrhagia, dysmenorrhea, delayed menstruation[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (up to 20%), back pain (up to 15%), extremity pain (up to 14%), muscle spasms (up to 10%)
Common (1% to 10%): Osteomyelitis, jaw pain, joint swelling, muscular weakness, myalgia, osteonecrosis, osteopenia, osteoporosis, spondylitis[Ref]

Hepatic

Very common (10% or more): AST increased (up to 69%), ALT increased (up to 51%), hepatitis C (up to 11%), bilirubin increased (up to 10%)
Common (1% to 10%): Transaminases increased[Ref]

Nervous system

Very common (10% or more): Headache (up to 30%), dysgeusia (22%), dizziness (up to 12%)
Common (1% to 10%): Tremor, paresthesia, hemiparesis, hypoesthesia, lethargy, neuralgia, somnolence, syncope
Uncommon (0.1% to 1%): Ageusia[Ref]

Psychiatric

Very common (10% or more): Behavioral disturbances (up to 21%), insomnia (up to 17%)
Common (1% to 10%): Depression, agitation, anxiety, hallucination[Ref]

Cardiovascular

Very common (10% or more): Hypertension (up to 30%)
Common (1% to 10%): Angina pectoris, hot flush, atrial fibrillation, congestive cardiac failure, hypotension, palpitations, tachycardia, venous thromboembolism (including deep vein thrombosis)[Ref]

Immunologic

Very common (10% or more): Infections (50%)
Common (1% to 10%): BK virus infection, bacteremia, candidiasis, influenza, otitis media, sepsis[Ref]

Renal

Common (1% to 10%): Renal failure, proteinuria, pyelonephritis, hydronephrosis, interstitial nephritis, renal artery thrombosis

Ocular

Common (1% to 10%): Cataract, conjunctivitis, blurred vision, eyelid edema[Ref]

Endocrine

Common (1% to 10%): Cushingoid, hyperparathyroidism[Ref]

Hypersensitivity

Common (1% to 10%): Hypersensitivity[Ref]

Some side effects of Afinitor Disperz may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Dose Adjustments

No adjustment recommended

Precautions

US BOXED WARNINGS (Zortress(R)):
-MANAGEMENT OF IMMUNOSUPPRESSION: Only physicians experienced in immunosuppressive therapy and management of transplant patients should use Zortress(R).
-INFECTION AND MALIGNANCIES: Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression.
-KIDNEY GRAFT THROMBOSIS: Increased incidence of kidney graft thrombosis.
-ZORTRESS AND CALCINEURIN INHIBITOR-INDUCED NEPHROTOXICITY: Reduced doses of cyclosporine are required for use in combination with Zortress(R) in order to reduce nephrotoxicity.
-HEART TRANSPLANTATION: Increased mortality in a heart transplant clinical trial. Use in heart transplantation is not recommended.

Safety and efficacy have not been established in patients younger than 1 year (Afinitor(R)).
Safety and efficacy have not been established in patients younger than 18 years (Zortress(R)).

Consult WARNINGS section for additional precautions.

Side effects

The following serious adverse reactions are described elsewhere in the labeling:

  • Non-Infectious Pneumonitis [see WARNINGS AND PRECAUTIONS].
  • Infections [see WARNINGS AND PRECAUTIONS].
  • Severe Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS].
  • Angioedema with Concomitant Use of ACE inhibitors [see WARNINGS AND PRECAUTIONS].
  • Stomatitis [see WARNINGS AND PRECAUTIONS].
  • Renal Failure [see WARNINGS AND PRECAUTIONS].
  • Impaired Wound Healing [see WARNINGS AND PRECAUTIONS].
  • Metabolic Disorders [see WARNINGS AND PRECAUTIONS].
  • Myelosuppression [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

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

Hormone Receptor-Positive, HER2-Negative Breast Cancer

The safety of AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 to 93 years), and 75% were White. The median follow-up was approximately 13 months.

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

Fatal adverse reactions occurred in 2% of patients who received AFINITOR. The rate of adverse reactions resulting in permanent discontinuation was 24% for the AFINITOR arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the AFINITOR arm.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR versus placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with AFINITOR was 23.9 weeks; 33% were exposed to AFINITOR for a period of ≥ 32 weeks.

Table 6: Adverse Reactions Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2

  AFINITOR with Exemestane
N = 482

Placebo with Exemestane
N = 238

All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Gastrointestinal
Stomatitisa 67 8d 11 0.8
Diarrhea 33 2 18 0.8
Nausea 29 0.4 28 1
Vomiting 17 1 12 0.8
Constipation 14 0.4d 13 0.4
Dry mouth 11 0 7 0
General
Fatigue 36 4 27 1d
Edema peripheral 19 1d 6 0.4d
Pyrexia 15 0.2d 7 0.4d
Asthenia 13 2 4 0
Infections
Infectionsb 50 6 25 2d
Investigations
Weight loss 25 1d 6 0
Metabolism and nutrition
Decreased appetite 30 1d 12 0.4d
Hyperglycemia 14 5 2 0.4d
Musculoskeletal and connective tissue
Arthralgia 20 0.8d 17 0
Back pain 14 0.2d 10 0.8d
Pain in extremity 9 0.4d 11 2d
Nervous system
Dysgeusia 22 0.2d 6 0
Headache 21 0.4d 14 0
Psychiatric
Insomnia 13 0.2d 8 0
Respiratory, thoracic and mediastinal
Cough 24 0.6d 12 0
Dyspnea 21 4 11 1
Epistaxis 17 0 1 0
Pneumonitisc 19 4 0.4 0
Skin and subcutaneous tissue
Rash 39 1d 6 0
Pruritus 13 0.2d 5 0
Alopecia 10 0 5 0
Vascular
Hot flush 6 0 14 0
Grading according to NCI CTCAE Version 3.0
aIncludes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration
bIncludes all reported infections including, but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections.
cIncludes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis
dNo Grade 4 adverse reactions were reported.

Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2

Laboratory Parameter AFINITOR with Exemestane
N =482
Placebo with Exemestane
N = 238
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematologya
Anemia 68 6 40 1
Leukopenia 58 2b 28 6
Thrombocytopenia 54 3 5 0.4
Lymphopenia 54 12 37 6
Neutropenia 31 2b 11 2
Chemistry
Hypercholesterolemia 70 1 38 2
Hyperglycemia 69 9 44 1
Increased aspartate 69 4 45 3
transaminase (AST)
Increased alanine 51 4 29 5b
transaminase (ALT)
Hypertriglyceridemia 50 0.8b 26 0
Hypoalbuminemia 33 0.8b 16 0.8b
Hypokalemia 29 4 7 1b
Increased creatinine 24 2 13 0
Grading according to NCI CTCAE Version 3.0
aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.
bNo Grade 4 laboratory abnormalities were reported.

Topical Prophylaxis For Stomatitis

In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) concurrently with AFINITOR and exemestane. No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone mouthwash. The primary objective of this study was to assess the incidence of Grade 2 to 4 stomatitis within 8 weeks. The incidence of Grade 2 to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the BOLERO-2 trial. The incidence of Grade 1 stomatitis was 19%. No cases of Grade 3 or 4 stomatitis were reported. Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO2 trial.

Coadministration of AFINITOR/AFINITOR DISPERZ and dexamethasone alcohol-free oral solution has not been studied in pediatric patients.

Pancreatic Neuroendocrine Tumors (PNET)

In a randomized, controlled trial (RADIANT-3) of AFINITOR (n = 204) vs. placebo (n = 203) in patients with advanced PNET the median age of patients was 58 years (20 to 87 years), 79% were White, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, anemia, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased AST, hypokalemia, and thrombocytopenia.

Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on AFINITOR. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rate of adverse reactions resulting in permanent discontinuation was 20% for the AFINITOR group. Dose delay or reduction was necessary in 61% of AFINITOR patients. Grade 3-4 renal failure occurred in six patients in the AFINITOR arm. Thrombotic events included five patients with pulmonary embolus in the AFINITOR arm as well as three patients with thrombosis in the AFINITOR arm.

Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo. Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received AFINITOR was 37 weeks.

In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females.

Table 8: Adverse Reactions Reported in ≥ 10% of Patients with PNET in RADIANT-3

  AFINITOR
N = 204
Placebo
N = 203
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Gastrointestinal
Stomatitisa 70 7d 20 0
Diarrheab 50 6 25 3d
Abdominal pain 36 4d 32 7
Nausea 32 2d 33 2d
Vomiting 29 1d 21 2d
Constipation 14 0 13 0.5d
Dry mouth 11 0 4 0
General
Fatigue/malaise 45 4 27 3
Edema (general and peripheral) 39 2 12 1d
Fever 31 1 13 0.5d
Asthenia 19 3d 20 3d
Infections
Nasopharyngitis /rhinitis/URI 25 0 13 0
Urinary tract infection 16 0 6 0.5d
Investigations
Weight loss 28 0.5d 11 0
Metabolism and nutrition
Decreased appetite 30 1d 18 1d
Diabetes mellitus 10 2d 0.5 0
Musculoskeletal and connective tissue
Arthralgia 15 1 7 0.5d
Back pain 15 1d 11 1d
Pain in extremity 14 0.5d 6 1d
Muscle spasms 10 0 4 0
Nervous system
Headache/migraine 30 0.5d 15 1d
Dysgeusia 19 0 5 0
Dizziness 12 0.5d 7 0
Psychiatric
Insomnia 14 0 8 0
Respiratory, thoracic and mediastinal
Cough/productive cough 25 0.5d 13 0
Epistaxis 22 0 1 0
Dyspnea/dyspnea exertional 20 3 7 0.5d
Pneumonitisc 17 4 0 0
Oropharyngeal pain 11 0 6 0
Skin and subcutaneous
Rash 59 0.5 19 0
Nail disorders 22 0.5 2 0
Pruritus/pruritus generalized 21 0 13 0
Dry skin/xeroderma 13 0 6 0
Vascular
Hypertension 13 1 6 1d
Grading according to NCI CTCAE Version 3.0
aIncludes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation.
bIncludes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea.
cIncludes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease.
dNo Grade 4 adverse reactions were reported.

Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with PNET in RADIANT-3

Laboratory parameter AFINITOR
N = 204
Placebo
N = 203
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematology
Anemia 86 15 63 1
Lymphopenia 45 16 22 4
Thrombocytopenia 45 3 11 0
Leukopenia 43 2 13 0
Neutropenia 30 4 17 2
Chemistry
Hyperglycemia (fasting) 75 17 53 6
Increased alkaline phosphatase 74 8 66 8
Hypercholesterolemia 66 0.5 22 0
Bicarbonate decreased 56 0 40 0
Increased AST 56 4 41 4
Increased ALT 48 5 35 2
Hypophosphatemia 40 10 14 3
Hypertriglyceridemia 39 0 10 0
Hypocalcemia 37 0.5 12 0
Hypokalemia 23 4 5 0
Increased creatinine 19 2 14 0
Hyponatremia 16 1 16 1
Hypoalbuminemia 13 1 8 0
Hyperbilirubinemia 10 1 14 2
Hyperkalemia 7 0 10 0.5
Grading according to NCI CTCAE Version 3.0

Neuroendocrine Tumors (NET) Of Gastrointestinal (GI) Or Lung Origin

In a randomized, controlled trial (RADIANT-4) of AFINITOR (n = 202 treated) vs. placebo (n = 98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (22-86 years), 76% were White, and 53% were female. The median duration of exposure to AFINITOR was 9.3 months; 64% of patients were treated for > 6 months and 39% were treated for > 12 months. AFINITOR was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of AFINITOR-treated patients.

Serious adverse reactions occurred in 42% of AFINITOR-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). Adverse reactions occurring at an incidence of ≥ 10% and at > 5% absolute incidence over placebo (all Grades) or > 2% higher incidence over placebo (Grade 3 and 4) are presented in Table 10. Laboratory abnormalities are presented in Table 11.

Table 10: Adverse Reactions in ≥ 10% of AFINITOR-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4

  AFINITOR
N = 202
Placebo
N = 98
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Gastrointestinal
Stomatitisa 63 9d 22 0
Diarrhea 41 9 31 2d
Nausea 26 3 17 1d
Vomiting 15 4d 12 2d
General
Peripheral edema 39 3d 6 1d
Fatigue 37 5 36 1d
Asthenia 23 3 8 0
Pyrexia 23 2 8 0
Infections
Infectionsb 58 11 29 2
Investigations
Weight loss 22 2d 11 1d
Metabolism and nutrition
Decreased appetite 22 1d 17 1d
Nervous system
Dysgeusia 18 1d 4 0
Respiratory, thoracic and mediastinal
Cough 27 0 20 0
Dyspnea 20 3d 11 2
Pneumonitisc 16 2d 2 0
Epistaxis 13 1d 3 0
Skin and subcutaneous
Rash 30 1d 9 0
Pruritus 17 1d 9 0
Grading according to NCI CTCAE Version 4.03
aIncludes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation.
bUrinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis.
cIncludes pneumonitis and interstitial lung disease.
dNo Grade 4 adverse reactions were reported.

Table 11: Selected Laboratory Abnormalities in ≥ 10% of AFINITOR-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4

  AFINITOR
N= 202
Placebo
N=98
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematology
Anemia 81 5a 41 2a
Lymphopenia 66 16 32 2a
Leukopenia 49 2a 17 0
Thrombocytopenia 33 2 11 0
Neutropenia 32 2a 15 3a
Chemistry
Hypercholesterolemia 71 0 37 0
Increased AST 57 2 34 2a
Hyperglycemia (fasting) 55 6a 36 1a
Increased ALT 46 5 39 1a
Hypophosphatemia 43 4a 15 2a
Hypertriglyceridemia 30 3 8 1a
Hypokalemia 27 6 12 3a
Hypoalbuminemia 18 0 8 0
Grading according to NCI CTCAE Version 4.03
aNo Grade 4 laboratory abnormalities were reported.

Renal Cell Carcinoma (RCC)

The data described below reflect exposure to AFINITOR (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (27 to 85 years), 88% were White, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving AFINITOR.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia.

Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the AFINITOR group. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR versus placebo are presented in Table 12. Laboratory abnormalities are presented in Table 13.

Table 12: Adverse Reactions Reported in ≥ 10% of Patients with RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm in RECORD-1

  AFINITOR
N = 274
Placebo
N = 137
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Gastrointestinal
Stomatitisa 44 4 8 0
Diarrhea 30 2d 7 0
Nausea 26 2d 19 0
Vomiting 20 2d 12 0
Infections b 37 10 18 2
General
Asthenia 33 4 23 4
Fatigue 31 6d 27 4
Edema peripheral 25 < 1d 8 < 1d
Pyrexia 20 < 1d 9 0
Mucosal inflammation 19 2d 1 0
Respiratory, thoracic and mediastinal
Cough 30 < 1d 16 0
Dyspnea 24 8 15 3d
Epistaxis 18 0 0 0
Pneumonitisc 14 4d 0 0
Skin and subcutaneous tissue
Rash 29 1d 7 0
Pruritus 14 < 1d 7 0
Dry skin 13 < 1d 5 0
Metabolism and nutrition
Anorexia 25 2d 14 < 1d
Nervous system
Headache 19 1 9 < 1d
Dysgeusia 10 0 2 0
Musculoskeletal and connective tissue
Pain in extremity 10 1d 7 0
Grading according to NCI CTCAE Version 3.0
aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration.
bIncludes all reported infections including, but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections.
cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.
dNo Grade 4 adverse reactions were reported.

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

Gastrointestinal: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)

General: Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%)

Respiratory, thoracic and mediastinal: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)

Skin and subcutaneous tissue: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (< 1%)

Metabolism and nutrition: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%)

Psychiatric: Insomnia (9%)

Nervous system: Dizziness (7%), paresthesia (5%)

Ocular: Eyelid edema (4%), conjunctivitis (2%)

Vascular: Hypertension (4%), deep vein thrombosis (< 1%)

Renal and urinary: Renal failure (3%)

Cardiac: Tachycardia (3%), congestive cardiac failure (1%)

Musculoskeletal and connective tissue: Jaw pain (3%)

Hematologic: Hemorrhage (3%)

Table 13: Selected Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm than the Placebo Arm in RECORD-1

Laboratory parameter AFINITOR
N = 274
Placebo
N = 137
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematologya
Anemia 92 13 79 6
Lymphopenia 51 18 28 5b
Thrombocytopenia 23 1b 2 < 1
Neutropenia 14 < 1 4 0
Chemistry
Hypercholestermia 77 4b 35 0
Hypertriglyceridemia 73 < 1b 34 0
Hyperglycemia 57 16 25 2b
Increased creatinine increased 50 2b 34 0
Hypophosphatemia 37 6b 8 0
Increased AST 25 1 7 0
Increased ALT 21 1b 4 0
Hyperbilirubinemia 3 1 2 0
Grading according to NCI CTCAE Version 3.0
aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency.
bNo Grade 4 laboratory abnormalities were reported.

Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of AFINITOR in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The median age of patients was 31 years (18 to 61 years), 89% were White, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving AFINITOR.

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

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

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15.

Table 14: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2

  AFINITOR
N = 79
Placebo
N = 39
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Gastrointestinal
Stomatitisa 78 6b 23 0
Vomiting 15 0 5 0
Diarrhea 14 0 5 0
General
Peripheral edema 13 0 8 0
Infections
Upper respiratory tract infection 11 0 5 0
Musculoskeletal and connective tissue
Arthralgia 13 0 5 0
Respiratory, thoracic and mediastinal
Cough 20 0 13 0
Skin and subcutaneous tissue
Acne 22 0 5 0
Grading according to NCI CTCAE Version 3.0
aIncludes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.
bNo Grade 4 adverse reactions were reported.

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

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

Table 15: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2

  AFINITOR
N = 79
Placebo
N = 39
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematology
Anemia 61 0 49 0
Leukopenia 37 0 21 0
Neutropenia 25 1 26 0
Lymphopenia 20 1a 8 0
Thrombocytopenia 19 0 3 0
Chemistry
Hypercholesterolemia 85 1a 46 0
Hypertriglyceridemia 52 0 10 0
Hypophosphatemia 49 5a 15 0
Increased alkaline phosphatase 32 1a 10 0
Increased AST 23 1a 8 0
Increased ALT 20 1a 15 0
Hyperglycemia (fasting) 14 0 8 0
Grading according to NCI CTCAE Version 3.0
aNo Grade 4 laboratory abnormalities were reported.

Updated safety information from 112 patients treated with AFINITOR for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%).

TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA)

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of AFINITOR in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were White, and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving AFINITOR.

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

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

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17.

Table 16: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients with TSC-Associated SEGA in EXIST-1

  AFINITOR
N = 78
Placebo
N=39
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Gastrointestinal
Stomatitisa 62 9f 26 3f
Vomiting 22 1f 13 0
Diarrhea 17 0 5 0
Constipation 10 0 3 0
Infections
Respiratory tract infectionb 31 3 23 0
Gastroenteritisc 10 5 3 0
Pharyngitis streptococcal 10 0 3 0
General
Pyrexia 23 6f 18 3f
Fatigue 14 0 3 0
Psychiatric
Anxiety, aggression or other behavioral disturbanced 21 5f 3 0
Skin and subcutaneous tissue
Rashe 21 0 8 0
Acne 10 0 5 0
Grading according to NCI CTCAE Version 3.0
aIncludes mouth ulceration, stomatitis, and lip ulceration
bIncludes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral
cIncludes gastroenteritis, gastroenteritis viral, and gastrointestinal infection
dIncludes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder
eIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria
fNo Grade 4 adverse reactions were reported.

Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18). For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%).

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

Table 17: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients with TSC-Associated SEGA in EXIST-1

  AFINITOR
N = 78
Placebo
N = 39
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematology
Elevated partial thromboplastin time 72 3a 44 5a
Neutropenia 46 9a 41 3a
Anemia 41 0 21 0
Chemistry
Hypercholesterolemia 81 0 39 0
Elevated aspartate transaminase (AST) 33 0 0 0
Hypertriglyceridemia 27 0 15 0
Elevated alanine transaminase (ALT) 18 0 3 0
Hypophosphatemia 9 1a 3 0
Grading according to NCI CTCAE Version 3.0
aNo Grade 4 laboratory abnormalities were reported.

Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions and key laboratory abnormalities: decreased appetite (14%), hyperglycemia (13%), hypertension (11%), urinary tract infection (9%), decreased fibrinogen (8%), cellulitis (6%), abdominal pain (5%), decreased weight (5%), elevated creatinine (5%), and azoospermia (1%).

TSC-Associated Partial-Onset Seizures

The data described below are based on the 18-week Core phase of a randomized, double-blind, multicenter, three-arm trial (EXIST-3) comparing two everolimus trough levels (3-7 ng/mL and 9-15 ng/mL) to placebo as adjunctive antiepileptic therapy in patients with TSC-associated partial-onset seizures. A total of 366 patients were randomized to AFINITOR DISPERZ low trough (LT) (n = 117), AFINITOR DISPERZ high trough (HT) (n = 130), or placebo (n = 119). The median age of patients was 10 years (2.2 to 56 years; 28% were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years), 65% were White, and 52% were male. Patients received between one and three concomitant antiepileptic drugs.

The most common adverse reaction reported for AFINITOR DISPERZ in both arms (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pneumonia, and irregular menstruation. The most common laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 2%) was neutropenia.

Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the LT and HT arms, respectively. The most common adverse reaction (incidence ≥ 1%) leading to discontinuation was stomatitis. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the LT and HT arms, respectively. The most common adverse reactions (incidence ≥ 3%) leading to dose adjustments in the AFINITOR DISPERZ arms were stomatitis, pneumonia, and pyrexia.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR DISPERZ are presented in Table 18. Laboratory abnormalities are presented in Table 19.

Table 18: Adverse Reactions Reported in ≥ 10% of AFINITOR DISPERZ-Treated Patients with TSC-Associated Partial-Onset Seizures in EXIST-3

  AFINITOR DISPERZ Placebo
N =119
Target of 3-7 ng/mL
N =117
Target of 9-15 ng/mL
N=130
All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Gastrointestinal
Stomatitisa 55 3b 64 4b 9 0
Diarrhea 17 0 22 0 5 0
Vomiting 12 0 10 2b 9 0
Infections
Nasopharyngitis 14 0 16 0 16 0
Upper respiratory tract infection 13 0 15 0 13 0.8b
General
Pyrexia 20 0 14 0.8b 5 0
Respiratory, thoracic and mediastinal
Cough 11 0 10 0 3 0
Skin and subcutaneous tissue
Rash 6 0 10 0 3 0
aIncludes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain
bNo Grade 4 adverse reactions were reported.

The following additional adverse reactions occurred in < 10% of AFINITOR DISPERZ treated patients (% AFINITOR LT, % AFINITOR HT): decreased appetite (9%, 7%), pneumonia (2%, 4%), aggression (2%, 0.8%), proteinuria (0%, 2%), menorrhagia (0.9%, 0.8%), and pneumonitis (0%, 0.8%).

Table 19: Selected Laboratory Abnormalities Reported in ≥ 10% AFINITOR DISPERZ-Treated Patients with TSC-Associated Partial-Onset Seizures

  AFINITOR DISPERZ Placebo
N = 119
Target of 3-7 ng/mL
N =117
Target of 9-15 ng/mL
N130
All Grades % Grade 3-4 % All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematology
Neutropenia 25 4a 37 6 23 7a
Anemia 27 0.9a 30 0 21 0.8a
Thrombocytopenia 12 0 15 0 6 0
Chemistry
Hypercholesterolemia 86 0 85 0.8a 58 0
Hypertriglyceridemia 43 2a 39 2 22 0
Increased ALT 17 0 22 0 6 0
Increased AST 13 0 19 0 4 0
Hyperglycemia 19 0 18 0 17 0
Increased alkaline phosphatase 24 0 16 0 29 0
Hypophosphatemia 9 0.9a 16 2 3 0
Grading according to NCI CTCAE version 4.03
aNo Grade 4 laboratory abnormalities were reported.

Updated safety information from 357 patients treated with AFINITOR DISPERZ for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%).

Postmarketing Experience

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

  • Gastrointestinal: Acute pancreatitis
  • Hepatobiliary: Cholecystitis and cholelithiasis
  • Vascular: Arterial thrombotic events
  • Nervous System: Reflex sympathetic dystrophy
  • Cardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event
  • Infections: Sepsis and septic shock
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