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Serious Infections: Patients treated with REMICADE 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, cryptococcosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, salmonellosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with REMICADE should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid 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 REMICADE, including patients who have previously received treatment for latent or active tuberculosis. Cases of active tuberculosis have also occurred in patients being treated with REMICADE during treatment for latent tuberculosis.
Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating REMICADE and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blockers 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 REMICADE, even for patients previously vaccinated with Bacille Calmette-Guérin (BCG).
Anti-tuberculosis therapy should also be considered prior to initiation of REMICADE 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 REMICADE 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 REMICADE, 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 REMICADE.
REMICADE should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with REMICADE 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.
Malignancies: Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF blockers (initiation of therapy ≤ 18 years of age), including REMICADE. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (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 post-marketing 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 blockers, 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 REMICADE clinical trials, 5 patients developed lymphomas among 5707 patients treated with REMICADE (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In RA 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 RA, CD, PsA, AS, UC, and Ps, 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 CD, RA or Ps, 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 blockers. Cases of acute and chronic leukemia have been reported with postmarketing TNF blocker use in RA and other diseases. Even in the absence of TNF blocker therapy, patients with RA 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 REMICADE. 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 REMICADE cases have occurred in patients with CD or UC 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 REMICADE 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 REMICADE monotherapy from the clinical trial data [see Hypersensitivity as follows; Clinical Trials Experience under Adverse Reactions].
Skin Cancer: Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including REMICADE [see Postmarketing Experience under Adverse Reactions]. 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 RA treated with REMICADE compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between REMICADE and cervical cancer cannot be excluded. Periodic screening should continue in women treated with REMICADE [see Postmarketing Experience under Adverse Reactions].
Other Malignancies: In the controlled portions of clinical trials of some TNF blockers including REMICADE, 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 REMICADE trials in patients with moderately to severely active RA, CD, PsA, AS, UC, and Ps, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 REMICADE-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among REMICADE-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for REMICADE-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 REMICADE-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 REMICADE 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 REMICADE-treated patients compared with control patients. All patients had a history of heavy smoking [see Clinical Trials Experience under Adverse Reactions]. Prescribers should exercise caution when considering the use of REMICADE in patients with moderate to severe COPD.
Ps patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for REMICADE, NMSCs were more common in patients with previous phototherapy [see Clinical Trials Experience under Adverse Reactions].
The potential role of TNF blockers in the development of malignancies is not known [see Clinical Trials Experience under Adverse Reactions]. Rates in clinical trials for REMICADE 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 REMICADE treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving REMICADE.
Hepatitis B Virus Reactivation: Use of TNF blockers, including REMICADE, 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 REMICADE. 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 antiviral 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.
Hepatotoxicity: Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported in postmarketing data in patients receiving REMICADE. 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 REMICADE; 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, REMICADE 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 REMICADE without progression to severe hepatic injury [see Clinical Trials Experience under Adverse Reactions].
Heart Failure: The use of REMICADE at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure. A randomized, double-blind, placebo-controlled study evaluated the use of REMICADE (5 mg/kg or 10 mg/kg at Weeks 0, 2, and 6) in patients with moderate or severe heart failure [New York Heart Association (NYHA) Functional Class III/IV]. Compared to patients who received placebo, there was a higher rate of mortality and a higher risk of hospitalization at Week 28 due to heart failure in patients who received the 10 mg/kg REMICADE dose, and higher rates of cardiovascular adverse events in patients who received REMICADE doses of 5 mg/kg and 10 mg/kg.
There have been post-marketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors (e.g., pre-existing cardiovascular disease), in REMICADE-treated patients. Some of these patients have been under 50 years of age.
If a decision is made to administer REMICADE (≤ 5 mg/kg) to patients with moderate or severe heart failure or to administer REMICADE (any approved dose) to patients with mild heart failure, they should be closely monitored during therapy, and REMICADE should be discontinued if new or worsening symptoms of heart failure appear [see Contraindications; Clinical Trials Experience under Adverse Reactions].
Hematologic Reactions: Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving REMICADE. The causal relationship to REMICADE therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with REMICADE 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 REMICADE. Discontinuation of REMICADE therapy should be considered in patients who develop significant hematologic abnormalities.
Hypersensitivity: REMICADE has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions (including anaphylaxis, urticaria, dyspnea, and/or hypotension), have occurred during or within 2 hours of REMICADE infusion.
However, in some cases, serum sickness-like reactions have been observed in patients after initial REMICADE therapy (i.e., as early as after the second dose), and when REMICADE therapy was reinstituted following an extended period without REMICADE 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, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy.
REMICADE 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 Administration Instructions Regarding Infusion Reactions under Dosage & Administration; Clinical Trials Experience under Adverse Reactions].
In RA, CD and Ps clinical trials, re-administration of REMICADE after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment [see Clinical Trials Experience under Adverse Reactions]. In general, the benefit-risk of re-administration of REMICADE after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where REMICADE maintenance therapy for Ps is interrupted, REMICADE should be reinitiated as a single dose followed by maintenance therapy.
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 REMICADE infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of REMICADE. 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].
Neurologic Reactions: REMICADE and other agents that inhibit TNF have been associated 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 REMICADE in patients with these neurologic disorders and should consider discontinuation of REMICADE if these disorders develop.
Concurrent Administration with Other Biological Products: Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNF blocker, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the concurrent use of etanercept and anakinra therapy, similar toxicities may also result from the concurrent use of anakinra and other TNF blockers. Therefore, the concurrent use of REMICADE and anakinra is not recommended.
In clinical studies, concurrent administration of TNF blockers and abatacept have been associated with an increased risk of infections including serious infections compared with TNF blockers alone, without increased clinical benefit. Therefore, the concurrent use of REMICADE and abatacept is not recommended [see Other Biological Products under Interactions].
There is insufficient information regarding the concurrent use of REMICADE with other biological products used to treat the same conditions as REMICADE. The concurrent use of REMICADE with these biological products is not recommended because of the possibility of an increased risk of infection [see Other Biological Products under Interactions].
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.
Autoimmunity: Treatment with REMICADE may result in the formation of autoantibodies and in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with REMICADE, treatment should be discontinued [see Clinical Trials Experience under Adverse Reactions].
Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents: Vaccinations: Prior to initiating REMICADE in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines.
Live Vaccines and Therapeutic Infectious Agents: In patients receiving TNF blockers, 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 can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with REMICADE 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. Infliximab is known to cross the placenta and has 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.
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 REMICADE.
Use in Children: The safety and effectiveness of REMICADE have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of CD and UC [see Dosage in Pediatric Crohn's Disease and Dosage in Pediatric Ulcerative Colitis under Dosage & Administration; Clinical Trials Experience under Adverse Reactions]. However, the safety and effectiveness of REMICADE in pediatric patients <6 years of age with CD or UC have not been established. The safety and effectiveness of REMICADE in the treatment of pediatric patients with Ps and juvenile rheumatoid arthritis (JRA) have not been established.
Pediatric Crohn's Disease: The safety and effectiveness of REMICADE have been established 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 CD who have had an inadequate response to conventional therapy. The use of REMICADE for this indication is supported by evidence from a randomized, open-label pediatric CD study in 112 pediatric patients aged 6 years and older [see Pharmacology: Pharmacodynamics: Clinical Studies: Pediatric Crohn's Disease under Actions].
REMICADE has been studied only in combination with conventional immunosuppressive therapy in pediatric CD. The longer term (greater than 1 year) safety and effectiveness of REMICADE in pediatric CD patients have not been established in clinical trials.
Postmarketing cases of HSTCL have been reported in pediatric patients treated with TNF blockers including REMICADE. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when REMICADE is used in combination with other immunosuppressants in pediatric CD patients [see Malignancies as previously mentioned; Warnings].
Pediatric Ulcerative Colitis: The safety and effectiveness of REMICADE for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active UC who have had an inadequate response to conventional therapy have been established. The use of REMICADE for this indication is supported by evidence from adequate and well-controlled studies of REMICADE in adults with additional safety and pharmacokinetic data from an open-label pediatric UC study in 60 pediatric patients aged 6 years and older [see Pharmacology: Pharmacodynamics: Clinical Studies: Pediatric Ulcerative Colitis under Actions; Dosage in Pediatric Ulcerative Colitis under Dosage & Administration; Clinical Trials Experience under Adverse Reactions]. The effectiveness of REMICADE in inducing and maintaining mucosal healing in pediatric UC was not established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54. Approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start.
Due to the risk of HSTCL, a careful risk-benefit assessment should be made when REMICADE is used in combination with other immunosuppressants in pediatric UC patients [see Malignancies as previously mentioned; Warnings].
The longer term (greater than 1 year) safety and effectiveness of REMICADE in pediatric UC patients have not been established in clinical trials.
Juvenile Rheumatoid Arthritis (JRA): The safety and effectiveness of REMICADE in the treatment of pediatric patients with juvenile rheumatoid arthritis (JRA) have not been established.
The safety and efficacy of REMICADE in patients with JRA were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤ 0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted.
Doses of 3 mg/kg REMICADE or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg REMICADE at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with REMICADE for up to 2 years in a companion extension study.
The study failed to establish the efficacy of REMICADE in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults.
Population pharmacokinetic analysis showed that in pediatric patients with JRA with a body weight of up to 35 kg receiving 6 mg/kg REMICADE and pediatric patients with JRA with body weight greater than 35 kg up to adult body weight receiving 3 mg/kg REMICADE, the steady state area under the concentration curve (AUCss) was similar to that observed in adults receiving 3 mg/kg of REMICADE.
A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg REMICADE was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg REMICADE group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg REMICADE group, 2 patients had a serious infusion reaction, 1 of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received REMICADE by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg REMICADE compared with 12% (6/49) of patients who received 6 mg/kg.
A total of 68% (41/60) of patients who received 3 mg/kg REMICADE in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg REMICADE in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient.
Use in the Elderly: Of the total number of REMICADE-treated patients in RA and Ps clinical studies, 256 (9.6%) were 65 years old and over, while 17 (0.6%) were 75 years old and over. In these trials, no overall differences in safety or effectiveness were observed between geriatric patients (patients ≥ 65 years old) and younger adult patients (patients 18 to 65 years old). However, the incidence of serious adverse reactions in geriatric patients was higher in both REMICADE and control groups compared to younger adult patients.
Of the total number of REMICADE-treated patients in CD, UC, AS, and PsA clinical studies, 76 (3.2%) were 65 years old and over, while 9 (0.4%) were 75 years old and over. In the CD, UC, AS, and PsA studies, there were insufficient numbers of geriatric patients to determine whether they respond differently from younger adults.
The incidence of serious infections in REMICADE-treated geriatric patients was greater than in REMICADE-treated younger adult patients; therefore close monitoring of geriatric patients for the development of serious infections is recommended [see Serious Infections as previously mentioned; Clinical Trials Experience under Adverse Reactions].
