Oncology related (including new drugs, antagonists, etc)

(ado-trastuzumab emtansine) – KADCYLA ®:

INDICATIONS AND USAGE:
KADCYLA is a HER2-targeted antibody and microtubule inhibitor conjugate indicated, as a single agent, for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:
Received prior therapy for metastatic disease, or
Developed disease recurrence during or within six months of completing adjuvant therapy.

HOW SUPPLIED: Lyophilized powder in single-use vials containing 100 mg per vial or 160 mg per vial.

(alectinib) – ALECENSA ®:

HOW SUPPLIED/STORAGE AND HANDLING:
Hard capsules, white 150 mg capsules with “ALE” printed in black ink on the cap and “150 mg” printed in black ink on the body, available in:
240 capsules per bottle: NDC 50242-130-01

Storage and stability: Do not store above 30°C (86°F). Store in the original container to protect from light and moisture.

axitinib – INLYTA®:

INDICATIONS AND USAGE:  INLYTA is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.

DOSAGE AND ADMINISTRATION
The starting dose is 5 mg orally twice daily. Dose adjustments can be made based on individual safety and tolerability. (2.1, 2.2)
Administer INLYTA dose approximately 12 hours apart with or without food. (2.1)
INLYTA should be swallowed whole with a glass of water. (2.1)
If a strong CYP3A4/5 inhibitor is required, decrease the INLYTA dose by approximately half. (2.2)
For patients with moderate hepatic impairment, decrease the starting dose by approximately half. (2.2)

HOW SUPPLIED: 1 mg and 5 mg tablets

WARNINGS AND PRECAUTIONS:
[See package insert – extensive list]

(belinostat) – BELEODAQ®:

INDICATIONS AND USAGE:  Beleodaq is a histone deacetylase inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

HOW SUPPLIED: For injection: 500 mg, lyophilized powder in single-use vial for reconstitution

(blinatumomab) – BLINCYTO™:

INDICATIONS AND USAGE:  BLINCYTO is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials .

HOW SUPPLIED: For injection: 35 mcg of lyophilized powder in a single-use vial for reconstitution.

bosutinib – BOSULIF®:

Mechanism of Action: Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. In mice, treatment with bosutinib reduced the size of CML tumors relative to controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl.

INDICATIONS AND USAGE: BOSULIF is a kinase inhibitor indicated for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.

DOSAGE AND ADMINISTRATION (see link above for recent package insert)
Recommended Dose: 500 mg orally once daily with food. (2.1)
Consider dose escalation to 600 mg daily in patients who do not reach complete hematologic response by week 8 or complete cytogenetic response by week 12 and do not have Grade 3 or greater adverse reactions. (2.2)
Adjust dosage for toxicity and organ impairment (2)

Recommended Starting Dosage with Hepatic Impairment or Renal Impairment

WARNINGS AND PRECAUTIONS:
Gastrointestinal toxicity: Monitor and manage as necessary. Withhold, dose reduce, or discontinue BOSULIF.

Myelosuppression: Monitor blood counts and manage as necessary.

Hepatic toxicity: Monitor liver enzymes at least monthly for the first three months and as needed. Withhold, dose reduce, or discontinue BOSULIF.

Fluid retention: Monitor patients and manage using standard of care treatment. Withhold, dose reduce, or discontinue BOSULIF.

Embryofetal toxicity: May cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated with BOSULIF.

HOW SUPPLIED: Tablets: 100 mg and 500 mg.

cabozantinib – COMETRIQ™:

Mechanism of Action:
In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

INDICATIONS AND USAGE:
CABOMETYX is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

DOSAGE AND ADMINISTRATION
Recommended Dose: 60 mg orally, once daily. (2.1)
Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking CABOMETYX. (2.1)
Do NOT substitute CABOMETYX tablets with cabozantinib capsules. (2.1)

HOW SUPPLIED:

DOSAGE FORMS AND STRENGTHS
20 mg, 40 mg, and 60 mg tablets.

Drug updates:
COMETRIQ ™ (cabozantinib) capsules, for oral use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2012

Mechanism of Action: In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

See package insert for Dosage Adjustments and when to Permanently discontinue

WARNINGS: PERFORATIONS AND FISTULAS, and HEMORRHAGE
See full prescribing information for complete boxed warning.

Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula.
Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

INDICATIONS AND USAGE
COMETRIQ is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

DOSAGE AND ADMINISTRATION
Recommended Dose: 140 mg orally, once daily.
Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ.

DOSAGE FORMS AND STRENGTHS
20 mg and 80 mg capsules.

WARNINGS AND PRECAUTIONS:
Thrombotic Events: Discontinue COMETRIQ for myocardial infarction, cerebral infarction, or other serious arterial thromboembolic events.

Wound Complications: Withhold COMETRIQ for dehiscence or complications requiring medical intervention.

Hypertension: Monitor blood pressure regularly. Discontinue COMETRIQ for hypertensive crisis.

Osteonecrosis of the jaw: Discontinue COMETRIQ.

Palmar-plantar Erythrodysesthesia syndrome (PPES): Interrupt COMETRIQ, decrease dose.

Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue COMETRIQ.

Embryofetal toxicity: Can cause fetal harm. Advise women of potential risk to a fetus.

carfilzomib – KYPROLIS®:

INDICATIONS AND USAGE:
Kyprolis is a proteasome inhibitor that is indicated:

in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. (1, 14)
as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. (1, 14)

DOSAGE AND ADMINISTRATION
ABBREVIATED MONOGRAPH – SEE PACKAGE INSERT.
See Full Prescribing Information for dosing.
Hydrate prior to and following Kyprolis administration as needed. (2.1)
Premedicate Kyprolis infusions with dexamethasone prior to all Cycle 1 doses and if infusion reaction symptoms develop or reappear. (2.1)
Administer the 20/56 mg/m² regimen by 30-minute infusion and the 20/27 mg/m² regimen by 10-minute infusion. (2.2)

DOSAGE FORMS AND STRENGTHS
For injection: 60 mg, lyophilized powder in single-dose vial for reconstitution

WARNINGS AND PRECAUTIONS :
[Extensive list – see package insert]

Cardiac Toxicities: Monitor for signs and symptoms of cardiac failure or ischemia. Withhold Kyprolis and evaluate promptly. (5.1)
Acute Renal Failure: Monitor serum creatinine regularly. (5.2)
Tumor Lysis Syndrome (TLS): Administer pre-treatment hydration. (2.1) Monitor for TLS, including uric acid levels and treat promptly. (5.3)
Pulmonary Toxicity, including Acute Respiratory Distress Syndrome, Acute Respiratory Failure, and Acute Diffuse Infiltrative Pulmonary Disease: Withhold Kyprolis and evaluate promptly. (5.4)
Pulmonary Hypertension: Withhold Kyprolis and evaluate. (5.5)
Dyspnea: For severe or life threatening dyspnea, withhold Kyprolis and evaluate. (5.6)
Hypertension Including Hypertensive Crisis: Monitor blood pressure regularly. If hypertension cannot be controlled, interrupt treatment with Kyprolis (5.7)
Venous Thrombosis: Thromboprophylaxis is recommended. (5.8)
Infusion Reactions: Premedicate with dexamethasone. (2.1, 5.9)
Thrombocytopenia: Monitor platelet counts; interrupt or reduce Kyprolis dosing as clinically indicated. (2.3, 5.10)
Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes regularly. Withhold Kyprolis if suspected. (5.11)
Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Kyprolis if suspected. (5.12)
Posterior Reversible Encephalopathy Syndrome (PRES): Consider neuro-radiological imaging (MRI) for onset of visual or neurological symptoms; discontinue Kyprolis if suspected. (5.13)
Embryo-Fetal Toxicity: Kyprolis can cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated. (5.14, 8.1)

cobimetinib fumarate- COTELLIC™:

HOW SUPPLIED/STORAGE AND HANDLING:
COTELLIC (cobimetinib) is supplied as 20 mg film-coated tablets debossed on one side with “COB”. COTELLIC tablets are available in bottles of 63 tablets.
NDC 50242-717-01
Storage and Stability: Store at room temperature below 30°C (86°F).

crizotinib – XALKORI®:

INDICATIONS AND USAGE:
XALKORI is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.  This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

DOSAGE AND ADMINISTRATION:
250 mg taken orally twice daily with or without food.
Dosing interruption and/or dose reduction to 200 mg taken orally twice daily may be required based on individual safety and tolerability, then to 250 mg taken orally once daily if further reduction is necessary.

DOSAGE FORMS AND STRENGTHS:
XALKORI Capsules: 250 mg and 200 mg.

CONTRAINDICATIONS:
None

WARNINGS AND PRECAUTIONS
Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has occurred. Monitor monthly and as clinically indicated with more frequent testing in patients with Grade 2-4 elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated.

Pneumonitis: Severe, including fatal, treatment-related pneumonitis has been observed. Monitor patients for pulmonary symptoms indicative of pneumonitis. Permanently discontinue in patients diagnosed with treatment-related pneumonitis.

QT Interval Prolongation: In patients who have a history of or predisposition for QTc prolongation, or who are taking medications that are known to prolong the QT interval, consider periodic monitoring with electrocardiograms and electrolytes.

ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI.

Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman.

ADVERSE REACTIONS
The most common adverse reactions (≥25%) are vision disorder, nausea, diarrhea, vomiting, edema, and constipation.

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
CYP3A Inhibitors: Avoid concurrent use of XALKORI with strong CYP3A inhibitors.
CYP3A Inducers: Avoid concurrent use of XALKORI with strong CYP3A inducers.
CYP3A Substrates: Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Avoid concurrent use of XALKORI with CYP3A substrates with narrow therapeutic indices.

daratumumab – DARZALEX ™:

INDICATIONS AND USAGE: DARZALEX is indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.

This indication is approved under accelerated approval based on response rate [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

HOW SUPPLIED:
DARZALEX is a colorless to pale yellow, preservative-free solution available as:

Injection:
100 mg/5 mL (20 mg/mL) in a single-dose vial.
400 mg/20 mL (20 mg/mL) in a single-dose vial.

dasatinib – SPRYCEL®:

INDICATIONS AND USAGE:
SPRYCEL is a kinase inhibitor indicated for the treatment of:
-newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. The trial is ongoing and further data will be required to determine long-term outcome.

-adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.

-adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

USE IN SPECIFIC POPULATIONS
Hepatic Impairment: Use SPRYCEL with caution in patients with hepatic impairment.

DOSAGE AND ADMINISTRATION:
Chronic phase CML: 100 mg once daily.
Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL: 140 mg once daily.

Administered orally, with or without a meal. Tablets should not be crushed or cut.

DOSAGE FORMS AND STRENGTHS:
Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg.

CONTRAINDICATIONS:
None

WARNINGS AND PRECAUTIONS
Myelosuppression: Severe thrombocytopenia, neutropenia, and anemia may occur and require dose interruption or reduction. Monitor complete blood counts regularly.
Bleeding Related Events (mostly associated with severe thrombocytopenia): CNS and gastrointestinal hemorrhages, including fatalities, have occurred. Severe hemorrhage may require treatment interruptions and transfusions. Use SPRYCEL with caution in patients requiring medications that inhibit platelet function or anticoagulants.
Fluid Retention: SPRYCEL is associated with fluid retention, sometimes severe, including ascites, edema, and pleural and pericardial effusions. Manage with appropriate supportive care measures.
QT Prolongation: Use SPRYCEL with caution in patients who have or may develop prolongation of the QT interval.
Congestive Heart Failure, Left Ventricular Dysfunction and Myocardial Infarction: Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.
Pulmonary Arterial Hypertension (PAH): SPRYCEL may increase the risk of developing PAH which may be reversible on discontinuation. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment.
Use in Pregnancy: Fetal harm may occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

ADVERSE REACTIONS
Most common adverse reactions (≥10%) in patients with newly diagnosed chronic phase CML included myelosuppression, fluid retention, diarrhea, headache, musculoskeletal pain, and rash. Most common adverse reactions (≥20%) in patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage.

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS
CYP3A4 Inhibitors: May increase dasatinib drug levels and should be avoided. If coadministration cannot be avoided, monitor closely and consider reducing SPRYCEL dose.

CYP3A4 Inducers: May decrease dasatinib drug levels. If coadministration cannot be avoided, consider increasing SPRYCEL dose.

Antacids: May decrease dasatinib drug levels. Avoid simultaneous administration. If needed, administer the antacid at least 2 hours prior to or 2 hours after the dose of SPRYCEL.

H2 Antagonists/Proton Pump Inhibitors: May decrease dasatinib drug levels. Consider antacids in place of H2 antagonists or proton pump inhibitors.

denosumab – Xgeva®:

INDICATIONS AND USAGE:
Xgeva is a RANK ligand (RANKL) inhibitor indicated for:

Prevention of skeletal-related events in patients with bone metastases from solid tumors.
Important limitation of use: Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

USE IN SPECIFIC POPULATIONS
Nursing mothers: Discontinue drug or nursing taking into consideration importance of drug to mother.
Pediatric patients: Safety and efficacy not established.

Renal impairment: Patients with creatinine clearance less than 30 mL/min or receiving dialysis are at risk for hypocalcemia. Adequately supplement with calcium and vitamin D.

DOSAGE AND ADMINISTRATION:
Administer 120 mg every 4 weeks as a subcutaneous injection in the upper arm, upper thigh, or abdomen.
Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

DOSAGE FORMS AND STRENGTHS:
120 mg/1.7 mL (70 mg/mL) single-use vial

CONTRAINDICATIONS:
Clinically significant hypersensitivity to any component of the product.

WARNINGS AND PRECAUTIONS
Hypocalcemia: Severe hypocalcemia can occur in patients receiving Xgeva. Correct hypocalcemia prior to initiating Xgeva. Monitor calcium levels and adequately supplement all patients with calcium and vitamin D.

Osteonecrosis of the jaw can occur in patients receiving Xgeva. Perform an oral examination prior to starting Xgeva. Monitor for symptoms. Avoid invasive dental procedures during treatment with Xgeva.

Atypical femoral fracture: Has been reported. Evaluate patients with thigh or groin pain to rule out a femoral fracture.
Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus.

ADVERSE REACTIONS
The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea.
To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

elotuzumab – EMPLICITI ™:

Elotuzumab directly activates Natural Killer cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with Natural Killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC). In preclinical models, the combination of elotuzumab and lenalidomide resulted in enhanced activation of Natural Killer cells that was greater than the effects of either agent alone and increased anti-tumor activity in vitro and in vivo.

INDICATIONS AND USAGE:  EMPLICITI is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

HOW SUPPLIED: For injection: 300 mg or 400 mg of elotuzumab as a white to off-white lyophilized powder in a single-dose vial for reconstitution.

enzalutamide – XTANDI® capsules:

INDICATIONS AND USAGE
XTANDI is an androgen receptor inhibitor indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

DOSAGE AND ADMINISTRATION
XTANDI 160 mg (four 40 mg capsules) administered orally once daily. Swallow capsules whole. XTANDI can be taken with or without food. (2.1)

DOSAGE FORMS AND STRENGTHS
Capsule 40 mg

CONTRAINDICATIONS
Pregnancy (4, 8.1)

WARNINGS AND PRECAUTIONS
Seizure occurred in 0.9% of patients receiving XTANDI who previously received docetaxel and in 0.1% of patients who were chemotherapy-naive. There is no clinical trial experience with XTANDI in patients who have had a seizure. Permanently discontinue XTANDI in patients who develop a seizure during treatment. ( 5.1)
Posterior reversible encephalopathy syndrome (PRES): Discontinue XTANDI. ( 5.2)

ADVERSE REACTIONS
The most common adverse reactions (≥ 5%) are asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.
Avoid strong or moderate CYP3A4 or CYP2C8 inducers as they can alter the plasma exposure to XTANDI.
Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

(idelalisib) – ZYDELIG®:

INDICATIONS AND USAGE:
1.1 Relapsed Chronic Lymphocytic Leukemia
Zydelig is indicated, in combination with rituximab, for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.

1.2 Relapsed Follicular B-cell non-Hodgkin Lymphoma
Zydelig is indicated for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval was granted for this indication based on Overall Response Rate [see Clinical Studies (14.2)]. An improvement in patient survival or disease related symptoms has not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

1.3 Relapsed Small Lymphocytic Lymphoma
Zydelig is indicated for the treatment of patients with relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies.

Accelerated approval was granted for this indication based on Overall Response Rate [see Clinical Studies (14.3)]. An improvement in patient survival or disease related symptoms has not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

HOW SUPPLIED:
150 mg tablets: pink, oval-shaped, film-coated tablet debossed with “GSI” on one side and “150” on the other side.
100 mg tablets: orange, oval-shaped, film-coated tablet debossed with “GSI” on one side and “100” on the other side.

(ipilimumab) – YERVOY ®:

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions [see Dosage and Administration (2.3)].
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5)].
Initial U.S. Approval:  2011

Mechanism of Action: CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T cell responsiveness, including the anti-tumor immune response.

INDICATIONS AND USAGE
YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for:
Treatment of unresectable or metastatic melanoma. (1.1)
Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. (1.2)

DOSAGE AND ADMINISTRATION
ABBREVIATED MONOGRAPH – SEE PACKAGE INSERT.
Unresectable or metastatic melanoma:
3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses. (2.1)

Adjuvant melanoma:
10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity. (2.2)

Permanently discontinue for severe adverse reactions. (2.3)

DOSAGE FORMS AND STRENGTHS
Injection: 50 mg/10 mL (5 mg/mL)
Injection: 200 mg/40 mL (5 mg/mL)

CONTRAINDICATIONS

None.
WARNINGS AND PRECAUTIONS
Immune-mediated adverse reactions: Permanently discontinue for severe reactions. Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving less than 7.5 mg prednisone or equivalent per day. Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions. (5.1, 5.2, 5.3, 5.4, 5.5)

Immune-mediated hepatitis: Evaluate liver function tests before each dose of YERVOY. (5.2)
Immune-mediated endocrinopathies: Monitor clinical chemistries, ACTH level, and thyroid function tests prior to each dose. Evaluate at each visit for signs and symptoms of endocrinopathy. Institute hormone replacement therapy as needed. (5.5)
Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.7)

irinotecan liposome – ONIVYDE™:

INDICATIONS AND USAGE:  ONIVYDE ™ is indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.
Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas

HOW SUPPLIED: Injection: 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal dispersion in a single-dose vial.

ixazomib citrate- NINLARO®:

Ixazomib induced apoptosis of multiple myeloma cell lines in vitro. Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumor activity in a mouse multiple myeloma tumor xenograft model.

INDICATIONS AND USAGE:  NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

HOW SUPPLIED:
NINLARO is available in the following capsule strengths:

4 mg: Light orange gelatin capsule imprinted with “Takeda” on the cap and “4.0 mg” on the body in black ink. NINLARO 4 mg capsules contain 4 mg of ixazomib equivalent to 5.7 mg of ixazomib citrate.
3 mg: Light grey gelatin capsule imprinted with “Takeda” on the cap and “3.0 mg” on the body in black ink. NINLARO 3 mg capsules contain 3 mg of ixazomib equivalent to 4.3 mg of ixazomib citrate.
2.3 mg: Light pink gelatin capsule imprinted with “Takeda” on the cap and “2.3 mg” on the body in black ink. NINLARO 2.3 mg capsules contain 2.3 mg of ixazomib equivalent to 3.3 mg of ixazomib citrate.

lenvatinib – LENVIMA™:

INDICATIONS AND USAGE: LENVIMA is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

HOW SUPPLIED:
4 mg hard capsule: A yellowish-red body and yellowish-red cap, marked in black ink with “?” on the cap and “LENV 4 mg” on the body.

10 mg hard capsule: A yellow body and yellowish-red cap, marked in black ink with “?” on the cap and “LENV 10 mg” on the body.

(mechlorethamine)- VALCHLOR®:

INDICATIONS AND USAGE:  VALCHLOR is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy

HOW SUPPLIED: Gel: 0.016% w/w of mechlorethamine (equivalent to 0.02% mechlorethamine HCl) in 60g tubes

(mercaptopurine) – PURIXAN®:

INDICATIONS AND USAGE:   PURIXAN (mercaptopurine) is a nucleoside metabolic inhibitor indicated for the treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a combination maintenance therapy regimen.

HOW SUPPLIED: Oral suspension: 2000 mg/100 mL (20 mg/mL).

necitumumab – PORTRAZZA ™:

In in vivo studies using xenograft models of human cancer, including non-small cell lung carcinoma, administration of necitumumab to implanted mice resulted in increased antitumor activity in combination with gemcitabine and cisplatin as compared to mice receiving gemcitabine and cisplatin alone.

INDICATIONS AND USAGE:  1.1 Squamous Non-Small Cell Lung Cancer (NSCLC)
PORTRAZZA™ is indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer.

1.2 Limitation of Use
PORTRAZZA is not indicated for treatment of non-squamous non-small cell lung cancer

HOW SUPPLIED: Injection: 800 mg/50 mL (16 mg/mL) solution in a single-dose vial

(nivolumab) – OPDIVO ®:

Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumor responses in metastatic melanoma. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity.

INDICATIONS AND USAGE:
1.1 Unresectable or Metastatic Melanoma
OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.1) ].
OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma [see Clinical Studies (14.1)].
This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
OPDIVO (nivolumab), in combination with ipilimumab, is indicated for the treatment of patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)].
This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.2 Metastatic Non-Small Cell Lung Cancer
OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO [see Clinical Studies (14.2)].

1.3 Renal Cell Carcinoma
OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy [see Clinical Studies (14.3)].

HOW SUPPLIED: Injection: 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL) solution in a single-dose vial.

(olaparib) – LYNPARZA™:

INDICATIONS AND USAGE:  Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. (1.1)
The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

HOW SUPPLIED: Capsules: 50 mg

(omacetaxine mepesuccinate) – SYNRIBO ®:

INDICATIONS AND USAGE
SYNRIBO for Injection is indicated for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI) (1).

DOSAGE AND ADMINISTRATION
ABBREVIATED MONOGRAPH – SEE PACKAGE INSERT.
Induction Dose: 1.25 mg/m 2 administered by subcutaneous injection twice daily for 14 consecutive days of a 28-day cycle ( 2.1).
Maintenance Dose: 1.25 mg/m 2 administered by subcutaneous injection twice daily for 7 consecutive days of a 28-day cycle ( 2.2).
Dose modifications are needed for toxicity ( 2.3).

DOSAGE FORMS AND STRENGTHS
Single-use vial containing 3.5 mg of omacetaxine mepesuccinate as a lyophilized powder

CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Myelosuppression: severe and fatal thrombocytopenia, neutropenia and anemia. Monitor hematologic parameters frequently ( 2.3, 5.1).
Bleeding: severe thrombocytopenia and increased risk of hemorrhage. Fatal cerebral hemorrhage and severe, non-fatal gastrointestinal hemorrhage ( 5.1, 5.2).
Hyperglycemia: glucose intolerance and hyperglycemia including hyperosmolar non-ketotic hyperglycemia ( 5.3).
Embryo-fetal toxicity: can cause fetal harm. Advise females of reproductive potential to avoid pregnancy ( 5.4, 8.1).

osimertinib – TAGRISSO ™:

INDICATIONS AND USAGE:  TAGRISSO is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

HOW SUPPLIED:
80 mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and plain on the reverse.
40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain on the reverse.

palbociclib – IBRANCE®:

INDICATIONS AND USAGE: IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

This indication is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

HOW SUPPLIED:
125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with white ink “Pfizer” on the cap, “PBC 125” on the body.
100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink “Pfizer” on the cap, “PBC 100” on the body.
75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed with white ink “Pfizer” on the cap, “PBC 75” on the body.

panobinostat lactate – FARYDAK ®:

INDICATIONS AND USAGE: FARYDAK, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. This indication is approved under accelerated approval based on progression free survival [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

HOW SUPPLIED:
Capsules: 10 mg, 15 mg, and 20 mg

pazopanib- VOTRIENT®:

Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

INDICATIONS AND USAGE:
VOTRIENT is a kinase inhibitor indicated for the treatment of patients with:

-advanced renal cell carcinoma.
-advanced soft tissue sarcoma who have received prior chemotherapy.

Limitation of Use:
The efficacy of VOTRIENT for the treatment of patients with adipocytic soft tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated.

DOSAGE AND ADMINISTRATION:
800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal).

Baseline moderate hepatic impairment – 200 mg orally once daily. Not recommended in patients with severe hepatic impairment.

DOSAGE FORMS AND STRENGTHS:
200 mg tablets

CONTRAINDICATIONS:
None

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS
The most common adverse reactions in patients with advanced renal cell carcinoma (≥20%) are diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting.

The most common adverse reactions in patients with advanced soft tissue sarcoma (≥20%) are fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation.

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS
CYP3A4 Inhibitors: Avoid use of strong inhibitors. Reduce the dose of VOTRIENT when administered with strong CYP3A4 inhibitors.

CYP3A4 Inducers: Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring.

(pembrolizumab) – KEYTRUDA ®:

INDICATIONS AND USAGE:
1.1 Melanoma
KEYTRUDA® (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)].

1.2 Non-Small Cell Lung Cancer
KEYTRUDA is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA [see Clinical Studies (14.2)].

This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

HOW SUPPLIED:
For injection: 50 mg lyophilized powder in a single-use vial for reconstitution
Injection: 100 mg/4 mL (25 mg/mL) solution in a single-use vial

pertuzumab -PERJETA™:

Mechanism of Action: Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC).

While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models.

INDICATIONS AND USAGE:
PERJETA is a HER2/neu receptor antagonist indicated for:
Use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. (1.1)
Use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival. (1.2, 2.1, 14.2)

Limitations of Use:
The safety of PERJETA as part of a doxorubicin-containing regimen has not been established.
The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established.

USE IN SPECIFIC POPULATIONS
Nursing mothers: Discontinue nursing or discontinue PERJETA, taking into consideration the importance of the drug to the mother.
Females of Reproductive Potential: Counsel females on pregnancy prevention and planning. Encourage patient participation in the MotHER Pregnancy Registry by contacting 1-800-690-6720.

DOSAGE AND ADMINISTRATION:
For intravenous infusion only. Do not administer as an intravenous push or bolus.
The initial dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30 to 60 minute intravenous infusion.

————————————–
Recommended Doses and Schedules
————————————–
The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.
When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks thereafter by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.
When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m2 administered as an intravenous infusion. The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.

————————————–
Dose Modification
————————————–
For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks, the 420 mg dose of PERJETA should be administered. Do not wait until the next planned dose. If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg PERJETA should be re-administered as a 60-minute intravenous infusion followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.

The infusion rate of PERJETA may be slowed or interrupted if the patient develops an infusion-associated reaction. The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction.
Left Ventricular Ejection Fraction (LVEF):

Withhold PERJETA and trastuzumab dosing for at least 3 weeks for either:

-a drop in LVEF to less than 40% or
-LVEF of 40% to 45% with a 10% or greater absolute decrease below pretreatment values.

PERJETA may be resumed if the LVEF has recovered to greater than 45% or to 40% to 45% associated with less than a 10% absolute decrease below pretreatment values.
If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, or has declined further, discontinuation of PERJETA and trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks.
PERJETA should be withheld or discontinued if trastuzumab treatment is withheld or discontinued.

If docetaxel is discontinued, treatment with PERJETA and trastuzumab may continue.
Dose reductions are not recommended for PERJETA.
For docetaxel dose modifications, see docetaxel prescribing information.

————————————–
Preparation for Administration
————————————–
Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix PERJETA with other drugs.

Preparation:
Prepare the solution for infusion, using aseptic technique, as follows:
-Parenteral drug products should be inspected visually for particulates and discoloration prior to administration.
-Withdraw the appropriate volume of PERJETA solution from the vial(s).
-Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag.
-Mix diluted solution by gentle inversion. Do not shake.
-Administer immediately once prepared.
-If the diluted infusion solution is not used immediately, it can be stored at 2°C to 8°C for up to 24 hours.
-Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.

DOSAGE FORMS AND STRENGTHS:
420 mg/14 mL single-use vial.

CONTRAINDICATIONS:
None

WARNINGS AND PRECAUTIONS
Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant woman.
Left Ventricular Dysfunction: Monitor LVEF and withhold dosing as appropriate.
Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis: Monitor for signs and symptoms. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.
HER2 testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency.

ADVERSE REACTIONS
The most common adverse reactions (> 30%) with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

(ponatinib) – ICLUSIG ®:

INDICATIONS AND USAGE:
Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. (1)

These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.
DOSAGE AND ADMINISTRATION
Recommended dose: 45 mg taken orally once daily with or without food (2.1)
Hepatic Impairment: 30 mg orally once daily (2.5)
Modify or interrupt dosing for hematologic and non-hematologic toxicity (2.2, 2.3)
ABBREVIATED MONOGRAPH – SEE PACKAGE INSERT.

HOW SUPPLIED: Tablets: 15 mg, 30 mg and 45 mg

regorafenib – STIVARGA® tablets:

INDICATIONS AND USAGE
Stivarga is a kinase inhibitor indicated for the treatment of patients with:

Metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. ( 1.1)

Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. ( 1.2)

DOSAGE AND ADMINISTRATION
Recommended Dose: 160 mg orally, once daily for the first 21 days of each 28-day cycle. ( 2.1)
Take Stivarga with a low-fat meal. ( 2.1, 12.3)

DOSAGE FORMS AND STRENGTHS
40 mg film-coated tablets

CONTRAINDICATIONS
None.

WARNINGS AND PRECAUTIONS
Hemorrhage: Permanently discontinue Stivarga for severe or life-threatening hemorrhage. ( 5.2)

Dermatological toxicity: Interrupt and then reduce or discontinue Stivarga depending on severity and persistence of dermatologic toxicity. ( 5.3)

Hypertension: Temporarily or permanently discontinue Stivarga for severe or uncontrolled hypertension. ( 5.4)

Cardiac ischemia and infarction: Withhold Stivarga for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events. ( 5.5)

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue Stivarga. ( 5.6)

Gastrointestinal perforation or fistulae: Discontinue Stivarga. ( 5.7)

Wound healing complications: Stop Stivarga before surgery. Discontinue in patients with wound dehiscence. ( 5.8)
Embryofetal toxicity: Can cause fetal harm. Advise women of potential risk to a fetus. ( 5.9, 8.1)

sonidegib phosphate – ODOMZO ®:

INDICATIONS AND USAGE:  ODOMZO (sonidegib) is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.

HOW SUPPLIED: 200 mg opaque pink colored capsules with ‘SONIDEGIB 200MG’ printed on the body and ‘NVR’ printed on the cap in black ink.

sorafenib – NEXAVAR®:

DOSAGE AND ADMINISTRATION:
400 mg (2 tablets) orally twice daily without food.

Treatment interruption and/or dose reduction may be needed to manage suspected adverse drug reactions. Dose may be reduced to 400 mg once daily or to 400 mg every other day.

DOSAGE FORMS AND STRENGTHS:
200 mg Tablets

CONTRAINDICATIONS:
NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR.
NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer.

WARNINGS AND PRECAUTIONS
• Cardiac ischemia and/or infarction may occur. Consider temporary or permanent discontinuation of NEXAVAR.
• Bleeding may occur. If bleeding necessitates medical intervention, consider discontinuation of NEXAVAR.
• Hypertension usually occurred early in the course of treatment and was managed with antihypertensive therapy. Monitor blood pressure weekly during the first 6 weeks and periodically thereafter and treat, as required.
• Hand-foot skin reaction and rash are common. Management may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification, or in severe or persistent cases, permanent discontinuation. Stevens-Johnson syndrome and toxic epidermal necrolysis have also occurred. Discontinue if suspected.
• Gastrointestinal perforation is an uncommon adverse reaction. In the event of a gastrointestinal perforation, NEXAVAR should be discontinued.
• Temporary interruption of NEXAVAR is recommended in patients undergoing major surgical procedures.
• QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid in patients with congenital long QT syndrome.
• Drug-induced hepatitis characterized by a hepatocellular pattern may result in hepatic failure and death. Monitor liver function tests regularly and discontinue if there is no alternative explanation for transaminase elevations.
• NEXAVAR may cause fetal harm when administered to a pregnant woman. Advise women of childbearing potential to avoid becoming pregnant while on NEXAVAR.

ADVERSE REACTIONS
The most common adverse reactions (≥20%), which were considered to be related to NEXAVAR, are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.

To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS
• CYP3A4 inducers: Can increase the metabolism of sorafenib and decrease the AUC of sorafenib.
USE IN SPECIFIC POPULATIONS

• Hepatic impairment: No dose adjustment is necessary for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. NEXAVAR has not been studied in patients with severe (Child-Pugh C) hepatic impairment.

• Renal impairment: No dose adjustment is necessary for patients with mild (CrCl 50-80 mL/min), moderate (CrCl 30 – <50 mL/min), or severe (CrCl < 30 mL/min) renal impairment. NEXAVAR has not been studied in patients who are on dialysis.

sunitinib malate – SUTENT®:

Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported.

INDICATIONS AND USAGE:
SUTENT is a kinase inhibitor indicated for the treatment of:
Gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.

Advanced renal cell carcinoma (RCC).

Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease.

DOSAGE AND ADMINISTRATION::
GIST and RCC:
50 mg orally once daily, with or without food, 4 weeks on treatment followed by 2 weeks off.

pNET:
37.5 mg orally once daily, with or without food, continuously without a scheduled off-treatment period. (

Dose Modification:
Dose interruptions and/or dose adjustments of 12.5 mg recommended based on individual safety and tolerability.

DOSAGE FORMS AND STRENGTHS:
Capsules: 12.5 mg, 25 mg, 50 mg

CONTRAINDICATIONS:
None

WARNINGS AND PRECAUTIONS
Hepatotoxicity, including liver failure, has been observed. Monitor liver function tests before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure.

Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

Cardiac toxicity including left ventricular ejection fraction declines to below the lower limit of normal and cardiac failure including death have occurred. Monitor patients for signs and symptoms of congestive heart failure.

Prolonged QT intervals and Torsade de Pointes have been observed. Use with caution in patients at higher risk for developing QT interval prolongation. When using SUTENT, monitoring with on-treatment electrocardiograms and electrolytes should be considered.

Hypertension may occur. Monitor blood pressure and treat as needed.

Hemorrhagic events including tumor-related hemorrhage have occurred. Perform serial complete blood counts and physical examinations.

Osteonecrosis of the jaw has been reported. Consider preventive dentistry prior to treatment with SUTENT. If possible, avoid invasive dental procedures, particularly in patients receiving intravenous bisphosphonate therapy.

Cases of Tumor Lysis Syndrome (TLS) have been reported primarily in patients with RCC and GIST with high tumor burden. Monitor these patients closely and treat as clinically indicated.

Thyroid dysfunction may occur. Patients with signs and/or symptoms suggestive of hypothyroidism or hyperthyroidism should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.

Temporary interruption of therapy with SUTENT is recommended in patients undergoing major surgical procedures.

Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress such as surgery, trauma or severe infection.

ADVERSE REACTIONS
The most common adverse reactions (≥20%) 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.

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
CYP3A4 Inhibitors: Consider dose reduction of SUTENT when administered with strong CYP3A4 inhibitors.
CYP3A4 Inducers: Consider dose increase of SUTENT when administered with CYP3A4 inducers.

trabectedin – YONDELIS ®:

INDICATIONS AND USAGE:  YONDELIS® is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.

HOW SUPPLIED: For injection: 1 mg, lyophilized powder in single-dose vial for reconstitution.

trifluridine and tipiracil HCL – LONSURF®:

INDICATIONS AND USAGE:  LONSURF is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

HOW SUPPLIED:
LONSURF (15 mg trifluridine/6.14 mg tipiracil) is a white, biconvex, round, film-coated tablet, imprinted with ‘15’ on one side, and ‘102’ and ‘15 mg’ on the other side, in gray ink.

LONSURF (20 mg trifluridine/8.19 mg tipiracil) is a pale red, biconvex, round, film-coated tablet, imprinted with ‘20’ on one side, and ‘102’ and ‘20 mg’ on the other side, in gray ink.

(vandetanib) – CAPRELSA®:

In vitro, vandetanib inhibited epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells.

In vivo, vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer.

INDICATIONS AND USAGE
CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. (1)

Use of CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA. (1)
DOSAGE AND ADMINISTRATION
300 mg once daily
CAPRELSA may be taken with or without food.
Dosage reduction may be necessary in the event of severe toxicities or QTc interval prolongation. (2.1)(2.1)
The starting dose is 200 mg in patients with moderate to severe renal impairment. (2.1)

DOSAGE FORMS AND STRENGTHS
100 mg and 300 mg tablets
CONTRAINDICATIONS
Do not use in patients with congenital long QT syndrome.

WARNINGS AND PRECAUTIONS
Prolonged QT Interval, Torsades de pointes, and sudden death: Monitor electrocardiograms and levels of serum potassium, calcium, magnesium and TSH. Reduce CAPRELSA dose as appropriate. ( 2.1, 5.1)
Severe skin reactions, including Stevens-Johnson syndrome, some resulting in death: Consider discontinuation of CAPRELSA for severe skin reactions. ( 2.1, 5.2)
Interstitial lung disease (ILD), including fatalities: investigate unexplained non-specific respiratory signs and symptoms. Discontinue CAPRELSA for confirmed ILD. ( 2.1, 5.3)
Ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypertension, and reversible posterior leukoencephalopathy syndrome: Discontinue or interrupt CAPRELSA. ( 2.1, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 5.10)
Embryofetal toxicity: Can cause fetal harm. Advise women of the potential risk to a fetus and to avoid pregnancy during and for four months following treatment with CAPRELSA. ( 5.14, 8.1)
RREMS: CAPRELSA is available only through a restricted distribution program called the CAPRELSA REMS Program. ( 5.15)

vemurafenib – ZELBORAF™:

Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.

USE IN SPECIFIC POPULATIONS
Nursing Mothers: Discontinue nursing when receiving ZELBORAF

DOSAGE AND ADMINISTRATION:
Recommended dose: 960 mg orally twice daily.
Administer ZELBORAF approximately 12 hours apart with or without a meal.
ZELBORAF should be swallowed whole with a glass of water. ZELBORAF should not be chewed or crushed.
Management of symptomatic adverse drug reactions may require dose reduction, treatment interruption, or treatment discontinuation of ZELBORAF. Dose reductions resulting in a dose below 480 mg twice daily are not recommended.

DOSAGE FORMS AND STRENGTHS:
Film-coated tablet: 240 mg

CONTRAINDICATIONS:
None

WARNINGS AND PRECAUTIONS
Cutaneous squamous cell carcinomas (cuSCC) occurred in 24% of patients. Perform dermatologic evaluations prior to initiation of therapy and every two months while on therapy. Manage with excision and continue treatment without dose adjustment.

Serious hypersensitivity reactions, including anaphylaxis, have been reported during and upon re-initiation of treatment. Discontinue ZELBORAF in patients who experience severe hypersensitivity reactions.

Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. Discontinue treatment in patients who experience severe dermatologic reactions.

QT prolongation has been reported. Monitor ECG and electrolytes before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first 3 months of treatment, every 3 months thereafter, or more often as clinically indicated. If the QTc exceeds 500 ms, temporarily interrupt ZELBORAF, correct electrolyte abnormalities, and control for cardiac risk factors for QT prolongation.

Liver laboratory abnormalities may occur. Monitor liver enzymes and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated.

Photosensitivity has been reported. Advise patients to avoid sun exposure while taking ZELBORAF.

Serious ophthalmologic reactions, including uveitis, iritis and retinal vein occlusion, have been reported. Monitor patients routinely for ophthalmologic reactions.

New primary malignant melanomas have been reported. Manage with excision, and continue treatment without dose modification. Perform dermatologic monitoring as outlined above.

Pregnancy: May cause fetal harm. Advise women of potential risk to the fetus.

BRAFV600E testing – confirmation of BRAFV600E mutation using an FDA-approved test is required for selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma.

ADVERSE REACTIONS
Most common adverse reactions (≥ 30%) are arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma.

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
CYP Substrates: Concomitant use of ZELBORAF with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP1A2 or CYP2D6 is not recommended. If coadministration cannot be avoided, exercise caution and consider a dose reduction of the concomitant CYP1A2 or CYP2D6 substrate drug.
ZZELBORAF may increase exposure to concomitantly administered warfarin. Exercise caution and consider additional INR monitoring when ZELBORAF is used concomitantly with warfarin.

vismodegib – ERIVEDGE™:

INDICATIONS AND USAGE:  ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

HOW SUPPLIED: ERIVEDGE (vismodegib) capsules, 150 mg. The capsule has a pink opaque body and a grey opaque cap, with “150 mg” printed on the capsule body and “VISMO” printed on the capsule cap in black ink.

WARNINGS: WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS
See full prescribing information for complete boxed warning.

ERIVEDGE can result in embryo-fetal death or severe birth defects. Verify pregnancy status prior to initiation of ERIVEDGE. Advise male and female patients of these risks. Advise females of the need for contraception and advise males of the potential risk of ERIVEDGE exposure through semen.
USE IN SPECIFIC POPULATIONS
Pregnancy: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus.
Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother.
Females of Reproductive Potential and Males: Counsel males and females on pregnancy prevention and planning. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage patient participation in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555.

DOSAGE AND ADMINISTRATION—————————–
The recommended dose is 150 mg orally once daily.

WARNINGS AND PRECAUTIONS:
-Embryo-fetal death and severe birth defects: ERIVEDGE can cause embryo-fetal death or severe birth defects.
Blood donation: Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE.

vorinostat – ZOLINZA® Capsules:

INDICATIONS AND USAGE:
ZOLINZA is a histone deacetylase (HDAC) inhibitor indicated for:

Treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies

DOSAGE AND ADMINISTRATION:
400 mg orally once daily with food.
If patient is intolerant to therapy, the dose may be reduced to 300 mg orally once daily with food. If necessary, the dose may be further reduced to 300 mg once daily with food for 5 consecutive days each week

DOSAGE FORMS AND STRENGTHS:
Capsules: 100 mg

CONTRAINDICATIONS:
Severe hepatic impairment

WARNINGS AND PRECAUTIONS
Pulmonary embolism and deep vein thrombosis have been reported. Monitor patient for pertinent signs and symptoms.

Dose-related thrombocytopenia and anemia have occurred and may require dose modification or discontinuation.

Gastrointestinal disturbances (e.g., nausea, vomiting and diarrhea) have been reported. Patients may require antiemetics, antidiarrheals and fluid and electrolyte replacement (to prevent dehydration).

Patients with mild and moderate hepatic impairment should be treated with caution.

Hyperglycemia has been observed. Adjustment of diet and/or therapy for increased glucose may be necessary.

Monitor electrolytes at baseline and periodically during treatment.

Monitor blood cell counts and chemistry tests, including electrolytes, glucose and serum creatinine, every 2 weeks during the first 2 months of therapy and monthly thereafter.

Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count.

Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus.

ADVERSE REACTIONS
The most common adverse reactions (incidence ≥20%) are diarrhea, fatigue, nausea, thrombocytopenia, anorexia and dysgeusia.

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Coumarin-derivative anticoagulants: Prolongation of prothrombin time and International Normalized Ratio have been observed with concomitant use. Monitor carefully.

ziv-aflibercept – ZALTRAP®:

Mechanism of Action: Ziv-aflibercept acts as a soluble receptor that binds to human VEGF-A (equilibrium dissociation constant KD of 0.5 pM for VEGF-A165 and 0.36 pM for VEGF-A121), to human VEGF-B (KD of 1.92 pM), and to human PlGF (KD of 39 pM for PlGF-2). By binding to these endogenous ligands, ziv-aflibercept can inhibit the binding and activation of their cognate receptors. This inhibition can result in decreased neovascularization and decreased vascular permeability.
In animals, ziv-aflibercept was shown to inhibit the proliferation of endothelial cells, thereby inhibiting the growth of new blood vessels. Ziv-aflibercept inhibited the growth of xenotransplanted colon tumors in mice.

INDICATIONS AND USAGE:   ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen

USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, ZALTRAP may cause fetal harm.
Nursing Mothers: Discontinue drug or nursing taking into account the importance of the drug to the mother.
Females and Males of Reproductive Potential: Use highly effective contraception during and up to a minimum of 3 months after the last dose

DOSAGE AND ADMINISTRATION:
4 mg/kg as an intravenous infusion over 1 hour every 2 weeks.
Do not administer as an intravenous (IV) push or bolus.

Recommended Dose and Schedule
Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment.

Continue ZALTRAP until disease progression or unacceptable toxicity.

Dose Modification / Treatment Delay Recommendations
Discontinue ZALTRAP for:
-Severe hemorrhage
-Gastrointestinal perforation
-Compromised wound healing
-Fistula formation
-Hypertensive crisis or hypertensive encephalopathy
-Arterial thromboembolic events
-Nephrotic syndrome or thrombotic microangiopathy (TMA)
-Reversible posterior leukoencephalopathy syndrome (RPLS)

Temporarily suspend ZALTRAP:
-At least 4 weeks prior to elective surgery.
-For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg.
-For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg.
-For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information.

2.3 Preparation for Administration

Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles.

Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial.

Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL.

Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags.

Store diluted ZALTRAP at 2°–8°C (36°–46°F) for up to 24 hours, or at controlled room temperature 20°–25°C (68°–77°F) for up to 8 hours. Discard any unused portion left in the infusion bag.

Administration
Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon.

Do not administer as an intravenous (IV) push or bolus.

Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line.

Administer ZALTRAP using an infusion set made of one of the following materials:
-PVC containing DEHP
-DEHP free PVC containing trioctyl-trimellitate (TOTM)
-polypropylene
-polyethylene lined PVC
-polyurethane

DOSAGE FORMS AND STRENGTHS:
Single-use vials: 100 mg/4 mL (25 mg/mL), 200 mg/8 mL (25 mg/mL)

CONTRAINDICATIONS:
None

WARNINGS AND PRECAUTIONS
Adverse reactions, sometimes severe and life-threatening or fatal, have been seen in clinical trials with ZALTRAP, including:

Fistula Formation: Discontinue ZALTRAP if fistula occurs.
Hypertension: Monitor blood pressure and treat hypertension. Temporarily suspend ZALTRAP if hypertension is not controlled. Discontinue ZALTRAP if hypertensive crisis develops.
Arterial Thromboembolic Events (ATE) (e.g., transient ischemic attacks, cerebrovascular accident, angina pectoris): Discontinue ZALTRAP if ATE develops.
Proteinuria: Monitor urine protein. Suspend ZALTRAP when proteinuria ≥ 2 grams per 24 hours. Discontinue ZALTRAP if nephrotic syndrome or thrombotic microangiopathy (TMA) develops.
Neutropenia and Neutropenic Complications: Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ≥ 1.5 × 10⁹/L.
Diarrhea and Dehydration: Incidence of severe diarrhea and dehydration is increased. Monitor elderly patients more closely.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue ZALTRAP.

ADVERSE REACTIONS
Most common adverse reactions (all grades, ≥20% incidence and at least 2% greater incidence for the ZALTRAP/FOLFIRI regimen) were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.

To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.