Prescribing Information

Click here to see prescribing information for Aranesp^® (darbepoetin alfa).

Important Safety Information

• Aranesp^® is contraindicated in patients with:
• Uncontrolled hypertension
• Pure red cell aplasia (PRCA) that begins after treatment with Aranesp^® or other erythropoietin protein drugs
• Serious allergic reactions to Aranesp^®
• Use caution in patients with CKD and coexistent cardiovascular disease and stroke.
• Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks.
• In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.
• Control hypertension prior to initiating and during treatment with Aranesp^®.
• Aranesp^® increases the risk of seizures in patients with CKD. Monitor patients closely for new-onset seizures, premonitory symptoms, or change in seizure frequency.
• For lack or loss of hemoglobin response to Aranesp^®, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA.
• Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp^®.
• This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration.
• PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp^® is not approved).
• If severe anemia and low reticulocyte count develop during treatment with Aranesp^®, withhold Aranesp^® and evaluate patients for neutralizing antibodies to erythropoietin.
• Permanently discontinue Aranesp^® in patients who develop PRCA following treatment with Aranesp^® or other erythropoietin protein drugs. Do not switch patients to other ESAs.
• Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp^®. Immediately and permanently discontinue Aranesp^® if a serious allergic reaction occurs.
• Adverse reactions (≥ 1%) in Aranesp^® clinical studies in cancer patients receiving chemotherapy were abdominal pain, edema, and thrombovascular events.

Prescribing Information

Click here to see prescribing information for Aranesp^® (darbepoetin alfa).

Important Safety Information

• Aranesp^® is contraindicated in patients with:
• Uncontrolled hypertension
• Pure red cell aplasia (PRCA) that begins after treatment with Aranesp^® or other erythropoietin protein drugs
• Serious allergic reactions to Aranesp^®
• Use caution in patients with CKD and coexistent cardiovascular disease and stroke.
• Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks.
• In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.
• Control hypertension prior to initiating and during treatment with Aranesp^®.
• Aranesp^® increases the risk of seizures in patients with CKD. Monitor patients closely for new-onset seizures, premonitory symptoms, or change in seizure frequency.
• For lack or loss of hemoglobin response to Aranesp^®, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA.
• Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp^®.
• This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration.
• PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp^® is not approved).
• If severe anemia and low reticulocyte count develop during treatment with Aranesp^®, withhold Aranesp^® and evaluate patients for neutralizing antibodies to erythropoietin.
• Permanently discontinue Aranesp^® in patients who develop PRCA following treatment with Aranesp^® or other erythropoietin protein drugs. Do not switch patients to other ESAs.
• Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp^®. Immediately and permanently discontinue Aranesp^® if a serious allergic reaction occurs.
• Adverse reactions (≥ 10%) in Aranesp^® clinical studies in patients with CKD were hypertension, dyspnea, peripheral edema, cough, and procedural hypotension.

Prescribing Information

Click here to see prescribing information for Enbrel^® (etanercept).

Important Safety Information

In adult clinical trials of all TNF blockers, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA and psoriasis patients. The role of TNF blocker therapy in the development of malignancies is unknown.

Cases of acute and chronic leukemia have been reported in association with postmarketing TNF blocker use in RA and other indications. The risk of leukemia may be higher in patients with RA (approximately 2-fold) than the general population.

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF blockers, including ENBREL. Periodic skin examinations should be considered for all patients at increased risk for skin cancer.

Pediatric Patients
In patients who initiated therapy at ≤ 18 years of age, approximately half of the reported malignancies were lymphomas (Hodgkin's and non-Hodgkin's lymphoma). Other cases included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.

NEUROLOGIC EVENTS
Treatment with TNF-blocking agents, including ENBREL, has been associated with rare (< 0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with ENBREL therapy. Prescribers should exercise caution in considering the use of ENBREL in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.

CONGESTIVE HEART FAILURE
Cases of worsening congestive heart failure (CHF) and, rarely, new-onset cases have been reported in patients taking ENBREL. Caution should be used when using ENBREL in patients with CHF. These patients should be carefully monitored.

HEMATOLOGIC EVENTS
Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. The causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL in patients who have a previous history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. Consider discontinuing ENBREL if significant hematologic abnormalities are confirmed.

HEPATITIS B VIRUS REACTIVATION
Use of TNF blockers, including ENBREL, has been associated with reactivation of hepatitis B virus (HBV) in chronic carriers of this virus. The majority of these reports occurred in patients on concomitant immunosuppressive agents, which may also contribute to HBV reactivation. Exercise caution when considering ENBREL in patients identified as carriers of HBV.

ALLERGIC REACTIONS
Allergic reactions have been reported in < 2% of patients in clinical trials of ENBREL.

IMMUNIZATIONS
Live vaccines should not be administered to patients on ENBREL. JIA patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, consider temporary discontinuation of ENBREL and prophylactic treatment with Varicella Zoster Immune Globulin.

AUTOIMMUNITY
Autoantibodies may develop with ENBREL, and rarely lupus-like syndrome or autoimmune hepatitis may occur. These may resolve upon withdrawal of ENBREL. Stop ENBREL if lupus-like syndrome or autoimmune hepatitis develops.

WEGENER'S GRANULOMATOSIS PATIENTS
The use of ENBREL in patients with Wegener's granulomatosis receiving immunosuppressive agents (e.g., cyclophosphamide) is not recommended.

MODERATE TO SEVERE ALCOHOLIC HEPATITIS
Based on a study of patients treated for alcoholic hepatitis, exercise caution when using ENBREL in patients with moderate to severe alcoholic hepatitis.

ADVERSE EVENTS
The most commonly reported adverse events in RA clinical trials were injection site reaction, infection, and headache. In clinical trials of all other adult indications, adverse events were similar to those reported in RA clinical trials.

In a JIA study, infection, headache, abdominal pain, vomiting, and nausea occurred more frequently than in adult RA patients in placebocontrolled trials. The types of infections reported in JIA patients were generally mild and consistent with those commonly seen in outpatient pediatric populations.

DRUG INTERACTIONS
The use of ENBREL in patients receiving concurrent cyclophosphamide therapy is not recommended. The risk of serious infection may increase with concomitant use of abatacept therapy. Concurrent therapy with ENBREL and anakinra is not recommended. Hypoglycemia has been reported following initiation of ENBREL therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

Prescribing Information

Click here to see prescribing information for EPOGEN^® (Epoetin alfa).

Indication

EPOGEN^® (epoetin alfa) is indicated for the treatment of anemia due to chronic kidney disease (CKD) in patients on dialysis to decrease the need for red blood cell (RBC) transfusion.

Limitations of Use:

• EPOGEN^® has not been shown to improve quality of life, fatigue, or patient well-being.
• EPOGEN^® is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

Important Safety Information

• EPOGEN^® is contraindicated in patients with:
• Uncontrolled hypertension
• Pure red cell aplasia (PRCA) that begins after treatment with EPOGEN^® or other erythropoietin protein drugs
• Serious allergic reactions to EPOGEN^®
• EPOGEN^® from multidose vials contains benzyl alcohol and is contraindicated in neonates, infants, pregnant women, and nursing mothers.
• Use caution in patients with coexistent cardiovascular disease and stroke.
• Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks.
• In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.
• Control hypertension prior to initiating and during treatment with EPOGEN^®.
• EPOGEN^® increases the risk of seizures in patients with CKD. Monitor patients closely for new-onset seizures, premonitory symptoms, or change in seizure frequency.
• For lack or loss of hemoglobin response to EPOGEN^®, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA.
• Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with EPOGEN^®.
• This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration.
• PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which EPOGEN^® is not approved).
• If severe anemia and low reticulocyte count develop during treatment with EPOGEN^®, withhold EPOGEN^® and evaluate patients for neutralizing antibodies to erythropoietin.
• Permanently discontinue EPOGEN^® in patients who develop PRCA following treatment with EPOGEN^® or other erythropoietin protein drugs. Do not switch patients to other ESAs.
• Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with EPOGEN^®. Immediately and permanently discontinue EPOGEN^® if a serious allergic reaction occurs.
• Adverse reactions (≥ 5%) in EPOGEN^® clinical studies in patients with CKD were hypertension, arthralgia, muscle spasm, pyrexia, dizziness, medical device malfunction, vascular occlusion, and upper respiratory tract infection.

Prescribing Information

Click here to see prescribing information for Neulasta^® (pegfilgrastim).

Click here to see patient product information for Neulasta^®.

Indication

Neulasta^® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Neulasta^® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information

Do not administer Neulasta^® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Splenic rupture, including fatal cases, can occur following the administration of Neulasta^®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta^®.

Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta^®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta^® for ARDS. Discontinue Neulasta^® in patients with ARDS.

Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta^®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta^® in patients with serious allergic reactions.

Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta^®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

Bone pain and pain in extremity occurred at a higher incidence in Neulasta^®-treated patients as compared with placebo-treated patients.

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Prescribing Information

Click here to see prescribing information for NEUPOGEN^® (Filgrastim).

Click here to see patient product information for NEUPOGEN^®.

Indication

Febrile Neutropenia: NEUPOGEN^® (Filgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever.

A complete blood count and platelet count should be obtained prior to chemotherapy, and twice a week during NEUPOGEN^® therapy to avoid leukocytosis and to monitor the neutrophil count. Induction or consolidation chemotherapy: NEUPOGEN^® is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid leukemia.

Cancer patients receiving bone marrow transplant: NEUPOGEN^® is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation. It is recommended that complete blood counts (CBCs) and platelet counts be obtained at a minimum of 3 times per week following marrow infusion.

Peripheral blood progenitor cell collection and therapy: NEUPOGEN^® is indicated for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Patients with severe chronic neutropenia (SCN): NEUPOGEN^® is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia. It is essential that serial CBCs with differential and platelet counts, and an evaluation of bone marrow morphology and karyotype be performed prior to initiation of NEUPOGEN^® therapy. The use of NEUPOGEN^® prior to confirmation of SCN may impair diagnostic efforts and may thus impair or delay evaluation and treatment of underlying condition, other than SCN, causing the neutropenia.

Important Safety Information

NEUPOGEN^® is contraindicated in patients with known hypersensitivity to E coli-derived proteins, such as Filgrastim, or any product component.

Allergic reactions, including anaphylaxis, occurred with initial or subsequent treatment. Some reactions occurred on initial exposure. Reactions tended to occur within the first 30 minutes after administration and appeared to occur more frequently in patients receiving NEUPOGEN^® IV. SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED. IF PATIENTS REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN, THEY SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE.

Acute respiratory distress syndrome (ARDS) has been reported. Evaluate patients who develop fever, lung infiltrates, or respiratory distress for ARDS. If patient is diagnosed with ARDS, discontinue and/or withhold NEUPOGEN^® until resolution. Alveolar hemorrhage, manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization, has been reported in healthy donors undergoing peripheral blood progenitor cell mobilization, an unapproved use of NEUPOGEN^®. Hemoptysis resolved with discontinuation of NEUPOGEN^®. The use of NEUPOGEN^® for peripheral blood progenitor cell mobilization in healthy donors is not an approved indication.

Severe sickle cell crises, in some cases resulting in death, have been associated with the use of NEUPOGEN^® in patients with sickle cell disorders.

The safety and efficacy of NEUPOGEN^® in the treatment of neutropenia due to other hematopoietic disorders (eg, myelodysplastic syndrome [MDS]) have not been established. Cytogenetic abnormalities, transformation to MDS, and acute myeloid leukemia (AML) have been observed in patients treated with NEUPOGEN^® for severe chronic neutropenia. The risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. If a patient with severe chronic neutropenia (SCN) develops abnormal cytogenetics or myelodysplasia, the risks and benefits of continuing NEUPOGEN^® should be carefully considered.

NEUPOGEN^® is a growth factor that primarily stimulates neutrophils. However, the possibility that NEUPOGEN^® can act as a growth factor for any tumor type cannot be excluded. Cutaneous vasculitis has been reported in patients treated with NEUPOGEN^®. Most cases were moderate or severe and involved patients with SCN receiving long-term NEUPOGEN^® therapy. Symptoms of vasculitis generally developed simultaneously with an increase in the ANC and abated when the ANC decreased. Many patients were able to continue NEUPOGEN^® at a reduced dose.

In clinical trials of cancer patients receiving myelosuppressive chemotherapy involving NEUPOGEN^®, medullary bone pain was the most frequently reported adverse event attributed to NEUPOGEN^® therapy.

In clinical trials of patients with AML, adverse events reported in ≥ 5% of patients and more frequently in patients receiving NEUPOGEN^® than placebo included: petechiae epistaxis, epistaxis, transfusion reactions, and hemorrhagic events (including severe or fatal hemorrhagic events).

In randomized clinical trials of cancer patients receiving bone marrow transplant, the following adverse events were reported in ≥ 5% of patients and more frequently in patients treated with NEUPOGEN^® than in controls included: nausea, vomiting, hypertension, rash, and peritonitis. In clinical trials of cancer patients undergoing peripheral blood progenitor cell collection and therapy, adverse events reported in ≥5% of patients and related to NEUPOGEN^® consisted primarily of mild-to-moderate musculoskeletal symptoms. These symptoms were predominantly events of medullary bone pain. Other reported events included headache and transient increases in alkaline phosphatase (reported in patients who had serum chemistries measured), mild to moderate anemia, and decreased platelet counts.

In clinical trials of patients with severe chronic neutropenia, the following were reported in ≥ 5% of patients: mild-to-moderate bone pain, palpable splenomegaly, epistaxis, anemia, and thrombocytopenia.

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Prescribing Information

Click here to see prescribing information for Nplate^® (romiplostim).

Indication

Nplate^® is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Nplate^® is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP. Nplate^® should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. Nplate^® should not be used in an attempt to normalize platelet counts.

Important Safety Information

Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous Leukemia

• In Nplate^® clinical trials of patients with myelodysplastic syndromes (MDS) and severe thrombocytopenia, progression from MDS to acute myelogenous leukemia (AML) has been observed.
• Nplate^® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.

Thrombotic/Thromboembolic Complications

• Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate^® use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate^®. Nplate^® should be used with caution in patients with ITP and chronic liver disease. 
• To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate^® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 x 109/L.

Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis

• Nplate^® administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Nplate^®.
• In a clinical study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate^® therapy. Clinical studies are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias.
• If new or worsening morphological abnormalities or cytopenia(s) occur, consider a bone marrow biopsy to include staining for fibrosis.

Worsened Thrombocytopenia after Cessation of Nplate®

• In clinical studies of patients with chronic ITP who had Nplate^® discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate^® therapy.  This worsened thrombocytopenia resolved within 14 days. 
• Following discontinuation of Nplate^®, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines.

Lack or Loss of Response to Nplate^®

• Hyporesponsiveness or failure to maintain a platelet response with Nplate^® should prompt a search for causative factors, including neutralizing antibodies to Nplate^®. 
• To detect antibody formation, submit blood samples to Amgen (1-800-772-6436).  Amgen will assay these samples for antibodies to Nplate^® and thrombopoietin (TPO). 
• Discontinue Nplate^® if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.

Laboratory Monitoring

• Obtain CBCs, including platelet counts, weekly during the dose adjustment phase of Nplate^® therapy and then monthly following establishment of a stable Nplate^® dose.
• Obtain CBCs, including platelet counts, weekly for at least two weeks following discontinuation of Nplate^®.

Adverse Reactions

• In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate® and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. 

• Most common adverse reactions (≥ 5% higher patient incidence in Nplate^® versus placebo) were Arthralgia (26%, 20%), Dizziness (17%, 0%), Insomnia (16%, 7%), Myalgia (14%, 2%), Pain in Extremity (13%, 5%) , Abdominal Pain (11%, 0%), Shoulder Pain (8%, 0%), Dyspepsia (7%, 0%), and Paresthesia (6%, 0%).

Prescribing Information

Click here to see prescribing information for Prolia^® (denosumab).

Indication

Prolia^® is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Prolia^® reduces the incidence of vertebral, nonvertebral, and hip fractures.

Prolia^® is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen-deprivation therapy for nonmetastatic prostate cancer. In these patients Prolia^® also reduced the incidence of vertebral fractures.

Important Safety Information

• Hypocalcemia: Prolia^® is contraindicated in patients with hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating Prolia^®. Hypocalcemia may worsen, especially in patients with severe renal impairment. In patients predisposed to hypocalcemia and disturbances of mineral metabolism, clinical monitoring of calcium and mineral levels is highly recommended. Adequately supplement all patients with calcium and vitamin D.
• Same Active Ingredient: Prolia^® contains the same active ingredient (denosumab) found in XGEVA^®. Patients receiving Prolia^® should not receive XGEVA^®.
• Serious Infections: In a clinical trial (N = 7808), serious infections leading to hospitalization were reported more frequently in the Prolia^® group than in the placebo group. Serious skin infections, as well as infections of the abdomen, urinary tract and ear, were more frequent in patients treated with Prolia^®.

	Prolia® (N = 3886)1,2	Placebo (N = 3876)1,2
Abdomen:	36 (0.9%)	28 (0.7%)
Urinary tract:	29 (0.7%)	20 (0.5%)
Skin:	15 (0.4%)	3 (< 0.1%)
Ear:	5 (0.1%)	0 (0.0%)

Endocarditis was also reported more frequently in Prolia^®-treated subjects. The incidence of opportunistic infections was balanced and the overall incidence of infections was similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis.

Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. In patients who develop serious infections while on Prolia^®, prescribers should assess the need for continued Prolia^® therapy.

• Dermatologic Adverse Reactions: Epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at a significantly higher rate in the Prolia^® group compared to the placebo group. Most of these events were not specific to the injection site. Consider discontinuing Prolia^® if severe symptoms develop.

	Prolia® (N = 3886)1,2	Placebo (N = 3876)1,2
Rash:	96 (2.5%)	79 (2.0%)
Eczema:	50 (1.3%)	25 (0.6%)
Dermatitis:	22 (0.6%)	14 (0.4%)

• Osteonecrosis of the Jaw (ONJ): ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients receiving Prolia^®. An oral exam should be performed by the prescriber prior to initiation of Prolia^®. A dental examination with appropriate preventive dentistry should be considered prior to treatment in patients with risk factors for ONJ. Good oral hygiene practices should be maintained during treatment with Prolia^®.
  
  For patients requiring invasive dental procedures, clinical judgment should guide the management plan of each patient. Patients who are suspected of having or who develop ONJ should receive care by a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Prolia^® should be considered based on individual benefit-risk assessment.
• Suppression of Bone Turnover: Prolia^® resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effect of long-term treatment are unknown. Monitor patients for consequences, including ONJ, atypical fractures, and delayed fracture healing.
• Adverse Reactions: The most common adverse reactions (> 5% and more common than placebo) are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.

	Prolia® (N = 3886)1	Placebo (N = 3876)1
Back pain:	1347 (34.7%)	1340 (34.6%)
Pain in extremity:	453 (11.7%)	430 (11.1%)
Musculoskeletal pain:	297 (7.6%)	291 (7.5%)
Hypercholesterolemia:	280 (7.2%)	236 (6.1%)
Cystitis:	228 (5.9%)	225 (5.8%)

Pancreatitis has been reported with Prolia^®. The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the Prolia^® groups. A causal relationship to drug exposure has not been established. Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity.

• Prolia^® Postmarketing Active Safety Surveillance Program: The Prolia^® Postmarketing Active Safety Surveillance Program is available to collect information from prescribers on specific adverse events. Please see www.proliasafety.com or call 1-800-772-6436 for more information about this program.

Prescribing Information

Click here to see prescribing information for Sensipar^® (cinacalcet).

Indication

Sensipar^® is indicated for the treatment of secondary hyperparathyroidism (HPT) in patients with chronic kidney disease on dialysis.

Sensipar^® is indicated for the treatment of severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy.

Important Safety Information

Sensipar^® treatment should not be initiated if serum calcium is less than the lower limit of the normal range (8.4 mg/dL).

Sensipar^® lowers serum calcium; therefore, it is important that patients are carefully monitored for the occurrence of hypocalcemia.

Significant reductions in calcium may lower the threshold for seizures. Secondary hyperparathyroidism (HPT) patients, particularly those with a history of seizure disorder, should be carefully monitored for the occurrence of low serum calcium or symptoms of hypocalcemia.

In Sensipar^® postmarketing use, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia were reported in patients with impaired cardiac function. The causal relationship to Sensipar^® therapy could not be completely excluded and may be mediated by reductions in serum calcium levels.

Adynamic bone disease may develop if intact parathyroid hormone (iPTH) levels are suppressed below 100 pg/mL

Patients with moderate to severe hepatic impairment should be monitored throughout treatment with Sensipar^®, as cinacalcet exposure assessed by area under the curve (AUC) was higher than in patients with normal hepatic function.

Serum calcium and serum phosphorus should be measured within 1 week and PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar^®. Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and PTH every 1 to 3 months.

The most commonly reported side effects were nausea, vomiting, and diarrhea.

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Prescribing Information

Click here to see prescribing information for Vectibix^® (panitumumab).

Indication

Vectibix^® (panitumumab) is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix^® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix^®.

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix^® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix^® is not recommended for the treatment of colorectal cancer with these mutations.

Important Safety Information, including Boxed WARNINGS.

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix^®. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold or discontinue Vectibix^® for severe or life-threatening dermatologic toxicity and monitor for inflammatory or infectious sequelae.

Terminate the infusion for severe infusion reactions

Vectibix^® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, the addition of Vectibix^® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Vectibix^® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix^® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix^®.

In a single-arm study of 19 patients receiving Vectibix^® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix^® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix^®. Patients with a history or evidence of interstitial pneumonitis, pulmonary fibrosis, were excluded from most clinical trials. Therefore, the estimated risk in a general population that includes such patients is uncertain. Cases of interstitial lung disease (ILD), including fatalities, have been reported in patients treated with Vectibix^®. Interrupt Vectibix^® therapy for the acute onset or worsening of pulmonary symptoms. Discontinue Vectibix^® therapy if ILD is confirmed.

In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix^® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix^®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients' electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix^® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed.

Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix^® and for 2 months after the last dose.

Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix for acute or worsening keratitis.

Adequate contraception in both males and females must be used while receiving Vectibix^® and for 6 months after the last dose of Vectibix^® therapy. Vectibix^® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women.

Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix^®.

The most common adverse events of Vectibix^® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix^® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

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Product Information

Click here to see prescribing information for XGEVA^®. (denosumab)

Indication

XGEVA^® (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

XGEVA^® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Important Safety Information

• Hypocalcemia:
  XGEVA^® can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to XGEVA^® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA^® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.
  
  Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.
   
• Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA^®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.
  
  Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA^® and periodically during XGEVA^® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA^®. Patients who are suspected of having or who develop ONJ while on XGEVA^® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Adverse Reactions:

The most common adverse reactions in patients receiving XGEVA^® were fatigue/asthenia, hypophosphatemia, and nausea.

The most common serious adverse reaction in patients receiving XGEVA^® was dyspnea.

The most common adverse reactions resulting in discontinuation of XGEVA^® were osteonecrosis and hypocalcemia.

Please see accompanying Prescribing Information.