Cetuximab:ErbituxBevacizumab:AvastinPanitumumab:VectibixTrastuzumab:HerceptinDaratumumab:DarzalexElotuzumab:EmplicitiPembrolizumab:KeytrudaRamucirumab:CyramzaNecitumumab:PortrazzaNivolumab:OpdivoPertuzumab:PerjetaIdarucizumab:PraxbindRamucirumab:CyramzaEverolimus: Afinitor Sunitinib:SutentErlotinib:TarcevaRegorafenib:StivargaAxitinib Pazopanib Sorafenib Vemurafenib Trametinib DaframenibCobimetinib

TepotinibCeritinib CrizotinibGefitinib Osimertinib Imatinib mesylate Ixazomib citrateCarfilzomibBortezomib Sonidegib Vismodegib Afatinib dimaleateTemsisolimusEvofosfamide PomalidomidePanobinostan Lenalidomide Alitretinoin Pimasertib Ziv-afiliberceptAdo-trastuzumab emtansineAnastrazoleExemestane Letrozole Lapatinib

FulvestranPalbociclib Tamoxifene Toremifene Abiraterone acetateCabazitaxelEnzalutamide Radium 223 dichloride

Cetuximab:ErbituxAdverse Effects

>10%Acneform rash (90%)

Fatigue (89%)

Hypomagnesemia (55%)

Asthenia/malaise (49%)

Fever (33%)

Nausea (29%)

Constipation (28%)

Diarrhea (28%)

Abdominal pain (25%)

Anorexia (25%)

Headache (25%)

Infusion reaction (25%)

Vomiting (25%)

Dyspnea (20%)

Pain (19%)

Nail disorder (16%)

Back pain (11%)

Stomatitis (11%)Anemia (10%)

Cough increased (10%)

Infection (11%)

1-10%Insomnia (10%)

Peripheral edema (10%)

Pruritus (10%)

Dehydration (9%)

Depression (9%)

Weight loss (9%)

Conjunctivitis (7%)

Dyspepsia (7%)

Alopecia (5%)

Skin disorder (5%)

Leukopenia (1%)

Frequency Not DefinedElectrolyte depletion

Postmarketing ReportsAseptic meningitis

Mucosal inflammation

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Life-threatening and fatal bullous mucocutaneous disease

Warnings

Black Box Warnings

Severe infusion reactions occurred with this agent in approximately in 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue cetuximab infusion for serious infusion reactions

Cardiopulmonary Arrest

Cardiopulmonary arrest and/or sudden death occurred in 2% (4/208) of patients with squamous cell carcinoma of the head and neck treated with radiation therapy and cetuximab. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after cetuximab therapy

Contraindications

Hypersensitivity (history of serious infusion reaction)

Cautions

Use in colorectal cancer only with confirmed KRAS mutation negative (wild-type)

Risk of cardiopulmonary arrest and sudden death

Increases risk of electrolyte depletion, especially hypomagnesemia; periodically monitor during and for at least 8 wk following completion of therapy; replete electrolytes as necessary

Risk of infusion reactions; monitor patients following infusion; discontinue therapy for serious infusion reactions (see dose modifications)

Mucocutaneous adverse reactions may occur; limit sun exposure; wear sunscreen and hats

Dermatologic toxicities include life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, skin sloughing, acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, Streptococcal aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis; monitor for inflammatory or infectious sequelae

Increased incidence of grade 3-4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances when used in combination with radiation and cisplatin; coadministration did not improve progression-free survival

Interstitial lung disease reported; interrupt treatment for acute onset or worsen of pulmonary symptoms

Increased tumor progression, increased mortality, or lack of benefit in patients with Ras-mutant metastatic colorectal cancer (mCRC)

Advise females of reproductive potential to use effective contraception during treatment with and for 6 months after the last dose

Bevacizumab:AvastinAdverse Effects

>10%

Weakness (73-74%)

Hypertension (23-67%; grades 3/4: 8-18%)

Pain (61-62%)

Abdominal pain (50-61%; grades 3/4: 8%)

Vomiting (47-52%, grades 3/4:6-11%)

URI (40-47%)

Constipation (29-40%)

Leukopenia (grades 3/4: 37%)

Proteinuria (36%, grades 3/4: 3%)

Epistaxis (32-35%)

Ovarian failure (with mFolfox) (34%)

Diarrhea (grades 3/4: 2-34%)

Stomatitis (30-32%)Alopecia (6-32%)

Neutropenia (grades 3/4: 6-27%)

Headache (26%; grades 3/4: 2-4%)

Dyspnea (25-26%)

Dizziness (19-26%)

GI hemorrhage (19-24%)

Dyspepsia (17-24%)

Taste alteration (14-21%)

Dry skin (7-20%)

Exfoliative dermatitis (3-19%)

Fatigue (grades 3/4: 5-19%)

Flatulence (11-19%)

Lacrimation disorder (6-18%)

Neuropathy (grades 3/4: 1-17%)

Weight loss (15-16%)

Hypokalemia (12-16%)

Skin discoloration (2-16%)

Thromboembolic events (grades 3/4: 15%)

Myalgia (8-15%)

Hypotension (7-15%)

Nausea (grades 3/4: 4-12%)

Back pain (undefined)

1-10%

Dehydration (grades 3/4: 3-10%)

DVT (6-9%; grades 3/4: 9%)

Polyuria (3-6%)

Bilirubinemia (1-6%)

Colitis (1-6%)

Confusion (1-6%)

Neutropenia (5%)

Thrombocytopenia (5%)

Xerostomia (4-7%)Ileus (grades 3/4: 4-5%)

Abnormal gait (1-5%)

Bone pain (grade 3/4: 4%)

Hyponatremia (grades 3/4: 4%)

GI perforations (<4%)

Arterial thrombosis (3-4%)

Intra-abdominal venous thrombosis (grades 3/4: 3%)

Rash desquamation (grades 3/4: 3%)

Syncope (grades 3/4: 3%)

Infusion reaction (<3%)

Cardio-cerebrovascular arterial thrombotic event (2-4%)

CHF (2%)

Wound dehiscence (1%)

Postmarketing Reports

Body as whole: Polyserositis

Cardiovascular: Pulmonary hypertension, RPLS, mesenteric venous occlusion

Osteonecrosis of the jaw

Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision, endophthalmitis (infectious and sterile), intraocular inflammation, retinal detachment, increased IOP, hemorrhage (including conjunctival, vitreous hemorrhage, or retinal hemorrhage), vitreous floaters, ocular hyperemia, ocular pain or discomfort

Gastrointestinal: Gastrointestinal ulcer, intestinal necrosis, anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Hepatobiliary disorders: Gallbladder perforation

Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation

Musculoskeletal: Osteonecrosis of the jaw

Renal: Renal thrombotic microangiopathy

Respiratory: Nasal septum perforation

Dysphonia

Systemic events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, hypertension, gastrointestinal perforation, hemorrhage

Non-mandibular osteonecrosis and posterior reversible encephalopathy syndrome (PRES)

Warnings

Black Box Warnings Gastrointestinal perforations

Gastrointestinal (GI) perforation, fistula formation, and/or intra-abdominal abscess unrelated to therapy duration reported in patients with colorectal cancer as well as other types of cancers

Typical presentation reported as abdominal pain associated with symptoms such as constipation and vomiting

Include GI perforation in the differential diagnosis of patients presenting with abdominal pain

Discontinue therapy permanently in patients with GI perforation

Surgery and wound healing complications

Administration may result in the development of fatal wound dehiscence Discontinue therapy in patients with wound dehiscence requiring medical intervention Discontinue at least 28 days prior to elective surgery Do not initiate bevacizumab for at least 28 days after surgery and until the surgical wound is

fully healed

Hemorrhage

Severe or fatal hemorrhage, hemoptysis, gastrointestinal bleeding, CNS hemorrhage, and vaginal bleeding are increased in bevacizumab-treated patients

Do not administer the drug to patients with serious hemorrhage or recent hemoptysis

Contraindications None

Cautions

Impairs wound healing; discontinue before elected surgeries and do not initiate following surgery (see Black Box Warnings)

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE; discontinue bevacizumab for severe ATE

Increased risk of venous thromboembolic events (VTE) reported in patients treated with bevacizumab for cervical cancer; discontinue bevacizumab for life-threatening VTE

Monitor blood pressure and treat hypertension; increased risk for severe hypertension; temporarily suspend treatment; discontinue if hypertensive crisis or hypertensive encephalopathy

Posterior reversible encephalopathy syndrome (PRES) reported (0.5%); discontinue if PRES develops

Proteinuria reported; temporarily suspend treatment for ≥2 g proteinuria/24 hr; discontinue if nephrotic syndrome occurs (incidence <1%)

Advise females of reproductive potential to use effective contraception during treatment with and for 6 months after the last dose

Infusion reactions may occur and include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis; stop infusion if severe and administer appropriate therapy

GI perforation and fistula formation

Serious and sometimes fatal GI perforation occurs at a higher incidence in bevacizumab treated patients compared to controls; incidence of perforation ranged from 0.3 to 3.2% across clinical studies

In a cervical cancer trial, the incidence of GI-vaginal fistulae was 8.2% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation

In a platinum-resistant ovarian cancer trial, the incidence of GI perforation was 1.7% Serious and sometimes fatal fistula formation involving tracheo-esophageal, bronchopleural,

biliary, vaginal, renal and bladder sites occurs at a higher incidence in bevacizumab-treated patients compared to controls

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer, 1.8% of bevacizumab-treated patients and 1.4% of control patients were reported to have had nongastrointestinal vaginal, vesical, or female genital tract fistulae

Panitumumab (Rx)Brand and Other Names:VectibixAdverse Effects

>10%

Erythema (65%)

Acneiform dermatitis (57%)

Pruritus (57%)

Hypomagnesemia (39%)

Fatigue (26%)

Abdominal pain (25%)

Paronychia (25%)

Skin exfoliation (25%)

Nausea (23%)

Rash (22%)

Constipation (21%)

Diarrhea (21%)

Vomiting (21%)

Skin fissures (20%)

Cough (14%)

Dermatologic toxicity, Grade 3 and 4 (14% )

Acne (13%)

Peripheral edema (12%)

1-10%

Abdominal pain, Grade 3 and 4 (7% )

Pulmonary embolism, Grades 3 to 5 (7% )

Hypomagnesemia, Grade 3 and 4 (4% )

Angioedema, All grades (3% to 4% )

Complication of infusion, All grades (3% to 4% )

Constipation, Grade 3 and 4 (3% )

Binding antibodies (0.4-3.8%)

Diarrhea, Grade 3 and 4 (2% )

Vomiting, Grade 3 and 4 (2% )

Nausea, Grade 3 and 4 (1% )

Anaphylaxis (1% )

Complication of infusion, Grade 3 and 4 (1% )

Sepsis (1%)

<1%

Pulmonary fibrosis

Frequency Not Defined

Conjunctivitis

Growth of eyelashes

Increased tears

Ocular hyperemia

Mucositis

Stomatitis

Postmarketing Reports

Skin and subcutaneous tissue disorders: Skin necrosis, angioedema

Immune system disorders: Anaphylactoid reaction

Eye disorders: Keratitis/ulcerative keratitis

Life threatening and fatal bullous mucocutaneous disease

Black Box Warnings

Dermatologic toxicity

Dermatologic toxicities, some severe (NCI-CTC grade 3 or higher), related to panitumumab blockade of EGF binding and subsequent inhibition of EGFR-mediated signaling pathways have been reported in patients receiving panitumumab monotherapy

Dermatologic toxicities were reported in 90% of patients and were severe in 15% of patients receiving monotherapy

Clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures

Severe dermatologic toxicities were complicated by infection including sepsis, septic death, and abscesses requiring incisions and drainage

It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens Johnson syndrome or toxic epidermal necrolysis)

Withhold or discontinue panitumumab and monitor for inflammatory or infectious sequelae in patients with severe dermatologic toxicities

Cautions Increased tumor progression, increased mortality, or lack of benefit in patients with RAS-

mutant mCRC; determine RAS-mutant tumor status in an experienced laboratory using an FDA-approved test before treatment

Monitor patients who develop dermatologic toxicities while receiving panitumumab for the development of inflammatory or infectious sequelae; limit sun exposure

Panitumumab is not indicated for use in combination with chemotherapy due to increase in mortality or toxicity

Permanently discontinue in patients developing pulmonary fibrosis/interstitial lung disease Monitor for keratitis or ulcerative keratitis; interrupt or discontinue panitumumab for acute

or worsening keratitis Monitor electrolytes and institute appropriate treatment if needed Terminate the infusion for severe infusion reactions Ocular toxicities reported; monitor for keratitis or ulcerative keratitis; interrupt or

discontinue for acute or worsening keratitis Discontinue permanently if patient develops interstitial lung disease, pneumonitis, or lung

infiltrates

Trastuzumab (Rx)Brand and Other Names:HerceptinAdverse Effects

>10%

Pain (47%)

Asthenia (42%)

Fever (36%)

Nausea (33%)

Chills (32%)

Cough (26%)

Headache (26%)

Diarrhea (25%)

Vomiting (23%)

Abdominal pain (22%)

Back pain (22%)

Dyspnea (22%)

Infection (20%)

Rash (18%)

Anorexia (14%)

Insomnia (14%)

Dizziness (13%)

1-10%

Flu-like syndrome (10%)

Peripheral edema (10%)

CHF (7%)

Depression (6%)

Tachycardia (5%)

UTI (5%)

Anemia (4%)

Hypersensitivity (3%)

Leukopenia (3%)

Black Box Warnings

Do not substitute ado-trastuzumab emtansine (Kadcyla) for or with trastuzumab (Herceptin); dosing and treatment schedules for Kadcyla and Herceptin are quite different, so confusion between these products could lead to dosing errors and potential harm to patients

Cardiomyopathy

Administration can result in subclinical and clinical cardiac failure manifesting as CHF and decreased left ventricular ejection fraction (LVEF)

Evaluate LVEF in all patients prior to and during treatment with trastuzumab Incidence and severity of left ventricular cardiac dysfunction is highest in patients who

receive the drug concurrently with anthracycline-containing chemotherapy regimens Discontinue if receiving adjuvant therapy for breast cancer, and strongly consider

discontinuation with metastatic breast cancer who develop a clinically significant decrease in left ventricular function

Infusion reactions, pulmonary toxicity

Can result in serious pulmonary toxicity and sometimes fatal infusion reactions In most cases, symptoms occurred during or within 24 hr of administration Interrupt infusion in patients experiencing dyspnea or clinically significant hypotension Monitor until signs and symptoms completely resolve Discontinue for infusion reactions manifesting as anaphylaxis, angioedema, interstitial

pneumonitis, or acute respiratory distress syndrome

Embryo-fetal toxicity

Exposure during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia, skeletal abnormalities, and neonatal death

Contraindications

Hypersensitivity to drug/class/component or hamster protein

Cautions

Use extreme cautioin in cardiac disease, cardiotoxic agent history, ejection fraction decrease, pulmonary disease, elderly

Risk of ventricular dysfunction and CHF - strongly consider discontinuation if clinically significant decrease in left ventricular function (concurrent anthracyclines and cyclophosphamide increase incidence and severity)

If patient becomes pregnant while in therapy or within 7 months following last dose of Herceptin, apprise patient of potential hazard to fetus; advise females of reproductive potential to avoid becoming pregnant while in therapy; if contraceptive methods are being considered, use effective contraception during treatment and for at least 7 months after receiving last dose of trastuzumab

CHF: At a median follow-up duration of 8 yr, the incidence of severe CHF (NYHA III and IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%

Patients who receive anthracycline after stopping trastuzumab therapy may be at increased risk of cardiac dysfunction

Possibility of severe hypersensitivity reactions (including anaphylaxis), infusion reactions, and pulmonary events - strongly consider discontinuation/suspension in patients showing signs of the above

Preinfusion treatment

Symptoms such as chills and/or fever observed in ~40% of patients Usually mild-to-moderate severity Pretreat with acetaminophen, diphenhydramine, and meperidine (with or without reduction

in infusion rate)

Daratumumab (Rx)Brand and Other Names:DarzalexAdverse EffectsAdverse reactions listed below are for any grade unless otherwise noted

>10%

Lymphopenia (72%)

Neutropenia (60%)

Infusion reaction (48%)

Thrombocytopenia (48%)

Anemia (45%)

Fatigue (39%)

Lymphopenia, grade 3 (30%)

Nausea (27%)

Back pain (23%)

Pyrexia (21%)

Cough (21%)

Upper respiratory tract infection (20%)

Anemia, grade 3 (19%)

Neutropenia, grade 3 (17%)

Nasal congestion (17%)

Arthralgia (17%)

Diarrhea (16%)

Constipation (15%)

Pain in extremity (15%)

Dyspnea (15%)

Nasopharyngitis (15%)

Decreased appetite (15%)

Vomiting (14%)

Musculoskeletal chest pain (12%)

Headache (12%)

Pneumonia (11%)

1-10%

Thrombocytopenia, grade 3 (10%)

Lymphopenia, grade 4 (10%)

Hypertension (10%)

Chills (10%)

Thrombocytopenia, grade 4 (8%)

Pneumonia, grade 3 (6%)

Hypertension, grade 3 (5%)

Neutropenia, grade 4 (3%)

Infusion reaction, grade 3 (3%)

Fatigue, grade 3 (2%)

Back pain, grade 3 (2%)

Pyrexia, grade 3 (1%)

Dyspnea, grade 3 (1%)

Pain in extremity, grade 3 (1%)

Musculoskeletal chest pain, grade 3 (1%)

Upper respiratory tract infection, grade 3 (1%)

Diarrhea, grade 3 (1%)

Decreased appetite, grade 3 (1%)

Headache, grade 3 (1%)

Warnings

Contraindications

None

Cautions

Binds to CD38 on RBCs and may result in a positive indirect antiglobulin test (Coombs test)

May cause false-positive results with serum protein electrophoresis (SPE) and immunofixation (IFE) assays

Severe infusion reactions

Severe infusion reactions reported in ~50% of all patients (most during the first infusion); may also occur with subsequent infusions

Nearly all reactions occurred during infusion or within 4 hr of completing infusion Prior to the introduction of postinfusion medication in clinical trials, infusion reactions

occurred up to 48 hr after infusion Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, and

hypertension Signs and symptoms may include respiratory symptoms (eg, cough, wheezing, larynx, throat

tightness and irritation), laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis

Less common symptoms were hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills

Premedicate patients with antihistamines, antipyretics, and corticosteroids Frequently monitor patients during the entire infusion Permanently discontinue for life-threatening (grade 4) reactions For grade 1, 2, or 3 reactions, reduce the infusion rate when restarting the infusion To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all

patients the first and second day after all infusions Patients with a history of obstructive pulmonary disorders may require additional

postinfusion medications to manage respiratory complications Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for

patients with obstructive pulmonary disorders

Elotuzumab (Rx)Brand and Other Names:EmplicitiAdverse EffectsAdverse reaction percentages listed are for all grades of toxicity unless otherwise stated

>10%

Heart rate <60 bpm (66%)

Fatigue (61.1%)

Heart rate ≥100 bpm (47.8%)

Diarrhea (46.9%)

Pyrexia (37.4%)

Cough (34.3%)

Systolic blood pressure ≥160 mmHg (33.3%)

Systolic blood pressure <90 mmHg (28.9%)

Infections, grades 3-4 (28%)

Peripheral neuropathy (26.7%)

Nasopharyngitis (24.5%)

Upper respiratory tract infection (22.6%)

Opportunistic infections, all (22%)

Decreased appetite (20.8%)

Pneumonia (20.1%)

Diastolic blood pressure ≥100 mmHg (17.3%)

Pain in extremities (16.4%)

Headache (15.4%)

Vomiting (14.5%)

Pneumonia, grades 3-4 (14.2%)

Decreased weight (13.8%)

Herpes zoster infections (13.5%)

Lymphopenia (13.2%)

Fatigue, grades 3-4 (12.6%)

Cataracts (11.9%)

Oropharyngeal pain (10.1%)

1-10%

Infusion related reactions (10%)

Fungal infections (9.7%)

Secondary primary malignancies (9.1%)

Lymphopenia, grades 3-4 (8.8%)

Cataracts, grades 3-4 (6.3%)

Diarrhea, grades 3-4 (5%)

Peripheral neuropathy, grades 3-4 (3.8%)

Pyrexia, grades 3-4 (2.5%)

Hepatotoxicity (2.5%)

Constipation, grades 3-4 (1.3%)

Decreased weight, grades 3-4 (1.3%)

Infusion reactions, grade 3 (1%)

Warnings

Contraindications

None for elotuzumab

See lenalidomide and dexamethasone prescribing information

Cautions

Infusion reactions can occur and may include fever, chills, and hypertension (see Dosage Modifications)

Infections reported, including opportunistic infections (eg, fungal infections, herpes zoster)

Second primary malignancies reported, including solid tumors and skin cancers

Elevations in liver enzymes (AST/ALT >3 x ULN, TB >2 x ULN, and alkaline phosphatase <2 x ULN) consistent with hepatotoxicity were reported; monitor liver enzymes periodically; stop elotuzumab for ≥grade 3 elevation of liver enzymes; may consider treatment continuation after return to baseline values

Humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPEP) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein; this interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein

Pembrolizumab (Rx)Brand and Other Names:KeytrudaAdverse Effects

>10%

Fatigue (47%)

Anemia (55%)

Hyperglycemia (40%)

Hyponatremia (35%)

Hypoalbuminemia (34%)

Nausea (30%)

Cough (30%)

Pruritus (30%)

Rash (29%)

Decreased appetite (26%)

Hypertriglyceridemia (25%)

Increased AST (24%)

Constipation (21%)

Diarrhea (20%)

Arthralgia (20%)

Pain in extremity (18%)

Dyspnea (18%)

Peripheral edema (17%)

Vomiting (16%)

Headache (16%)

Myalgia (14%)

Chills (14%)

Insomnia (14%)

Abdominal pain (12%)

Back pain (12%)

Dizziness (11%)

Pyrexia (11%)

Upper respiratory tract infection (11%)

Vitiligo (11%)

1-10%

Sepsis (up to 10%)

Immune-mediated hypothyroidism (8.3%)

Immune-mediated pneumonitis (2.9%)

Immune-mediated hyperthyroidism (1.2%)

Immune-mediated colitis (1%)

<1%

Immune-mediated nephritis (0.7%)

Renal failure (0.5%)

Immune-mediated hepatitis (0.5%)

Immune-mediated hypophysitis (0.5%)

Postmarketing reports

Infusion-related reactions

Warnings

Contraindications

None

Cautions

Clinical trials reported immune-mediated pneumonitis, colitis, hepatitis, nephritis and other immune-mediated adverse reactions (eg, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia,

partial seizures arising in a patient with inflammatory foci in brain parenchyma, myasthenic syndrome, optic neuritis, and rhabdomyolysis)

Severe dermatitis including bullous pemphigoid and exfoliative dermatitis reported

Immune-mediated endocrinopathies reported adrenal insufficiency, changes in thyroid function, and type 1 diabetes mellitus including diabetic ketoacidosis (withhold therapy in case of severe hyperglycemia until metabolic control achieved)

Infusion-related reactions, including severe and life-threatening reactions, reported; monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritis, flushing, rash, hypotension, hypoxemia, and fever; permanently discontinue therapy for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions

Hypophysitis reported; monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency); administer corticosteroids for Grade 2 or greater hypophysitis; withhold therapy for moderate (Grade 2) hypophysitis, withhold or discontinue for severe (Grade 3) hypophysitis, and permanently discontinue for life-threatening (Grade 4) hypophysitis

Thyroid disorders can occur; monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders

Administer corticosteroids for Grade 3 or greater hyperthyroidism; withhold treatment for severe (Grade 3) hyperthyroidism, and permanently discontinue for life-threatening (Grade 4) hyperthyroidism; isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids

Renal failure reported

Embryofetal toxicity is likely, based on the drug’s mechanism of action; women of reproductive potential should use highly effective contraception during treatment and for 4 months after the last dose

Ramucirumab (Rx)Brand and Other Names:CyramzaAdverse Effects

>10%

All grades unless otherwise states

GI cancer (plus paclitaxel)

Fatigue/asthenia (57%) Neutropenia (54%) Diarrhea (32%) Epistaxis (31%) Peripheral edema (25%)

Stomatitis (20%) Proteinuria (17%) Hypertension (25%) Infusion-related reactions (16%) Hypertension grade 3-4 (15%) Thrombocytopenia (13%) Hypoalbuminemia (11%)

NSCLC (plus docetaxel)

Neutropenia (55%) Fatigue/asthenia (55%)

Stomatitis/mucosal inflammation (37%) Epistaxis (19%) Febrile neutropenia (16%) Peripheral edema (16%) Thrombocytopenia (13%) Lacrimation increased (13%) Hypertension (11%)

1-10%

GI hemorrhage events, gastric cancer (10%)

<1%

Gastrointestinal perforation (single agent) (0.7%)

Reversible posterior leukoencephalopathy syndrome (<0.1%)

Warnings

Black Box Warnings

Hemorrhage

Increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events Permanently discontinue patients who experience severe bleeding

Gastrointestinal perforation

Can increase the risk of gastrointestinal perforation, a potentially fatal event Permanently discontinue in patients who experience a gastrointestinal perforation

Impaired wound healing

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway Discontinue in patients with impaired wound healing Withhold drug prior to surgery and discontinue if a patient develops wound healing

complications

Contraindications

None

Cautions

Increased risk of hemorrhage and GI hemorrhage, including severe and sometimes fatal hemorrhagic events; permanently discontinue in patients who experience severe bleeding (see Black Box Warnings)

Serious, sometimes fatal, arterial thromboembolic events including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia reported during clinical trials

Increased incidence of severe hypertension reported; control hypertension before initiating treatment and monitor blood pressure q2weeks or more frequently as indicated; temporarily suspend therapy for severe hypertension

Infusion-related reactions observed that include rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia; in severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension

Ramucirumab is an antiangiogenic therapy that can increase the risk of GI perforation and affect wound healing; withhold prior to surgery; permanently discontinue ramucirumab in patients who experience a gastrointestinal perforation (see Black Box Warnings)

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway; withhold drug before surgery and discontinue if patient develops wound healing complications (see Black Box Warnings)

Clinical deterioration, manifested by new-onset or worsening encephalopathy, ascites, or hepatorenal syndrome, reported in patients with Child-Pugh B or C cirrhosis; use only if the benefits outweigh the risks

Reversible posterior leukoencephalopathy syndrome (RPLS) reported (rare); discontinue ramucirumab

Severe proteinuria reported, particularly when administered with FOLFIRI (see Dosage Modifications)

May cause hypothyroidism; monitor thyroid function during treatment

Based on its mechanism of action, ramucirumab can cause fetal harm when administered to pregnant women

Necitumumab (Rx)Brand and Other Names:PortrazzaAdverse EffectsPercentages listed below are for all grades of toxicity unless otherwise noted

>10%

Hypomagnesemia (83%)

Hypocalcemia (45%)

Rash (44%)

Hypocalcemia (albumin corrected) (36%)

Hypophosphatemia (31%)

Vomiting (29%)

Hypokalemia (28%)

Hypomagnesemia, grade 3-4 (20%)

Diarrhea (16%)

Dermatitis acneiform (15%)

Weight decreased (13%)

Stomatitis (11%)Headache (11%)

1-10%

Hemoptysis (10%)

Venous thromboembolic events (9%)

Acne (9%)

Hypophosphatemia, grade 3-4 (8%)

Paronychia (7%)

Conjunctivitis (7%)

Pruritus (7%)

Dry skin (7%)

Hypocalcemia, grade 3-4 (6%)

Hypokalemia, grade 3-4 (5%)

Skin fissures (5%)

Pulmonary embolism (5%)

Venous thromboembolic events, grade 3-4 (5%)

Hypocalcemia (albumin corrected), grade 3-4 (4%)

Vomiting, grade 3-4 (3%)

Diarrhea, grade 3-4 (2%)

Stomatitis, grade 3-4 (1%)

Warnings - Black Box Warnings

Cardiopulmonary arrest and/or sudden death occurred in 3% of patients treated with necitumumab in combination with gemcitabine and cisplatin

Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, with aggressive replacement when warranted during and after necitumumab (administer drug through dedicated IV line; do not mix with electrolyte or dextrose solutions) (see Administration)

Hypomagnesemia occurred in 83% of patients receiving necitumumab in combination with gemcitabine and cisplatin, and was severe in 20% of patients

Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each dose during treatment and for at least 8 weeks following completion

Withhold drug for grade 3 or 4 electrolyte abnormalities

Replete electrolytes as medically appropriate

Contraindications None

Cautions

Cardiopulmonary arrest reported in 3% of patients with necitumumab plus gemcitabine and cisplatin compared with 0.6% with gemcitabine and cisplatin; closely monitor serum electrolytes during and after dose

Monitor for hypomagnesemia (see Black Box Warnings) Discontinue if severe venous or arterial thrombosis occurs

Dermatologic toxicities, including rash, dermatitis acneiform, acne, dry skin, pruritus, generalized rash, skin fissures, maculopapular rash and erythema, occurred in 79% of patients, typically within the first 2 weeks of therapy; limit sun exposure and discontinue for severe toxicity (see Dosage Modifications)

Infusion-related reactions may occur; discontinue for severe reactions (see Dosage Modifications)

Not indicated for nonsquamous NSCLC; increased toxicity and increased mortality occurred when necitumumab was added to pemetrexed and cisplatin therapy for these patients

Based on animal data and its mechanism of action, can cause fetal harm when administered to a pregnant woman (see Pregnancy)

Nivolumab (Rx)Brand and Other Names:OpdivoAdverse Effects

>10% (All grades)

Melanoma

Increased AST (28%) Hyponatremia (25%) Increased alkaline phosphatase (22%) Rash (21%) Pruritus (19%) Cough (17%) Increased ALT (16%) Hyperkalemia (15%) URTI (11%)

NSCLC

Fatigue (50%) Lymphopenia (47%) Dyspnea, hyponatremia (38%) Musculoskeletal pain (36%) Cough (32%) Nausea (29%), anemia (28%), constipation (24%) Increases creatinine (22%) Hypercalcemia, hypokalemia, hypomagnesemia (20%) Vomiting, asthenia (19%) Hypocalcemia, hyperkalemia, diarrhea (18%) Edema, pyrexia (17%) Abdominal pain, rash, increased AST (16%) Increased alkaline phosphatase, thrombocytopenia (14%) Chest pain, arthralgia, decreased appetite and weight (13%) Increased ALT (12%), pruritus (11%)

1-10% (all grades)

Melanoma

Peripheral edema (10%)

NSCLC

Pneumonia (10%) Pain (10%)

1-10% (grades 3-4)

Melanoma

Hyponatremia (5%) Increased AST (2.4%) Increased alkaline phosphatase (2.4%) Hyperkalemia (2%) Increased ALT (1.6%)

NSCLC

Dyspnea (9%) Fatigue (7%) Musculoskeletal pain (6%) Pneumonia (5%) Decreased appetite (2.6%) Pain (2.6%) Nausea (1.7%) Abdominal pain (1.7%) Asthenia (1.7%) Edema (1.7%) Cough (1.7%)

1-10% (other clinically important adverse effects)

Melanoma

Cardiac disorders: Ventricular arrhythmia Eye disorders: Iridocyclitis General disorders and administration site conditions: Infusion-related reactions Immune-mediated disorders: Severe pneumonitis or interstitial lung disease, including fatal

cases; colitis; hepatitis; nephritis; thyroid disorders; other immune disorders (pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, facial and abducens nerve paresis, hypophysitis, polymyalgia rheumatica, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, myasthenic syndrome)

Investigations: Increased amylase, increased lipase Nervous system disorders: Dizziness, peripheral and sensory neuropathy Skin and subcutaneous tissue disorders: Exfoliative dermatitis, erythema multiforme,

vitiligo, psoriasis

NSCLC

General disorders and administration site conditions: Stomatitis

Nervous system disorders: Peripheral neuropathy Infections and infestations: Bronchitis, upper respiratory tract infection

Warnings

Contraindications None

Cautions Immune-mediated pneumonitis may occur; withhold for moderate and permanently

discontinue for severe or life-threatening pneumonitis

Immune-mediated colitis reported; withhold for moderate or severe and permanently discontinue for life-threatening colitis

Colitis reported when used in combination with dacarbazine

Immune-mediated hepatitis observed in clinical trials; monitor for changes in liver function; withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation

Immune-mediated nephritis and renal dysfunction may occur; monitor for changes in renal function; withhold for moderate and permanently discontinue for severe or life-threatening serum creatinine elevation

Immune-mediated hypothyroidism and hyperthyroidism reported; monitor for changes in thyroid function and initiate thyroid hormone replacement as needed

Hypothyroidism reported when used in combination with dacarbazine

Adrenal insufficiency may occur; monitor for signs and symptoms of adrenal insufficiency during and after treatment

Hypophysitis may occur in combination with ipilimumab

Immune-mediated encephalitis can occur; withhold therapy in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration; evaluation may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture; if other etiologies ruled out, administer corticosteroids at a dose of 1 - 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper; permanently discontinue therapy for immune-mediated encephalitis

Other clinically significant immune-mediated adverse reactions (eg, rash) can occur after therapy discontinuation

Immune mediated rash reported in combination with ipilimumab

Severe infusion reactions reported (rare, <1%); discontinue if severe or life-threatening, interrupt or slow infusion rate if mild or moderate reaction

Can cause fetal harm; advise of potential risk to a fetus and use of effective contraception (see Pregnancy and Lactation

Pertuzumab (Rx)Brand and Other Names:PerjetaAdverse Effects

>10%

Diarrhea (66.8%)

Alopecia (60.9%)

Neutropenia (52.8%)

Nausea (42.3%)

Fatigue (37.6%)

Rash (33.7%)

Peripheral neuropathy (32.4%)

Decreased appetite (29.2%)

Mucosal inflammation (27.8%)Asthenia (26%)

Vomiting (24.1%)

Anemia (23.1%)

Peripheral edema (23.1%)

Nail disorder (22.9%)

Myalgia (22.9%)

Headache (20.9%)

Stomatitis (18.9%)Pyrexia (18.7%)

Dysgeusia (18.4%)

Leukopenia (18.2%)

Upper respiratory tract infection (16.7%)

Arthralgia (15.5%)

Constipation (15%)

Pruritus (14%)

Dyspnea (14%)

Increased lacrimation (14%)

Febrile neutropenia (13.8%)

Insomnia (13.3%)

Dizziness (12.5%)

Nasopharyngitis (11.8%)

Dry skin (10.6%)

1-10%

Hypersensitivity (10%)

Paronychia (7.1%)

Pleural effusion (5.2%)

Left ventricular dysfunction (4.4%)

Congestive heart failure (1%)

Note: Adverse reaction were reported less frequently after discontinuing docetaxel; all adverse reactions in the pertuzumab/trastuzumab treatment group occurred in <10% of patients with the exception of diarrhea (19.1%), UTI (12.8%), rash (11.75%), headache (11.4%), and fatigue (11.1%)

Warnings

Black Box Warnings

Exposure in pregnant women may result in embryo-fetal death and birth defects

Animal studies have observed oligohydramnios, delayed renal development, and death

Advise patients of these risks and the need for effective contraception

Therapy can result in subclinical and clinical cardiac failure; evaluate left ventricular function in all patients prior to and during therapy; discontinue therapy if significant decrease in left ventricular function confirmed

Contraindications

Hypersensitivity

Cautions

If pertuzumab administered during pregnancy or if patient becomes pregnant while receiving pertuzumab or within 7 months following last dose of pertuzumab in combination with trastuzumab, immediately report exposure to Genentech Adverse Event Line at 1-888-835-2555; encourage women who may be exposed during pregnancy or within 7 months for pertuzumab in combination with trastuzumab prior to conception, to enroll in the MOTHER Pregnancy Registry by contacting 1-800-690-6720; if pregnancy occurs during treatment, monitor for oligohydramnios

Infusion related adverse effects reported; monitor during and after infusion (see Administration)

Decreased left ventricular ejection fraction (LVEF) reported with HER2 blockers; assess LVEF at baseline and q3 months (also see Dosage Modifications)

Severe hypersensitivity, including anaphylaxis observed

HER2 testing: Detection of HER2 protein overexpression required for selection of patients appropriate for pertuzumab therapy

Idarucizumab (Rx)Brand and Other Names:PraxbindAdverse Effects

1-10%

Hypokalemia (7%)

Delirium (7%)

Constipation (7%)

Pyrexia (6%)

Pneumonia (6%)

Headache (5%)

Frequency Not Defined

Thromboembolic events

Hypersensitivity

Warnings

Contraindications

None

Cautions

Patients treated with dabigatran have underlying disease states that predispose them to thromboembolic events; reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease; to reduce this risk, resume anticoagulant therapy as soon as medically appropriate

There is insufficient clinical experience to evaluate risk of hypersensitivity to idarucizumab; discontinue if a serious hypersensitivity reaction occurs

Caution with hereditary fructose intolerance; the recommended dose of idarucizumab contains 4 g sorbitol as an excipient; when prescribing to patients with hereditary fructose intolerance, consider the combined daily metabolic load of sorbitol/fructose from all sources; administration of sorbitol in

these patients is known to cause serious adverse reactions, including fatal reactions including hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, and acute liver failure with breakdown of excretory and synthetic function

Re-elevation of coagulation parameters

In a limited number of patients in the clinical program, between 12-24 hr after administrating idarucizumab 5 g, elevated coagulation parameters (eg, aPTT, ECT) have been observed

If reappearance of clinically relevant bleeding together with elevated coagulation parameters is observed after administering idarucizumab 5 g, administration of an additional 5 g dose may be considered

Similarly, patients who require a second emergency surgery/urgent procedure and have elevated coagulation parameters may receive an additional 5-g dose

The safety and effectiveness of repeat treatment with idarucizumab have not been established

Ramucirumab (Rx)Brand and Other Names:CyramzaAdverse Effects

>10%

All grades unless otherwise states

GI cancer (plus paclitaxel)

Fatigue/asthenia (57%) Neutropenia (54%) Diarrhea (32%) Epistaxis (31%) Peripheral edema (25%)

Stomatitis (20%) Proteinuria (17%) Hypertension (25%) Infusion-related reactions (16%) Hypertension grade 3-4 (15%) Thrombocytopenia (13%) Hypoalbuminemia (11%)

NSCLC (plus docetaxel)

Neutropenia (55%) Fatigue/asthenia (55%)

Stomatitis/mucosal inflammation (37%) Epistaxis (19%) Febrile neutropenia (16%) Peripheral edema (16%) Thrombocytopenia (13%) Lacrimation increased (13%) Hypertension (11%)

1-10%

GI hemorrhage events, gastric cancer (10%)

<1%

Gastrointestinal perforation (single agent) (0.7%)

Reversible posterior leukoencephalopathy syndrome (<0.1%)

Warnings --- Black Box Warnings

Hemorrhage

Increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events Permanently discontinue patients who experience severe bleeding

Gastrointestinal perforation

Can increase the risk of gastrointestinal perforation, a potentially fatal event Permanently discontinue in patients who experience a gastrointestinal perforation

Impaired wound healing

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway Discontinue in patients with impaired wound healing Withhold drug prior to surgery and discontinue if a patient develops wound healing

complications

Contraindications None

CautionsIncreased risk of hemorrhage and GI hemorrhage, including severe and sometimes fatal hemorrhagic events; permanently discontinue in patients who experience severe bleeding (see Black Box Warnings)

Serious, sometimes fatal, arterial thromboembolic events including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia reported during clinical trials

Increased incidence of severe hypertension reported; control hypertension before initiating treatment and monitor blood pressure q2weeks or more frequently as indicated; temporarily suspend therapy for severe hypertension

Infusion-related reactions observed that include rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia; in severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension

Ramucirumab is an antiangiogenic therapy that can increase the risk of GI perforation and affect wound healing; withhold prior to surgery; permanently discontinue ramucirumab in patients who experience a gastrointestinal perforation (see Black Box Warnings)

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway; withhold drug before surgery and discontinue if patient develops wound healing complications (see Black Box Warnings)

Clinical deterioration, manifested by new-onset or worsening encephalopathy, ascites, or hepatorenal syndrome, reported in patients with Child-Pugh B or C cirrhosis; use only if the benefits outweigh the risks

Reversible posterior leukoencephalopathy syndrome (RPLS) reported (rare); discontinue ramucirumab

Severe proteinuria reported, particularly when administered with FOLFIRI (see Dosage Modifications)

May cause hypothyroidism; monitor thyroid function during treatment

Based on its mechanism of action, ramucirumab can cause fetal harm when administered to pregnant women

Everolimus – Afinitor Common side effectsMore than 10 in every 100 people have one or more of the side effects listed below.

An increased risk of getting an infection from a drop in white blood cells – it is harder to fight infections and you can become very ill. You may have headaches, aching muscles, a cough, a sore throat, pain passing urine, or you may feel cold and shivery. If you have a severe infection this can be life threatening. Contact your treatment centre straight away if you have any of these effects or if your temperature goes above 38°C

Tiredness and breathlessness due to a drop in red blood cells (anaemia) – you may need a blood transfusion

A change in blood sugar levels. Your nurse will check the levels regularly. If you are diabetic, talk to your diabetes doctor or nurse about the best way to control your diabetes

A sore mouth (stomatitis) occurs in more than 4 out of 10 people (44%). Your nurse will give you mouthwashes to use. Avoid mouthwashes containing alcohol, peroxide, iodine or thyme as these can make the soreness worse

Feeling weak affects 3 out of 10 people (30%) Tiredness (fatigue) and weakness during and after treatment – this happens in 3 out of 10 people

(30%) Some kind of skin reaction affects 1 to 3 out of 10 people (10 to 30%) – you may have a rash or

itchy or dry skin. Or you may have red, peeling skin on the palms of your hands and soles of your feet.

Loss of appetite happens in 1 in 4 people (25%) Feeling or being sick happens in about 2 out of every 10 people (20%). It is usually well controlled

with anti sickness medicines Headaches Taste changes Diarrhoea – drink plenty of fluids. If your diarrhoea is severe or continues you could get

dehydrated so let your doctor or nurse know Inflammation of the lungs (pneumonitis) – let your doctor know if you have breathlessness, a

high temperature and chills, extreme tiredness, a dry cough, or pain in your lungs when you take a deep breath

Fluid build up – your ankles, hands or other parts of the body may be swollen and you may put on weight

Women may stop having periods (amenorrhoea) but this may be temporary Loss of fertility – you may not be able to become pregnant or father a child after this treatment.

Talk to your doctor before starting treatment if you think you may want to have a baby in the future. Men may be able to store sperm before starting treatment

Weight loss High levels of fats called cholesterol in the blood

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Occasional side effectsBetween 1 and 10 in every 100 people have one or more of these.

Kidney changes – you will have regular blood tests to check how well your kidneys are working and will have fluids to flush the drugs through. Let your nurse know if you pass less urine than usual

Liver changes – you are unlikely to notice any symptoms and your liver function will almost certainly go back to normal when you finish treatment. You will have regular blood tests to check how well your liver is working

Sore, red eyes or dry eyes – steroid eye drops can help Difficulty sleeping An allergic reaction to the drug. Let your doctor or nurse know straight away if you suddenly

feel breathless, have difficulty swallowing, or have a severe itchy rash, chest pain, or swelling of the lips, tongue or throat

Bruising more easily due to a drop in platelets – you may have nosebleeds, or bleeding gums after brushing your teeth. Or you may have lots of tiny red spots or bruises on your arms or legs (known as petechiae)

Joint pain – mild painkillers can help Heartburn or indigestion (dyspepsia) Difficulty swallowing – let your doctor or nurse know straight away if you have this Abdominal (tummy) pain Joint pains – your doctor or nurse can give you painkillers to help Low levels of potassium in your blood (hypokalaemia) – let your doctor or nurse know if you

have cramping in your arm or leg muscles, tingling or numbness, palpitations (feeling your heart beat irregularly), or if you feel faint

Low levels of calcium in the blood – tell your doctor or nurse if you have painful muscle spasm and cramps, muscle twitching, or numbness or tingling in your feet and hands or around your mouth

Nail changes – your nails may become brittle and break easily Hair thinning Sticky eyes with itching, redness and swelling – your nurse can give you eye drops to help

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Rare side effectsFewer than 1 in 100 people have these effects.

Heart problems that cause chest pain, swollen ankles, breathlessness and a fast heart rate – tell your doctor or nurse if you have any of these symptoms

A type of anaemia called pure red cell aplasia Blood clots in the leg – let your doctor or nurse know if you have swelling, pain or redness

in your leg or if the area feels warm Blood clots in the lung – let your doctor or nurse know if you have breathlessness, chest

pain or coughing up blood Hot flushes Severe liver changes leading to yellowing of the skin and whites of the eyes (jaundice). Let your

doctor or nurse know straight away if you have these signsBack to top

 

Important points to remember

Talk to your doctor, pharmacist or nurse about all your side effects so they can help you manage them. They can give you advice or reassure you. Your nurse will give you a contact number to ring if you have any questions or problems. If in doubt, call them.

SUNITINIBSIDE EFFECTSThe data described below reflect exposure to SUTENT in 660 patients who participated in the double-blind treatment phase of a placebo-controlled trial (n=202) for the treatment of GIST [see Clinical Studies], an active-controlled trial (n=375) for the treatment of RCC [see Clinical Studies] or a placebo-controlled trial (n=83) for the treatment of pNET [see Clinical Studies]. The GIST and RCC patients received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles, and the pNET patients received a starting oral dose of 37.5 mg daily without scheduled off-treatment periods.

The most common adverse reactions ( ≥ 20%) in patients with GIST, RCC or pNET are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, and bleeding. The potentially serious adverse reactions of hepatotoxicity, left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function are discussed in WARNINGS AND PRECAUTIONS. Other adverse reactions occurring in GIST, RCC and pNET studies are described below.

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

Adverse Reactions In GIST Study A

Median duration of blinded study treatment was two cycles for patients on SUTENT (mean 3.0, range 1-9) and one cycle (mean 1.8, range 1-6) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on SUTENT and none on placebo. Dose interruptions occurred in 59 patients (29%) on SUTENT and 31 patients (30%) on placebo. The rates of treatment-emergent, non-fatal adverse reactions resulting in permanent discontinuation were 7% and 6% in the SUTENT and placebo groups, respectively.

Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 56% versus 51% of patients on SUTENT versus placebo, respectively, in the double-blind treatment phase of the trial. Table 1 compares the incidence of common ( ≥ 10%) treatment-emergent adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.

Table 1: Adverse Reactions Reported in Study A in at Least 10% of GIST Patients who Received SUTENT in the Double-Blind Treatment Phase and More Commonly Than in Patients Given

Placebo*

ADVERSE REACTION, (%)

GIST

SUTENT(N=202)

PLACEBO(N=102)

ALL GRADES

GRADE 3/4

ALL GRADES

GRADE 3/4

Any 114 (56) 52 (51)

Gastrointestinal

  Diarrhea 81 (40) 9 (4) 27 (27) 0 (0)

  Mucositis/stomatitis

58 (29) 2 (1) 18 (18) 2 (2)

  Constipation 41 (20) 0 (0) 14 (14) 2 (2)

Cardiac

  Hypertension 31 (15) 9 (4) 11 (11) 0 (0)

Dermatology

  Skin discoloration 61 (30) 0 (0) 23 (23) 0 (0)

  Rash 28 (14) 2 (1) 9 (9) 0 (0)

  Hand-foot syndrome 28 (14) 9 (4) 10 (10) 3 (3)

Neurology

  Altered taste 42 (21) 0 (0) 12 (12) 0 (0)

Musculoskeletal

  Myalgia/limb pain 28 (14) 1 (1) 9 (9) 1 (1)

Metabolism/Nutrition

  Anorexiaa 67 (33) 1 (1) 30 (29) 5 (5)

  Asthenia 45 (22) 10 (5) 11 (11) 3 (3)

* Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 aIncludes decreased appetite

In the double-blind treatment phase of GIST Study A, oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on SUTENT versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on SUTENT versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on SUTENT versus 2 (2%) on placebo.

Table 2 provides common ( ≥ 10%) treatment-emergent laboratory abnormalities.

Table 2: Laboratory Abnormalities Reported in Study A in at Least 10% of GIST Patients Who Received SUTENT or Placebo in the Double-Blind Treatment Phase*

LABORATORY PARAMETER, N (%)

GIST

SUTENT(N=202)

PLACEBO(N=102)

ALL GRADES*

GRADE 3/4*A

ALL GRADES*

GRADE 3/4*B

Any 68 (34) 22 (22)

Gastrointestinal

  AST / ALT 78 (39) 3 (2) 23 (23) 1 (1)

  Lipase 50 (25) 20 (10) 17 (17) 7 (7)

  Alkaline phosphatase 48 (24) 7 (4) 21 (21) 4 (4)

  Amylase 35 (17) 10 (5) 12 (12) 3 (3)

  Total bilirubin 32 (16) 2 (1) 8 (8) 0 (0)

  Indirect bilirubin 20 (10) 0 (0) 4 (4) 0 (0)

Cardiac

  Decreased LVEF 22 (11) 2 (1) 3 (3) 0 (0)

Renal/Metabolic

  Creatinine 25 (12) 1 (1) 7 (7) 0 (0)

  Potassium decreased 24 (12) 1 (1) 4 (4) 0 (0)

  Sodium increased 20 (10) 0 (0) 4 (4) 1 (1)

Hematology

  Neutrophils 107 (53) 20 (10) 4 (4) 0 (0)

  Lymphocytes 76 (38) 0 (0) 16 (16) 0 (0)

  Platelets 76 (38) 10 (5) 4 (4) 0 (0)

  Hemoglobin 52 (26) 6 (3) 22 (22) 2 (2)

LVEF=Left ventricular ejection fraction * Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 aGrade 4 laboratory abnormalities in patients on SUTENT included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%). bGrade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%).

After an interim analysis, the study was unblinded, and patients on the placebo arm were given the opportunity to receive open-label SUTENT treatment [see Clinical Studies]. For 241 patients randomized to the SUTENT arm, including 139 who received SUTENT in both the double-blind and open-label treatment phases, the median duration of SUTENT treatment was 6 cycles (mean 8.5, range 1 – 44). For the 255 patients who ultimately received open-label SUTENT treatment, median duration of study treatment was 6 cycles (mean 7.8, range 1 – 37) from the time of the unblinding. A total of 118 patients (46%) required dosing interruptions, and a total of 72 patients (28%) required dose reductions. The incidence of treatment-emergent adverse reactions resulting in permanent discontinuation was 20%. The most common Grade 3 or 4 treatment-related adverse reactions experienced by patients receiving SUTENT in the open-label treatment phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).

Adverse Reactions In The Treatment-Naïve RCC Study

The as-treated patient population for the treatment-naive RCC study included 735 patients, 375 randomized to SUTENT and 360 randomized to IFN-α. The median duration of treatment was 11.1 months (range: 0.4 -46.1) for SUTENT treatment and 4.1 months (range: 0.1 – 45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on SUTENT and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on SUTENT and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for SUTENT and 24% for IFN-α. Most

treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 77% versus 55% of patients on SUTENT versus IFN-α, respectively.

Table 3 compares the incidence of common ( ≥ 10%) treatment-emergent adverse reactions for patients receiving SUTENT versus IFN-α.

Table 3: Adverse Reactions Reported in at Least 10% of Patients with RCC Who Received SUTENT or IFN-α*

ADVERSE REACTION, N (%)

TREATMENT-NAIVE RCC

SUTENT (N=375)

IFN-Α (N=360)

ALL GRADES

GRADE 3/4A

ALL GRADES

GRADE 3/4B

Any 372 (99) 290 (77) 355 (99) 197 (55)

Constitutional

  Fatigue 233 (62) 55 (15) 202 (56) 54 (15)

  Asthenia 96 (26) 42 (11) 81 (22) 21 (6)

  Fever 84 (22) 3 (1) 134 (37) 1 ( < 1)

  Weight decreased 60 (16) 1 ( < 1) 60 (17) 3 (1)

  Chills 53 (14) 3 (1) 111 (31) 0 (0)

  Chest Pain 50 (13) 7 (2) 24 (7) 3 (1)

  Influenza like illness 18 (5) 0 (0) 54 (15) 1 ( < 1)

Gastrointestinal

  Diarrhea 246 (66) 37 (10) 76 (21) 1 ( < 1)

  Nausea 216 (58) 21 (6) 147 (41) 6 (2)

  Mucositis/stomatitis

178 (47) 13 (3) 19 (5) 2 ( < 1)

  Vomiting 148 (39) 19 (5) 62 (17) 4 (1)

  Dyspepsia 128 (34) 8 (2) 16 (4) 0 (0)

  Abdominal painc 113 (30) 20 (5) 42 (12) 5 (1)

  Constipation 85 (23) 4 (1) 49 (14) 1 ( < 1)

  Dry mouth 50 (13) 0 (0) 27 (7) 1 ( < 1)

  GERD/reflux esophagitis 47 (12) 1 ( < 1) 3 (1) 0(0)

  Flatulence 52 (14) 0 (0) 8 (2) 0 (0)

  Oral pain 54 (14) 2 ( < 1) 2 (1) 0 (0)

  Glossodynia 40 (11) 0 (0) 2 (1) 0 (0)

  Hemorrhoids 38 (10) 0 (0) 6 (2) 0 (0)

Cardiac

  Hypertension 127 (34) 50 (13) 13 (4) 1 ( < 1)

  Edema, peripheral 91 (24) 7 (2) 17 (5) 2 (1)

  Ejection fraction decreased 61 (16) 10 (3) 19 (5) 6 (2)

Dermatology

  Rash 109 (29) 6 (2) 39 (11) 1 ( < 1)

  Hand-foot syndrome 108 (29) 32 (8) 3 (1) 0 (0)

  Skin discoloration/yellow skin 94 (25) 1 ( < 1) 0 (0) 0 (0)

  Dry skin 85 (23) 1 ( < 1) 26 (7) 0 (0)

  Hair color changes 75 (20) 0 (0) 1 ( < 1) 0 (0)

  Alopecia 51 (14) 0 (0) 34 (9) 0 (0)

  Erythema 46 (12) 2 ( < 1) 5 (1) 0 (0)

  Pruritus 44 (12) 1 ( < 1) 24 (7) 1 ( < 1)

Neurology

  Altered tasted 178 (47) 1 ( < 1) 54 (15) 0 (0)

  Headache 86 (23) 4 (1) 69 (19) 0 (0)

  Dizziness 43 (11) 2 ( < 1) 50 (14) 2 (1)

Musculoskeletal

  Back pain 105 (28) 19 (5) 52 (14) 7 (2)

  Arthralgia 111 (30) 10 (3) 69 (19) 4 (1)

  Pain in extremity/limb discomfort 150 (40) 19 (5) 107 (30) 7 (2)

Endocrine

  Hypothyroidism 61 (16) 6 (2) 3 (1) 0 (0)

Respiratory

  Cough 100 (27) 3 (1) 51(14) 1 ( < 1)

  Dyspnea 99 (26) 24 (6) 71 (20) 15 (4)

  Nasopharyngitis 54 (14) 0 (0) 8 (2) 0 (0)

  Oropharyngeal Pain 51 (14) 2 ( < 1) 9 (2) 0 (0)

  Upper respiratory tract infection 43 (11) 2 ( < 1) 9 (2) 0 (0)

Metabolism/Nutrition

  Anorexiae 182 (48) 11 (3) 153(42) 7 (2)

Hemorrhage/Bleeding

  Bleeding, all sites 140 (37) 16 (4)f 35 (10) 3 (1)

Psychiatric

  Insomnia 57 (15) 3 ( < 1) 37 (10) 0 (0)

  Depressiong 40 (11) 0 (0) 51(14) 5 (1)

*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 aGrade 4 ARs in patients on SUTENT included back pain (1%), arthralgia ( < 1%), dyspnea ( < 1%), asthenia ( < 1%), fatigue ( < 1%), limb pain ( < 1%) and rash ( < 1%). bGrade 4 ARs in patients on IFN-α included dyspnea (1%), fatigue (1%), abdominal pain ( < 1%) and depression ( < 1%). cIncludes flank pain dIncludes ageusia, hypogeusia and dysgeusia eIncludes decreased appetite fIncludes one patient with Grade 5 gastric hemorrhage gIncludes depressed mood

Treatment-emergent Grade 3/4 laboratory abnormalities are presented in Table 4.

Table 4: Laboratory Abnormalities Reported in at Least 10% of Treatment-Naïve RCC Patients Who Received SUTENT or IFN-α

LABORATORY PARAMETER, N (%)

TREATMENT-NAIVE RCC

SUTENT(N=375)

IFN-Α(N=360)

ALL GRADES*

GRADE 3/4*A

ALL GRADES*

GRADE 3/4*B

Gastrointestinal

  AST 211 (56) 6 (2) 136 (38) 8 (2)

  ALT 192 (51) 10 (3) 144 (40) 9 (2)

  Lipase 211 (56) 69 (18) 165 (46) 29 (8)

  Alkaline phosphatase 171 (46) 7 (2) 132 (37) 6 (2)

  Amylase 130 (35) 22 (6) 114 (32) 12 (3)

  Total bilirubin 75 (20) 3 (1) 8 (2) 0 (0)

  Indirect bilirubin 49 (13) 4 (1) 3 (1) 0 (0)

Renal/Metabolic

  Creatinine 262 (70) 2 ( < 1) 183 (51) 1 ( < 1)

  Creatine kinase 183 (49) 9 (2) 40 (11) 4 (1)

  Uric acid 173 (46) 54 (14) 119 (33) 29 (8)

  Calcium decreased 156 (42) 4 (1) 145 (40) 4 (1)

  Phosphorus 116 (31) 22 (6) 87 (24) 23 (6)

  Albumin 106 (28) 4 (1) 72 (20) 0 (0)

  Glucose increased 86 (23) 21 (6) 55(15) 22 (6)

  Sodium decreased 75 (20) 31 (8) 55 (15) 13 (4)

  Glucose decreased 65 (17) 0 (0) 43 (12) 1 ( < 1)

  Potassium increased 61 (16) 13 (3) 61 (17) 15 (4)

  Calcium increased 50 (13) 2 ( < 1) 35 (10) 5 (1)

  Potassium decreased 49 (13) 3 (1) 7 (2) 1 ( < 1)

  Sodium increased 48 (13) 0 (0) 38 (10) 0 (0)

Hematology

  Neutrophils 289 (77) 65 (17) 178 (49) 31 (9)

  Hemoglobin 298 (79) 29 (8) 250 (69) 18 (5)

  Platelets 255 (68) 35 (9) 85(24) 2 (1)

  Lymphocytes 256 (68) 66 (18) 245 (68) 93 (26)

  Leukocytes 293 (78) 29 (8) 202 (56) 8 (2)

*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 aGrade 4 laboratory abnormalities in patients on SUTENT included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT ( < 1%), creatine kinase ( < 1%), creatinine ( < 1%), glucose increased ( < 1%), calcium decreased ( < 1%), phosphorous ( < 1%), potassium increased ( < 1%), and sodium decreased ( < 1%). bGrade 4 laboratory abnormalities in patients on IFN-α included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase ( < 1%), calcium

increased ( < 1%), glucose decreased ( < 1%), potassium increased ( < 1%), and hemoglobin ( < 1%).

Adverse Reactions In The Phase 3 pNET Study

The median number of days on treatment was 139 days (range 13-532 days) for patients on SUTENT and 113 days (range 1-614 days) for patients on placebo. Nineteen patients (23%) on SUTENT and 4 patients (5%) on placebo were on study for > 1 year. Dose interruptions occurred in 25 patients (30%) on SUTENT and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on SUTENT and 9 patients (11%) on placebo. Discontinuation rates due to adverse reactions were 22% for SUTENT and 17% for placebo.

Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 54% versus 50% of patients on SUTENT versus placebo, respectively. Table 5 compares the incidence of common ( ≥ 10%) treatment-emergent adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.

Table 5: Adverse Reactions Reported in the Phase 3 pNET Study in at Least 10% of Patients who Received SUTENT and More Commonly Than in Patients Given Placebo*

ADVERSE REACTION,N (%)

PNET

SUTENT(N=83)

PLACEBO(N=82)

ALL GRADES GRADE 3/4A ALL

GRADES GRADE 3/4

Any 82 (99) 45 (54) 78(95) 41 (50)

Constitutional

Asthenia 28 (34) 4 (5) 22 (27) 3 (4)

Fatigue 27 (33) 4 (5) 22 (27) 7 (9)

Weight decreased 13 (16) 1(1) 9 (11) 0 (0)

Gastrointestinal

Diarrhea 49 (59) 4 (5) 32 (39) 2 (2)

Stomatitis/oral syndromesb 40 (48) 5 (6) 15(18) 0 (0)

Nausea 37 (45) 1 (1) 24 (29) 1 (1)

Abdominal painc 32 (39) 4 (5) 28 (34) 8 (10)

Vomiting 28 (34) 0 (0) 25 (31) 2 (2)

Dyspepsia 12 (15) 0 (0) 5 (6) 0 (0)

Cardiac

Hypertension 22 (27) 8 (10) 4 (5) 1 (1)

Dermatology

Hair color changes 24 (29) 1 (1) 1 (1) 0 (0)

Hand-foot syndrome 19 (23) 5 (6) 2 (2) 0 (0)

Rash 15 (18) 0 (0) 4 (5) 0 (0)

Dry skin 12 (15) 0 (0) 9 (11) 0 (0)

Neurology

Dysgeusia 17 (21) 0 (0) 4 (5) 0 (0)

Headache 15 (18) 0 (0) 11(13) 1 (1)

Musculoskeletal

Arthralgia 12 (15) 0 (0) 5 (6) 0 (0)

Psychiatric

Insomnia 15 (18) 0 (0) 10 (12) 0 (0)

Hemorrhage/Bleeding

Bleeding eventsd 18 (22) 0 (0) 8 (10) 3 (4)

Epistaxis 17 (21) 1 (1) 4 (5) 0 (0)

* Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 aGrade 4 ARs in patients on SUTENT included fatigue (1%). bIncludes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth.

cIncludes abdominal discomfort, abdominal pain, and abdominal pain upper. dIncludes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia.

Table 6 provides common ( ≥ 10%) treatment-emergent laboratory abnormalities.

Table 6: Laboratory Abnormalities Reported in the Phase 3 pNET Study in at Least 10% of Patients Who Received SUTENT

LABORATORY PARAMETER, N (%)

PNET

SUTENT PLACEBO

N ALL GRADES*

GRADE 3/4*A N ALL

GRADES*GRADE

3/4*B

Gastrointestinal

AST increased 82 59 (72) 4 (5) 80 56 (70) 2 (3)

ALT increased 82 50 (61) 3 (4) 80 44 (55) 2 (3)

Alkaline phosphatase increased 82 52 (63) 8 (10) 80 56 (70) 9 (11)

Total bilirubin increased 82 30 (37) 1 (1) 80 22 (28) 3 (4)

Amylase increased 74 15 (20) 3 (4) 74 7 (10) 1 (1)

Lipase increased 75 13 (17) 4 (5) 72 8 (11) 3 (4)

Renal/Metabolic

Glucose increased 82 58 (71) 10 (12) 80 62 (78) 14 (18)

Albumin decreased 81 33 (41) 1 (1) 79 29 (37) 1 (1)

Phosphorus decreased 81 29 (36) 6 (7) 77 17 (22) 4 (5)

Calcium decreased 82 28 (34) 0 (0) 80 15 (19) 0 (0)

Sodium decreased 82 24 (29) 2 (2) 80 27 (34) 2 (3)

Creatinine increased 82 22 (27) 4 (5) 80 22 (28) 4 (5)

Glucose decreased 82 18 (22) 2 (2) 80 12 (15) 3 (4)

Potassium decreased 82 17 (21) 3 (4) 80 11 (14) 0 (0)

Magnesium decreased 52 10 (19) 0 (0) 39 4 (10) 0 (0)

Potassium increased 82 15 (18) 1 (1) 80 9 (11) 1 (1)

Hematology

Neutrophils decreased 82 58 (71) 13 (16) 80 13 (16) 0 (0)

Hemoglobin decreased 82 53 (65) 0 (0) 80 44 (55) 1 (1)

Platelets decreased 82 49 (60) 4 (5) 80 12 (15) 0 (0)

Lymphocytes decreased 82 46 (56) 6 (7) 80 28 (35) 3 (4)

* Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 aGrade 4 laboratory abnormalities in patients on SUTENT included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%) and total bilirubin (1%). bGrade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increase d (1%) and lipase (1%).

Venous Thromboembolic Events

Seven patients (3%) on SUTENT and none on placebo in the double-blind treatment phase of GIST Study A experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT), and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT.

Thirteen (3%) patients receiving SUTENT for treatment-naïve RCC had venous thromboembolic events reported. Seven (2%) of these patients had pulmonary embolism, one was Grade 2 and six were Grade 4, and six (2%) patients had DVT, including three Grade 3. One patient was permanently withdrawn from SUTENT due to pulmonary embolism; dose interruption occurred in two patients with pulmonary embolism and one with DVT. In treatment-naïve RCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient ( < 1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, all Grade 4. One patient (1%) receiving SUTENT for pNET had a venous thromboembolic event reported compared to 5 patients (6%) receiving placebo. The SUTENT patient had Grade 2 thrombosis. Two placebo patients had DVT, one was Grade 3, two placebo patients had pulmonary embolism, one was Grade 3 and one was Grade 4, and one placebo patient had Grade 3 jugular thrombosis.

Reversible Posterior Leukoencephalopathy Syndrome

There have been reports ( < 1%), some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered

mental functioning, and visual loss, including cortical blindness should be controlled with medical management including control of hypertension. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

Pancreatic And Hepatic Function

If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued. Pancreatitis was observed in 5 (1%) patients receiving SUTENT for treatment-naïve RCC compared to 1 ( < 1%) patient receiving IFN-α. Pancreatitis was observed in 1 (1%) patient receiving SUTENT for pNET and 1 (1%) patient receiving placebo. Hepatotoxicity was observed in patients receiving SUTENT [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Post-marketing Experience

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

Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia*. Suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

Gastrointestinal disorders: esophagitis.

Hepatobiliary disorders: cholecystitis, particularly acalculous cholecystitis.

Immune system disorders: hypersensitivity reactions, including angioedema.

Infections and infestations: serious infection (with or without neutropenia)*. The infections most commonly observed with sunitinib treatment include respiratory, urinary tract, skin infections, sepsis/septic shock.

Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression*; myopathy and/or rhabdomyolysis with or without acute renal failure*. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.

Renal and urinary disorders: renal impairment and/or failure*.

Respiratory disorders: pulmonary embolism*.

Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive dechallenges.

Vascular disorders: arterial thromboembolic events*. The most frequent events included cerebrovascular

accident, transient ischemic attack and cerebral infarction.

*including some fatalities

Read the Sutent (sunitinib malate) Side Effects Center for a complete guide to possible side effects

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DRUG INTERACTIONSCYP3A4 Inhibitors

Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib. A dose reduction for SUTENT should be considered when it must be co-administered with strong CYP3A4 inhibitors [seeDOSAGE AND ADMINISTRATION].

CYP3A4 Inducers

CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) may decrease sunitinib concentrations. St. John's Wort may decrease sunitinib plasma concentrations unpredictably. Patients receiving SUTENT should not take St. John's Wort concomitantly. A dose increase for SUTENT should be considered when it must be co-administered with CYP3A4 inducers [seeDOSAGE AND ADMINISTRATION].

In Vitro Studies Of CYP Inhibition And Induction

In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.

Read the Sutent Drug Interactions Center for a complete guide to possible interactions

Erlotinib:TarcevaSIDE EFFECTSThe following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling:

Interstitial Lung Disease (ILD) [see WARNINGS AND PRECAUTIONS] Renal Failure [see WARNINGS AND PRECAUTIONS] Hepatotoxicity with or without Hepatic Impairment [see WARNINGS AND PRECAUTIONS] Gastrointestinal Perforation [see WARNINGS AND PRECAUTIONS] Bullous and Exfoliative Skin Disorders [see WARNINGS AND PRECAUTIONS] Myocardial Infarction/Ischemia [see WARNINGS AND PRECAUTIONS] Cerebrovascular Accident [see WARNINGS AND PRECAUTIONS] Microangiopathic Hemolytic Anemia with Thrombocytopenia [see WARNINGS AND

PRECAUTIONS] Ocular Disorders [see WARNINGS AND PRECAUTIONS] Hemorrhage in Patients Taking Warfarin [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

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

Safety evaluation of TARCEVA is based on more than 1200 cancer patients who received TARCEVA as monotherapy, more than 300 patients who received TARCEVA 100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVA concurrently with other chemotherapies. The most common adverse reactions with TARCEVA are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of TARCEVA for the treatment of NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea.

Non-Small Cell Lung Cancer

First-Line Treatment of Patients with EGFR Mutations

The most frequent ( ≥ 30%) adverse reactions in TARCEVA-treated patients were diarrhea, asthenia, rash, cough, dyspnea and decreased appetite. In TARCEVA-treated patients the median time to onset of rash was 15 days and the median time to onset of diarrhea was 32 days.

The most frequent Grade 3-4 adverse reactions in TARCEVA-treated patients were rash and diarrhea.

Dose interruptions or reductions due to adverse reactions occurred in 37% of TARCEVA-treated patients, and 14.3% of TARCEVA-treated patients discontinued therapy due to adverse reactions. In TARCEVA-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%).

Selected, common adverse reactions in Study 4, occurring in at least 10% of patients who received TARCEVA or chemotherapy and an increase in ≥ 5% in the TARCEVA treated group, are summarized by NCI-CTC (version 3.0) Grade in Table 1. The median duration of TARCEVA treatment was 9.6 months in Study 4.

Table 1: Selected Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the TARCEVA-treated Group (Study 4)

MEDDRA PREFERRED TERM

TARCEVA N = 84

CHEMOTHERAPY † N = 83

ALL GRADES

%GRADES

3-4 %ALL

GRADES %

GRADES 3-4 %

  Rash ‡ 85 14 5 0

  Diarrhea 62 5 21 1

  Cough 48 1 40 0

  Dyspnea 45 8 30 4

  Dry skin 21 1 2 0

  Back pain 19 2 5 0

  Chest pain 18 1 12 0

  Conjunctivitis 18 0 0 0

  Mucosal inflammation 18 1 6 0

  Pruritus 16 0 1 0

  Paronychia 14 0 0 0

  Arthralgia 13 1 6 1

  Musculoskeletal pain 11 1 1 0

† Platinum based doublet chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel)

‡ Rash as a composite term includes: rash, acne, folliculitis, erythema, dermatitis acneiform, dermatitis, palmar-plantar erythrodysaesthesia syndrome, exfoliative rash, rash erythematous, rash pruritic, skin toxicity, eczema, rash follicular, skin ulcer.

Hepatic Toxicity: One TARCEVA-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 4 [see WARNINGS AND PRECAUTIONS].

Maintenance Treatment

Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTC (version 3.0) Grade in Table 2.

The most common adverse reactions in patients receiving single-agent TARCEVA 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in TARCEVA-treated patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of TARCEVA-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In TARCEVA-treated patients the median time to onset of rash was 10 days, and the median time to onset of diarrhea was 15 days.

Table 2: NSCLC Maintenance Study: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent TARCEVA Group compared to the

Placebo Group (Study 3)

NCI-CTC GRADE

TARCEVA N = 433

PLACEBO N = 445

ANY GRADE

GRADE 3

GRADE 4

ANY GRADE

GRADE 3

GRADE 4

MedDRA Preferred Term % % % % % %

Rash † 60 9 0 9 0 0

Diarrhea 20 2 0 4 0 0

† Rash as a composite term includes: rash, acne, dermatitis acneiform, skin fissures, erythema, rash papular, rash generalized, rash pruritic, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, dermatitis exfoliative, furuncle, rash macular, rash pustular, skin hyperpigmentation, skin reaction, skin ulcer.

Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of TARCEVA-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of TARCEVA-treated patients and in < 1% in the placebo group [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Second/Third Line Treatment

Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent TARCEVA at 150 mg and at least 5% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 3.

The most common adverse reactions in this patient population were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 6%, respectively, in TARCEVA-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of TARCEVA-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days.

Table 3: NSCLC 2nd/3rd Line Study: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent TARCEVA Group compared to the Placebo

Group (Study 1)

NCI-CTC GRADE

TARCEVA 150 MG N=485

PLACEBO N=242

ANY GRADE

GRADE 3

GRADE 4

ANY GRADE

GRADE 3

GRADE 4

MedDRA Preferred Term % % % % % %

Rash † 75 8 < 1 17 0 0

Diarrhea 54 6 < 1 18 < 1 0

Anorexia 52 8 1 38 5 < 1

Fatigue 52 14 4 45 16 4

Dyspnea 41 17 11 35 15 11

Nausea 33 3 0 24 2 0

Infection 24 4 0 15 2 0

Stomatitis 17 < 1 0 3 0 0

Pruritus 13 < 1 0 5 0 0

Dry skin 12 0 0 4 0 0

Conjunctivitis 12 < 1 0 2 < 1 0

Keratoconjunctivitis sicca 12 0 0 3 0 0

† Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, dermatitis exfoliative, rash papular, skin desquamation.

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent TARCEVA 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 ( > 2.5 – 5.0 x ULN) ALT elevations occurred in 4% and < 1% of TARCEVA and placebo treated patients, respectively. Grade 3 ( > 5.0 – 20.0 x ULN) elevations were not observed in TARCEVA-treated patients. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see DOSAGE AND ADMINISTRATION].

Pancreatic Cancer -TARCEVA Administered Concurrently with Gemcitabine

This was a randomized, double blind placebo-controlled study of TARCEVA (150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m² IV) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). The safety population comprised 282 patients in the erlotinib group (259 in the 100 mg cohort and 23 in the 150 mg cohort) and 280 patients in the placebo group (256 in the 100 mg cohort and 24 in the 150 mg cohort).

Adverse reactions that occurred in at least 10% of patients treated with TARCEVA 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 2) are summarized by NCI-CTC (version 2.0) Grade in Table 4.

The most common adverse reactions in pancreatic cancer patients receiving TARCEVA 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the TARCEVA plus gemcitabine arm, Grade 3-4 rash and diarrhea were each reported in 5% of patients. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. Rash and diarrhea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving TARCEVA plus gemcitabine. Severe adverse reactions ( ≥ Grade 3 NCI-CTC) in the TARCEVA plus gemcitabine group with incidences < 5% included syncope, arrhythmias, ileus, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency [see WARNINGS AND PRECAUTIONS].

The 150 mg cohort was associated with a higher rate of certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption.

Table 4: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in TARCEVA-treated Pancreatic Cancer Patients: 100 mg cohort (Study 2)

NCI-CTC GRADE

TARCEVA + GEMCITABINE 1000 MG/M²

IV N=259

PLACEBO + GEMCITABINE 1000 MG/M²

IV N=256

ANY GRADE

GRADE 3

GRADE 4

ANY GRADE

GRADE 3

GRADE 4

MedDRA Preferred Term % % % % % %

Rash † 70 5 0 30 1 0

Diarrhea 48 5 < 1 36 2 0

Weight decreased 39 2 0 29 < 1 0

Infection * 39 13 3 30 9 2

Pyrexia 36 3 0 30 4 0

Stomatitis 22 < 1 0 12 0 0

Depression 19 2 0 14 < 1 0

Cough 16 0 0 11 0 0

Headache 15 < 1 0 10 0 0

* Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class † Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, pigmentation disorder, dermatitis acneiform, folliculitis, photosensitivity reaction, Stevens-Johnson syndrome, urticaria, erythematous rash, skin disorder, skin ulcer.

Ten patients (4%) in the TARCEVA/gemcitabine group and three patients (1%) in the placebo/gemcitabine group developed deep venous thrombosis. The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis was 11% for TARCEVA plus gemcitabine and 9% for placebo plus gemcitabine.

The incidences of liver test abnormalities ( ≥ Grade 2) in Study 2 are provided in Table 5 [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Table 5: Liver Test Abnormalities in Pancreatic Cancer Patients: 100 mg Cohort (Study 2)

NCI-CTC GRADE

TARCEVA + GEMCITABINE 1000 MG/M² IV

N=259

PLACEBO + GEMCITABINE 1000 MG/M² IV

N=256

GRADE 2 GRADE 3 GRADE 4 GRADE 2 GRADE 3 GRADE 4

Bilirubin 17% 10% < 1% 11% 10% 3%

ALT 31% 13% < 1% 22% 9% 0%

AST 24% 10% < 1% 19% 9% 0%

NSCLC and Pancreatic Indications: Selected Low Frequency Adverse Reactions

Gastrointestinal Disorders

Cases of gastrointestinal bleeding (including fatalities) have been reported, some associated with concomitant warfarin or NSAID administration [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.

Post-Marketing Experience

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

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis, in combination with statin therapy

Regorafenib

SIDE EFFECTSThe following serious adverse reactions are discussed elsewhere in the labeling:

Hepatotoxicity [See WARNINGS AND PRECAUTIONS] Hemorrhage [See WARNINGS AND PRECAUTIONS] Dermatological Toxicity [See WARNINGS AND PRECAUTIONS] Hypertension [See WARNINGS AND PRECAUTIONS] Cardiac Ischemia and Infarction [See WARNINGS AND PRECAUTIONS] Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See WARNINGS AND

PRECAUTIONS] Gastrointestinal Perforation or Fistula [See WARNINGS AND PRECAUTIONS]

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

The most frequently observed adverse drug reactions ( ≥ 20%) in patients receiving Stivarga are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea.

The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation.

Clinical Trials Experience

Colorectal Cancer

The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 7.3 (range 0.3, 47.0) weeks for

patients receiving Stivarga. Due to adverse reactions, 61% of the patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Stivarga-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of Stivarga.

Table 1 compares the incidence of adverse reactions ( ≥ 10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1).

Table 1 : Adverse drug reactions ( ≥ 10%) reported in patients treated with Stivarga in Study 1 and reported more commonly than in patients receiving placebo

ADVERSE REACTIONS

STIVARGA (N=500)

PLACEBO(N=253)

GRADE GRADE

ALL % ≥ 3 % ALL % ≥ 3 %

General disorders and administration site conditions

  Asthenia/fatigue 64 15 46 9

  Pain 29 3 21 2

  Fever 28 2 15 0

Metabolism and nutrition disorders

  Decreased appetite and food intake 47 5 28 4

Skin and subcutaneous tissue disorders

  HFSR/PPE 45 17 7 0

  Rash a 26 6 4 < 1

Gastrointestinal disorders

  Diarrhea 43 8 17 2

  Mucositis 33 4 5 0

Investigations

  Weight loss 32 < 1 10 0

Infections and infestations

  Infection 31 9 17 6

Vascular disorders

  Hypertension 30 8 8 < 1

  Hemorrhage b 21 2 8 < 1

Respiratory, thoracic and mediastinal disorders

  Dysphonia 30 0 6 0

Nervous system disorders

  Headache 10 < 1 7 0

aThe term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash.bFatal outcomes observed.

Laboratory Abnormalities

Laboratory abnormalities observed in Study 1 are shown in Table 2.

Table 2 : Laboratory test abnormalities reported in Study 1

LABORATORY PARAMETER

STIVARGA (N=500 A)

PLACEBO(N=253 A)

GRADE B GRADE B

ALL % 3 % 4 % ALL % 3 % 4 %

Blood and lymphatic system disorders

Anemia 79 5 1 66 3 0

Thrombocytopenia 41 2 < 1 17 < 1 0

Neutropenia 3 1 0 0 0 0

Lymphopenia 54 9 0 34 3 0

Metabolism and nutrition disorders

Hypocalcemia 59 1 < 1 18 1 0

Hypokalemia 26 4 0 8 < 1 0

Hyponatremia 30 7 1 22 4 0

Hypophosphatemia 57 31 1 11 4 0

Hepatobiliary disorders

Hyperbilirubinemia 45 10 3 17 5 3

Increased AST 65 5 1 46 4 1

Increased ALT 45 5 1 30 3 < 1

Renal and urinary disorders

Proteinuria 60 < 1 0 34 < 1 0

Investigations

Increased INRc 24 4 N/A 17 2 N/A

Increased Lipase 46 9 2 19 3 2

Increased Amylase 26 2 < 1 17 2 < 1

a% based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo). bCommon Terminology Criteria for Adverse Events (CTCAE), v3.0. cInternational normalized ratio: No Grade 4 denoted in CTCAE, v3.0.

Gastrointestinal Stromal Tumors

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 2) in which 132 patients (median age 60 years; 64% men) with previously-treated GIST received Stivarga as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64% men) received placebo. The median duration of therapy was 22.9 (range 0.1, 50.9) weeks for patients receiving Stivarga. Dose interruptions for adverse events were required in 58% of patients receiving Stivarga and 50% of patients had their

dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivargatreated patients compared to 1.5% of patients who received placebo.

Table 3 compares the incidence of adverse reactions ( ≥ 10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 2).

Table 3 : Adverse reactions ( ≥ 10%) reported in patients treated with Stivarga in Study 2 and reported more commonly than in patients receiving placebo

ADVERSE REACTIONS

STIVARGA (N=132)

PLACEBO(N=66)

GRADE GRADE

ALL % ≥ 3 % ALL % ≥ 3 %

Skin and subcutaneous tissue disorders

HFSR/PPE 67 22 12 2

Rash a 30 7 3 0

Alopecia 24 2 2 0

General disorders and administration site conditions

Asthenia/Fatigue 52 4 39 2

Fever 21 0 11 2

Vascular disorders

Hypertension 59 28 27 5

Hemorrhage 11 4 3 0

Gastrointestinal disorders

Diarrhea 47 8 9 0

Mucositis 40 2 8 2

Nausea 20 2 12 2

Vomiting 17 < 1 8 0

Respiratory, thoracic and mediastinal disorders

Dysphonia 39 0 9 0

Infections and infestations

Infection 32 5 5 0

Metabolism and nutrition disorders

Decreased appetite and food intake 31 < 1 21 3

Hypothyroidism b 18 0 6 0

Nervous system disorders

Headache 16 0 9 0

Investigations

Weight loss 14 0 8 0

Musculoskeletal and connective tissue disorders

Musculoskeletal stiffness 14 0 3 0

aThe term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash. bHypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline.

Laboratory Abnormalities

Laboratory abnormalities observed in Study 2 are shown in Table 4.

Table 4 : Laboratory test abnormalities reported in Study 2

LABORATORY PARAMETER

STIVARGA (N=132 A)

PLACEBO (N=66 A)

GRADE B GRADE B

ALL % 3 % 4 % ALL % 3 % 4 %

Blood and lymphatic system disorders

Thrombocytopenia 13 1 0 2 0 2

Neutropenia 16 2 0 12 3 0

Lymphopenia 30 8 0 24 3 0

Metabolism and nutrition disorders

Hypocalcemia 17 2 0 5 0 0

Hypokalemia 21 3 0 3 0 0

Hypophosphatemia 55 20 2 3 2 0

Hepatobiliary disorders

Hyperbilirubinemia 33 3 1 12 2 0

Increased AST 58 3 1 47 3 0

Increased ALT 39 4 1 39 2 0

Renal and urinary disorders

Proteinuria 33 3 -c 30 3 -c

Investigations Increased Lipase 14 0 1 5 0 0

a% based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo). bCTCAE, v4.0. cNo Grade 4 denoted in CTCAE, v4.0.

Postmarketing Experience

The following adverse reaction has been identified during postapproval use of Stivarga. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

hypersensitivity reaction

Read the Stivarga (regorafenib tablets) Side Effects Center for a complete guide to possible side effects

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SONIDEGIB OdomzoSIDE EFFECTSThe following serious adverse reactions are discussed in greater detail in other sections of the label:

Musculoskeletal Adverse Reactions [see WARNINGS AND PRECAUTIONS].

Clinical Trial Experience

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

The safety of ODOMZO was evaluated in Study 1, a randomized, double-blind, multiple cohort trial in which 229 patients received ODOMZO at either 200 mg (n=79) or 800 mg (n=150) daily. The frequency of common adverse reactions including muscle spasms, alopecia, dysgeusia, fatigue, nausea, decreased weight, decreased appetite, myalgia, pain, and vomiting was greater in patients treated with ODOMZO 800 mg as compared to 200 mg.

The data described below reflect exposure to ODOMZO 200 mg daily in 79 patients with locally advanced BCC (laBCC; n=66) or metastatic BCC (mBCC; n=13) enrolled in Study 1. Patients were followed for at least 18 months unless discontinued earlier. The median duration of treatment with ODOMZO was 11.0 months (range 1.3 to 33.5 months). The study population characteristics were: median age of 67 years (range 25 to 92; 59% were ≥ 65 years), 61% male, and 90% white. The majority of patients had prior surgery (75%), radiotherapy (24%), systemic chemotherapy (4%), or topical or photodynamic therapies (18%) for treatment of BCC. No patient had prior exposure to a hedgehog pathway inhibitor.

ODOMZO was permanently discontinued in 34% of patients or temporarily interrupted in 20% of patients for adverse reactions. Adverse reactions reported in at least two patients that led to discontinuation of the drug were: muscle spasms and dysgeusia (each 5%), asthenia, increased lipase, and nausea (each 4%), fatigue, decreased appetite, alopecia, and decreased weight (each 3%). Serious adverse reactions occurred in 18% of patients.

The most common adverse reactions occurring in ≥ 10% of patients treated with ODOMZO 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (Table 1).

The key laboratory abnormalities are described in Table 2.

Table 1: Adverse Reactions Occurring in ≥ 10% of Patients in Study 1

ADVERSE REACTION ODOMZO 200 MG

(N=79)

ALL GRADES3 % GRADE 3 %

Musculoskeletal and connective tissue disorders

  Muscle spasms 54 3

  Musculoskeletal pain 32 1

  Myalgia 19 0

Skin and subcutaneous tissue disorder

  Alopecia 53 0

  Pruritus 10 0

Nervous system disorders

  Dysgeusia 46 0

  Headache 15 1

General disorders and administration site conditions

  Fatigue 41 4

  Pain 14 1

Gastrointestinal disorders

  Nausea 39 1

  Diarrhea 32 1

  Abdominal pain 18 0

  Vomiting 11 1

Investigations

  Decreased weight 30 3

Metabolism and nutrition disorders

  Decreased appetite 23 1

a No Grade 4 adverse reactions were reported.

Table 2: Key Laboratory Abnormalitiesa

LABORATORY TEST

ODOMZO 200 MG (N=79)

ALL GRADES % GRADES 3-4%

Chemistry

  Increased serum creatinine 92b 0

  Increased serum creatine kinase (CK) 61 8

  Hyperglycemia 51 4

  Increased lipase 43 13

  Increased alanine aminotransferase 19 4

  Increased aspartate aminotransferase 19 4

  Increased amylase 16 1

Hematology

  Anemia 32 0

  Lymphopenia 28 3

a Based on worst post-treatment laboratory value regardless of baseline; grading by CTCAE v4.03. b The serum creatinine level remained within normal range in 76% (60/79) of patients.

Amenorrhea

Amenorrhea lasting for at least 18 months occurred in two of 14 pre-menopausal women treated with ODOMZO 200 mg or 800 mg once daily.

Read the Odomzo (sonidegib capsules) Side Effects Center for a complete guide to possible side effects