Afinitor (Everolimus) - Side Effects and Adverse Reactions

6.1 Clinical S tudies E xperience

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.

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 1 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 1      Adverse Reactions Reported in at least 10% of Patients 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 R eaction	97	52	13	93	23	5
Gastrointestinal D isorders
Stomatitis a	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 I nfestations b	37	7	3	18	1	0
General Disorders and Administration Site C onditions
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 D isorders
Cough	30	<1	0	16	0	0
Dyspnea	24	6	1	15	3	0
Epistaxis	18	0	0	0	0	0
Pneumonitis c	14	4	0	0	0	0
Skin and Subcutaneous Tissue D isorders
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 D isorders
Anorexia	25	1	0	14	<1	0
Nervous S ystem D isorders
Headache	19	<1	<1	9	<1	0
Dysgeusia	10	0	0	2	0	0
Musculoskeletal and Connective Tissue D isorders
Pain in extremity	10	1	0	7	0	0
Medi an Duration of T reatment (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%)

      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%)

      Nervous system disorders: Insomnia (9%), 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 treatment-emergent laboratory abnormalities are presented in Table 2.

Table 2      Key Laboratory Abnormalities Reported at a Higher rate in the AFINITOR Arm than the Placebo Arm

Laboratory P arameter	AFINITOR 10 mg/day N=274			Placebo N=137
	All grades	Grade 3	Grade 4	All grades	Grade 3	Grade 4
	%	%	%	%	%	%
Hematology a
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 C hemistry
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.