1. CTCAE 4.03
`
`
`
`Common Terminology Criteria
`for Adverse Events (CTCAE)
`Version 4.0
`Published: May 28, 2009 (v4.03: June 14, 2010)
`
`U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES
`National Institutes of Health
`National Cancer Institute
`
`MYLAN PHARMS. INC. EXHIBIT 1093 PAGE 1
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`

`
`Common Terminology Criteria for Adverse Events v4.0 (CTCAE)
`Publish Date: May 28, 2009
`
`Quick Reference
`
`Definitions
`
`for
`The NCI Common Terminology Criteria
`Adverse Events is a descriptive terminology which
`can be utilized for Adverse Event (AE) reporting.
`A grading (severity) scale is provided for each AE
`term.
`
`Components and Organization
`
`SOC
`
`System Organ Class, the highest level of the
`MedDRA hierarchy, is identified by anatomical or
`physiological system, etiology, or purpose (e.g.,
`SOC Investigations for laboratory test results).
`CTCAE terms are grouped by MedDRA Primary
`SOCs. Within each SOC, AEs are
`listed and
`accompanied by descriptions of severity (Grade).
`
`CTCAE Terms
`
`An Adverse Event (AE) is any unfavorable and
`unintended
`sign
`(including
`an
`abnormal
`laboratory
`finding),
`symptom, or disease
`temporally associated with the use of a medical
`treatment or procedure that may or may not be
`considered related to the medical treatment or
`procedure. An AE is a term that is a unique
`representation of a specific event used for
`medical documentation and scientific analyses.
`Each CTCAE v4.0 term is a MedDRA LLT (Lowest
`Level Term).
`
`
`
`is provided to clarify the
`A brief definition
`meaning of each AE term.
`
`Not all Grades are appropriate for all AEs.
`Therefore, some AEs are listed with fewer than
`five options for Grade selection.
`
`Grades
`
`Grade 5
`
`Grade 5 (Death) is not appropriate for some AEs
`and therefore is not an option.
`
`Activities of Daily Living (ADL)
`
`*Instrumental ADL refer to preparing meals,
`shopping for groceries or clothes, using the
`telephone, managing money, etc.
`
`**Self care ADL refer to bathing, dressing and
`undressing, feeding self, using the toilet, taking
`medications, and not bedridden.
`
`Grade refers to the severity of the AE. The CTCAE
`displays Grades 1 through 5 with unique clinical
`descriptions of severity for each AE based on this
`general guideline:
`
`or mild
`asymptomatic
` Grade 1 Mild;
`symptoms; clinical or diagnostic
`observations only; intervention not
`indicated.
`
`or
`local
` Grade 2 Moderate; minimal,
`noninvasive intervention indicated;
`limiting
`age-appropriate
`instrumental ADL*.
`Severe or medically significant but
`not
`immediately
`life-threatening;
`hospitalization or prolongation of
`hospitalization indicated; disabling;
`limiting self care ADL**.
`
` Grade 3
`
` Grade 4
`
`consequences;
`Life-threatening
`urgent intervention indicated.
`
` Grade 5 Death related to AE.
`
`A Semi-colon indicates ‘or’ within the description
`of the grade.
`
`A single dash (-) indicates a grade is not available.
`
`__________
`† CTCAE v4.0 incorporates certain elements of the MedDRA terminology. For further details on MedDRA refer to the MedDRA MSSO Web site (http://www.meddramsso.com).
`
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`

`
`SOC
`
`Blood and lymphatic system disorders
`Cardiac disorders
`Congenital, familial and genetic disorders
`Ear and labyrinth disorders
`Endocrine disorders
`Eye disorders
`Gastrointestinal disorders
`General disorders and administration site conditions
`Hepatobiliary disorders
`Immune system disorders
`Infections and infestations
`Injury, poisoning and procedural complications
`Investigations
`Metabolism and nutrition disorders
`Musculoskeletal and connective tissue disorders
`Neoplasms benign, malignant and unspecified (incl cysts and polyps)
`Nervous system disorders
`Pregnancy, puerperium and perinatal conditions
`Psychiatric disorders
`Renal and urinary disorders
`Reproductive system and breast disorders
`Respiratory, thoracic and mediastinal disorders
`Skin and subcutaneous tissue disorders
`Social circumstances
`Surgical and medical procedures
`Vascular disorders
`
`Page
`3
`6
`15
`16
`19
`22
`28
`55
`61
`65
`68
`87
`107
`114
`119
`128
`129
`141
`142
`147
`153
`164
`179
`188
`189
`190
`
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`

`
`2. Blood and lymphatic system disorders
`
`Blood and lymphatic system disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Anemia
`
`Hemoglobin (Hgb) <LLN -
`10.0 g/dL; <LLN - 6.2 mmol/L;
`<LLN - 100 g/L
`
`Hgb <10.0 - 8.0 g/dL; <6.2 -
`4.9 mmol/L; <100 - 80g/L
`
`Hgb <8.0 g/dL; <4.9 mmol/L;
`<80 g/L; transfusion indicated
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`5
`
`Death
`
`Definition: A disorder characterized by an reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and
`mucous membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.
`
`Bone marrow hypocellular
`
`Mildly hypocellular or <=25%
`reduction from normal
`cellularity for age
`
`Moderately hypocellular or
`>25 - <50% reduction from
`normal cellularity for age
`
`Severely hypocellular or >50 -
`<=75% reduction cellularity
`from normal for age
`
`Aplastic persistent for longer
`than 2 weeks
`
`Death
`
`Definition: A disorder characterized by the inability of the bone marrow to produce hematopoietic elements.
`
`Disseminated intravascular
`coagulation
`
` -
`
`Laboratory findings with no
`bleeding
`
`Laboratory findings and
`bleeding
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`Definition: A disorder characterized by systemic pathological activation of blood clotting mechanisms which results in clot formation throughout the body. There is an
`increase in the risk of hemorrhage as the body is depleted of platelets and coagulation factors.
`
`Febrile neutropenia
`
` -
`
` -
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`ANC <1000/mm3 with a single
`temperature of >38.3 degrees
`C (101 degrees F) or a
`sustained temperature of
`>=38 degrees C (100.4
`degrees F) for more than one
`hour.
`
`Definition: A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 degrees C
`(100.4 degrees F) for more than one hour.
`
`CTCAE 4.03 - June 14, 2010
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`

`
`Blood and lymphatic system disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Hemolysis
`
`Laboratory evidence of
`hemolysis only (e.g., direct
`antiglobulin test; DAT;
`Coombs'; schistocytes;
`decreased haptoglobin)
`
`Evidence of hemolysis and
`>=2 gm decrease in
`hemoglobin.
`
`Transfusion or medical
`intervention indicated (e.g.,
`steroids)
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Definition: A disorder characterized by laboratory test results that indicate widespread erythrocyte cell membrane destruction.
`
`Hemolytic uremic syndrome
`
`Evidence of RBC destruction
`(schistocytosis) without
`clinical consequences
`
` -
`
`Laboratory findings with
`clinical consequences (e.g.,
`renal insufficiency, petechiae)
`
`Life-threatening
`consequences, (e.g., CNS
`hemorrhage or
`thrombosis/embolism or renal
`failure)
`
`Definition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, and severe thrombocytopenia.
`
`Leukocytosis
`
` -
`
` -
`
`>100,000/mm3
`
`Clinical manifestations of
`leucostasis; urgent
`intervention indicated
`
`Definition: A disorder characterized by laboratory test results that indicate an increased number of white blood cells in the blood.
`
`Lymph node pain
`
`Mild pain
`
`Moderate pain; limiting
`instrumental ADL
`
`Severe pain; limiting self care
`ADL
`
` -
`
`Definition: A disorder characterized by a sensation of marked discomfort in a lymph node.
`
`Spleen disorder
`
`Incidental findings (e.g.,
`Howell-Jolly bodies); mild
`degree of thrombocytosis and
`leukocytosis
`
`Prophylactic antibiotics
`indicated
`
` -
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`5
`
`Death
`
`Death
`
`Death
`
` -
`
`Death
`
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`

`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Blood and lymphatic system disorders
`Grade
`
`Definition: A disorder of the spleen.
`
`Thrombotic thrombocytopenic
`purpura
`
`Evidence of RBC destruction
`(schistocytosis) without
`clinical consequences
`
` -
`
`Laboratory findings with
`clinical consequences (e.g.,
`renal insufficiency, petechiae)
`
`Death
`
`Life-threatening
`consequences, (e.g., CNS
`hemorrhage or
`thrombosis/embolism or renal
`failure)
`
`Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurological
`abnormalities such as seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition.
`
`Blood and lymphatic system
`disorders - Other, specify
`
`Asymptomatic or mild
`symptoms; clinical or
`diagnostic observations only;
`intervention not indicated
`
`Moderate; minimal, local or
`noninvasive intervention
`indicated; limiting age-
`appropriate instrumental ADL
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`Severe or medically significant
`but not immediately life-
`threatening; hospitalization or
`prolongation of existing
`hospitalization indicated;
`disabling; limiting self care
`ADL
`
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`

`
`3. Cardiac disorders
`
`Cardiac disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Acute coronary syndrome
`
` -
`
`Symptomatic, progressive
`angina; cardiac enzymes
`normal; hemodynamically
`stable
`
`Symptomatic, unstable angina
`and/or acute myocardial
`infarction, cardiac enzymes
`abnormal, hemodynamically
`stable
`
`Symptomatic, unstable angina
`and/or acute myocardial
`infarction, cardiac enzymes
`abnormal, hemodynamically
`unstable
`
`5
`
`Death
`
`Definition: A disorder characterized by signs and symptoms related to acute ischemia of the myocardium secondary to coronary artery disease. The clinical presentation
`covers a spectrum of heart diseases from unstable angina to myocardial infarction.
`
`Aortic valve disease
`
`Asymptomatic valvular
`thickening with or without mild
`valvular regurgitation or
`stenosis by imaging
`
`Asymptomatic; moderate
`regurgitation or stenosis by
`imaging
`
`Symptomatic; severe
`regurgitation or stenosis by
`imaging; symptoms controlled
`with medical intervention
`
`Definition: A disorder characterized by a defect in aortic valve function or structure.
`
`Asystole
`
`Periods of asystole; non-
`urgent medical management
`indicated
`
` -
`
` -
`
`Life-threatening
`consequences; urgent
`intervention indicated (e.g.,
`valve replacement,
`valvuloplasty)
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`Death
`
`Definition: A disorder characterized by a dysrhythmia without cardiac electrical activity. Typically, this is accompanied by cessation of the pumping function of the heart.
`
`Atrial fibrillation
`
`Asymptomatic, intervention
`not indicated
`
`Non-urgent medical
`intervention indicated
`
`Symptomatic and
`incompletely controlled
`medically, or controlled with
`device (e.g., pacemaker), or
`ablation
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
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`

`
`Cardiac disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Definition: A disorder characterized by a dysrhythmia without discernible P waves and an irregular ventricular response due to multiple reentry circuits. The rhythm
`disturbance originates above the ventricles.
`
`Atrial flutter
`
`Asymptomatic, intervention
`not indicated
`
`Non-urgent medical
`intervention indicated
`
`Symptomatic and
`incompletely controlled
`medically, or controlled with
`device (e.g., pacemaker), or
`ablation
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`Definition: A disorder characterized by a dysrhythmia with organized rhythmic atrial contractions with a rate of 200-300 beats per minute. The rhythm disturbance originates
`in the atria.
`
`Atrioventricular block
`complete
`
` -
`
`Non-urgent intervention
`indicated
`
`Symptomatic and
`incompletely controlled
`medically, or controlled with
`device (e.g., pacemaker)
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical impulse conduction through the AV node to the ventricles.
`
`Atrioventricular block first
`degree
`
`Asymptomatic, intervention
`not indicated
`
`Non-urgent intervention
`indicated
`
` -
`
` -
`
` -
`
`Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the conduction of an electrical impulse through the atrioventricular (AV) node
`beyond 0.2 seconds; prolongation of the PR interval greater than 200 milliseconds.
`
`Cardiac arrest
`
` -
`
` -
`
` -
`
`Definition: A disorder characterized by cessation of the pumping function of the heart.
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
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`

`
`Cardiac disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Chest pain - cardiac
`
`Mild pain
`
`Moderate pain; limiting
`instrumental ADL
`
`Pain at rest; limiting self care
`ADL
`
` -
`
`Definition: A disorder characterized by substernal discomfort due to insufficient myocardial oxygenation.
`
`Conduction disorder
`
`Mild symptoms; intervention
`not indicated
`
`Moderate symptoms
`
`Severe symptoms;
`intervention indicated
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`5
`
` -
`
`Death
`
`Definition: A disorder characterized by pathological irregularities in the cardiac conduction system.
`
`Constrictive pericarditis
`
` -
`
` -
`
`Symptomatic heart failure or
`other cardiac symptoms,
`responsive to intervention
`
`Refractory heart failure or
`other poorly controlled cardiac
`symptoms
`
`Death
`
`Definition: A disorder characterized by a thickened and fibrotic pericardial sac; these fibrotic changes impede normal myocardial function by restricting myocardial muscle
`action.
`
`Heart failure
`
`Asymptomatic with laboratory
`(e.g., BNP [B-Natriuretic
`Peptide ]) or cardiac imaging
`abnormalities
`
`Symptoms with mild to
`moderate activity or exertion
`
`Severe with symptoms at rest
`or with minimal activity or
`exertion; intervention
`indicated
`
`Death
`
`Life-threatening
`consequences; urgent
`intervention indicated (e.g.,
`continuous IV therapy or
`mechanical hemodynamic
`support)
`
`Definition: A disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements, or, the ability to do so only at an
`elevation in the filling pressure.
`
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`

`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Cardiac disorders
`Grade
`
`Left ventricular systolic
`dysfunction
`
` -
`
` -
`
`Symptomatic due to drop in
`ejection fraction responsive to
`intervention
`
`Refractory or poorly controlled
`heart failure due to drop in
`ejection fraction; intervention
`such as ventricular assist
`device, intravenous
`vasopressor support, or heart
`transplant indicated
`
`5
`
`Death
`
`Definition: A disorder characterized by failure of the left ventricle to produce adequate output despite an increase in distending pressure and in end-diastolic volume. Clinical
`manifestations mayinclude dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema.
`
`Mitral valve disease
`
`Asymptomatic valvular
`thickening with or without mild
`valvular regurgitation or
`stenosis by imaging
`
`Asymptomatic; moderate
`regurgitation or stenosis by
`imaging
`
`Symptomatic; severe
`regurgitation or stenosis by
`imaging; symptoms controlled
`with medical intervention
`
`Life-threatening
`consequences; urgent
`intervention indicated (e.g.,
`valve replacement,
`valvuloplasty)
`
`Definition: A disorder characterized by a defect in mitral valve function or structure.
`
`Mobitz (type) II atrioventricular
`block
`
`Asymptomatic, intervention
`not indicated
`
`Symptomatic; medical
`intervention indicated
`
`Symptomatic and
`incompletely controlled
`medically, or controlled with
`device (e.g., pacemaker)
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`Death
`
`Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior to the block of an atrial impulse. This is the result of intermittent failure of atrial
`electrical impulse conduction through the atrioventricular (AV) node to the ventricles.
`
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`

`
`Cardiac disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Mobitz type I
`
`Asymptomatic, intervention
`not indicated
`
`Symptomatic; medical
`intervention indicated
`
`Symptomatic and
`incompletely controlled
`medically, or controlled with
`device (e.g., pacemaker)
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`5
`
`Death
`
`Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR interval prior to the blocking of an atrial impulse. This is the result of intermittent
`failure of atrial electrical impulse conduction through the atrioventricular (AV) node to the ventricles.
`
`Myocardial infarction
`
` -
`
`Asymptomatic and cardiac
`enzymes minimally abnormal
`and no evidence of ischemic
`ECG changes
`
`Severe symptoms; cardiac
`enzymes abnormal;
`hemodynamically stable; ECG
`changes consistent with
`infarction
`
`Life-threatening
`consequences;
`hemodynamically unstable
`
`Death
`
`Definition: A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood supply to the area.
`
`Myocarditis
`
`Asymptomatic with laboratory
`(e.g., BNP [B-Natriuretic
`Peptide ]) or cardiac imaging
`abnormalities
`
`Symptoms with mild to
`moderate activity or exertion
`
`Severe with symptoms at rest
`or with minimal activity or
`exertion; intervention
`indicated
`
`Death
`
`Life-threatening
`consequences; urgent
`intervention indicated (e.g.,
`continuous IV therapy or
`mechanical hemodynamic
`support)
`
`Definition: A disorder characterized by inflammation of the muscle tissue of the heart.
`
`Palpitations
`
`Mild symptoms; intervention
`not indicated
`
`Intervention indicated
`
` -
`
` -
`
` -
`
`Definition: A disorder characterized by an unpleasant sensation of irregular and/or forceful beating of the heart.
`
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`

`
`Cardiac disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Paroxysmal atrial tachycardia Asymptomatic, intervention
`not indicated
`
`Symptomatic; medical
`management indicated
`
`IV medication indicated
`
`Life-threatening
`consequences; incompletely
`controlled medically;
`cardioversion indicated
`
`5
`
`Death
`
`Definition: A disorder characterized by a dysrhythmia with abrupt onset and sudden termination of atrial contractions with a rate of 150-250 beats per minute. The rhythm
`disturbance originates in the atria.
`
`Pericardial effusion
`
` -
`
`Asymptomatic effusion size
`small to moderate
`
`Effusion with physiologic
`consequences
`
`Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.
`
`Pericardial tamponade
`
` -
`
` -
`
` -
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.
`
`Pericarditis
`
`Asymptomatic, ECG or
`physical findings (e.g., rub)
`consistent with pericarditis
`
`Symptomatic pericarditis (e.g.,
`chest pain)
`
`Pericarditis with physiologic
`consequences (e.g.,
`pericardial constriction)
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Definition: A disorder characterized by irritation to the layers of the pericardium (the protective sac around the heart).
`
`Pulmonary valve disease
`
`Asymptomatic valvular
`thickening with or without mild
`valvular regurgitation or
`stenosis by imaging
`
`Asymptomatic; moderate
`regurgitation or stenosis by
`imaging
`
`Symptomatic; severe
`regurgitation or stenosis by
`imaging; symptoms controlled
`with medical intervention
`
`Life-threatening
`consequences; urgent
`intervention indicated (e.g.,
`valve replacement,
`valvuloplasty)
`
`Death
`
`Death
`
`Death
`
`Death
`
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`

`
`Cardiac disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Definition: A disorder characterized by a defect in pulmonary valve function or structure.
`
`Restrictive cardiomyopathy
`
` -
`
` -
`
`Symptomatic heart failure or
`other cardiac symptoms,
`responsive to intervention
`
`Refractory heart failure or
`other poorly controlled cardiac
`symptoms
`
`Death
`
`Definition: A disorder characterized by an inability of the ventricles to fill with blood because the myocardium (heart muscle) stiffens and loses its flexibility.
`
`Right ventricular dysfunction
`
`Asymptomatic with laboratory
`(e.g., BNP [B-Natriuretic
`Peptide ]) or cardiac imaging
`abnormalities
`
`Symptoms with mild to
`moderate activity or exertion
`
`Severe symptoms, associated
`with hypoxemia, right heart
`failure; oxygen indicated
`
`Death
`
`Life-threatening
`consequences; urgent
`intervention indicated (e.g.,
`ventricular assist device);
`heart transplant indicated
`
`Definition: A disorder characterized by impairment of right ventricular function associated with low ejection fraction and a decrease in motility of the right ventricular wall.
`
`Sick sinus syndrome
`
`Asymptomatic, intervention
`not indicated
`
`Non-urgent intervention
`indicated
`
`Severe, medically significant;
`medical intervention indicated
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`Definition: A disorder characterized by a dysrhythmia with alternating periods of bradycardia and atrial tachycardia accompanied by syncope, fatigue and dizziness.
`
`Sinus bradycardia
`
`Asymptomatic, intervention
`not indicated
`
`Symptomatic, medical
`intervention indicated
`
`Severe, medically significant,
`medical intervention indicated
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per minute that originates in the sinus node.
`
`Sinus tachycardia
`
`Asymptomatic, intervention
`not indicated
`
`Symptomatic; non-urgent
`medical intervention indicated
`
`Urgent medical intervention
`indicated
`
` -
`
`Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates in the sinus node.
`
`Death
`
` -
`
`CTCAE 4.03 - June 14, 2010 : Cardiac disorders
`12
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`

`
`Cardiac disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Supraventricular tachycardia
`
`Asymptomatic, intervention
`not indicated
`
`Non-urgent medical
`intervention indicated
`
`Medical intervention indicated Life-threatening
`consequences; urgent
`intervention indicated
`
`Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates above the ventricles.
`
`Tricuspid valve disease
`
`Asymptomatic valvular
`thickening with or without mild
`valvular regurgitation or
`stenosis
`
`Asymptomatic; moderate
`regurgitation or stenosis by
`imaging
`
`Symptomatic; severe
`regurgitation or stenosis;
`symptoms controlled with
`medical intervention
`
`Life-threatening
`consequences; urgent
`intervention indicated (e.g.,
`valve replacement,
`valvuloplasty)
`
`5
`
`Death
`
`Death
`
`Definition: A disorder characterized by a defect in tricuspid valve function or structure.
`
`Ventricular arrhythmia
`
`Asymptomatic, intervention
`not indicated
`
`Non-urgent medical
`intervention indicated
`
`Medical intervention indicated Life-threatening
`consequences; hemodynamic
`compromise; urgent
`intervention indicated
`
`Death
`
`Definition: A disorder characterized by a dysrhythmia that originates in the ventricles.
`
`Ventricular fibrillation
`
` -
`
` -
`
` -
`
`Life-threatening
`consequences; hemodynamic
`compromise; urgent
`intervention indicated
`
`Death
`
`Definition: A disorder characterized by a dysrhythmia without discernible QRS complexes due to rapid repetitive excitation of myocardial fibers without coordinated
`contraction of the ventricles.
`
`CTCAE 4.03 - June 14, 2010 : Cardiac disorders
`13
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`MYLAN PHARMS. INC. EXHIBIT 1093 PAGE 14
`
`

`
`Cardiac disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Ventricular tachycardia
`
` -
`
`Non-urgent medical
`intervention indicated
`
`Medical intervention indicated Life-threatening
`consequences; hemodynamic
`compromise; urgent
`intervention indicated
`
`Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates distal to the bundle of His.
`
`Wolff-Parkinson-White
`syndrome
`
`Asymptomatic, intervention
`not indicated
`
`Non-urgent medical
`intervention indicated
`
`Symptomatic and
`incompletely controlled
`medically or controlled with
`procedure
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`5
`
`Death
`
`Death
`
`Definition: A disorder characterized by the presence of an accessory conductive pathway between the atria and the ventricles that causes premature ventricular activation.
`
`Cardiac disorders - Other,
`specify
`
`Asymptomatic or mild
`symptoms; clinical or
`diagnostic observations only;
`intervention not indicated
`
`Moderate; minimal, local or
`noninvasive intervention
`indicated; limiting age-
`appropriate instrumental ADL
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`Severe or medically significant
`but not immediately life-
`threatening; hospitalization or
`prolongation of existing
`hospitalization indicated;
`disabling; limiting self care
`ADL
`
`CTCAE 4.03 - June 14, 2010 : Cardiac disorders
`14
`
`MYLAN PHARMS. INC. EXHIBIT 1093 PAGE 15
`
`

`
`4. Congenital, familial and genetic disorders
`
`Congenital, familial and genetic disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Congenital, familial and
`genetic disorders - Other,
`specify
`
`Asymptomatic or mild
`symptoms; clinical or
`diagnostic observations only;
`intervention not indicated
`
`Moderate; minimal, local or
`noninvasive intervention
`indicated; limiting age-
`appropriate instrumental ADL
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Severe or medically significant
`but not immediately life-
`threatening; hospitalization or
`prolongation of existing
`hospitalization indicated;
`disabling; limiting self care
`ADL
`
`5
`
`Death
`
`CTCAE 4.03 - June 14, 2010 : Congenital, familial and genetic disorders
`15
`
`MYLAN PHARMS. INC. EXHIBIT 1093 PAGE 16
`
`

`
`5. Ear and labyrinth disorders
`
`Ear and labyrinth disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Ear pain
`
`Mild pain
`
`Moderate pain; limiting
`instrumental ADL
`
`Severe pain; limiting self care
`ADL
`
` -
`
`Definition: A disorder characterized by a sensation of marked discomfort in the ear.
`
`5
`
` -
`
`External ear inflammation
`
`External otitis with erythema
`or dry desquamation
`
`External otitis with moist
`desquamation, edema,
`enhanced cerumen or
`discharge; tympanic
`membrane perforation;
`tympanostomy
`
`External otitis with mastoiditis;
`stenosis or osteomyelitis;
`necrosis of soft tissue or bone
`
`Urgent operative intervention
`indicated
`
`Death
`
`Definition: A disorder characterized by inflammation, swelling and redness to the outer ear and ear canal.
`
`External ear pain
`
`Mild pain
`
`Moderate pain; limiting
`instrumental ADL
`
`Severe pain; limiting self care
`ADL
`
` -
`
` -
`
`Definition: A disorder characterized by a sensation of marked discomfort in the external ear region.
`
`CTCAE 4.03 - June 14, 2010 : Ear and labyrinth disorders
`16
`
`MYLAN PHARMS. INC. EXHIBIT 1093 PAGE 17
`
`

`
`5
`
` -
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Ear and labyrinth disorders
`Grade
`
`Hearing impaired
`
`Adults: Decrease in hearing to
`profound bilateral loss
`(absolute threshold >80 dB HL
`at 2 kHz and above); non-
`servicable hearing.
`
`Pediatric: Audiologic
`indication for cochlear implant
`and additional speech-
`language related services
`indicated.
`
`Adults enrolled on a
`Monitoring Program (on a 1,
`2, 3, 4, 6 and 8 kHz
`audiogram): Threshold shift of
`15 - 25 dB averaged at 2
`contiguous test frequencies in
`at least one ear.
`
`Adults enrolled in Monitoring
`Program (on a 1, 2, 3, 4, 6
`and 8 kHz audiogram):
`Threshold shift of >25 dB
`averaged at 2 contiguous test
`frequencies in at least one
`ear.
`
`Adults not enrolled in
`Monitoring Program:
`subjective change in hearing
`in the absence of documented
`hearing loss.
`
`Adults not enrolled in
`Monitoring Program: hearing
`loss but hearing aid or
`intervention not indicated;
`limiting instrumental ADL.
`
`Pediatric (on a 1, 2, 3, 4, 6
`and 8 kHz audiogram):
`Threshold shift >20 dB at 8
`kHz in at least one ear.
`
`Pediatric (on a 1, 2, 3, 4, 6
`and 8 kHz audiogram):
`Threshold shift >20 dB at 4
`kHz and above in at least one
`ear.
`
`Adults enrolled in Monitoring
`Program (on a 1, 2, 3, 4, 6
`and 8 kHz audiogram):
`Threshold shift of >25 dB
`averaged at 3 contiguous test
`frequencies in at least one
`ear; therapeutic intervention
`indicated.
`
`Adults not enrolled in
`Monitoring Program: hearing
`loss with hearing aid or
`intervention indicated; limiting
`self care ADL.
`
`Pediatric (on a 1, 2, 3, 4, 6
`and 8 kHz audiogram):
`hearing loss sufficient to
`indicate therapeutic
`intervention, including hearing
`aids; threshold shift >20 dB at
`3 kHz and above in at least
`one ear; additional speech-
`language related services
`indicated.
`
`CTCAE 4.03 - June 14, 2010 : Ear and labyrinth disorders
`17
`
`MYLAN PHARMS. INC. EXHIBIT 1093 PAGE 18
`
`

`
`Ear and labyrinth disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Definition: A disorder characterized by partial or complete loss of the ability to detect or understand sounds resulting from damage to ear structures.
`
`Middle ear inflammation
`
`Serous otitis
`
`Serous otitis, medical
`intervention indicated
`
`Mastoiditis; necrosis of canal
`soft tissue or bone
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Death
`
`Definition: A disorder characterized by inflammation (physiologic response to irritation), swelling and redness to the middle ear.
`
`Tinnitus
`
`Mild symptoms; intervention
`not indicated
`
`Moderate symptoms; limiting
`instrumental ADL
`
`Severe symptoms; limiting self
`care ADL
`
`Definition: A disorder characterized by noise in the ears, such as ringing, buzzing, roaring or clicking.
`
`Vertigo
`
`Mild symptoms
`
`Moderate symptoms; limiting
`instrumental ADL
`
`Severe symptoms; limiting self
`care ADL
`
` -
`
` -
`
` -
`
` -
`
`Definition: A disorder characterized by a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space
`(subjective vertigo).
`
`Vestibular disorder
`
` -
`
`Symptomatic; limiting
`instrumental ADL
`
`Severe symptoms; limiting self
`care ADL
`
` -
`
`Definition: A disorder characterized by dizziness, imbalance, nausea, and vision problems.
`
`Ear and labyrinth disorders -
`Other, specify
`
`Asymptomatic or mild
`symptoms; clinical or
`diagnostic observations only;
`intervention not indicated
`
`Moderate; minimal, local or
`noninvasive intervention
`indicated; limiting age-
`appropriate instrumental ADL
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`Severe or medically significant
`but not immediately life-
`threatening; hospitalization or
`prolongation of existing
`hospitalization indicated;
`disabling; limiting self care
`ADL
`
` -
`
`Death
`
`CTCAE 4.03 - June 14, 2010 : Ear and labyrinth disorders
`18
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`MYLAN PHARMS. INC. EXHIBIT 1093 PAGE 19
`
`

`
`6. Endocrine disorders
`
`Endocrine disorders
`Grade
`
`Adverse Event
`
`1
`
`2
`
`3
`
`4
`
`Adrenal insufficiency
`
`Asymptomatic; clinical or
`diagnostic observations only;
`intervention not indicated
`
`Moderate symptoms; medical
`intervention indicated
`
`Severe symptoms;
`hospitalization indicated
`
`Life-threatening
`consequences; urgent
`intervention indicated
`
`5
`
`Death
`
`Definition: A disorder that occurs when the adrenal cortex does not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. It may be due to a
`disorder of the adrenal cortex as in Addison's disease or primary adrenal insufficiency.
`
`Cushingoid
`
`Mild symptoms; intervention
`not indicated
`
`Moderate symptoms; medical
`intervention indicated
`
`Severe symptoms, medical
`intervention or hospitalization
`indicated
`
` -
`
` -
`
`Definition: A disorder characterized by signs and symptoms that resemble Cushing's disease or syndrome: buffalo hump obesity, striations, adiposity, hypertension,
`diabetes, and osteoporosis, usually due to exogenous corticosteroids.
`
`Delayed puberty
`
` -
`
`No breast development by
`age 13 yrs for females; testes
`volume of <3 cc or no Tanner
`Stage 2 development by age
`14.5 yrs for males
`
`No breast development by
`age 14 yrs for females; no
`increase in testes volume or
`no Tanner Stage 2 by age 16
`yrs for males; hormone
`replacement indicated
`
`Definition: A disorder characterized by unusually late sexual maturity.
`
`Growth accelerated
`
` -
`
`>= +2 SD (standard deviation)
`above mid parental height or
`target height
`
`Definition: A disorder characterized by greater growth than expected for age.
`
`Hyperparathyroidism
`
`Mild symptoms; intervention
`not indicated
`
`Moderate sympto