Afinitor Side Effects

Generic Name: everolimus

Please note - some side effects for Afinitor may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Afinitor - for the Consumer

Afinitor

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Afinitor:

Acne; constipation; diarrhea; dizziness; dry skin; fingernail or toenail changes; headache; joint, back, arm, or leg pain; loss of appetite; mild itching; muscle spasms; nausea; nosebleed; stomach pain or upset; stuffy or runny nose; taste changes; tiredness or weakness; trouble sleeping; vomiting; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur when using Afinitor:

Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; flushing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); bloody stools; burning, numbness, or tingling (especially of the palms of the hands and soles of the feet); chest pain; decreased, difficult, or painful urination; dry mouth or increased thirst; fast or irregular heartbeat; fever, chills, or persistent sore throat; interrupted breathing while sleeping; new or worsening cough; pain, discomfort, or sores of the mouth or tongue; personality changes; seizure; severe or persistent diarrhea, nausea, stomach pain, or vomiting; severe or persistent dizziness or headache; severe or persistent tiredness or weakness; shortness of breath or other breathing problems; swelling of the arms, hands, feet, or ankles; symptoms of high blood sugar (eg, increased hunger, thirst, or urination; confusion; unusual drowsiness); unusual bruising or bleeding; wheezing; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Afinitor Side Effects - for the Professional

Afinitor

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

• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].
  
• Infections [see Warnings and Precautions (5.2)].

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 Pancreatic Neuroendocrine Tumors

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 Caucasian, 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 AE was the primary cause occurred in 7 patients on Afinitor and 1 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 1 death due to pulmonary embolism on the placebo arm. After cross-over to open-label Afinitor, there were 3 additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to MI with CHF, 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 6 patients in the everolimus arm and 3 patients in the placebo arm. Thrombotic events included 5 patients with pulmonary embolus in the everolimus arm and 1 in the placebo arm as well as 3 patients with thrombosis in the everolimus arm and 2 in the placebo arm.

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 PNET 

	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
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.

Key observed laboratory abnormalities are presented in Table 3. 

Table 3:  Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced PNET 

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
CTCAE Version 3.0

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) for patients receiving Afinitor and 60 days (range 21-295) 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 4 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 4: 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

	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
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.

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%)

      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%)

      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 5.

Table 5: Key Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the Afinitor Arm than the Placebo Arm

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
CTCAE Version 3.0 a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia.

Clinical Study Experience in Subependymal Giant Cell Astrocytoma

The data described below reflect exposure to Afinitor (n=28) in an open-label, single-arm trial for the treatment of patients with SEGA. The reliability of the frequency of adverse reactions and laboratory abnormalities reported in this trial is limited because of the small number of patients. The median age of patients was 11 years (range 3-34), 86% were Caucasian, and 61% were male. In total, 17 of the 28 patients were exposed to Afinitor for ≥ 21 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, upper respiratory tract infection, sinusitis, otitis media, and pyrexia. The grade 3 adverse reactions were convulsion, infections (single cases of sinusitis, pneumonia, tooth infection, and bronchitis viral), and single cases of stomatitis, aspiration, cyclic neutropenia, sleep apnea syndrome, vomiting, dizziness, white blood cell count decreased, and neutrophil count decreased. A grade 4 convulsion was also reported. 

Table 6 summarizes the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10%. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Table 6: Adverse Reactions Reported in at least 10% of Patients with SEGA

	Afinitor N=28
	All grades	Grade 3	Grade 4
	%	%	%
Any adverse reaction	100	36	4
Gastrointestinal disorders
Stomatitis	86	4	0
Diarrhea	25	0	0
Vomiting	21	4	0
Abdominal pain	11	0	0
Constipation	11	0	0
Infections and infestations
Upper respiratory tract infection	82	0	0
Sinusitis	39	4	0
Otitis media	36	0	0
Cellulitis	21	0	0
Body tinea	18	0	0
Gastroenteritis	18	0	0
Skin infection	18	0	0
Gastric infection	14	0	0
Otitis externa	14	0	0
Pharyngitis	11	0	0
General disorders and administration site conditions
Pyrexia	32	0	0
Nervous system disorders
Convulsion	29	7	4
Headache	18	0	0
Dizziness	14	4	0
Skin and subcutaneous tissue disorders
Dermatitis acneiform	25	0	0
Dry skin	18	0	0
Rash	18	0	0
Dermatitis contact	14	0	0
Acne	11	0	0
Respiratory, thoracic and mediastinal disorders
Cough	21	0	0
Nasal congestion	14	0	0
Rhinitis allergic	14	0	0
Psychiatric disorders
Personality change	18	0	0
Injury, poisoning and procedural complications
Excoriation	14	0	0
CTCAE Version 3.0

Other notable adverse reactions occurring with an incidence of < 10% include:

      Gastrointestinal disorders: Gastritis (7%)

      Skin and subcutaneous tissue disorders: Pityriasis rosea (4%)

      Investigations: Chest x-ray abnormal (4%)

      General disorders and administration site conditions: Fatigue (7%), edema peripheral (4%)

      Respiratory, thoracic and mediastinal disorders: Pharyngeal inflammation (7%)

      Nervous system disorders: Somnolence (7%)

      Psychiatric disorders: Anxiety (7%)

      Renal and urinary disorders: Proteinuria (7%)

      Eye disorders: Ocular hyperemia (4%)

      Vascular disorders: Hypertension (4%)

Key Laboratory Abnormalities

Single cases of grade 3 elevated aspartate transaminase (AST) concentrations and low absolute neutrophil count (ANC) were reported. No grade 4 laboratory abnormalities were noted. Laboratory abnormalities observed in > 1 patient (and listed in decreasing order of frequency) included elevations in AST concentrations (89%), total cholesterol (68%), alanine transaminase (ALT) (46%), triglycerides (43%) (hypertriglyceridemia reported as adverse reaction in 11% of patients, blood triglycerides increased reported as adverse reaction in 7% of patients), glucose (25%), and creatinine (11%), and reductions in white blood cell counts (54%) (reported as adverse reaction in 11% of patients), hemoglobin (39%), glucose (32%), and platelet counts (21%). Most of these laboratory abnormalities were mild (grade 1).

Two cases of neutrophil count decreased and blood immunoglobulin G decreased were reported as adverse reactions. 

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Side Effects by Body System - for Healthcare Professionals

Hypersensitivity

Hypersensitivity side effects manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

Hematologic

Hematologic side effects including decreased hemoglobin (92%), decreased lymphocytes (51%), decreased platelets (23%), decreased neutrophils (14%), and hemorrhage (3%) have been reported.

Metabolic

Metabolic side effects including increased cholesterol (77%), increased triglycerides (73%), increased glucose (57%), increased creatinine (50%), decreased phosphate (37%), anorexia (25%), exacerbation of preexisting diabetes mellitus (2%), and new onset of diabetes mellitus (less than 1%) have been reported.

Gastrointestinal

Gastrointestinal side effects including stomatitis (44%), diarrhea (30%), nausea (26%), vomiting (20%), abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), and dysphagia (4%) have been reported.

Other

Other side effects including infections and infestations (37%) have been reported.

General

General side effects including asthenia (33%), fatigue (31%), peripheral edema (25%), pyrexia (20%), mucosal inflammation (19%), decreased weight (9%), chest pain (5%), and chills (4%) have been reported.

Respiratory

Respiratory side effects including cough (30%), dyspnea (24%), epistaxis (18%), pneumonitis (14%), pleural effusion (7%), pharyngolaryngeal pain (4%), and rhinorrhea (3%) have been reported.

Dermatologic

Dermatologic side effects including rash (29%), pruritus (14%), dry skin (13%), hand-foot syndrome (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), and acneiform dermatitis (3%) have been reported.

Hepatic

Hepatic side effects including increased aspartate transaminase (AST) (25%), increased alanine transaminase (ALT) (21%), and increased bilirubin (3%) have been reported.

Nervous system

Nervous system side effects including headache (19%), dysgeusia (10%), insomnia (9%), dizziness (7%), and paresthesia (5%) have been reported.

Musculoskeletal

Musculoskeletal side effects including pain in extremity (10%) and jaw pain (3%) have been reported.

Cardiovascular

Cardiovascular side effects including hypertension (4%), tachycardia (3%), and congestive heart failure (1%) have been reported.

Ocular

Ocular side effects including eyelid edema (4%) and conjunctivitis (2%) have been reported.

Renal

Renal side effects including renal failure (3%) have been reported.

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