Sorry, you need to enable JavaScript to visit this website.

Biosimilars

Biosimilars
Biosimilars are highly similar versions of approved and authorized biological medicines.

Biosimilars Medications

Please select a product from the list to view its approved indications as well as the link to its full prescribing information. The list is not an all-inclusive list of Pfizer medications in a therapeutic area and inclusion of a product within this list should not suggest it is approved for a broad therapeutic area. Please refer to each medication’s individual prescribing information for specific details.
INFLECTRA

INFLECTRA® (infliximab-dyyb)

These highlights do not include all the information needed to use INFLECTRA safety and effectively. See full prescribing information for INFLECTRA.

WARNING: SERIOUS INFECTIONS and MALIGNANCY

SERIOUS INFECTIONS

Patients treated with infliximab products are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

INFLECTRA should be discontinued if a patient develops a serious infection or sepsis.

Reported infections include:

  • Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before INFLECTRA use and during therapy.1,2 Treatment for latent infection should be initiated prior to INFLECTRA 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. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. 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 INFLECTRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with INFLECTRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCY

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including infliximab products [see Warnings and Precautions (5.2)].

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including infliximab products. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and most were in adolescent and young adult males.

4 CONTRAINDICATIONS

INFLECTRA at doses >5 mg/kg should not be administered to patients with moderate to severe heart failure. In a randomized study evaluating infliximab in patients with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV), infliximab treatment at 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening heart failure [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

INFLECTRA should not be readministered to patients who have experienced a severe hypersensitivity reaction to infliximab products. Additionally, INFLECTRA should not be administered to patients with known hypersensitivity to inactive components of the product or to any murine proteins.

5 WARNINGS AND PRECAUTIONS

5.1 Serious Infections

Patients treated with infliximab products are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.

Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.

Treatment with INFLECTRA should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with comorbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:

  • with chronic or recurrent infection;
  • who have been exposed to tuberculosis;
  • with a history of an opportunistic infection;
  • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
  • with underlying conditions that may predispose them to infection.

Tuberculosis

Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving infliximab products, including patients who have previously received treatment for latent or active tuberculosis. Cases of active tuberculosis have also occurred in patients being treated with infliximab products during treatment for latent tuberculosis.

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating INFLECTRA and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating INFLECTRA, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).

Anti-tuberculosis therapy should also be considered prior to initiation of INFLECTRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Tuberculosis should be strongly considered in patients who develop a new infection during INFLECTRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

Monitoring

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with INFLECTRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with INFLECTRA.

INFLECTRA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with INFLECTRA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.

Invasive Fungal Infections

For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

5.2 Malignancies

Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF blocking agents (initiation of therapy ≤18 years of age), including infliximab products. 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 (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.

Lymphomas

In the controlled portions of clinical trials of all the TNF blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of infliximab clinical trials, 5 patients developed lymphomas among 5707 patients treated with infliximab (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately three-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately four-fold higher than expected in the general population. Patients with Crohn's disease, rheumatoid arthritis or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Hepatosplenic T-cell Lymphoma (HSTCL)

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab products. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF blockers or TNF blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use INFLECTRA alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with infliximab product monotherapy from the clinical trial data from studies with infliximab [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].

Skin Cancer

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab products [see Adverse Reactions (6.2)]. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Cervical Cancer

A population-based retrospective cohort study using data from Swedish national health registries found a 2 to 3 fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between infliximab products and cervical cancer cannot be excluded. Periodic screening should continue in women treated with infliximab products [see Adverse Reactions (6.2)].

Other Malignancies

In the controlled portions of clinical trials of some TNF blocking agents, including infliximab products, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF blockers compared with control patients. During the controlled portions of trials with infliximab, in patients with moderately to severely active rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 infliximab-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among infliximab-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for infliximab-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of malignancies among infliximab-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected.

In a clinical trial exploring the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking [see Adverse Reactions (6.1)]. Prescribers should exercise caution when considering the use of INFLECTRA in patients with moderate to severe COPD.

Psoriasis patients should be monitored for NMSCs, particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for infliximab, NMSCs were more common in patients with previous phototherapy [see Adverse Reactions (6.1)].

The potential role of TNF blocking therapy in the development of malignancies is not known [see Adverse Reactions (6.1)]. Rates in clinical trials for infliximab cannot be compared to rates in clinical trials of other TNF blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering INFLECTRA treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving INFLECTRA.

5.3 Hepatitis B Virus Reactivation

Use of TNF blockers, including infliximab products, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients should be tested for HBV infection before initiating TNF blocker therapy, including INFLECTRA. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF blockers should be stopped and anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely.

5.4 Hepatotoxicity

Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported rarely in postmarketing data in patients receiving infliximab products. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of infliximab; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥5 times the upper limit of normal) develop, INFLECTRA should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximab products without progression to severe hepatic injury [see Adverse Reactions (6.1)].

5.5 Patients with Heart Failure

Infliximab products have been associated with adverse outcomes in patients with heart failure, and INFLECTRA should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been rare postmarketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. If a decision is made to administer INFLECTRA to patients with heart failure, they should be closely monitored during therapy, and INFLECTRA should be discontinued if new or worsening symptoms of heart failure appear [see Contraindications (4) and Adverse Reactions (6.1)].

5.6 Hematologic Reactions

Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving infliximab products. The causal relationship to infliximab therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with INFLECTRA who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on INFLECTRA. Discontinuation of INFLECTRA therapy should be considered in patients who develop significant hematologic abnormalities.

5.7 Hypersensitivity

Infliximab products have been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include anaphylaxis, urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of infusion. However, in some cases, serum sickness-like reactions have been observed in patients after initial therapy with infliximab products (i.e., as early as after the second dose), and when therapy with infliximab products was reinstituted following an extended period without treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with a marked increase in antibodies to infliximab product, loss of detectable serum concentrations of infliximab products, and possible loss of drug efficacy.

INFLECTRA should be discontinued for severe hypersensitivity reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction [see Adverse Reactions (6.1)].

In rheumatoid arthritis, Crohn's disease and psoriasis clinical trials, readministration of infliximab after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment [see Adverse Reactions (6.1)]. In general, the benefit-risk of readministration of INFLECTRA after a period of no-treatment, especially as a reinduction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where INFLECTRA maintenance therapy for psoriasis is interrupted, INFLECTRA should be reinitiated as a single dose followed by maintenance therapy.

5.8 Cardiovascular and Cerebrovascular Reactions During and After Infusion

Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of infliximab infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of infliximab. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms [See Adverse Reactions (6)]

5.9 Neurologic Reactions

Agents that inhibit TNF have been associated in rare cases with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of INFLECTRA in patients with these neurologic disorders and should consider discontinuation of INFLECTRA if these disorders develop.

5.10 Use with Anakinra

Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα blocking agents. Therefore, the combination of INFLECTRA and anakinra is not recommended.

5.11 Use with Abatacept

In clinical studies, concurrent administration of TNF blocking agents and abatacept have been associated with an increased risk of infections including serious infections compared with TNF blocking agents alone, without increased clinical benefit. Therefore, the combination of INFLECTRA and abatacept is not recommended [see Drug Interactions (7.1)].

5.12 Concurrent Administration with other Biological Therapeutics

There is insufficient information regarding the concomitant use of infliximab products with other biological therapeutics used to treat the same conditions as INFLECTRA. The concomitant use of INFLECTRA with these biologics is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.3)].

5.13 Switching between Biological Disease-Modifying Antirheumatic Drugs (DMARDs)

Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

5.14 Autoimmunity

Treatment with infliximab products may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with INFLECTRA, treatment should be discontinued [see Adverse Reactions (6.1)].

5.15 Live Vaccines/Therapeutic Infectious Agents

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with INFLECTRA is not recommended.

Fatal outcome due to disseminated BCG infection has been reported in an infant who received a BCG vaccine after in utero exposure to infliximab products. Infliximab products are known to cross the placenta and have been detected up to 6 months following birth. At least a six month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to infliximab products.

Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with INFLECTRA.

It is recommended that all pediatric patients be brought up to date with all vaccinations prior to initiating INFLECTRA therapy. The interval between vaccination and initiation of INFLECTRA therapy should be in accordance with current vaccination guidelines.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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

Adverse Reactions in Adults

The data described herein reflect exposure to infliximab in 4779 adult patients (1304 patients with rheumatoid arthritis, 1106 patients with Crohn's disease, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 484 with ulcerative colitis, 1373 with plaque psoriasis, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. [For information on adverse reactions in pediatric patients see Adverse Reactions (6.1)]. One of the most common reasons for discontinuation of treatment was infusion-related reactions (e.g., dyspnea, flushing, headache and rash).

Infusion-related Reactions

An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In phase 3 clinical studies, 18% of patients treated with infliximab experienced an infusion reaction compared to 5% of placebo-treated patients. Of these infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.

Among all infusions with infliximab, 3% were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), and <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3% of patients discontinued treatment with infliximab because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. Infliximab infusions beyond the initial infusion were not associated with a higher incidence of reactions. The infusion reaction rates remained stable in psoriasis through 1 year in psoriasis Study I. In psoriasis Study II, the rates were variable over time and somewhat higher following the final infusion than after the initial infusion. Across the 3 psoriasis studies, the percent of total infusions resulting in infusion reactions (i.e., an adverse event occurring within 1 hour) was 7% in the 3 mg/kg group, 4% in the 5 mg/kg group, and 1% in the placebo group.

Patients who became positive for antibodies to infliximab were more likely (approximately two to three-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions [see Adverse Reactions (6.1) and Drug Interactions (7.4)].

Infusion reactions following re-administration

In a clinical trial of patients with moderate to severe psoriasis designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction regimen of infliximab following disease flare, 4% (8/219) of patients in the re-treatment therapy arm experienced serious infusion reactions versus <1% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, treatment with infliximab was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.

Delayed Reactions/Reactions Following Readministration

In psoriasis studies, approximately 1% of patients treated with infliximab experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion.

Infections

In infliximab clinical studies, treated infections were reported in 36% of patients treated with infliximab (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among patients treated with infliximab, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported postmarketing. Most of these cases of tuberculosis occurred within the first 2 months after initiation of therapy with infliximab and may reflect recrudescence of latent disease [see Warnings and Precautions (5.1)]. In the 1-year placebo-controlled studies RA I and RA II, 5.3% of patients receiving infliximab every 8 weeks with methotrexate (MTX) developed serious infections as compared to 3.4% of placebo patients receiving MTX. Of 924 patients receiving infliximab, 1.7% developed pneumonia and 0.4% developed tuberculosis, when compared to 0.3% and 0.0% in the placebo arm respectively. In a shorter (22-week) placebo-controlled study of 1082 RA patients randomized to receive placebo, 3 mg/kg or 10 mg/kg infusions with infliximab at 0, 2, and 6 weeks, followed by every 8 weeks with MTX, serious infections were more frequent in the 10 mg/kg infliximab group (5.3%) than the 3 mg/kg or placebo groups (1.7% in both). During the 54-week Crohn's II Study, 15% of patients with fistulizing Crohn's disease developed a new fistula-related abscess.

In clinical studies with infliximab in patients with ulcerative colitis, infections treated with antimicrobials were reported in 27% of patients treated with infliximab (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 weeks of follow-up). The types of infections, including serious infections, reported in patients with ulcerative colitis were similar to those reported in other clinical studies.

The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection.

Autoantibodies/Lupus-like Syndrome

Approximately half of patients treated with infliximab in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately one-fifth of patients treated with infliximab compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.

Malignancies

In controlled trials, more patients treated with infliximab developed malignancies than placebo-treated patients [see Warnings and Precautions (5.2)].

In a randomized controlled clinical trial exploring the use of infliximab in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease. Of these patients treated with infliximab, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% confidence interval [CI] 3.51 – 14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 – 9.10). The majority of the malignancies developed in the lung or head and neck.

Patients with Heart Failure

In a randomized study evaluating infliximab in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of infliximab at 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg infliximab dose. At 1 year, 8 patients in the 10 mg/kg infliximab group had died compared with 4 deaths each in the 5 mg/kg infliximab and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg infliximab treatment groups, versus placebo. Infliximab has not been studied in patients with mild heart failure (NYHA Class I/II) [see Contraindications (4) and Warnings and Precautions (5.5)].

Immunogenicity

Treatment with infliximab products can be associated with the development of antibodies to infliximab. An enzyme immunoassay (EIA) method was originally used to measure anti-infliximab antibodies in clinical studies of infliximab. The EIA method is subject to interference by serum infliximab, possibly resulting in an underestimation of the rate of patient antibody formation. A separate, drug-tolerant electrochemiluminescence immunoassay (ECLIA) method for detecting antibodies to infliximab was subsequently developed and validated. This method is 60-fold more sensitive than the original EIA. With the ECLIA method, all clinical samples can be classified as either positive or negative for antibodies to infliximab without the need for the inconclusive category.

The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of treatment with infliximab. A higher incidence of antibodies to infliximab was observed in Crohn's disease patients receiving infliximab after drug-free intervals >16 weeks. In a study of psoriatic arthritis in which 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and to experience an infusion reaction [see Adverse Reactions (6.1)] than were patients who were antibody negative. Antibody development was lower among rheumatoid arthritis and Crohn's disease patients receiving immunosuppressant therapies such as 6-mercaptopurine /azathioprine (6-MP/AZA) or MTX.

In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1% – 23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with infliximab products over the long term is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to infliximab in an ELISA assay, and they are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to infliximab products with the incidence of antibodies to other products may be misleading.

Hepatotoxicity

Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported rarely in patients receiving infliximab products [see Warnings and Precautions (5.4)]. Reactivation of HBV has occurred in patients receiving TNF blocking agents, including infliximab products, who are chronic carriers of this virus [see Warnings and Precautions (5.3)].

In clinical trials in rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab than in controls (Table 1), both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of infliximab, or modification of concomitant medications.

Table 1 Proportion of patients with elevated ALT in clinical trials
Proportion of patients with elevated ALT
>1 to 3 × ULN ≥3 × ULN ≥5 × ULN
Placebo Infliximab Placebo Infliximab Placebo Infliximab
*
Placebo patients received methotrexate while patients treated with infliximab received both infliximab and methotrexate. Median follow-up was 58 weeks.
Placebo patients in the 2 Phase 3 trials in Crohn's disease received an initial dose of 5 mg/kg infliximab at study start and were on placebo in the maintenance phase. Patients who were randomized to the placebo maintenance group and then later crossed over to infliximab are included in the infliximab group in ALT analysis. Median follow-up was 54 weeks.
Median follow-up was 30 weeks. Specifically, the median duration of follow-up was 30 weeks for placebo and 31 weeks for infliximab.
§
Median follow-up was 24 weeks for the placebo group and 102 weeks for infliximab group.
Median follow-up was 39 weeks for infliximab group and 18 weeks for the placebo group.
#
ALT values are obtained in 2 Phase 3 psoriasis studies with median follow-up of 50 weeks for infliximab and 16 weeks for placebo.
Rheumatoid arthritis* 24% 34% 3% 4% <1% <1%
Crohn's disease 34% 39% 4% 5% 0% 2%
Ulcerative colitis 12% 17% 1% 2% <1% <1%
Ankylosing spondylitis§ 15% 51% 0% 10% 0% 4%
Psoriatic arthritis 16% 50% 0% 7% 0% 2%
Plaque psoriasis# 24% 49% <1% 8% 0% 3%

Adverse Reactions in Psoriasis Studies

During the placebo-controlled portion across the 3 clinical trials up to week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg infliximab group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg infliximab group.

Among patients in the 2 Phase 3 studies, 12.4% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving infliximab 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 year of maintenance treatment experienced at least 1 SAE.

One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg of infliximab. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving infliximab 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg infliximab group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting infliximab.

In the placebo-controlled portion of the psoriasis studies, 7 of 1123 patients who received infliximab at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo.

In the psoriasis studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility.

Other Adverse Reactions

Safety data are available from 4779 adult patients treated with infliximab, including 1304 with rheumatoid arthritis, 1106 with Crohn's disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis and 17 with other conditions. [For information on other adverse reactions in pediatric patients, see Adverse Reactions (6.1)]. Adverse reactions reported in ≥5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn's disease patients treated with infliximab except for abdominal pain, which occurred in 26% of patients with Crohn's disease. In the Crohn's disease studies, there were insufficient numbers and duration of follow-up for patients who never received infliximab to provide meaningful comparisons.

Table 2 Adverse reactions occurring in 5% or more of patients receiving 4 or more infusions for rheumatoid arthritis
Placebo Infliximab
(n=350) (n=1129)
Average weeks of follow-up 59 66
Gastrointestinal
  Nausea 20% 21%
  Abdominal pain 8% 12%
  Diarrhea 12% 12%
  Dyspepsia 7% 10%
Respiratory
  Upper respiratory tract infection 25% 32%
  Sinusitis 8% 14%
  Pharyngitis 8% 12%
  Coughing 8% 12%
  Bronchitis 9% 10%
Skin and appendages disorders
  Rash 5% 10%
  Pruritus 2% 7%
Body as a whole-general disorder
  Fatigue 7% 9%
  Pain 7% 8%
Resistance mechanism disorders
  Fever 4% 7%
  Moniliasis 3% 5%
Central and peripheral nervous system disorders
  Headache 14% 18%
Musculoskeletal system disorders
  Arthralgia 7% 8%
Urinary system disorders
  Urinary tract infection 6% 8%
Cardiovascular disorders, general
  Hypertension 5% 7%

The most common serious adverse reactions observed in clinical trials of infliximab were infections [see Adverse Reactions (6.1)]. Other serious, medically relevant adverse reactions ≥0.2% or clinically significant adverse reactions by body system were as follows:

 
Body as a whole: allergic reaction, edema
 
Blood: pancytopenia
 
Cardiovascular: hypotension
 
Gastrointestinal: constipation, intestinal obstruction
 
Central and Peripheral Nervous: dizziness
 
Heart Rate and Rhythm: bradycardia
 
Liver and Biliary: hepatitis
 
Metabolic and Nutritional: dehydration
 
Platelet, Bleeding and Clotting: thrombocytopenia
 
Neoplasms: lymphoma
 
Red Blood Cell: anemia, hemolytic anemia
 
Resistance Mechanism: cellulitis, sepsis, serum sickness, sarcoidosis
 
Respiratory: lower respiratory tract infection (including pneumonia), pleurisy, pulmonary edema
 
Skin and Appendages: increased sweating
 
Vascular (Extracardiac): thrombophlebitis
 
White Cell and Reticuloendothelial: leukopenia, lymphadenopathy

Adverse Reactions in Pediatric Patients

Pediatric Crohn's Disease

There were some differences in the adverse reactions observed in the pediatric patients receiving infliximab compared to those observed in adults with Crohn's disease. These differences are discussed in the following paragraphs.

The following adverse reactions were reported more commonly in 103 randomized pediatric Crohn's disease patients administered 5 mg/kg infliximab through 54 weeks than in 385 adult Crohn's disease patients receiving a similar treatment regimen: anemia (11%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), and respiratory tract allergic reaction (6%).

Infections were reported in 56% of randomized pediatric patients in Study Peds Crohn's and in 50% of adult patients in Study Crohn's I. In Study Peds Crohn's, infections were reported more frequently for patients who received every 8-week as opposed to every 12-week infusions (74% and 38%, respectively), while serious infections were reported for 3 patients in the every 8-week and 4 patients in the every 12-week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Pneumonia was reported for 3 patients, (2 in the every 8-week and 1 in the every 12-week maintenance treatment groups). Herpes zoster was reported for 2 patients in the every 8-week maintenance treatment group.

In Study Peds Crohn's, 18% of randomized patients experienced 1 or more infusion reactions, with no notable difference between treatment groups. Of the 112 patients in Study Peds Crohn's, there were no serious infusion reactions, and 2 patients had non-serious anaphylactoid reactions. In Study Peds Crohn's, in which all patients received stable doses of 6-MP, AZA, or MTX, excluding inconclusive samples, 3 of 24 patients had antibodies to infliximab. Although 105 patients were tested for antibodies to infliximab, 81 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.

Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in Crohn's disease clinical trials; 4% had ALT elevations ≥3 × ULN, and 1% had elevations ≥5 × ULN. (Median follow-up was 53 weeks.)

6.2 Postmarketing Experience

Adverse reactions have been identified during post approval use of infliximab products in adult and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions, some with fatal outcome, have been reported during postapproval use of infliximab products: neutropenia [see Warnings and Precautions (5.6)], agranulocytosis (including infants exposed in utero to infliximab), interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and very rare rapidly progressive disease), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), transverse myelitis, and neuropathies (additional neurologic reactions have also been observed) [see Warnings and Precautions (5.9)], acute liver failure, jaundice, hepatitis, and cholestasis [see Warnings and Precautions (5.4)], serious infections [see Warnings and Precautions (5.1)] and malignancies, including melanoma and Merkel cell carcinoma, and cervical cancer [see Warnings and Precautions (5.2)] and vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab [see Warnings and Precautions (5.15)].

Infusion-related Reactions

In postmarketing experience, cases of anaphylactic reactions, including laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with administration of infliximab products.

Cases of transient visual loss have been reported in association with infliximab products during or within 2 hours of infusion. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported [see Warnings and Precautions (5.8)].

Adverse Reactions in Pediatric Patients

The following serious adverse reactions have been reported in the postmarketing experience in children: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions.

Serious adverse reactions in the postmarketing experience with infliximab products in the pediatric population have also included malignancies, including HSTCL [see Boxed Warning and Warnings and Precautions (5.2)], transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.

1 INDICATIONS AND USAGE

1.1 Crohn's Disease

INFLECTRA 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.

INFLECTRA is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn's disease.

1.2 Pediatric Crohn's Disease

INFLECTRA 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.

1.3 Ulcerative Colitis

INFLECTRA 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.

1.4 Rheumatoid Arthritis

INFLECTRA, 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.

1.5 Ankylosing Spondylitis

INFLECTRA is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

1.6 Psoriatic Arthritis

INFLECTRA 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.

1.7 Plaque Psoriasis

INFLECTRA is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. INFLECTRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warning, Warnings and Precautions (5)].

NIVESTYM

NIVESTYM™ (filgrastim-aafi)

These highlights do not include all the information needed to use NIVESTYM safety and effectively. See full prescribing information for NIVESTYM.

4 CONTRAINDICATIONS

NIVESTYM is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Splenic Rupture

Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue NIVESTYM in patients with ARDS.

5.3 Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue NIVESTYM in patients with serious allergic reactions. NIVESTYM is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim.

5.4 Sickle Cell Disorders

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue NIVESTYM if sickle cell crisis occurs.

5.5 Glomerulonephritis

Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of NIVESTYM.

5.6 Alveolar Hemorrhage and Hemoptysis

Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim products for peripheral blood progenitor cell (PBPC) \ mobilization. Hemoptysis resolved with discontinuation of filgrastim products. The use of NIVESTYM for PBPC mobilization in healthy donors is not an approved indication.

5.7 Capillary Leak Syndrome

Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.8 Patients with Severe Chronic Neutropenia

Confirm the diagnosis of SCN before initiating NIVESTYM therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim products for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim products administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing NIVESTYM should be carefully considered.

5.9 Thrombocytopenia

Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.

5.10 Leukocytosis

Patients with Cancer Receiving Myelosuppressive Chemotherapy

White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving NIVESTYM as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that NIVESTYM therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy. Dosages of NIVESTYM that increase the ANC beyond 10‚000/mm3 may not result in any additional clinical benefit. In patients with cancer receiving myelosuppressive chemotherapy‚ discontinuation of filgrastim therapy usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels in 1 to 7 days.

Peripheral Blood Progenitor Cell Collection and Therapy

During the period of administration of NIVESTYM for PBPC mobilization in patients with cancer, discontinue NIVESTYM if the leukocyte count rises to > 100,000/mm3.

5.11 Cutaneous Vasculitis

Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold NIVESTYM therapy in patients with cutaneous vasculitis. NIVESTYM may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

5.12 Potential Effect on Malignant Cells

NIVESTYM is a growth factor that primarily stimulates neutrophils. The granulocyte-colony-stimulating factor (G-CSF) receptor through which NIVESTYM acts has also been found on tumor cell lines. The possibility that NIVESTYM acts as a growth factor for any tumor type cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established.

When NIVESTYM is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied‚ and the limited data available are inconclusive.

5.13 Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended

The safety and efficacy of NIVESTYM given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ do not use NIVESTYM in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy [see Dosage and Administration (2.2)].

The safety and efficacy of NIVESTYM have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of NIVESTYM with chemotherapy and radiation therapy.

5.14 Nuclear Imaging

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes. This should be considered when interpreting bone-imaging results.

5.15 Aortitis

Aortitis has been reported in patients receiving filgrastim products. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue NIVESTYM if aortitis is suspected.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

6.1 Clinical Trials Experience

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

Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy

The following adverse reaction data in Table 2 are from three randomized, placebo-controlled studies in patients with:

  • small cell lung cancer receiving standard dose chemotherapy with cyclophosphamide‚ doxorubicin‚ and etoposide (Study 1)
  • small cell lung cancer receiving ifosfamide, doxorubicin‚ and etoposide (Study 2), and
  • non-Hodgkin's lymphoma (NHL) receiving doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, and methotrexate ("ACVBP") or mitoxantrone, ifosfamide, mitoguazone, teniposide, methotrexate, folinic acid, methylprednisolone, and methotrexate ("VIM3") (Study 3).

A total of 451 patients were randomized to receive subcutaneous filgrastim 230 mcg/m2 (Study 1), 240 mcg/m2 (Study 2) or 4 or 5 mcg/kg/day (Study 3) (n = 294) or placebo (n = 157). The patients in these studies were median age 61 (range 29 to 78) years and 64% were male. The ethnicity was 95% Caucasian, 4% African American, and 1% Asian.

Table 2. Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy (With ≥ 5% Higher Incidence in Filgrastim Compared to Placebo)
System Organ Class
Preferred Term
Filgrastim
(N = 294)
Placebo
(N = 157)
*
Percent difference (Filgrastim – Placebo) was 4%.
Blood and lymphatic system disorders
  Thrombocytopenia 38% 29%
Gastrointestinal disorders
  Nausea 43% 32%
General disorders and administration site conditions
  Pyrexia 48% 29%
  Chest pain 13% 6%
  Pain 12% 6%
  Fatigue 20% 10%
Musculoskeletal and connective tissue disorders
  Back pain 15% 8%
  Arthralgia 9% 2%
  Bone pain 11% 6%
  Pain in extremity* 7% 3%
Nervous system disorders
  Dizziness 14% 3%
Respiratory, thoracic and mediastinal disorders
  Cough 14% 8%
  Dyspnea 13% 8%
Skin and subcutaneous tissue disorders
  Rash 14% 5%
Investigations
  Blood lactate dehydrogenase increased 6% 1%
  Blood alkaline phosphatase increased 6% 1%

Adverse events with ≥ 5% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy delivered included anemia, constipation, diarrhea, oral pain, vomiting, asthenia, malaise, edema peripheral, hemoglobin decreased, decreased appetite, oropharyngeal pain, and alopecia.

Adverse Reactions in Patients with Acute Myeloid Leukemia

Adverse reaction data below are from a randomized, double-blind, placebo-controlled study in patients with AML (Study 4) who received an induction chemotherapy regimen of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5 and up to 3 additional courses of therapy (induction 2, and consolidation 1, 2) of intravenous daunorubicin, cytosine arabinoside, and etoposide. The safety population included 518 patients randomized to receive either 5 mcg/kg/day filgrastim (n = 257) or placebo (n = 261). The median age was 54 (range 16 to 89) years and 54% were male.

Adverse reactions with ≥ 2% higher incidence in filgrastim patients compared to placebo included epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular.

Adverse events with ≥ 2% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy included diarrhea, constipation, and transfusion reaction.

Adverse Reactions in Patients with Cancer Undergoing Bone Marrow Transplantation

The following adverse reaction data are from one randomized, no treatment-controlled study in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma receiving high-dose chemotherapy (cyclophosphamide or cytarabine, and melphalan) and total body irradiation (Study 5) and one randomized, no treatment controlled study in patients with Hodgkin's disease (HD) and NHL undergoing high-dose chemotherapy and autologous bone marrow transplantation (Study 6). Patients receiving autologous bone marrow transplantation only were included in the analysis. A total of 100 patients received either 30 mcg/kg/day as a 4 hour infusion (Study 5) or 10 mcg/kg/day or 30 mcg/kg/day as a 24 hour infusion (Study 6) filgrastim (n = 72), no treatment control or placebo (n = 28). The median age was 30 (range 15 to 57) years, 57% were male.

Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included rash and hypersensitivity.

Adverse reactions in patients receiving intensive chemotherapy followed by autologous BMT with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included thrombocytopenia, anemia, hypertension, sepsis, bronchitis, and insomnia.

Adverse Reactions in Patients with Cancer Undergoing Autologous Peripheral Blood Progenitor Cell Collection

The adverse reaction data in Table 3 are from a series of 7 trials in patients with cancer undergoing mobilization of autologous peripheral blood progenitor cells for collection by leukapheresis. Patients (n = 166) in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for 6 to 8 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dosage of filgrastim ranged between 5 to 30 mcg/kg/day and was administered subcutaneously by injection or continuous infusion. The median age was 39 (range 15 to 67) years, and 48% were male.

Table 3. Adverse Reactions in Patients with Cancer Undergoing Autologous PBPC in the Mobilization Phase (≥ 5% Incidence in Filgrastim Patients)
System Organ Class
Preferred Term
Mobilization Phase
(N = 166)
Musculoskeletal and connective tissue disorders
  Bone pain 30%
General disorders and administration site conditions
  Pyrexia 16%
Investigations
  Blood alkaline phosphatase increased 11%
Nervous system disorders
  Headache 10%

Adverse Reactions in Patients with Severe Chronic Neutropenia

The following adverse reaction data were identified in a randomized, controlled study in patients with SCN receiving filgrastim (Study 7). 123 patients were randomized to a 4 month observation period followed by subcutaneous filgrastim treatment or immediate subcutaneous filgrastim treatment. The median age was 12 years (range 7 months to 76 years) and 46% were male. The dosage of filgrastim was determined by the category of neutropenia. Initial dosage of filgrastim:

  • Idiopathic neutropenia: 3.6 mcg/kg/day
  • Cyclic neutropenia: 6 mcg/kg/day
  • Congenital neutropenia: 6 mcg/kg/day divided 2 times per day

The dosage was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response.

Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, and urinary tract infection (upper respiratory tract infection and urinary tract infection were higher in the filgrastim arm, total infection related events were lower in filgrastim treated patients), epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia.

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to filgrastim in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

The incidence of antibody development in patients receiving filgrastim products has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to filgrastim products, the nature and specificity of these antibodies has not been adequately studied. In clinical studies using filgrastim, the incidence of antibodies binding to filgrastim was 3% (11/333). In these 11 patients, no evidence of a neutralizing response was observed using a cell-based bioassay.

Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors.

6.3 Postmarketing Experience

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

1 INDICATIONS AND USAGE

1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy

NIVESTYM 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 significant incidence of severe neutropenia with fever [see Clinical Studies (14.1)].

1.2 Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy

NIVESTYM is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) [see Clinical Studies (14.2)].

1.3 Patients with Cancer Undergoing Bone Marrow Transplantation

NIVESTYM 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 bone marrow transplantation [see Clinical Studies (14.3)].

1.4 Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy

NIVESTYM is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis [see Clinical Studies (14.4)].

1.5 Patients with Severe Chronic Neutropenia

NIVESTYM is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia [see Clinical Studies (14.5)].

RETACRIT

RETACRIT™ (epoetin alfa-epbx)

These highlights do not include all the information needed to use RETACRIT safety and effectively. See full prescribing information for RETACRIT.

WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE

Chronic Kidney Disease:

  • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL [see Warnings and Precautions (5.1)].
  • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [see Dosage and Administration (2.2)].
  • Use the lowest RETACRIT dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions (5.1)].

Cancer:

  • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers [see Warnings and Precautions (5.2)].
  • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions [see Dosage and Administration (2.4)].
  • Use ESAs only for anemia from myelosuppressive chemotherapy [see Indications and Usage (1.3)].
  • ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure [see Indications and Usage (1.5)].
  • Discontinue following the completion of a chemotherapy course [see Dosage and Administration (2.4)].

Perisurgery:

4 CONTRAINDICATIONS

RETACRIT is contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

5.1 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), epoetin alfa 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 [see Clinical Studies (14.1)]. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration (2.2)]. 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, epoetin alfa 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.

The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 1.

Table 1. Randomized Controlled Trials Showing Adverse Cardiovascular Outcomes in Patients with CKD
Normal Hematocrit Study (NHS)
(N = 1265)
CHOIR
(N = 1432)
TREAT
(N = 4038)
Time Period of Trial 1993 to 1996 2003 to 2006 2004 to 2009
Population CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa CKD patients not on dialysis with hemoglobin < 11 g/dL not previously administered epoetin alfa CKD patients not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL
Hemoglobin Target; Higher vs. Lower (g/dL) 14.0 vs. 10.0 13.5 vs. 11.3 13.0 vs. ≥ 9.0
Median (Q1, Q3) Achieved Hemoglobin level (g/dL) 12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7) 13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6) 12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3)
Primary Endpoint All-cause mortality or non-fatal MI All-cause mortality, MI, hospitalization for CHF, or stroke All-cause mortality, MI, myocardial ischemia, heart failure, and stroke
Hazard Ratio or Relative Risk (95% CI) 1.28 (1.06 – 1.56) 1.34 (1.03 – 1.74) 1.05 (0.94 – 1.17)
Adverse Outcome for Higher Target Group All-cause mortality All-cause mortality Stroke
Hazard Ratio or Relative Risk (95% CI) 1.27 (1.04 – 1.54) 1.48 (0.97 – 2.27) 1.92 (1.38 – 2.68)

Patients with Chronic Kidney Disease

Normal Hematocrit Study (NHS): A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR=1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.

CHOIR: A randomized, prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy were randomized to epoetin alfa treatment targeting a maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 of the 715 patients (18%) in the higher hemoglobin group compared to 97 of the 717 patients (14%) in the lower hemoglobin group [hazard ratio (HR) 1.34, 95% CI: 1.03, 1.74; p=0.03].

TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment (see Table 1), but the risk of stroke was increased nearly two-fold in the darbepoetin alfa-treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa-treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among darbepoetin alfa-treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.

Patients with Cancer

An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.

In a randomized, placebo-controlled study (Study 2 in Table 2 [see Warnings and Precautions (5.2)]) of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

Patients Having Surgery

An increased incidence of deep venous thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated [see Adverse Reactions (6.1)]. In a randomized, controlled study, 680 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, were randomized to 4 doses of 600 Units/kg epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment (n = 340) or to SOC treatment alone (n = 340). A higher incidence of DVTs, determined by either color flow duplex imaging or by clinical symptoms, was observed in the epoetin alfa group (16 [4.7%] patients) compared with the SOC group (7 [2.1%] patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 [2.8%] patients (n = 680) experienced 1 other thrombovascular event (TVE) each (12 [3.5%] in the epoetin alfa group and 7 [2.1%] in the SOC group). Deep venous thrombosis prophylaxis is strongly recommended when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients [see Dosage and Administration (2.5)].

Increased mortality was observed in a randomized, placebo-controlled study of epoetin alfa in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to epoetin alfa versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all 4 deaths were associated with thrombotic events.

5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer

ESAs resulted in decreased locoregional control/progression-free survival (PFS) and/or overall survival (OS) (see Table 2).

Adverse effects on PFS and/or OS were observed in studies of patients receiving chemotherapy for breast cancer (Studies 1, 2, and 4), lymphoid malignancy (Study 3), and cervical cancer (Study 5); in patients with advanced head and neck cancer receiving radiation therapy (Studies 6 and 7); and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 8 and 9).

Table 2. Randomized, Controlled Studies with Decreased Survival and/or Decreased Locoregional Control
Study/Tumor/(n) Hemoglobin Target Achieved Hemoglobin (Median; Q1, Q3*) Primary Efficacy Outcome Adverse Outcome for ESA-containing Arm
*
Q1 = 25th percentile
Q3 = 75th percentile
This study did not include a defined hemoglobin target. Doses were titrated to achieve and maintain the lowest hemoglobin level sufficient to avoid transfusion and not to exceed 12 g/dL.
Chemotherapy
Study 1
Metastatic breast cancer
(n = 2098)
≤12 g/dL 11.6 g/dL;
10.7, 12.1 g/dL
Progression-free survival (PFS) Decreased progression-free and overall survival
Study 2
Metastatic breast cancer
(n = 939)
12–14 g/dL 12.9 g/dL;
12.2, 13.3 g/dL
12-month overall survival Decreased 12-month survival
Study 3
Lymphoid malignancy
(n = 344)
13–15 g/dL (M)
13–14 g/dL (F)
11 g/dL;
9.8, 12.1 g/dL
Proportion of patients achieving a hemoglobin response Decreased overall survival
Study 4
Early breast cancer
(n = 733)
12.5–13 g/dL 13.1 g/dL;
12.5, 13.7 g/dL
Relapse-free and overall survival Decreased 3-year relapse-free and overall survival
Study 5
Cervical cancer
(n = 114)
12–14 g/dL 12.7 g/dL;
12.1, 13.3 g/dL
Progression-free and overall survival and locoregional control Decreased 3-year progression-free and overall survival and locoregional control
Radiotherapy Alone
Study 6
Head and neck cancer
(n = 351)
≥ 15 g/dL (M)
≥ 14 g/dL (F)
Not available Locoregional progression-free survival Decreased 5-year locoregional progression-free and overall survival
Study 7
Head and neck cancer
(n = 522)
14–15.5 g/dL Not available Locoregional disease control Decreased locoregional disease control
No Chemotherapy or Radiotherapy
Study 8
Non-small cell lung cancer
(n = 70)
12–14 g/dL Not available Quality of life Decreased overall survival
Study 9
Non-myeloid malignancy
(n = 989)
12–13 g/dL 10.6 g/dL;
9.4, 11.8 g/dL
RBC transfusions Decreased overall survival

Decreased Overall Survival

Study 2 was described in the previous section [see Warnings and Precautions (5.1)]. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator-assessed time to tumor progression was not different between the 2 groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

Study 3 was a randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02,1.82).

Study 8 was a multicenter, randomized, double-blind study (epoetin alfa vs. placebo) in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 patients (planned accrual 300 patients), a significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).

Study 9 was a randomized, double-blind study (darbepoetin alfa vs. placebo) in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).

Decreased Progression-free Survival and Overall Survival

Study 1 was a randomized, open-label, multicenter study in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a non inferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. The median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. At the time of clinical data cutoff, 1337 deaths were reported. Median overall survival in the epoetin alfa plus SOC group was 17.2 months compared with 17.4 months in the SOC alone group (HR 1.06, 95% CI: 0.95, 1.18). There were more deaths from disease progression in the epoetin alfa plus SOC arm (59% vs. 56%) and more thrombotic vascular events in the epoetin alfa plus SOC arm (3% vs. 1%).

Study 4 was a randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.

Study 5 was a randomized, open-label, controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%; HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68, 2.42).

Study 6 was a randomized, placebo-controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 14 and ≥ 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms, respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).

Decreased Locoregional Control

Study 7 was a randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to 15.5 g/dL or no darbepoetin alfa. An interim analysis performed on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).

5.3 Hypertension

RETACRIT is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of epoetin alfa, 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 epoetin alfa.

Appropriately control hypertension prior to initiation of and during treatment with RETACRIT. Reduce or withhold RETACRIT if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [see Patient Counseling Information (17)].

5.4 Seizures

Epoetin alfa products, including RETACRIT, increase the risk of seizures in patients with CKD. During the first several months following initiation of RETACRIT, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.

5.5 Lack or Loss of Hemoglobin Response to RETACRIT

For lack or loss of hemoglobin response to RETACRIT, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA [see Warnings and Precautions (5.6)]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to RETACRIT therapy [see Dosage and Administration (2.2)].

5.6 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 epoetin alfa. 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 RETACRIT is not approved).

If severe anemia and low reticulocyte count develop during treatment with RETACRIT, withhold RETACRIT and evaluate patients for neutralizing antibodies to erythropoietin. Contact Hospira, Inc., a Pfizer company (1-800-438-1985) to perform assays for binding and neutralizing antibodies. Permanently discontinue RETACRIT in patients who develop PRCA following treatment with RETACRIT or other erythropoietin protein drugs. Do not switch patients to other ESAs.

5.7 Serious Allergic Reactions

Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with epoetin alfa products. Immediately and permanently discontinue RETACRIT and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.

5.8 Severe Cutaneous Reactions

Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including epoetin alfa) in the postmarketing setting. Discontinue RETACRIT therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

5.9 Risk in Patients with Phenylketonuria

Phenylalanine can be harmful to patients with phenylketonuria (PKU). RETACRIT contains phenylalanine, a component of aspartame. Each 1 mL single-dose vial of 2,000, 3,000, 4,000, 10,000, and 40,000 Units of epoetin alfa-epbx injection contains 0.5 mg of phenylalanine. Before prescribing RETACRIT to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including RETACRIT.

5.10 Dialysis Management

Patients may require adjustments in their dialysis prescriptions after initiation of RETACRIT. Patients receiving RETACRIT may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

6.1 Clinical Trial Experience

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

Patients with Chronic Kidney Disease

Adult Patients

Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to epoetin alfa. In these studies, the mean age of patients was 48 years (range: 20 to 80 years). One hundred and thirty-three (55%) patients were men. The racial distribution was as follows: 177 (73%) patients were white, 48 (20%) patients were black, 4 (2%) patients were Asian, 12 (5%) patients were other, and racial information was missing for 3 (1%) patients.

Two double-blind, placebo-controlled studies, including 210 patients with CKD not on dialysis, were used to identify the adverse reactions to epoetin alfa. In these studies, the mean age of patients was 57 years (range: 24 to 79 years). One hundred and twenty-one (58%) patients were men. The racial distribution was as follows: 164 (78%) patients were white, 38 (18%) patients were black, 3 (1%) patients were Asian, 3 (1%) patients were other, and racial information was missing for 2 (1%) patients.

The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

Table 3. Adverse Reactions in Patients with CKD on Dialysis
Adverse Reaction Epoetin alfa-treated Patients
(n = 148)
Placebo-treated Patients
(n = 96)
Hypertension 27.7% 12.5%
Arthralgia 16.2% 3.1%
Muscle spasm 7.4% 6.3%
Pyrexia 10.1% 8.3%
Dizziness 9.5% 8.3%
Medical Device Malfunction (artificial kidney clotting during dialysis) 8.1% 4.2%
Vascular Occlusion (vascular access thrombosis) 8.1% 2.1%
Upper respiratory tract infection 6.8% 5.2%

An additional serious adverse reaction that occurred in less than 5% of epoetin alfa-treated dialysis patients and greater than placebo was thrombosis (2.7% epoetin alfa and 1% placebo) [see Warnings and Precautions (5.1)].

The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

Table 4. Adverse Reactions in Patients with CKD Not on Dialysis
Adverse Reactions Epoetin alfa-treated Patients
(n = 131)
Placebo-treated Patients
(n = 79)
Hypertension 13.7% 10.1%
Arthralgia 12.2% 7.6%

Additional serious adverse reactions that occurred in less than 5% of epoetin alfa-treated patients not on dialysis and greater than placebo were erythema (0.8% epoetin alfa and 0% placebo) and myocardial infarction (0.8% epoetin alfa and 0% placebo) [see Warnings and Precautions (5.1)].

Pediatric Patients

In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults.

Zidovudine-treated Patients with HIV-infection

A total of 297 zidovudine-treated patients with HIV-infection were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive epoetin alfa and 153 (52%) patients were randomly assigned to receive placebo. Epoetin alfa was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.

For the combined epoetin alfa treatment groups, a total of 141 (98%) men and 3 (2%) women between the ages of 24 and 64 years were enrolled. The racial distribution of the combined epoetin alfa treatment groups was as follows: 129 (90%) white, 8 (6%) black, 1 (1%) Asian, and 6 (4%) other.

In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 zidovudine-treated patients with HIV-infection, adverse reactions with an incidence of ≥ 1% in patients treated with epoetin alfa were:

Table 5. Adverse Reactions in Zidovudine-treated Patients with HIV-infection
Adverse Reaction Epoetin alfa
(n = 144)
Placebo
(n = 153)
Pyrexia 42% 34%
Cough 26% 14%
Rash 19% 7%
Injection site irritation 7% 4%
Urticaria 3% 1%
Respiratory tract congestion 1% Not reported
Pulmonary embolism 1% Not reported

Patients with cancer on Chemotherapy

The data below were obtained in Study C1, a 16-week, double-blind, placebo-controlled study that enrolled 344 patients with anemia secondary to chemotherapy. There were 333 patients who were evaluable for safety; 168 of 174 patients (97%) randomized to epoetin alfa received at least 1 dose of study drug, and 165 of 170 patients (97%) randomized to placebo received at least 1 placebo dose. For the once weekly epoetin alfa treatment group, a total of 76 men (45%) and 92 women (55%) between the ages of 20 and 88 years were treated. The racial distribution of the epoetin alfa-treatment group was 158 white (94%) and 10 black (6%). Epoetin alfa was administered once weekly for an average of 13 weeks at a dose of 20,000 to 60,000 IU subcutaneously (mean weekly dose was 49,000 IU).

The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Table 6. Adverse Reactions in Cancer Patients with Cancer
Adverse Reaction Epoetin alfa
(n = 168)
Placebo
(n = 165)
Nausea 35% 30%
Vomiting 20% 16%
Myalgia 10% 5%
Arthralgia 10% 6%
Stomatitis 10% 8%
Cough 9% 7%
Weight decrease 9% 5%
Leukopenia 8% 7%
Bone pain 7% 4%
Rash 7% 5%
Hyperglycemia 6% 4%
Insomnia 6% 2%
Headache 5% 4%
Depression 5% 4%
Dysphagia 5% 2%
Hypokalemia 5% 3%
Thrombosis 5% 3%

Surgery Patients

Four hundred sixty-one patients undergoing major orthopedic surgery were studied in a placebo-controlled study (S1) and a comparative dosing study (2 dosing regimens, S2). A total of 358 patients were randomly assigned to receive epoetin alfa and 103 (22%) patients were randomly assigned to receive placebo. Epoetin alfa was administered daily at a dose of 100 to 300 IU/kg subcutaneously for 15 days or at 600 IU/kg once weekly for 4 weeks.

For the combined epoetin alfa treatment groups, a total of 90 (25%) men and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined epoetin alfa treatment groups was as follows: 288 (80%) white, 64 (18%) black, 1 (< 1%) Asian, and 5 (1%) other.

The adverse reactions with a reported incidence of ≥ 1% in epoetin alfa-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Table 7. Adverse Reactions in Surgery Patients
Adverse Reaction Study S1 Study S2
Epoetin alfa
300 U/kg
Epoetin alfa
100 U/kg
Placebo Epoetin alfa
600 U/kg × 4 weeks
Epoetin alfa
300 U/kg × 15 days
(n = 112)* (n = 101)* (n = 103)* (n = 73) (n = 72)
*
Study included patients undergoing orthopedic surgery treated with epoetin alfa or placebo for 15 days.
Study included patients undergoing orthopedic surgery treated with epoetin alfa 600 U/kg weekly for 4 weeks or 300 U/kg daily for 15 days.
DVTs were determined by clinical symptoms.
Nausea 47% 43% 45% 45% 56%
Vomiting 21% 12% 14% 19% 28%
Pruritus 16% 16% 14% 12% 21%
Headache 13% 11% 9% 10% 18%
Injection site pain 13% 9% 8% 12% 11%
Chills 7% 4% 1% 1% 0%
Deep vein thrombosis 6% 3% 3% 0% 0%
Cough 5% 4% 0% 4% 4%
Hypertension 5% 3% 5% 5% 6%
Rash 2% 2% 1% 3% 3%
Edema 1% 2% 2% 1% 3%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of epoetin alfa.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

6.3 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to epoetin alfa with the incidence of antibodies to other products may be misleading.

Neutralizing antibodies to epoetin alfa that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias) [see Warnings and Precautions (5.6)].

1 INDICATIONS AND USAGE

1.1 Anemia Due to Chronic Kidney Disease

RETACRIT 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.

1.2 Anemia Due to Zidovudine in Patients with HIV-infection

RETACRIT is indicated for the treatment of anemia due to zidovudine administered at ≤ 4,200 mg/week in patients with HIV-infection with endogenous serum erythropoietin levels of ≤ 500 mUnits/mL.

1.3 Anemia Due to Chemotherapy in Patients with Cancer

RETACRIT is indicated for the treatment of anemia in patients with non-myeloid 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.

1.4 Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery

RETACRIT 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. RETACRIT is not indicated for patients who are willing to donate autologous blood pre-operatively.

1.5 Limitations of Use

RETACRIT has not been shown to improve quality of life, fatigue, or patient well-being.

RETACRIT 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 with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.
  • 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.