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Black Box Warning
WARNING: SERIOUS INFECTIONS AND MALIGNANCY
See full prescribing information for complete Boxed Warning.
SERIOUS INFECTIONS
Patients treated with certolizumab are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
Certolizumab 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 certolizumab use and during therapy. Treatment for latent infection should be initiated prior to certolizumab 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 certolizumab 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 certolizumab, 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, of which certolizumab is a member. Certolizumab is not indicated for use in pediatric patients.
Certolizumab is indicated for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis
Certolizumab is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA).
Psoriatic Arthritis
Certolizumab is indicated for the treatment of adult patients with active psoriatic arthritis (PsA).
Ankylosing Spondylitis
Certolizumab is indicated for the treatment of adults with active ankylosing spondylitis (AS).
Storage
Certolizumab is administered by subcutaneous injection. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red or hard. When a 400 mg dose is needed (given as two subcutaneous injections of 200 mg), injections should occur at separate sites in the thigh or abdomen.
The solution should be carefully inspected visually for particulate matter and discoloration prior to administration. The solution should be a clear colorless to yellow liquid, essentially free from particulates and should not be used if cloudy or if foreign particulate matter is present. Certolizumab does not contain preservatives; therefore, unused portions of drug remaining in the syringe or vial should be discarded.
Crohn's Disease
The recommended initial adult dose of certolizumab is 400 mg (given as two subcutaneous injections of 200 mg) initially, and at Weeks 2 and 4. In patients who obtain a clinical response, the recommended maintenance regimen is 400 mg every four weeks.
Rheumatoid Arthritis
The recommended dose of certolizumab for adult patients with rheumatoid arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, certolizumab 400 mg every 4 weeks can be considered.
Psoriatic Arthritis
The recommended dose of certolizumab for adult patients with psoriatic arthritis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at week 2 and 4, followed by 200 mg every other week. For maintenance dosing, certolizumab 400 mg every 4 weeks can be considered.
Ankylosing Spondylitis
The recommended dose of certolizumab for adult patients with ankylosing spondylitis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks.
Preparation and Administration of Certolizumab Using the Lyophilized Powder for Injection
Certolizumab Lyophilized powder should be prepared and administered by a health care professional. certolizumab is provided in a package that contains everything required to reconstitute and inject the drug. Step-by-step preparation and administration instructions are provided below.
Preparation and Storage
Certolizumab should be brought to room temperature before reconstituting.
Use appropriate aseptic technique when preparing and administering certolizumab.
Reconstitute the vial(s) of certolizumab with 1 mL of Sterile Water for Injection, USP using the 20-gauge needle provided.
Gently swirl each vial of certolizumab without shaking, assuring that all of the powder comes in contact with the Sterile Water for Injection.
Leave the vial(s) undisturbed to fully reconstitute, which may take approximately 30 minutes.
The final reconstituted solution contains 200 mg/mL and should be clear to opalescent, colorless to pale yellow liquid essentially free from particulates.
Once reconstituted, certolizumab can be stored in the vials for up to 24 hours between 2° to 8° C (36° to 46° F) prior to injection. Do not freeze.
Administration
Prior to injecting, reconstituted certolizumab should be at room temperature but do not leave reconstituted certolizumab at room temperature for more than two hours prior to administration.
Withdraw the reconstituted solution into a separate syringe for each vial using a new 20-gauge needle for each vial so that each syringe contains 1 mL of certolizumab (200 mg of certolizumab pegol).
Replace the 20-gauge needle(s) on the syringes with a 23-gauge(s) for administration.
Inject the full contents of the syringe(s) subcutaneously into thigh or abdomen. Where a 400 mg dose is required, two injections are required, therefore, separate sites should be used for each 200 mg injection.
Preparation and Administration of Certolizumab Using the Prefilled Syringe
After proper training in subcutaneous injection technique, a patient may self-inject with the certolizumab Prefilled Syringe if a physician determines that it is appropriate.
Patients using the Certolizumab Prefilled Syringe should be instructed to inject the full amount in the syringe (1 mL), according to the directions provided in the Instructions for Use booklet.
Monitoring to Assess Safety
Before initiation of therapy with certolizumab, all patients must be evaluated for both active and inactive (latent) tuberculosis infection. The possibility of undetected latent tuberculosis should be considered in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or had close contact with a person with active tuberculosis. Appropriate screening tests (e.g. tuberculin skin test and chest x-ray) should be performed in all patients.
Concomitant Medications
Certolizumab may be used as monotherapy or concomitantly with non-biological disease modifying anti-rheumatic drugs (DMARDs).
The use of certolizumab in combination with biological DMARDs or other tumor necrosis factor (TNF) blocker therapy is not recommended.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Certolizumab in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Certolizumab in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Certolizumab in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Certolizumab in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Certolizumab in pediatric patients.
Contraindications
There is limited information regarding Certolizumab Contraindications in the drug label.
Warnings
WARNING: SERIOUS INFECTIONS AND MALIGNANCY
See full prescribing information for complete Boxed Warning.
SERIOUS INFECTIONS
Patients treated with certolizumab are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
Certolizumab 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 certolizumab use and during therapy. Treatment for latent infection should be initiated prior to certolizumab 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 certolizumab 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 certolizumab, 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, of which certolizumab is a member. Certolizumab is not indicated for use in pediatric patients.
Risk of Serious Infections
Patients treated with certolizumab are at an increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Treatment with certolizumab 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 (e.g. corticosteroids or methotrexate) may be at a greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:
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 certolizumab, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating certolizumab and periodically during therapy.
Anti-tuberculosis therapy should also be considered prior to initiation of certolizumab 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 of whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Tuberculosis should be strongly considered in patients who develop a new infection during certolizumab 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 certolizumab, 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 certolizumab.
certolizumab should be discontinued if a patient develops a serious infection or sepsis.
A patient who develops a new infection during treatment with certolizumab 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 risks of antifungal therapy.
Malignancies
In the controlled portions of clinical studies of some TNF blockers, more cases of malignancies have been observed among patients receiving TNF blockers compared to control patients. During controlled and open-labeled portions of certolizumab studies of Crohn's disease and other diseases, malignancies (excluding non-melanoma skin cancer) were observed at a rate (95% confidence interval) of 0.5 (0.4, 0.7) per 100 patient-years among 4,650 certolizumab-treated patients versus a rate of 0.6 (0.1, 1.7) per 100 patient-years among 1,319 placebo-treated patients. The size of the control group and limited duration of the controlled portions of the studies precludes the ability to draw firm conclusions.
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), of which certolizumab is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). 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 post-marketing reports. Certolizumab is not indicated for use in pediatric patients.
In the controlled portions of clinical trials of all the TNF blockers, more cases of lymphoma have been observed among patients receiving TNF blockers compared to control patients. In controlled studies of certolizumab for Crohn's disease and other investigational uses, there was one case of lymphoma among 2,657 certolizumab-treated patients and one case of Hodgkin's lymphoma among 1,319 placebo-treated patients.
In the certolizumab RA clinical trials (placebo-controlled and open label) a total of three cases of lymphoma were observed among 2,367 patients. This is approximately 2-fold higher than expected in the general population. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma.
Rates in clinical studies for certolizumab cannot be compared to the rates of clinical trials of other TNF blockers and may not predict the rates observed when certolizumab is used in a broader patient population. Patients with Crohn's disease that require chronic exposure to immunosuppressant therapies may be at higher risk than the general population for the development of lymphoma, even in the absence of TNF blocker therapy. The potential role of TNF blocker therapy in the development of malignancies in adults is not known.
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma that has a very aggressive disease course and is usually fatal, have been reported in patients treated with TNF blockers, including certolizumab. The majority of reported TNF blocker cases occurred in adolescent and young adult males with Crohn's disease or ulcerative colitis. Almost all of these patients had received treatment with the immunosuppressantsazathioprine and/or 6-mercaptopurine (6-MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk of using a TNF blocker in combination with azathioprine or 6-MP should be carefully considered.
Cases of acute and chronic leukemia have been reported in association with post-marketing TNF-blocker use in RA and other indications. 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.
Periodic skin examinations are recommended for all patients, particularly those with risk factors for skin cancer.
Heart Failure
Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers, including certolizumab. Certolizumab has not been formally studied in patients with CHF; however, in clinical studies in patients with CHF with another TNF blocker, worsening congestive heart failure (CHF) and increased mortality due to CHF were observed. Exercise caution in patients with heart failure and monitor them carefully.
Hypersensitivity Reactions
The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following certolizumab administration to patients: angioedema, dyspnea, hypotension, rash, serum sickness, and urticaria. Some of these reactions occurred after the first administration of certolizumab. If such reactions occur, discontinue further administration of certolizumab and institute appropriate therapy. There are no data on the risks of using certolizumab in patients who have experienced a severe hypersensitivity reaction towards another TNF blocker; in these patients caution is needed.
Hepatitis B Virus Reactivation
Use of TNF blockers, including certolizumab, 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 reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation.
Test patients for HBV infection before initiating treatment with certolizumab. For patients who test positive for HBV infection, 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 certolizumab 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, discontinue certolizumab and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of certolizumab therapy in this situation and monitor patients closely.
Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., leukopenia, pancytopenia, thrombocytopenia) have been infrequently reported with certolizumab. The causal relationship of these events to certolizumab remains unclear.
Although no high risk group has been identified, exercise caution in patients being treated with certolizumab who have ongoing, or a history of, significant hematologic abnormalities. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on certolizumab. Consider discontinuation of certolizumab therapy in patients with confirmed significant hematologic abnormalities.
Use with Biological Disease-Modifying Antirheumatic Drugs (Biological DMARDs)
Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF blocker, etanercept, with no added benefit compared to etanercept alone. A higher risk of serious infections was also observed in combination use of TNF blockers with abatacept and rituximab. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from the use of certolizumab in this combination. Therefore, the use of certolizumab in combination with other biological DMARDs is not recommended.
Autoimmunity
Treatment with certolizumab 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 certolizumab, discontinue treatment.
Immunizations
Patients treated with certolizumab may receive vaccinations, except for live or live attenuated vaccines. No data are available on the response to live vaccinations or the secondary transmission of infection by live vaccines in patients receiving certolizumab.
In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in antibody response to vaccine between certolizumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with certolizumab. Similar proportions of patients developed protective levels of anti-vaccine antibodies between certolizumab and placebo treatment groups; however patients receiving certolizumab and concomitant methotrexate had a lower humoral response compared with patients receiving certolizumab alone. The clinical significance of this is unknown.
Immunosuppression
Since TNF mediates inflammation and modulates cellular immune responses, the possibility exists for TNF blockers, including certolizumab, to affect host defenses against infections and malignancies. The impact of treatment with certolizumab on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood. The safety and efficacy of certolizumab in patients with immunosuppression has not been formally evaluated.
Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.
Adverse Reactions Most Commonly Leading to Discontinuation of Treatment in Premarketing Controlled Trials
The proportion of patients with Crohn's disease who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for certolizumab and 7% for placebo. The most common adverse reactions leading to the discontinuation of certolizumab (for at least 2 patients and with a higher incidence than placebo) were abdominal pain (0.4% certolizumab, 0.2% placebo), diarrhea (0.4% certolizumab, 0% placebo), and intestinal obstruction (0.4% certolizumab, 0% placebo).
The proportion of patients with rheumatoid arthritis who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for certolizumab and 2.5% for placebo. The most common adverse reactions leading to discontinuation of certolizumab were tuberculosis infections (0.5%); and pyrexia, urticaria, pneumonia, and rash (0.3%).
Controlled Studies with Crohn's Disease
The data described below reflect exposure to certolizumab at 400 mg subcutaneous dosing in studies of patients with Crohn's disease. In the safety population in controlled studies, a total of 620 patients with Crohn's disease received certolizumab at a dose of 400 mg, and 614 subjects received placebo (including subjects randomized to placebo in Study CD2 following open label dosing of certolizumab at Weeks 0, 2, 4). In controlled and uncontrolled studies, 1,564 patients received certolizumab at some dose level, of whom 1,350 patients received 400 mg certolizumab. Approximately 55% of subjects were female, 45% were male, and 94% were Caucasian. The majority of patients in the active group were between the ages of 18 and 64.
During controlled clinical studies, the proportion of patients with serious adverse reactions was 10% for certolizumab and 9% for placebo. The most common adverse reactions (occurring in ≥ 5% of certolizumab-treated patients, and with a higher incidence compared to placebo) in controlled clinical studies with certolizumab were upper respiratory infections (e.g. nasopharyngitis, laryngitis, viral infection) in 20% of certolizumab-treated patients and 13% of placebo-treated patients, urinary tract infections (e.g. bladder infection, bacteriuria, cystitis) in 7% of certolizumab-treated patients and in 6% of placebo-treated patients, and arthralgia (6% certolizumab, 4% placebo).
Other Adverse Reactions
The most commonly occurring adverse reactions in controlled trials of Crohn's disease were described above. Other serious or significant adverse reactions reported in controlled and uncontrolled studies in Crohn's disease and other diseases, occurring in patients receiving certolizumab at doses of 400 mg or other doses include:
Certolizumab was studied primarily in placebo-controlled trials and in long-term follow-up studies. The data described below reflect the exposure to certolizumab in 2,367 RA patients, including 2,030 exposed for at least 6 months, 1,663 exposed for at least one year and 282 for at least 2 years; and 1,774 in adequate and well-controlled studies. In placebo-controlled studies, the population had a median age of 53 years at entry; approximately 80% were females, 93% were Caucasian and all patients were suffering from active rheumatoid arthritis, with a median disease duration of 6.2 years. Most patients received the recommended dose of certolizumab or higher.
Table 1 summarizes the reactions reported at a rate of at least 3% in patients treated with certolizumab 200 mg every other week compared to placebo (saline formulation), given concomitantly with methotrexate.
This image is provided by the National Library of Medicine.
Hypertensive adverse reactions were observed more frequently in patients receiving CIMZIA than in controls. These adverse reactions occurred more frequently among patients with a baseline history of hypertension and among patients receiving concomitant corticosteroids and non-steroidal anti-inflammatory drugs.
Patients receiving certolizumab 400 mg as monotherapy every 4 weeks in rheumatoid arthritis controlled clinical trials had similar adverse reactions to those patients receiving certolizumab 200 mg every other week.
Other Adverse Reactions
Other infrequent adverse reactions (occurring in less than 3% of RA patients) were similar to those seen in Crohn's disease patients.
Psoriatic Arthritis Clinical Study
Certolizumab has been studied in 409 patients with psoriatic arthritis (PsA) in a placebo-controlled trial. The safety profile for patients with PsA treated with certolizumab was similar to the safety profile seen in patients with RA and previous experience with certolizumab.
Ankylosing Spondylitis Clinical Study
Certolizumab has been studied in 325 patients with axial spondyloarthritis of whom the majority had ankylosing spondylitis (AS) in a placebo-controlled study (AS-1). The safety profile for patients in study AS-1 treated with certolizumab was similar to the safety profile seen in patients with RA.
Infections
The incidence of infections in controlled studies in Crohn's disease was 38% for certolizumab-treated patients and 30% for placebo-treated patients. The infections consisted primarily of [upper respiratory infections]] (20% for certolizumab, 13% for placebo). The incidence of serious infections during the controlled clinical studies was 3% per patient-year for certolizumab-treated patients and 1% for placebo-treated patients. Serious infections observed included bacterial and viral infections, pneumonia, and pyelonephritis.
The incidence of new cases of infections in controlled clinical studies in rheumatoid arthritis was 0.91 per patient-year for all certolizumab-treated patients and 0.72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections, and lower respiratory tract infections. In the controlled rheumatoid arthritis studies, there were more new cases of serious infection adverse reactions in the certolizumab treatment groups, compared to the placebo groups (0.06 per patient-year for all certolizumab doses vs. 0.02 per patient-year for placebo). Rates of serious infections in the 200 mg every other week dose group were 0.06 per patient-year and in the 400 mg every 4 weeks dose group were 0.04 per patient-year. Serious infections included tuberculosis, pneumonia, cellulitis, and pyelonephritis. In the placebo group, no serious infection occurred in more than one subject. There is no evidence of increased risk of infections with continued exposure over time.
Tuberculosis and Opportunistic Infections
In completed and ongoing global clinical studies in all indications including 5,118 certolizumab-treated patients, the overall rate of tuberculosis is approximately 0.61 per 100 patient-years across all indications.
The majority of cases occurred in countries with high endemic rates of TB. Reports include cases of miliary, lymphatic, peritoneal, as well as pulmonary TB. The median time to onset of TB for all patients exposed to certolizumab across all indications was 345 days. In the studies with certolizumab in RA, there were 36 cases of TB among 2,367 exposed patients, including some fatal cases. Rare cases of opportunistic infections have also been reported in these clinical trials.
Malignancies
In clinical studies of certolizumab, the overall incidence rate of malignancies was similar for certolizumab-treated and control patients. For some TNF blockers, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients.
Heart Failure
In placebo-controlled and open-label rheumatoid arthritis studies, cases of new or worsening heart failure have been reported for certolizumab-treated patients. The majority of these cases were mild to moderate and occurred during the first year of exposure.
Autoantibodies
In clinical studies in Crohn's disease, 4% of patients treated with certolizumab and 2% of patients treated with placebo that had negative baseline ANA titers developed positive titers during the studies. One of the 1,564 Crohn's disease patients treated with certolizumab developed symptoms of a lupus-like syndrome.
In clinical trials of TNF blockers, including certolizumab, in patients with RA, some patients have developed ANA. Four patients out of 2,367 patients treated with certolizumab in RA clinical studies developed clinical signs suggestive of a lupus-like syndrome. The impact of long-term treatment with certolizumab on the development of autoimmune diseases is unknown.
Immunogenicity
Patients were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. The overall percentage of antibody positive patients was 8% in patients continuously exposed to certolizumab, approximately 6% were neutralizing in vitro. No apparent correlation of antibody development to adverse events or efficacy was observed. Patients treated with concomitant immunosuppressants had a lower rate of antibody development than patients not taking immunosuppressants at baseline (3% and 11%, respectively). The following adverse events were reported in Crohn's disease patients who were antibody-positive (N = 100) at an incidence at least 3% higher compared to antibody-negative patients (N = 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, injection site erythema, injection site pain, pain in extremity, and upper respiratory tract infection.
The overall percentage of patients with antibodies to certolizumab pegol detectable on at least one occasion was 7% (105 of 1,509) in the rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 of 1,509) of these patients had antibodies with neutralizing activity in vitro. Patients treated with concomitant immunosuppressants (MTX) had a lower rate of antibody development than patients not taking immunosuppressants at baseline. Patients treated with concomitant immunosuppressant therapy (MTX) in RA-I, RA-II, RA-III had a lower rate of neutralizing antibody formation overall than patients treated with certolizumab monotherapy in RA-IV (2% vs. 8%). Both the loading dose of 400 mg every other week at Weeks 0, 2 and 4 and concomitant use of MTX were associated with reduced immunogenicity.
Antibody formation was associated with lowered drug plasma concentration and reduced efficacy. In patients receiving the recommended certolizumab dosage of 200 mg every other week with concomitant MTX, the ACR20 response was lower among antibody positive patients than among antibody-negative patients (Study RA-I, 48% versus 60%; Study RA-II 35% versus 59%, respectively). In Study RA-III, too few patients developed antibodies to allow for meaningful analysis of ACR20 response by antibody status. In Study RA-IV (monotherapy), the ACR20 response was 33% versus 56%, antibody-positive versus antibody-negative status, respectively. No association was seen between antibody development and the development of adverse events.
The data reflect the percentage of patients whose test results were considered positive for antibodies to certolizumab pegol in an ELISA, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to certolizumab pegol with the incidence of antibodies to other products may be misleading.
The following adverse reactions have been identified during post-approval use of CIMZIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.
Vascular disorder: systemic vasculitis has been identified during post-approval use of TNF blockers.
Use with Anakinra, Abatacept, Rituximab, and Natalizumab
An increased risk of serious infections has been seen in clinical studies of other TNF-blocking agents used in combination with anakinra or abatacept, with no added benefit. Formal drug interaction studies have not been performed with rituximab or natalizumab. Because of the nature of the adverse events seen with these combinations with TNF blocker therapy, similar toxicities may also result from the use of certolizumab in these combinations. There is not enough information to assess the safety and efficacy of such combination therapy. Therefore, the use of certolizumab in combination with anakinra, abatacept, rituximab, or natalizumab is not recommended.
Live Vaccines
Avoid use of live (including attenuated) vaccines concurrently with certolizumab.
Laboratory Tests
Interference with certain coagulation assays has been detected in patients treated with CIMZIA. Certolizumab pegol may cause erroneously elevated activated partial thromboplastin time (aPTT) assay results in patients without coagulation abnormalities. This effect has been observed with the PTT-Lupus Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL APTT-SP liquid and HemosIL lyophilized silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. Interference with thrombin time (TT) and prothrombin time (PT) assays has not been observed. There is no evidence that certolizumab therapy has an effect on in vivo coagulation.
Adequate and well-controlled studies with certolizumab have not been conducted in pregnant women.
Certolizumab pegol plasma concentrations obtained from 10 women treated with certolizumab during pregnancy and their newborn infants demonstrated low placental transfer of certolizumab pegol. Certolizumab may be eliminated at a slower rate in exposed infants than in adult patients. No fetal harm was observed in animal reproduction studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to certolizumab during pregnancy. To enroll, healthcare providers or patients can call 1-877-311-8972.
Human Data
In an independent clinical study conducted in 10 pregnant women with Crohn´s disease treated with certolizumab, certolizumab pegol concentrations were measured in maternal blood as well as in cord and infant blood (n=12) at the day of birth. The last dose of certolizumab (400 mg for every mother) was given on average 19 days prior to delivery (range 5-42 days). Plasma certolizumab pegol concentrations were <0.41 –1.66 μg/mL in cord blood, <0.41 – 1.58 μg/mL in infant blood, and 1.87–59.57 μg/mL in maternal blood. Plasma certolizumab pegol concentrations were lower (by at least 75%) in the infants than in mothers suggesting low placental transfer of certolizumab pegol. In one infant, the plasma certolizumab pegol concentration declined from 1.02 to 0.84 μg /mL over 4 weeks suggesting that certolizumab may be eliminated at a slower rate in infants than adults.
Animal Data
Because certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα pegylated Fab' fragment (cTN3 PF) similar to certolizumab pegol. Reproduction studies have been performed in rats at doses up to 100 mg/kg and have revealed no evidence of impaired fertility or harm to the fetus due to cTN3 PF.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Certolizumab in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Certolizumab during labor and delivery.
Nursing Mothers
It is not known whether certolizumab pegol is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from certolizumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Due to its inhibition of TNFα, certolizumab administered during pregnancy could affect immune responses in the in utero-exposed newborn and infant. Although certolizumab pegol levels were low in 12 infants exposed to certolizumab in utero, the clinical significance of these low levels is unknown. Additional data available from one exposed infant suggests that certolizumab may be eliminated at a slower rate in infants than in adults. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.
Geriatic Use
Clinical studies of certolizumab did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Population pharmacokinetic analyses of patients enrolled in certolizumab clinical studies concluded that there was no apparent difference in drug concentration regardless of age. Because there is a higher incidence of infections in the elderly population in general, use caution when treating the elderly with certolizumab.
Gender
There is no FDA guidance on the use of Certolizumab with respect to specific gender populations.
Race
There is no FDA guidance on the use of Certolizumab with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Certolizumab in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Certolizumab in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Certolizumab in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Certolizumab in patients who are immunocompromised.
There is limited information regarding Monitoring of Certolizumab in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Certolizumab in the drug label.
Overdosage
The maximum tolerated dose of certolizumab pegol has not been established. Doses of up to 800 mg subcutaneous and 20 mg/kg intravenous have been administered without evidence of dose-limiting toxicities. In cases of overdosage, it is recommended that patients be monitored closely for any adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.
Certolizumab (certolizumab pegol) is a TNF blocker. Certolizumab is a recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFα), conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). The Fab' fragment is manufactured in E. coli and is subsequently subjected to purification and conjugation to PEG2MAL40K, to generate certolizumab pegol. The Fab' fragment is composed of a light chain with 214 amino acids and a heavy chain with 229 amino acids. The molecular weight of certolizumab pegol is approximately 91 kiloDaltons.
Certolizumab is supplied as either a sterile, white, lyophilized powder for solution or as a sterile, solution in a single-use prefilled 1 mL glass syringe for subcutaneous injection. After reconstitution of the lyophilized powder with 1 mL sterile Water for Injection, USP, the resulting pH is approximately 5.2. Each single-use vial provides approximately 200 mg certolizumab pegol, 0.9 mg lactic acid, 0.1 mg polysorbate, and 100 mg sucrose.
Each single-use prefilled syringe of certolizumab delivers 200 mg in 1 mL of solution with a pH of approximately 4.7 for subcutaneous use. Each 1 mL syringe of certolizumab contains certolizumab pegol (200 mg), sodium acetate (1.36 mg), sodium chloride (7.31 mg), and Water for Injection, USP.
Certolizumab is a clear to opalescent solution that is colorless to pale yellow and essentially free from particulates. No preservatives are present.
Certolizumab pegol binds to human TNFα with a KD of 90pM. TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Certolizumab pegol selectively neutralizes TNFα (IC90 of 4 ng/mL for inhibition of human TNFα in the in vitro L929 murine fibrosarcoma cytotoxicity assay) but does not neutralize lymphotoxin α (TNFβ). Certolizumab pegol cross-reacts poorly with TNF from rodents and rabbits, therefore in vivo efficacy was evaluated using animal models in which human TNFα was the physiologically active molecule.
Certolizumab pegol was shown to neutralize membrane-associated and soluble human TNFα in a dose-dependent manner. Incubation of monocytes with certolizumab pegol resulted in a dose-dependent inhibition of LPS-induced TNFα and IL-1β production in human monocytes.
Certolizumab pegol does not contain a fragment crystallizable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, nor does certolizumab pegol induce neutrophil degranulation.
A tissue reactivity study was carried out ex vivo to evaluate potential cross-reactivity of certolizumab pegol with cryosections of normal human tissues. Certolizumab pegol showed no reactivity with a designated standard panel of normal human tissues.
Structure
Certolizumab (certolizumab pegol) is a TNF blocker. certolizumab is a recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFα), conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). The Fab' fragment is manufactured in E. coli and is subsequently subjected to purification and conjugation to PEG2MAL40K, to generate certolizumab pegol. The Fab' fragment is composed of a light chain with 214 amino acids and a heavy chain with 229 amino acids. The molecular weight of certolizumab pegol is approximately 91 kiloDaltons.
Certolizumab is supplied as either a sterile, white, lyophilized powder for solution or as a sterile, solution in a single-use prefilled 1 mL glass syringe for subcutaneous injection. After reconstitution of the lyophilized powder with 1 mL sterile Water for Injection, USP, the resulting pH is approximately 5.2. Each single-use vial provides approximately 200 mg certolizumab pegol, 0.9 mg lactic acid, 0.1 mg polysorbate, and 100 mg sucrose.
Each single-use prefilled syringe of certolizumab delivers 200 mg in 1 mL of solution with a pH of approximately 4.7 for subcutaneous use. Each 1 mL syringe of certolizumab contains certolizumab pegol (200 mg), sodium acetate (1.36 mg), sodium chloride (7.31 mg), and Water for Injection, USP.
certolizumab is a clear to opalescent solution that is colorless to pale yellow and essentially free from particulates. No preservatives are present.
Certolizumab pegol binds to human TNFα with a KD of 90pM. TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Certolizumab pegol selectively neutralizes TNFα (IC90 of 4 ng/mL for inhibition of human TNFα in the in vitro L929 murine fibrosarcoma cytotoxicity assay) but does not neutralize lymphotoxin α (TNFβ). Certolizumab pegol cross-reacts poorly with TNF from rodents and rabbits, therefore in vivo efficacy was evaluated using animal models in which human TNFα was the physiologically active molecule.
Certolizumab pegol was shown to neutralize membrane-associated and soluble human TNFα in a dose-dependent manner. Incubation of monocytes with certolizumab pegol resulted in a dose-dependent inhibition of LPS-induced TNFα and IL-1β production in human monocytes.
Certolizumab pegol does not contain a fragment crystallizable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, nor does certolizumab pegol induce neutrophil degranulation.
A tissue reactivity study was carried out ex vivo to evaluate potential cross-reactivity of certolizumab pegol with cryosections of normal human tissues. Certolizumab pegol showed no reactivity with a designated standard panel of normal human tissues.
Pharmacokinetics
Absorption
A total of 126 healthy subjects received doses of up to 800 mg certolizumab pegol subcutaneously (sc) and up to 10 mg/kg intravenously (IV) in four pharmacokinetic studies. Data from these studies demonstrate that single intravenous and subcutaneous doses of certolizumab pegol have predictable dose-related plasma concentrations with a linear relationship between the dose administered and the maximum plasma concentration (Cmax), and the Area Under the certolizumab pegol plasma concentration versus time Curve (AUC). A mean Cmax of approximately 43 to 49 mcg/mL occurred at Week 5 during the initial loading dose period using the recommended dose regimen for the treatment of patients with rheumatoid arthritis (400 mg sc at Weeks 0, 2 and 4 followed by 200 mg every other week).
Certolizumab pegol plasma concentrations were broadly dose-proportional and pharmacokinetics observed in patients with rheumatoid arthritis and Crohn's disease were consistent with those seen in healthy subjects.
Following subcutaneous administration, peak plasma concentrations of certolizumab pegol were attained between 54 and 171 hours post-injection. Certolizumab pegol has bioavailability (F) of approximately 80% (ranging from 76% to 88%) following subcutaneous administration compared to intravenous administration.
Distribution
The steady state volume of distribution (Vss) was estimated as 6 to 8 L in the population pharmacokinetic analysis for patients with Crohn's disease and patients with rheumatoid arthritis.
Metabolism
The metabolism of certolizumab pegol has not been studied in human subjects. Data from animals indicate that once cleaved from the Fab' fragment the PEG moiety is mainly excreted in urine without further metabolism.
Elimination
PEGylation, the covalent attachment of PEG polymers to peptides, delays the metabolism and elimination of these entities from the circulation by a variety of mechanisms, including decreased renal clearance, proteolysis, and immunogenicity.
Accordingly, certolizumab pegol is an antibody Fab' fragment conjugated with PEG in order to extend the terminal plasma elimination half-life (t1/2) of the Fab'. The terminal elimination phase half-life (t1/2) was approximately 14 days for all doses tested. The clearance following IV administration to healthy subjects ranged from 9.21 mL/h to 14.38 mL/h. The clearance following sc dosing was estimated 17 mL/h in the Crohn's disease population PK analysis with an inter-subject variability of 38% (CV) and an inter-occasion variability of 16%. Similarly, the clearance following sc dosing was estimated as 21.0 mL/h in the RA population PK analysis, with an inter-subject variability of 30.8% (%CV) and inter-occasion variability 22.0%. The route of elimination of certolizumab pegol has not been studied in human subjects. Studies in animals indicate that the major route of elimination of the PEG component is via urinary excretion.
Special Populations
Population pharmacokinetic analysis was conducted on data from patients with rheumatoid arthritis and patients with Crohn's disease, to evaluate the effect of age, race, gender, methotrexate use, concomitant medication, creatinine clearance and presence of anti-certolizumab antibodies on pharmacokinetics of certolizumab pegol.
Only bodyweight and presence of anti-certolizumab antibodies significantly affected certolizumab pegol pharmacokinetics. Pharmacokinetic exposure was inversely related to body weight but pharmacodynamic exposure-response analysis showed that no additional therapeutic benefit would be expected from a weight-adjusted dose regimen. The presence of anti-certolizumab antibodies was associated with a 3.6-fold increase in clearance.
Age: Pharmacokinetics of certolizumab pegol was not different in elderly compared to young adults.
Gender: Pharmacokinetics of certolizumab pegol was similar in male and female subjects.
Renal Impairment: Specific clinical studies have not been performed to assess the effect of renal impairment on the pharmacokinetics of certolizumab. The pharmacokinetics of the PEG (polyethylene glycol) fraction of certolizumab pegol is expected to be dependent on renal function but has not been assessed in renal impairment. There are insufficient data to provide a dosing recommendation in moderate and severe renal impairment.
Race: A specific clinical study showed no difference in pharmacokinetics between Caucasian and Japanese subjects.
Drug Interaction Studies
Methotrexate pharmacokinetics is not altered by concomitant administration with certolizumab in patients with rheumatoid arthritis. The effect of methotrexate on certolizumab pharmacokinetics was not studied. However, methotrexate-treated patients have lower incidence of antibodies to certolizumab. Thus, therapeutic plasma levels are more likely to be sustained when certolizumab is administered with methotrexate in patients with rheumatoid arthritis.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies of certolizumab have not been conducted to assess its carcinogenic potential. Certolizumab pegol was not genotoxic in the Ames test, the human peripheral blood lymphocytes chromosomal aberration assay, or the mouse bone marrow micronucleus assay.
Since certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα pegylated Fab fragment (cTN3 PF), similar to certolizumab pegol. The cTN3 PF had no effects on the fertility and general reproductive performance of male and female rats at intravenous doses up 100 mg/kg, administered twice weekly.
Clinical Studies
Crohn's Disease
The efficacy and safety of certolizumab were assessed in two double-blind, randomized, placebo-controlled studies in patients aged 18 years and older with moderately to severely active Crohn's disease, as defined by a Crohn's Disease Activity Index (CDAI1) of 220 to 450 points, inclusive. certolizumab was administered subcutaneously at a dose of 400 mg in both studies. Stable concomitant medications for Crohn's disease were permitted.
Study CD1
Study CD1 was a randomized placebo-controlled study in 662 patients with active Crohn's disease. Certolizumab or placebo was administered at Weeks 0, 2, and 4 and then every four weeks to Week 24. Assessments were done at Weeks 6 and 26. Clinical response was defined as at least a 100-point reduction in CDAI score compared to baseline, and clinical remission was defined as an absolute CDAI score of 150 points or lower.
The results for Study CD1 are provided in Table 2. At Week 6, the proportion of clinical responders was statistically significantly greater for certolizumab-treated patients compared to controls. The difference in clinical remission rates was not statistically significant at Week 6. The difference in the proportion of patients who were in clinical response at both Weeks 6 and 26 was also statistically significant, demonstrating maintenance of clinical response.
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How Supplied
Refrigerate intact carton between 2 to 8 °C (36 to 46 °F)
Storage
Do not freeze. Do not separate contents of carton prior to use. Do not use beyond expiration date, which is located on the drug label and carton. Protect solution from light.
Images
Drug Images
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Package and Label Display Panel
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Advise patients of the potential risks and benefits of certolizumab therapy. Be sure that patients receive the Medication Guide and allow them time to read it prior to starting certolizumab therapy and to review it periodically. Any questions resulting from the patient's reading of the Medication Guide should be discussed. Because caution should be exercised in prescribing certolizumab to patients with clinically important active infections, advise patients of the importance of informing their health care providers about all aspects of their health.
Immunosuppression
Inform patients that certolizumab may lower the ability of the immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis and reactivation of hepatitis B virus infections.
Counsel patients about the possible risk of lymphoma and other malignancies while receiving certolizumab.
Allergic Reactions
Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. The prefilled syringe components do not contain any latex or dry natural rubber.
Other Medical Conditions
Advise patients to report any signs of new or worsening medical conditions such as heart disease, neurological disease, or autoimmune disorders. Advise patients to report promptly any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.
Instruction on Prefilled Syringe Self-Injection Technique
After proper training by a qualified healthcare professional in subcutaneous injection technique, a patient may self inject with certolizumab using the Prefilled Syringe if a healthcare provider determines that it is appropriate. A patient's ability to administer certolizumab subcutaneous injections should be checked to ensure correct administration. Suitable sites for injection include the thigh or abdomen. Certolizumab should be injected when the liquid is at room temperature.
Full injection instructions are provided in the Instructions for Use booklet for the Prefilled Syringe, packaged in each certolizumab Prefilled Syringe kit.
To avoid needle-stick injury, patients and healthcare providers should not attempt to place the needle cover back on the syringe or otherwise recap the needle. Be sure to properly dispose of needles and syringes in a puncture-proof container, and instruct patients and caregivers in proper syringe and needle disposal technique. Actively discourage any reuse of the injection materials.
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Precautions with Alcohol
Alcohol-Certolizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
