INTRODUCTION
REMICADE® (infliximab)
PROCRIT® (Epoetin alfa)
DOXIL® (doxorubicin HCl liposome injection)
SIMPONI® (golimumab)
STELARA® (ustekinumab)
ZYTIGA® (abiraterone acetate)
XARELTO® (rivaroxaban tablets)
REMICADE® (infliximab)
Indications for REMICADE® (infliximab)
Crohn's Disease
REMICADE® is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.
REMICADE® is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn's disease.
Pediatric Crohn's Disease
REMICADE® is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.
Ulcerative Colitis
REMICADE® is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
Pediatric Ulcerative Colitis
REMICADE® is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis
REMICADE®, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
Ankylosing Spondylitis
REMICADE® is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
Psoriatic Arthritis
REMICADE® is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
Plaque Psoriasis
REMICADE® is indicated for the treatment of adult patients with chronic severe (ie, extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE® should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.
Important Safety Information for REMICADE® (infliximab)
SERIOUS INFECTIONS
Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®.1, 2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.
Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including REMICADE®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE® cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6‑mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.
In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn's disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).
CONTRAINDICATIONS
REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.
HEPATITIS B REACTIVATION
TNF inhibitors, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating REMICADE®. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.
HEPATOTOXICITY
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, > 5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.
HEMATOLOGIC EVENTS
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.
HYPERSENSITIVITY
REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.
NEUROLOGIC EVENTS
TNF inhibitors, including REMICADE®, have been associated in rare cases with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering REMICADE® in patients with these disorders and consider discontinuation if these disorders develop.
AUTOIMMUNITY
Treatment with REMICADE® may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.ADVERSE REACTIONS
In clinical trials, the most common REMICADE® adverse reactions occurring in > 10% of patients included infections (eg, upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.USE WITH OTHER DRUGS
The use of REMICADE® in combination with anakinra, abatacept or tocilizumab is not recommended. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.VACCINATIONS
Live vaccines should not be given with REMICADE®. Bring pediatric patients up to date with all vaccinations prior to initiating REMICADE®. Exercise caution in the administration of live vaccines to infants born to female patients treated with REMICADE® during pregnancy.Please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.
| References: | 1. | American Thoracic Society, Centers for Disease Control and Prevention. "Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection." Am J Respir Crit Care Med. 2000;161:S221-S247. |  |
| 2. | See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients. |
PROCRIT® (Epoetin alfa)
Indications for PROCRIT® (Epoetin alfa)
Anemia Due to Chronic Kidney Disease
PROCRIT® is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and not on dialysis to decrease the need for red blood cell (RBC) transfusion.
Anemia Due to Zidovudine in HIV-infected Patients
PROCRIT® is indicated for the treatment of anemia due to zidovudine administered at < 4200 mg/week in HIV-infected patients with endogenous serum erythropoietin levels of < 500 mUnits/mL.
Anemia Due to Chemotherapy in Patients With Cancer
PROCRIT® is indicated for the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.
PROCRIT® is indicated to reduce the need for allogeneic RBC transfusions among patients with perioperative hemoglobin > 10 to < 13 g/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery. PROCRIT® is not indicated for patients who are willing to donate autologous blood pre‑operatively.
PROCRIT® has not been shown to improve quality of life, fatigue, or patient well-being.
PROCRIT® is not indicated for use:
- In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
- In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
- In patients scheduled for surgery who are willing to donate autologous blood.
- In patients undergoing cardiac or vascular surgery.
- As a substitute for RBC transfusions in patients who require immediate correction of anemia.
Important Safety Information for PROCRIT® (Epoetin alfa)
WARNINGS: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCEChronic Kidney Disease:
Cancer:
Perisurgery:
(See WARNINGS AND PRECAUTIONS: Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism, WARNINGS AND PRECAUTIONS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION.) |
Contraindications
PROCRIT® is contraindicated in patients with:
- Uncontrolled hypertension
- Pure red cell aplasia (PRCA) that begins after treatment with PROCRIT® or other erythropoietin protein drugs
- Serious allergic reactions to PROCRIT®
PROCRIT® from multidose vials contains benzyl alcohol and is contraindicated in:
- Neonates, infants, pregnant women, and nursing mothers. When therapy with PROCRIT® is needed in neonates and infants, use single-dose vials; do not admix with bacteriostatic saline containing benzyl alcohol.
Additional Important Safety Information
Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism- In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13-14 g/dL) to lower targets (9-11.3 g/dL), PROCRIT® and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
- Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. 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 greater than 1 g/dL over 2 weeks may contribute to these risks.
- In controlled clinical trials of patients with cancer, PROCRIT® and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
- 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.
Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer
- ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival. These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy, in patients receiving chemotherapy for metastatic breast cancer or lymphoid malignancy, and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy.
Hypertension
- PROCRIT® is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of PROCRIT®, approximately 25% of patients on dialysis required initiation of or increases in antihypertensive therapy; hypertensive encephalopathy and seizures have been reported in patients with CKD receiving PROCRIT®.
- Appropriately control hypertension prior to initiation of and during treatment with PROCRIT®. Reduce or withhold PROCRIT® if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.
Seizures
- PROCRIT® increases the risk of seizures in patients with CKD. During the first several months following initiation of PROCRIT®, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their health care practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.
Lack or Loss of Hemoglobin Response to PROCRIT®
- For lack or loss of hemoglobin response to PROCRIT®, initiate a search for causative factors (eg, iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to PROCRIT® therapy.
Pure Red Cell Aplasia
- 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 PROCRIT®. 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 PROCRIT® is not approved).
- If severe anemia and low reticulocyte count develop during treatment with PROCRIT®, withhold PROCRIT® and evaluate patients for neutralizing antibodies to erythropoietin. Contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) to perform assays for binding and neutralizing antibodies. Permanently discontinue PROCRIT® in patients who develop PRCA following treatment with PROCRIT® or other erythropoietin protein drugs. Do not switch patients to other ESAs.
Serious Allergic Reactions
- Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with PROCRIT®. Immediately and permanently discontinue PROCRIT® and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.
Laboratory Monitoring
- Evaluate transferrin saturation and serum ferritin prior to and during PROCRIT® treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.
PROCRIT® is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.
Anemia in Patients with Chronic Kidney Disease Not on Dialysis
- Consider initiating PROCRIT® treatment only when the hemoglobin level is less than 10 g/dL and:
- The patient's rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and
- Reducing the risk of alloimmunization and/or other RBC transfusion related risks is a goal.
- If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of PROCRIT®, and use the lowest dose of PROCRIT® sufficient to reduce the need for RBC transfusions.
- When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
- Do not increase the dose more frequently than once every 4 weeks. Decreases in doses can occur more frequently. Avoid frequent dose adjustments.
- If the hemoglobin rises rapidly (eg, more than 1 g/dL in any 2-week period), reduce the dose of PROCRIT® by 25% or more as needed to reduce rapid responses.
- For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
- For patients who do not respond adequately over a 12-week escalation period, increasing the PROCRIT® dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue PROCRIT® if responsiveness does not improve.
- Adverse reactions in > 5% of PROCRIT®-treated patients in clinical studies were hypertension and arthralgia.
Chemotherapy-Induced Anemia
- PROCRIT® is not indicated for use in patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
- PROCRIT® is not indicated for use in patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
- Initiate PROCRIT® in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
- Use the lowest dose of PROCRIT® necessary to avoid RBC transfusions.
- Reduce dose by 25% if:
- Hemoglobin increases greater than 1 g/dL in any 2-week period or
- Hemoglobin reaches a level needed to avoid RBC transfusion.
- Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.
- Adverse reactions in > 5% of PROCRIT®-treated patients in clinical studies were nausea, vomiting, myalgia, arthralgia, stomatitis, cough, weight decrease, leukopenia, bone pain, rash, hyperglycemia, insomnia, headache, depression, dysphagia, hypokalemia, and thrombosis.
Surgery/Perisurgery
- PROCRIT® is not indicated for use in patients scheduled for surgery who are willing to donate autologous blood.
- PROCRIT® is not indicated for use in patients undergoing cardiac or vascular surgery.
- Deep venous thrombosis prophylaxis is recommended during PROCRIT® therapy.
- Adverse reactions in > 5% of PROCRIT®-treated patients in clinical studies were nausea, vomiting, pruritus, headache, injection site pain, chills, deep vein thrombosis, cough, and hypertension.
Anemia in Zidovudine-treated HIV-infected Patients
- Withhold PROCRIT® if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.
- Discontinue PROCRIT® if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
- Adverse reactions in > 5% of PROCRIT®-treated patients in clinical studies were pyrexia, cough, rash, and injection site irritation.
Please see accompanying full Prescribing Information, including Boxed WARNINGS.
Medication Guide for PROCRIT®
Provide the Medication Guide to your patients and encourage discussion.
Patient Instructions for Use
Instructions if the patient or caregiver has been trained to give PROCRIT® injections at home.
DOXIL® (doxorubicin HCl liposome injection)
Indications for DOXIL® (doxorubicin HCl liposome injection)
- DOXIL® (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after prior platinum-based therapy
- DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE® and have received at least one prior therapy
Important Safety Information for DOXIL® (doxorubicin HCl liposome injection)
BOXED WARNINGS:
Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution
-
The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2
- Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose
- Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy
-
Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate
- Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use
- The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions
- Severe myelosuppression may occur
- DOXIL® dosage should be reduced in patients with impaired hepatic function
- Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis.
Contraindications
- Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL®
- Nursing mothers
Additional Safety Information
-
Cardiac function should be carefully monitored
- Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy
- For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury
- In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE® for Injection arm and 42 patients (13%) in the VELCADE® plus DOXIL® arm experienced left ventricular ejection fraction decrease (defined as absolute decrease > 15% over baseline or a > 5% decrease below institutional lower limit of normal)
-
Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL®
- In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL®
- In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE®
- Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage
- Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death
- DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow
-
Hand-foot syndrome (HFS) may occur during therapy with DOXIL®
- Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required
-
HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier
- The reaction was mild in most patients, resolving in 1 to 2 weeks
- The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy
- DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation
- DOXIL® can cause fetal harm when used during pregnancy
- Recall reaction has occurred with DOXIL® administration after radiotherapy
- DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl
- In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) > 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%)
- In addition, 19% vs 52.3% reported alopecia (all grades)
- Grade 3/4 hematologic ARs reported in > 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%)
-
In patients with multiple myeloma, the most common all-grade ARs > 20% (VELCADE® plus DOXIL® vs VELCADE®, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%)
- In addition, 19% vs < 1% reported HFS
Please click here for DOXIL® full Prescribing Information, including Boxed WARNINGS.
SIMPONI® (golimumab)
Indications for SIMPONI® (golimumab)
SIMPONI® is a tumor necrosis factor (TNF) blocker indicated for the treatment of:
- Moderately to severely active Rheumatoid Arthritis (RA) in adults, in combination with methotrexate
- Active Psoriatic Arthritis (PsA) in adults, alone or in combination with methotrexate
- Active Ankylosing Spondylitis (AS) in adults
Important Safety Information for SIMPONI® (golimumab)
SERIOUS INFECTIONS
Patients treated with SIMPONI® (golimumab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI® if a patient develops a serious infection.
Reported infections with TNF blockers, of which SIMPONI® is a member, include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before SIMPONI® use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI® use.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with SIMPONI® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Do not start SIMPONI® in patients with clinically important active infections, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
Risk of infection may be higher in patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. Other serious infections observed in patients treated with SIMPONI® included sepsis, pneumonia, cellulitis, abscess and hepatitis B infection.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers of which SIMPONI® is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children or adolescents. Malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.
In the controlled portions of clinical trials of all TNF‑blocking agents including SIMPONI®, more cases of lymphoma have been observed among patients receiving TNF‑blocking treatment compared with control patients. In clinical trials, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI® group compared with an incidence of 0 (95% CI: 0, 0.96) in the placebo group. In clinical trials, the incidence of malignancies other than lymphoma was not increased with exposure to SIMPONI® and was similar to what would be expected in the general population. Cases of acute and chronic leukemia have been reported with postmarketing TNF‑blocker use. The risks and benefits of TNF‑blocker therapy should be considered prior to initiating therapy in patients with a known malignancy or who develop a malignancy.
HEPATITIS B REACTIVATION
The use of TNF‑blocking agents including SIMPONI® has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in conjunction with TNF‑blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.
All patients should be tested for HBV infection before initiating TNF‑blocker therapy. For patients who test positive for hepatitis B surface antigen, consult a physician with expertise in the treatment of hepatitis B before initiating TNF‑blocker therapy. Exercise caution when prescribing SIMPONI® for patients identified as carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with SIMPONI®. Discontinue SIMPONI® in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI®, and monitor patients closely.
HEART FAILURE
Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported. Exercise caution and monitor patients with heart failure. Discontinue SIMPONI® if new or worsening symptoms of heart failure appear.
DEMYELINATING DISORDERS
TNF‑blocking agents, of which SIMPONI® is a member, have been associated with rare cases of new-onset or exacerbation of demyelinating disorders, including multiple sclerosis (MS) and Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported with SIMPONI®. Exercise caution in considering the use of SIMPONI® in patients with these disorders. Consider discontinuation if these disorders develop.
HEMATOLOGIC CYTOPENIAS
There have been reports of pancytopenia, leukopenia, neutropenia, and thrombocytopenia in patients receiving SIMPONI® in clinical trials. Additionally, aplastic anemia has been reported in patients receiving TNF‑blocking agents, of which SIMPONI® is a member. Exercise caution when using SIMPONI® in patients who have or had significant cytopenias.
USE WITH OTHER DRUGS
The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections, therefore the use of SIMPONI® in combination with these products is not recommended. Care should be taken when switching from one biologic to another since overlapping biological activity may further increase the risk of infection. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker.
VACCINATIONS
People receiving SIMPONI® can receive vaccinations, except for live vaccines. Administration of live vaccines to infants exposed to SIMPONI® in utero is not recommended for 6 months following the mother's last SIMPONI® injection during pregnancy due to an increased risk of infection.
HYPERSENSITIVITY REACTIONS
Serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported with SIMPONI®, some occurring after the first dose. If an anaphylactic or other serious allergic reaction occurs, discontinue SIMPONI® immediately and institute appropriate therapy.
ADVERSE REACTIONS
The most serious adverse reactions were serious infections and malignancies.
Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 trials through Week 16, occurring in 7% and 6% of patients treated with SIMPONI® as compared with 6% and 5% of patients in the control group, respectively. The rate of injection-site reactions was 6% with patients treated with SIMPONI® compared with 2% of patients in the control group.
Please see accompanying full Prescribing Information and Medication Guide for SIMPONI®. Provide the Medication Guide to your patients and encourage discussion.
STELARA® (ustekinumab)
Indication for STELARA® (ustekinumab)
STELARA® is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Important Safety Information for STELARA® (ustekinumab)
Infections
STELARA® (ustekinumab) may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were reported. Infections requiring hospitalization included cellulitis, diverticulitis, osteomyelitis, gastroenteritis, pneumonia, and urinary tract infections. STELARA® should not be given to patients with a clinically important active infection and should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering use of STELARA® in patients with a chronic infection or a history of recurrent infection.
Theoretical Risk for Vulnerability to Particular Infections
Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacterium, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® will be susceptible to these types of infections. Consider appropriate diagnostic testing as dictated by clinical circumstances.
Pre-Treatment Evaluation of Tuberculosis (TB)
Evaluate patients for TB prior to initiating treatment with STELARA®. STELARA® should not be given to patients with active TB. Initiate treatment of latent TB before administering STELARA®. Patients should be monitored closely for signs and symptoms of active TB during and after treatment with STELARA®.
Malignancies
STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA® in clinical studies. The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy.
Hypersensitivity Reactions
Serious allergic reactions, including angioedema and possible anaphylaxis, have been reported. Discontinue STELARA® and institute appropriate therapy if an anaphylactic or other serious allergic reaction occurs.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
One case of RPLS has been reported in a STELARA®-treated patient. If RPLS is suspected, discontinue STELARA® and administer appropriate treatment.
RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. RPLS has been associated with fatal outcomes.
Immunizations
Prior to initiating therapy with STELARA®, patients should receive all immunizations recommended by current guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA®. Exercise caution when administering live vaccines to household contacts of STELARA® patients, as shedding and subsequent transmission to STELARA® patients may occur. Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.
Concomitant Therapies
The safety of STELARA® in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone. The relevance of these findings in mouse models for malignancy risk in humans is unknown.
Theoretical Risk of Immunotherapy
STELARA® may decrease the protective effect of allergy immunotherapy and may increase the risk of allergic reaction to allergen immunotherapy. Exercise caution in patients receiving or who have received allergy immunotherapy, particularly for anaphylaxis.
Most Common Adverse Reactions
The most common adverse reactions (> 3% and higher than that with placebo) in clinical trials for STELARA® 45 mg, STELARA® 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively.
Please click here to read full Prescribing Information and Medication Guide for STELARA®.
ZYTIGA® (abiraterone acetate)
Indication for ZYTIGA® (abiraterone acetate)
ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.
Important Safety Information for ZYTIGA® (abiraterone acetate)
Contraindications
ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess
Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.
Adrenocortical Insufficiency (AI)
AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.
Hepatotoxicity
Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the UNL, interrupt ZYTIGA® treatment and closely monitor liver function.
Food Effect
ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0‑∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.
Adverse Reactions
The most common adverse reactions (> 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.
Drug Interactions
ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.
Use in Specific Populations
The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.
Please see accompanying full Prescribing Information for ZYTIGA®.
XARELTO® (rivaroxaban tablets)
Indications for XARELTO® (rivaroxaban)
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.
Prophylaxis of Deep Vein Thrombosis
XARELTO® (rivaroxaban) is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery.
Important Safety Information for XARELTO® (rivaroxaban)
WARNINGS: (A) DISCONTINUING XARELTO® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMAA. DISCONTINUING XARELTO® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION B. SPINAL/EPIDURAL HEMATOMA
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. |
CONTRAINDICATIONS
- Active pathological bleeding
- Severe hypersensitivity reaction to XARELTO®
WARNINGS AND PRECAUTIONS
- Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.
- Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage.
- A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.
- Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.
- Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.
- Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.
An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs. - Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C
- Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®.
DOSING AND ADMINISTRATION
- Nonvalvular Atrial Fibrillation: For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO® is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal.
- Prophylaxis of Deep Vein Thrombosis: The recommended dose of XARELTO® is 10 mg taken orally once daily with or without food. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established.
- For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.
- For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.
- Missed Dose: If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day.
- Instructions for Patient Use
- Remind patients to not discontinue XARELTO® without first talking to their healthcare professional to minimize the risk of post-discontinuation thrombotic events.
- Advise patients with atrial fibrillation to take XARELTO® once daily with the evening meal.
DRUG INTERACTIONS
- Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.
- Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John's wort) due to decreases in rivaroxaban exposure that may decrease efficacy.
- NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.
- Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.
- Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk (eg, amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, azithromycin, chloramphenicol, and cimetidine).
- Prophylaxis of Deep Vein Thrombosis
- Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: When clinical data suggest a change in exposure is unlikely to affect bleeding risk (eg, clarithromycin, erythromycin), no precautions are necessary during coadministration with drugs that are P-gp and CYP3A4 inhibitors.
- Anticoagulants: Avoid concurrent use of XARELTO® with other anticoagulants due to the increased bleeding risk. Promptly evaluate any signs or symptoms of blood loss.
USE IN SPECIFIC POPULATIONS
- Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother.
- Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.
- Renal Impairment
- Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.
- Nonvalvular Atrial Fibrillation: For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.
- Prophylaxis of Deep Vein Thrombosis: Avoid use in severe renal impairment (CrCl <30 mL/min) due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with moderate renal impairment (CrCl 30 mL/min to 50 mL/min). Patients who develop acute renal failure while on XARELTO® should discontinue treatment.
- Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.
OVERDOSAGE
- Overdose of XARELTO® may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.
ADVERSE REACTIONS IN CLINICAL STUDIES
- Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications.
- Nonvalvular Atrial Fibrillation: The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarin-treated patients, respectively, major bleeding events were 5.6% versus 5.4%.
- Prophylaxis of Deep Vein Thrombosis: In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO®. In XARELTO®- versus enoxaparin-treated patients, respectively, major bleeding event rates reported in hip surgery studies were 0.2% versus 0.1% and any bleeding events were 6.1% versus 5.8%; major bleeding events reported in the knee surgery study were 0.6% versus 0.5% and any bleeding events were 5.0% versus 4.9%. Other adverse drug reactions included wound secretion (2.8% vs 2.0%) and syncope (1.2% vs 0.7%) in XARELTO®- versus enoxaparin-treated patients, respectively.
- Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.
Please click here to see full Prescribing Information, including Boxed WARNINGS; or visit www.XARELTOhcp.com.
