Afinitor

Name: Afinitor

Afinitor and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant. 

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy. 

Afinitor falls into category D. Based on how the medication works, Afinitor can cause harm to an unborn baby when used by a pregnant woman.

 

Other Requirements

  • Store Afinitor at 59°–86°F (15°–30°C). 
  • Store in the original container, protect from light and moisture.
  • Keep this and all drugs out of the reach of children.

What happens if I miss a dose?

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.

Before Using Afinitor

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of everolimus when used for SEGA brain tumors in children. However, use is not recommended in children younger than 1 year.

Appropriate studies have not been performed on the relationship of age to the effects of everolimus when used for kidney cancer, neuroendocrine tumors, and kidney or liver transplants in children. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of everolimus in the elderly. However, elderly patients are more likely to have unwanted side effects, which may require caution and an adjustment in the dose for patients receiving everolimus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Ritonavir

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Adenovirus Vaccine Type 4, Live
  • Adenovirus Vaccine Type 7, Live
  • Bacillus of Calmette and Guerin Vaccine, Live
  • Benazepril
  • Boceprevir
  • Captopril
  • Carbamazepine
  • Ceritinib
  • Cholera Vaccine, Live
  • Clarithromycin
  • Cobicistat
  • Conivaptan
  • Dronedarone
  • Eliglustat
  • Enalapril
  • Enalaprilat
  • Enzalutamide
  • Fosinopril
  • Fosphenytoin
  • Idelalisib
  • Indinavir
  • Influenza Virus Vaccine, Live
  • Itraconazole
  • Ketoconazole
  • Lisinopril
  • Lopinavir
  • Lumacaftor
  • Measles Virus Vaccine, Live
  • Mitotane
  • Moexipril
  • Mumps Virus Vaccine, Live
  • Nefazodone
  • Nelfinavir
  • Perindopril
  • Phenytoin
  • Poliovirus Vaccine, Live
  • Posaconazole
  • Quinapril
  • Ramipril
  • Ribociclib
  • Rifampin
  • Rotavirus Vaccine, Live
  • Rubella Virus Vaccine, Live
  • Saquinavir
  • Smallpox Vaccine
  • St John's Wort
  • Telaprevir
  • Telithromycin
  • Trandolapril
  • Typhoid Vaccine
  • Varicella Virus Vaccine
  • Venetoclax
  • Verapamil
  • Voriconazole
  • Yellow Fever Vaccine
  • Zofenopril

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

  • Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Blood clotting problems or
  • Diabetes or
  • Hepatitis B infection, history of or
  • Hyperglycemia (high sugar in the blood) or
  • Hyperlipidemia (high cholesterol in the blood) or
  • Hypertriglyceridemia (high fat in the blood) or
  • Hypoxia (low oxygen in the blood) or
  • Infection (eg, bacteria, fungus, virus) or
  • Lung or breathing problems or
  • Lymphoma (cancer of the lymph glands) or
  • Proteinuria (protein in the urine) or
  • Skin cancer—Use with caution. May make these conditions worse.
  • Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Afinitor 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.

Uses of Afinitor

  • It is used to treat cancer.
  • It is used to treat certain kinds of kidney cysts.
  • It may be given to you for other reasons. Talk with the doctor.

How do I store and/or throw out Afinitor?

  • Store in the original container at room temperature.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Afinitor, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Afinitor. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Afinitor.

Review Date: October 4, 2017

Indications and usage

     Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC)

Afinitor® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

     Advanced Neuroendocrine Tumors (NET)

Afinitor® is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.

Afinitor® is indicated for the treatment of adult patients with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.

Afinitor® is not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2)].

     Advanced Renal Cell Carcinoma (RCC)

Afinitor® is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.

     Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC)

Afinitor® is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

     Subependymal Giant Cell Astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC)

Afinitor® Tablets and Afinitor® DISPERZ are indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

Adverse reactions

The following serious adverse reactions are discussed in greater detail in another section of the label [see Warnings and Precautions (5)]:

  • Non-infectious pneumonitis [see Warnings and Precautions (5.1)].
  • Infections [see Warnings and Precautions (5.2)].
  • Angioedema with concomitant use of ACE inhibitors [see Warnings and Precautions (5.3)].
  • Oral ulceration [see Warnings and Precautions (5.4)].
  • Renal failure [see Warnings and Precautions (5.5)].
  • Impaired wound healing [see Warnings and Precautions (5.6)].

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

     Clinical Study Experience in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer

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

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

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

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

Table 2: Adverse Reactions Reported ≥10% of Patients with Advanced HR+ BC*
Grading according to CTCAE Version 3.0
* 160 patients (33.2%) were exposed to Afinitor therapy for a period of ≥ 32 weeks
a Exemestane (25 mg/day)
b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration
c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%).
d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis
e Exposure to Afinitor or placebo
Afinitor (10 mg/day)
+ exemestanea
N=482
Placebo
+ exemestanea
N=238
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
% % % % % %
Any adverse reaction 100 41 9 90 22 5
Gastrointestinal disorders
      Stomatitisb 67 8 0 11 0.8 0
      Diarrhea 33 2 0.2 18 0.8 0
      Nausea 29 0.2 0.2 28 1 0
      Vomiting 17 0.8 0.2 12 0.8 0
      Constipation 14 0.4 0 13 0.4 0
      Dry mouth 11 0 0 7 0 0
General disorders and administration site conditions
      Fatigue 36 4 0.4 27 1 0
      Edema peripheral 19 1 0 6 0.4 0
      Pyrexia 15 0.2 0 7 0.4 0
      Asthenia 13 2 0.2 4 0 0
Infections and infestations
      Infectionsc 50 4 1 25 2 0
Investigations
      Weight decreased 25 1 0 6 0 0
Metabolism and nutrition disorders
      Decreased appetite 30 1 0 12 0.4 0
      Hyperglycemia 14 5 0.4 2 0.4 0
Musculoskeletal and connective tissue disorders
      Arthralgia 20 0.8 0 17 0 0
      Back pain 14 0.2 0 10 0.8 0
      Pain in extremity 9 0.4 0 11 2 0
Nervous system disorders
      Dysgeusia 22 0.2 0 6 0 0
      Headache 21 0.4 0 14 0 0
Psychiatric disorders
      Insomnia 13 0.2 0 8 0 0
Respiratory, thoracic and mediastinal disorders
      Cough 24 0.6 0 12 0 0
      Dyspnea 21 4 0.2 11 0.8 0.4
      Epistaxis 17 0 0 1 0 0
      Pneumonitisd 19 4 0.2 0.4 0 0
Skin and subcutaneous tissue disorders
      Rash 39 1 0 6 0 0
      Pruritus 13 0.2 0 5 0 0
      Alopecia 10 0 0 5 0 0
Vascular disorders
      Hot flush 6 0 0 14 0 0
Median duration of treatmente 23.9 weeks 13.4 weeks

Key observed laboratory abnormalities are presented in Table 3.

Table 3: Key Laboratory Abnormalities Reported in ≥10% of Patients with Advanced HR+ BC
Grading according to CTCAE Version 3.0
a Exemestane (25 mg/day)
b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.
Laboratory parameter Afinitor (10 mg/day)
+ exemestanea
N=482
Placebo
+ exemestanea
N=238
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
% % % % % %
Hematologyb
Hemoglobin decreased 68 6 0.6 40 0.8 0.4
WBC decreased 58 1 0 28 5 0.8
Platelets decreased 54 3 0.2 5 0 0.4
Lymphocytes decreased 54 11 0.6 37 5 0.8
Neutrophils decreased 31 2 0 11 0.8 0.8
Clinical chemistry
Glucose increased 69 9 0.4 44 0.8 0.4
Cholesterol increased 70 0.6 0.2 38 0.8 0.8
Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4
Alanine transaminase (ALT) increased 51 4 0.2 29 5 0
Triglycerides increased 50 0.8 0 26 0 0
Albumin decreased 33 0.8 0 16 0.8 0
Potassium decreased 29 4 0.2 7 1 0
Creatinine increased 24 2 0.2 13 0 0

     Clinical Study Experience in Advanced Neuroendocrine Tumors

Advanced Pancreatic Neuroendocrine Tumors (PNET)

In a randomized, controlled trial of Afinitor (n=204) versus placebo (n=203) in patients with advanced PNET the median age of patients was 58 years (range 20-87), 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 decreased hemoglobin, hyperglycemia, alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST). The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia.  Deaths during double-blind treatment where an adverse event was the primary cause occurred in seven patients on Afinitor and one patient on placebo. 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. There was one death due to pulmonary embolism on the placebo arm. 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 rates of treatment-emergent adverse events resulting in permanent discontinuation were 20% and 6% for the Afinitor and placebo treatment groups, respectively. Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. Grade 3-4 renal failure occurred in six patients in the everolimus arm and three patients in the placebo arm. Thrombotic events included five patients with pulmonary embolus in the everolimus arm and one in the placebo arm as well as three patients with thrombosis in the everolimus arm and two in the placebo arm.

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

Table 4:  Adverse Reactions Reported ≥10% of Patients with Advanced PNET 
Grading according to CTCAE Version 3.0
a Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation.
b Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea.
c Includes pneumonitis, interstitial lung disease, pulmonary fibrosis and restrictive pulmonary disease.
Afinitor
N=204
Placebo
N=203
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
% % % % % %
Any adverse reaction 100 49 13 98 32 8
Gastrointestinal disorders
      Stomatitisa 70 7 0 20 0 0
      Diarrheab 50 5 0.5 25 3 0
      Abdominal pain 36 4 0 32 6 1
      Nausea 32 2 0 33 2 0
      Vomiting 29 1 0 21 2 0
      Constipation 14 0 0 13 0.5 0
      Dry mouth 11 0 0 4 0 0
General disorders and administration site conditions
      Fatigue/malaise 45 3 0.5 27 2 0.5
      Edema (general and peripheral) 39 1 0.5 12 1 0
      Fever 31 0.5 0.5 13 0.5 0
      Asthenia 19 3 0 20 3 0
Infections and infestations
       Nasopharyngitis/rhinitis/URI 25 0 0 13 0 0
      Urinary tract infection 16 0 0 6 0.5 0
Investigations
      Weight decreased 28 0.5 0 11 0 0
Metabolism and nutrition disorders
      Decreased appetite 30 1 0 18 1 0
      Diabetes mellitus 10 2 0 0.5 0 0
Musculoskeletal and connective tissue disorders
      Arthralgia 15 1 0.5 7 0.5 0
      Back pain 15 1 0 11 1 0
      Pain in extremity 14 0.5 0 6 1 0
      Muscle spasms 10 0 0 4 0 0
Nervous system disorders
      Headache/migraine 30 0.5 0 15 1 0
      Dysgeusia 19 0 0 5 0 0
      Dizziness 12 0.5 0 7 0 0
Psychiatric disorders
      Insomnia 14 0 0 8 0 0
Respiratory, thoracic and mediastinal disorders
      Cough/productive cough 25 0.5 0 13 0 0
      Epistaxis 22 0 0 1 0 0
      Dyspnea/dyspnea exertional 20 2 0.5 7 0.5 0
      Pneumonitisc 17 3 0.5 0 0 0
      Oropharyngeal pain 11 0 0 6 0 0
Skin and subcutaneous disorders
      Rash 59 0.5 0 19 0 0
      Nail disorders 22 0.5 0 2 0 0
      Pruritus/pruritus generalized 21 0 0 13 0 0
      Dry skin/xeroderma 13 0 0 6 0 0
Vascular disorders
      Hypertension 13 1 0 6 1 0
Median duration of treatment (wks) 37 16

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

Key observed laboratory abnormalities are presented in Table 5. 

Table 5:  Key Laboratory Abnormalities Reported in ≥10% of Patients with Advanced PNET 
Grading according to CTCAE Version 3.0
Laboratory parameter Afinitor

N=204
Placebo
N=203
All grades Grade 3-4 All grades Grade 3-4
% % % %
Hematology
      Hemoglobin decreased 86 15 63 1
      Lymphocytes decreased 45 16 22 4
      Platelets decreased 45 3 11 0
      WBC decreased 43 2 13 0
      Neutrophils decreased 30 4 17 2
Clinical chemistry
       Alkaline phosphatase increased 74 8 66 8
      Glucose (fasting) increased 75 17 53 6
      Cholesterol increased 66 0.5 22 0
      Bicarbonate decreased 56 0 40 0
      Aspartate transaminase (AST) increased 56 4 41 4
      Alanine transaminase (ALT) increased 48 2 35 2
      Phosphate decreased 40 10 14 3
      Triglycerides increased 39 0 10 0
      Calcium decreased 37 0.5 12 0
      Potassium decreased 23 4 5 0
      Creatinine increased 19 2 14 0
      Sodium decreased 16 1 16 1
      Albumin decreased 13 1 8 0
      Bilirubin increased 10 1 14 2
      Potassium increased 7 0 10 0.5

Unresectable, Locally Advanced or Metastatic, Well-Differentiated, Non-Functional Neuroendocrine Tumors of Gastrointestinal or Lung Origin

In a randomized, controlled trial of Afinitor (n=202 treated) versus placebo (n=98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (range 22-86), 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).

Table 6 and Table 7 summarize the incidence of adverse reactions of Afinitor 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).

Table 6: Adverse Reactions in ≥10% of Afinitor-Treated Patients with Non-Functional NET of Gastrointestinal or Lung Origin†
† Grading according to NCI CTCAE Version 4.03
a Includes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration and mucosal inflammation.
b Urinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis.
c Includes pneumonitis and interstitial lung disease.
Afinitor
N=202
Placebo
N=98
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
% % % % % %
Any adverse reaction 99 57 12 89 21 7
Gastrointestinal disorders
      Stomatitisa 63 9 0 22 0 0
      Diarrhea 41 8 1 31 2 0
      Nausea 26 3 1 17 1 0
      Vomiting 15 4 0 12 2 0
General disorders and administration site conditions
      Peripheral edema 39 3 0 6 1 0
      Fatigue 37 4 1 36 1 0
      Asthenia 23 2 1 8 0 0
      Pyrexia 23 1 1 8 0 0
Infections
      Infectionsb 58 8 3 29 1 1
Investigations
      Decreased weight 22 1 0 17 1 0
Metabolism and nutrition disorders
      Decreased appetite 22 1 0 17 1 0
Nervous system disorders
      Dysgeusia 18 1 0 4 0 0
Respiratory, thoracic and mediastinal disorders
      Cough 27 0 0 20 0 0
      Dyspnea 20 3 0 11 1 1
      Pneumonitisc 16 2 0 2 0 0
      Epistaxis 13 1 0 3 0 0
Skin and subcutaneous disorders
      Rash 30 1 0 9 0 0
      Pruritus 17 1 0 9 0 0
Table 7: Laboratory Abnormalities in ≥10% of Afinitor-Treated Patients with Non-Functional NET of Gastrointestinal or Lung Origin†
† Grading according to NCI CTCAE Version 4.03
Afinitor
N=202
Placebo
N=98
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
% % % % % %
Hematology
      Anemia 81 5 0 41 2 0
      Lymphopenia 66 15 2 32 2 0
      Leukopenia 49 2 0 17 0 0
      Thrombocytopenia 33 2 1 11 0 0
      Neutropenia 32 2 0 15 3 0
Clinical chemistry
      Hypercholesterolemia 71 0 0 37 0 0
      Elevated Aspartate transaminase (AST) 57 1 1 34 2 0
      Hyperglycemia(fasting) 55 6 0 36 1 0
      Elevated Alanine transaminase (ALT) 46 5 1 39 1 0
      Hypophosphatemia 43 4 0 15 2 0
      Hypertriglyceridemia 30 3 1 8 1 0
      Hypokalemia 27 4 2 12 3 0
      Hypoalbuminemia 18 0 0 8 0 0

     Clinical Study Experience in Advanced Renal Cell Carcinoma

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

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

Table 8 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving Afinitor 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Table 8: Adverse Reactions Reported in at Least 10% of Patients with RCC and at a Higher Rate in the Afinitor Arm than in the Placebo Arm
Grading according to CTCAE Version 3.0
a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration.
b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%).
c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.
Afinitor 10 mg/day
N=274
Placebo
N=137
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
% % % % % %
Any adverse reaction 97 52 13 93 23 5
Gastrointestinal disorders
      Stomatitisa 44 4 <1 8 0 0
      Diarrhea 30 1 0 7 0 0
      Nausea 26 1 0 19 0 0
      Vomiting 20 2 0 12 0 0
Infections and infestationsb 37 7 3 18 1 0
General disorders and administration site conditions
      Asthenia 33 3 <1 23 4 0
      Fatigue 31 5 0 27 3 <1
      Edema peripheral 25 <1 0 8 <1 0
      Pyrexia 20 <1 0 9 0 0
      Mucosal inflammation 19 1 0 1 0 0
Respiratory, thoracic and mediastinal disorders
      Cough 30 <1 0 16 0 0
      Dyspnea 24 6 1 15 3 0
      Epistaxis 18 0 0 0 0 0
      Pneumonitisc 14 4 0 0 0 0
Skin and subcutaneous tissue disorders
      Rash 29 1 0 7 0 0
      Pruritus 14 <1 0 7 0 0
      Dry skin 13 <1 0 5 0 0
Metabolism and nutrition disorders
      Anorexia 25 1 0 14 <1 0
Nervous system disorders
      Headache 19 <1 <1 9 <1 0
      Dysgeusia 10 0 0 2 0 0
Musculoskeletal and connective tissue disorders
      Pain in extremity 10 1 0 7 0 0
Median duration of treatment (d) 141 60

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

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

      General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%)

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

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

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

      Psychiatric disorders: Insomnia (9%)

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

      Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

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

      Renal and urinary disorders: Renal failure (3%)

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

      Musculoskeletal and connective tissue disorders: Jaw pain (3%)

      Hematologic disorders: Hemorrhage (3%)

Key laboratory abnormalities are presented in Table 9.

Table 9: Key Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the Afinitor Arm than the Placebo Arm
Grading according to CTCAE Version 3.0
a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency.
Laboratory parameter Afinitor 10 mg/day
N=274
Placebo
N=137
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
% % % % % %
Hematologya
      Hemoglobin decreased 92 12 1 79 5 <1
      Lymphocytes decreased 51 16 2 28 5 0
      Platelets decreased 23 1 0 2 0 <1
      Neutrophils decreased 14 0 <1 4 0 0
Clinical chemistry
      Cholesterol increased 77 4 0 35 0 0
      Triglycerides increased 73 <1 0 34 0 0
      Glucose increased 57 15 <1 25 1 0
      Creatinine increased 50 1 0 34 0 0
      Phosphate decreased 37 6 0 8 0 0
      Aspartate transaminase (AST) increased 25 <1 <1 7 0 0
      Alanine transaminase (ALT) increased 21 1 0 4 0 0
      Bilirubin increased 3 <1 <1 2 0 0

     Clinical Study Experience in Renal Angiomyolipoma with Tuberous Sclerosis Complex

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial of 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 (range 18 to 61 years), 89% were Caucasian, and 34% were male. The median duration of blinded study treatment was 48 weeks (range 2 to 115 weeks) for patients receiving Afinitor and 45 weeks (range 9 to 115 weeks) for those receiving placebo.

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.

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

Table 10: Adverse Reactions Reported in ≥10% of Afinitor-treated Patients with Renal Angiomyolipoma
Grading according to CTCAE Version 3.0
a Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.
Afinitor 
N=79
Placebo 
N=39
All grades
%
Grade 3
%
Grade 4
%
All grades
%
Grade 3
%
Grade 4
%
Any adverse reaction 100 25 5 97 8 5
Gastrointestinal disorders
      Stomatitisa 78 6 0 23 0 0
      Vomiting 15 0 0 5 0 0
      Diarrhea 14 0 0 5 0 0
General disorders and administration site conditions
      Peripheral edema 13 0 0 8 0 0
Infections and infestations
      Upper respiratory tract infection 11 0 0 5 0 0
Musculoskeletal and connective tissue disorders
      Arthralgia 13 0 0 5 0 0
Respiratory, thoracic and mediastinal disorders
      Cough 20 0 0 13 0 0
Skin and subcutaneous tissue disorders
      Acne 22 0 0 5 0 0

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

The following additional adverse reactions occurred in less than 10% of 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 11: Key Laboratory Abnormalities Reported in Afinitor-treated Patients with Renal Angiomyolipoma
Grading according to CTCAE Version 3.0
Afinitor 
N=79
Placebo 
N=39
All grades
%
Grade 3
%
Grade 4
%
All grades
%
Grade 3
%
Grade 4
%
Hematology
      Anemia 61 0 0 49 0 0
      Leucopenia 37 0 0 21 0 0
      Neutropenia 25 0 1 26 0 0
      Lymphopenia 20 1 0 8 0 0
      Thrombocytopenia 19 0 0 3 0 0
Clinical chemistry
      Hypercholesterolemia 85 1 0 46 0 0
      Hypertriglyceridemia 52 0 0 10 0 0
      Hypophosphatemia 49 5 0 15 0 0
      Alkaline phosphatase increased 32 1 0 10 0 0
      Elevated aspartate transaminase (AST) 23 1 0 8 0 0
      Elevated alanine transaminase (ALT) 20 1 0 15 0 0
      Fasting hyperglycemia 14 0 0 8 0 0

Updated safety information from 112 patients treated with Afinitor for a median duration of 3.9 years identified the following additional adverse reactions and key 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%).

     Clinical Study Experience in Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis Complex

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

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.

Table 12 compares the incidence of adverse reactions reported with an incidence of ≥10% for patients receiving Afinitor and occurring more frequently with Afinitor than with placebo. Laboratory abnormalities are described separately in Table 13.

Table 12: Adverse Reactions Reported in ≥10% of Afinitor-treated Patients with SEGA in Study 1
Grading according to CTCAE Version 3.0
a Includes mouth ulceration, stomatitis, and lip ulceration
b Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral
c Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection
d Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder
e Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria
Afinitor
N=78
Placebo
N=39
All grades
%
Grade 3
%
Grade 4
%
All grades
%
Grade 3
%
Grade 4
%
Any adverse reaction 97 36 3 92 23 3
Gastrointestinal disorders
      Stomatitisa 62 9 0 26 3 0
      Vomiting 22 1 0 13 0 0
      Diarrhea 17 0 0 5 0 0
      Constipation 10 0 0 3 0 0
Infections and infestations
      Respiratory tract infectionb 31 1 1 23 0 0
      Gastroenteritisc 10 4 1 3 0 0
      Pharyngitis streptococcal 10 0 0 3 0 0
General disorders and administration site conditions
      Pyrexia 23 6 0 18 3 0
      Fatigue 14 0 0 3 0 0
Psychiatric disorders
      Anxiety, aggression or other behavioral disturbanced 21 5 0 3 0 0
Skin and subcutaneous tissue disorders
      Rashe 21 0 0 8 0 0
      Acne 10 0 0 5 0 0

Amenorrhea occurred in 17% of Afinitor-treated females aged 10 to 55 years (3 of 18) and none of the females in the placebo group. 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 13: Key Laboratory Abnormalities Reported in Afinitor-treated Patients with SEGA in Study 1
Grading according to CTCAE Version 3.0
Afinitor
N=78
Placebo
N=39
All grades
%
Grade 3
%
Grade 4
%
All grades
%
Grade 3
%
Grade 4
%
Hematology
      Elevated partial thromboplastin time 72 3 0 44 5 0
      Neutropenia 46 9 0 41 3 0
      Anemia 41 0 0 21 0 0
Clinical chemistry
      Hypercholesterolemia 81 0 0 39 0 0
      Elevated aspartate transaminase (AST) 33 0 0 0 0 0
      Hypertriglyceridemia 27 0 0 15 0 0
      Elevated alanine transaminase (ALT) 18 0 0 3 0 0
      Hypophosphatemia 9 1 0 3 0 0

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 azospermia (1%).

     Postmarketing Experience

The following adverse reactions have been identified during post approval use of Afinitor. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: acute pancreatitis, cholecystitis, cholelithiasis, arterial thrombotic events, reflex sympathetic dystrophy, and cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event.

How should I take Afinitor?

Take Afinitor exactly as prescribed by your doctor. 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.

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

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

Take the 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 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.

What happens if I miss a dose?

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.

What happens if I overdose?

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

Afinitor side effects

Get emergency medical help if you have any signs of an allergic reaction to Afinitor: hives; chest pain, difficult breathing; swelling of your face, lips, tongue, or throat. You may be more likely to have some of these symptoms if you also take an "ACE inhibitor" heart or blood pressure medication.

Stop using Afinitor and call your doctor at once if you have:

  • new or worsening cough, chest pain, wheezing, feeling short of breath;

  • signs of infection - fever, chills, joint pain, red or swollen gums, painful mouth sores, skin sores, rapid heart rate, pale skin, easy bruising, unusual bleeding, feeling light-headed;

  • kidney problems - little or no urination; painful or difficult urination; swelling in your feet or ankles; feeling tired or short of breath;

  • liver problems - nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

  • any wound that will not heal; or

  • a surgical incision that is red, warm, swollen, painful, bleeding, or oozing pus.

Common Afinitor side effects may include:

  • infections, cough, nosebleeds;

  • mouth sores, taste problems, dry mouth;

  • nausea, vomiting, diarrhea, constipation;

  • weight loss, feeling weak or tired;

  • pain or swelling anywhere in your body;

  • dry skin, rash, acne;

  • missed menstrual periods;

  • unusual changes in mood or behavior;

  • sleep problems (insomnia);

  • dizziness, headache; or

  • high blood sugar - increased thirst or urination, hunger, fruity breath odor, blurred vision.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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