Tizabri

Overdose

Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of Tizabri that can be safely administered has not been determined.

Contraindications

• Tizabri is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML).
• Tizabri is contraindicated in patients who have had a hypersensitivity reaction to Tizabri. Observed reactions range from urticaria to anaphylaxis.

Pharmaceutical form

Undesirable effects

The following serious adverse reactions are described below and elsewhere in the labeling:

• Progressive Multifocal Leukoencephalopathy (PML)
• Herpes Infections
• Hepatotoxicity
• Hypersensitivity/Antibody Formation
• Immunosuppression/Infections

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 another drug and may not reflect the rates observed in practice.

The most common adverse reactions (incidence ≥ 10%) were headache and fatigue in both the multiple sclerosis (MS) and Crohn's disease (CD) studies. Other common adverse reactions (incidence ≥ 10%) in the MS population were arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash. Other common adverse reactions (incidence ≥ 10%) in the CD population were upper respiratory tract infections and nausea.

The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of Tizabri) in the MS studies were urticaria (1%) and other hypersensitivity reactions (1%), and in the CD studies (Studies CD1 and CD2) were the exacerbation of Crohn's disease (4.2%) and acute hypersensitivity reactions (1.5%).

A total of 1617 multiple sclerosis patients in controlled studies received Tizabri, with a median duration of exposure of 28 months. A total of 1563 patients received Tizabri in all CD studies for a median exposure of 5 months; of these patients, 33% (n=518) received at least one year of treatment and 19% (n=297) received at least two years of treatment.

The most common serious adverse reactions in Study MS1 with Tizabri were infections (3.2% versus 2.6% in placebo, including urinary tract infection [0.8% versus 0.3%] and pneumonia [0.6% versus 0%]), acute hypersensitivity reactions (1.1% versus 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% versus 0%]), depression (1.0% versus 1.0%, including suicidal ideation or attempt [0.6% versus 0.3%]), and cholelithiasis (1.0% versus 0.3%). In Study MS2, serious adverse reactions of appendicitis were also more common in patients who received Tizabri (0.8% versus 0.2% in placebo).

Table 2 enumerates adverse reactions and selected laboratory abnormalities that occurred in Study MS1 at an incidence of at least 1 percentage point higher in Tizabri-treated patients than was observed in placebo-treated patients.

Table 2: Adverse Reactions in Study MS1 (Monotherapy Study)

In Study MS2, peripheral edema was more common in patients who received Tizabri (5% versus 1% in placebo).

The following serious adverse reactions in the induction Studies CD1 and CD2 were reported more commonly with Tizabri than placebo and occurred at an incidence of at least 0.3%: intestinal obstruction or stenosis (2% vs. 1% in placebo), acute hypersensitivity reactions (0.5% vs. 0%), abdominal adhesions (0.3% vs. 0%), and cholelithiasis (0.3% vs. 0%). Similar serious adverse reactions were seen in the maintenance Study CD3. Table 3 enumerates adverse reactions that occurred in Studies CD1 and CD2 (median exposure of 2.8 months). Table 4 enumerates adverse reactions that occurred in Study CD3 (median exposure of 11.0 months).

Table 3: Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Table 4: Adverse Reactions in Study CD3 (Maintenance Study)

Progressive Multifocal Leukoencephalopathy (PML) occurred in three patients who received Tizabri in clinical trials. Two cases of PML were observed in the 1869 patients with multiple sclerosis who were treated for a median of 120 weeks. These two patients had received Tizabri in addition to interferon beta-1a. The third case occurred after eight doses in one of the 1043 patients with Crohn's disease who were evaluated for PML. In the postmarketing setting, additional cases of PML have been reported in Tizabri-treated multiple sclerosis and Crohn's disease patients who were not receiving concomitant immunomodulatory therapy.

In Studies MS1 and MS2 , the rate of any type of infection was approximately 1.5 per patient-year in both Tizabri-treated patients and placebo-treated patients. The infections were predominately upper respiratory tract infections, influenza, and urinary tract infections. In Study MS1, the incidence of serious infection was approximately 3% in Tizabri-treated patients and placebo-treated patients. Most patients did not interrupt treatment with Tizabri during infections. The only opportunistic infection in the multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course.

In Studies CD1 and CD2 , the rate of any type of infection was 1.7 per patient-year in Tizabri-treated patients and 1.4 per patient-year in placebo-treated patients. In Study CD3, the incidence of any type of infection was 1.7 per patient-year in Tizabri-treated patients and was similar in placebo-treated patients. The most common infections were nasopharyngitis, upper respiratory tract infection, and influenza. The majority of patients did not interrupt Tizabri therapy during infections, and recovery occurred with appropriate treatment. Concurrent use of Tizabri in CD clinical trials with chronic steroids and/or methotrexate, 6-MP, and azathioprine did not result in an increase in overall infections compared to Tizabri alone; however, the concomitant use of such agents could lead to an increased risk of serious infections.

In Studies CD1 and CD2, the incidence of serious infection was approximately 2.1% in both Tizabri-treated patients and placebo-treated patients. In Study CD3, the incidence of serious infection was approximately 3.3% in Tizabri-treated patients and approximately 2.8% in placebo-treated patients.

In clinical studies for CD, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of Tizabri-treated patients; some of these patients were receiving concurrent immunosuppressants. Two serious non-bacterial meningitides occurred in Tizabri-treated patients compared to none in placebo-treated patients.

An infusion-related reaction was defined in clinical trials as any adverse event occurring within two hours of the start of an infusion. In MS clinical trials, approximately 24% of Tizabri-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 18% of placebo-treated patients. In the controlled CD clinical trials, infusion-related reactions occurred in approximately 11% of patients treated with Tizabri compared to 7% of placebo-treated patients. Reactions more common in the Tizabri-treated MS patients compared to the placebo-treated MS patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors. Acute urticaria was observed in approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients receiving Tizabri. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients. All patients recovered with treatment and/or discontinuation of the infusion.

Infusion-related reactions that were more common in CD patients receiving Tizabri than those receiving placebo included headache, nausea, urticaria, pruritus, and flushing. Serious infusion reactions occurred in Studies CD1, CD2, and CD3 at an incidence of <1% in Tizabri-treated patients.

MS and CD patients who became persistently positive for antibodies to Tizabri were more likely to have an infusion-related reaction than those who were antibody-negative.

Patients in Study MS1 were tested for antibodies to natalizumab every 12 weeks. The assays used were unable to detect low to moderate levels of antibodies to natalizumab. Approximately 9% of patients receiving Tizabri developed detectable antibodies at least once during treatment. Approximately 6% of patients had positive antibodies on more than one occasion. Approximately 82% of patients who became persistently antibody-positive developed detectable antibodies by 12 weeks. Anti-natalizumab antibodies were neutralizing in vitro.

The presence of anti-natalizumab antibodies was correlated with a reduction in serum natalizumab levels. In Study MS1, the Week 12 pre-infusion mean natalizumab serum concentration in antibody-negative patients was 15 mcg/mL compared to 1.3 mcg/mL in antibody-positive patients. Persistent antibody-positivity resulted in a substantial decrease in the effectiveness of Tizabri. The risk of increased disability and the annualized relapse rate were similar in persistently antibody-positive Tizabri-treated patients and patients who received placebo. A similar phenomenon was also observed in Study MS2.

Infusion-related reactions that were most often associated with persistent antibody-positivity included urticaria, rigors, nausea, vomiting, headache, flushing, dizziness, pruritus, tremor, feeling cold, and pyrexia. Additional adverse reactions more common in persistently antibody-positive patients included myalgia, hypertension, dyspnea, anxiety, and tachycardia.

Patients in CD studies were first tested for antibodies at Week 12, and in a substantial proportion of patients, this was the only test performed given the 12-week duration of placebo-controlled studies. Approximately 10% of patients were found to have antinatalizumab antibodies on at least one occasion. Five percent (5%) of patients had positive antibodies on more than one occasion. Persistent antibodies resulted in reduced efficacy and an increase in infusion-related reactions with symptoms that include urticaria, pruritus, nausea, flushing, and dyspnea.

The long-term immunogenicity of Tizabri and the effects of low to moderate levels of antibody to natalizumab are unknown.

Immunogenicity data 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 medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Tizabri with the incidence of antibodies to other products may be misleading.

The following adverse reactions have been identified during post approval use of Tizabri. 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.

Blood disorders: hemolytic anemia

Therapeutic indications

Tizabri is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. Tizabri increases the risk of PML. When initiating and continuing treatment with Tizabri, physicians should consider whether the expected benefit of Tizabri is sufficient to offset this risk. See important information regarding the risk of PML with Tizabri.

Tizabri is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. Tizabri should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α.

Pharmacodynamic properties

Tizabri administration increases the number of circulating leukocytes (including lymphocytes, monocytes, basophils, and eosinophils) due to inhibition of transmigration out of the vascular space. Tizabri does not affect the absolute count of circulating neutrophils.

Pharmacokinetic properties

In patients with MS, following the repeat intravenous administration of a 300 mg dose of Tizabri, the mean ± SD maximum observed serum concentration was 110 ± 52 mcg/mL. Mean average steady-state trough concentrations ranged from 23 mcg/mL to 29 mcg/mL. The observed time to steady-state was approximately 24 weeks after every four weeks of dosing. The mean ± SD half-life, volume of distribution, and clearance of natalizumab were 11 ± 4 days, 5.7 ± 1.9 L, and 16 ± 5 mL/hour, respectively.

The effects of covariates such as body weight, age, gender, and presence of anti-natalizumab antibodies on natalizumab pharmacokinetics were investigated in a population pharmacokinetic study (n=2195). Natalizumab clearance increased with body weight in a less than proportional manner such that a 43% increase in body weight resulted in a 32% increase in clearance. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold.

In patients with CD, following the repeat intravenous administration of a 300 mg dose of Tizabri, the mean ± SD maximum observed serum concentration was 101 ± 34 mcg/mL. The mean ± SD average steady-state trough concentration was 10 ± 9 mcg/mL. The estimated time to steady-state was approximately 16 to 24 weeks after every four weeks of dosing. The mean ± SD half-life, volume of distribution, and clearance of natalizumab were 10 ± 7 days, 5.2 ± 2.8 L, and 22 ± 22 mL/hour, respectively.

The effects of total body weight, age, gender, race, selected hematology and serum chemistry measures, co-administered medications (infliximab, immunosuppressants, or steroids), and the presence of anti-natalizumab antibodies were investigated in a population pharmacokinetic analysis (n=1156). The presence of anti-natalizumab antibodies was observed to increase natalizumab clearance.

Pharmacokinetics of natalizumab in patients with renal or hepatic insufficiency have not been studied.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability, has occurred in patients who have received Tizabri.

Three factors that are known to increase the risk of PML in Tizabri-treated patients have been identified:

• Longer treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 6 years of Tizabri treatment.
• Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil).
• The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk for developing PML.

These factors should be considered in the context of expected benefit when initiating and continuing treatment with Tizabri.

Table 1: Estimated United States Incidence of PML Stratified by Risk Factor

Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with Tizabri. Infection by the JC virus is required for the development of PML. Anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody negative status indicates that antibodies to the JC virus have not been detected. Patients who are anti-JCV antibody negative have a lower risk of PML than those who are positive. Patients who are anti-JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. The reported rate of seroconversion in patients with MS (changing from anti-JCV antibody negative to positive and remaining positive in subsequent testing) is 3 to 8 percent annually. In addition, some patients' serostatus may change intermittently. Therefore, patients with a negative anti-JCV antibody test result should be retested periodically. For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody testing. When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay. After plasma exchange, wait at least two weeks to test for anti-JCV antibodies to avoid false negative test results caused by the removal of serum antibodies. After infusion of intravenous immunoglobulin (IVIg), wait at least 6 months (5 half-lives) for the IVIg to clear in order to avoid false positive anti-JCV antibody test results.

Healthcare professionals should monitor patients on Tizabri for any new sign or symptom suggestive of PML. Symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. Withhold Tizabri dosing immediately and perform an appropriate diagnostic evaluation at the first sign or symptom suggestive of PML.

MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported. Many of these patients subsequently became symptomatic. Periodic monitoring for radiographic signs consistent with PML should be considered to allow for an early diagnosis of PML. Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following Tizabri discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of Tizabri or due to differences in disease in these patients.

There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs. PML has been reported following discontinuation of Tizabri in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least six months following discontinuation of Tizabri.

Because of the risk of PML, Tizabri is available only under a restricted distribution program, the TOUCH® Prescribing Program.

In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with Tizabri. This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML.

In Crohn's disease patients, a baseline brain MRI may also be helpful to distinguish pre-existent lesions from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on Tizabri therapy are uncommon.

For diagnosis of PML, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. If the initial evaluations for PML are negative but clinical suspicion for PML remains, continue to withhold Tizabri dosing, and repeat the evaluations.

There are no known interventions that can adequately treat PML if it occurs. Three sessions of plasma exchange over 5 to 8 days were shown to accelerate Tizabri clearance in a study of 12 patients with MS who did not have PML, although in the majority of patients, alpha-4 integrin receptor binding remained high. Adverse events which may occur during plasma exchange include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although plasma exchange has not been studied in Tizabri treated patients with PML, it has been used in such patients in the postmarketing setting to remove Tizabri more quickly from the circulation.

JC virus infection of granule cell neurons in the cerebellum (i.e., JC virus granule cell neuronopathy [JCV GCN]) has been reported in patients treated with Tizabri. JCV GCN can occur with or without concomitant PML. JCV GCN can cause cerebellar dysfunction (e.g., ataxia, incoordination, apraxia, visual disorders), and neuroimaging can show cerebellar atrophy. For diagnosis of JCV GCN, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA, is recommended. JCV GCN should be managed similarly toPML.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of Tizabri treated patients who developed PML and subsequently discontinued Tizabri. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating  Tizabri. It presents as a clinical decline in the patient's condition after Tizabri removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI. Tizabri has not been associated with IRIS in patients discontinuing treatment with Tizabri for reasons unrelated to PML. In Tizabri treated patients with PML, IRIS has been reported within days to several weeks after plasma exchange. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

Tizabri is available only through a restricted program under a REMS called the TOUCH® Prescribing Program because of the risk of PML.

For prescribers and patients, the TOUCH® Prescribing Program has two components: MS TOUCH® (for patients with multiple sclerosis) and CD TOUCH® (for patients with Crohn's disease).

Selected requirements of the TOUCH® Prescribing Program include the following:

• Prescribers must be certified and comply with the following:
  • Review the TOUCH® Prescribing Program prescriber educational materials, including the full prescribing information.
  • Educate patients on the benefits and risks of treatment with Tizabri, ensure that patients receive the Medication Guide, and encourage them to ask questions.
  • Review, complete, and sign the Patient-Prescriber Enrollment Form.
  • Evaluate patients three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing Tizabri.
  • Determine every six months whether patients should continue on treatment and, if so, authorize treatment for another six months.
  • Submit to Biogen the “Tizabri Patient Status Report and Reauthorization Questionnaire” six months after initiating treatment and every six months thereafter.
  • Complete an “Initial Discontinuation Questionnaire” when Tizabri is discontinued, and a “6-Month Discontinuation Questionnaire” following discontinuation of Tizabri.
  • Report cases of PML, hospitalizations due to opportunistic infections, and deaths to Biogen at 1-800-456-2255 as soon as possible.
• Patients must be enrolled in the TOUCH® Prescribing Program, read the Medication Guide, understand the risks associated with Tizabri, and complete and sign the Patient-Prescriber Enrollment Form.
• Pharmacies and infusion centers must be specially certified to dispense or infuse Tizabri.

Tizabri increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving Tizabri. Laboratory confirmation in those cases was based on positive PCR for viral DNA in the cerebrospinal fluid. The duration of treatment with Tizabri prior to onset ranged from a few months to several years. Monitor patients receiving Tizabri for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, Tizabri should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered.

Acute retinal necrosis (ARN) is a fulminant viral infection of the retina caused by the family of herpes viruses (e.g., varicella zoster, herpes simplex virus). A higher risk of ARN has been observed in patients being administered Tizabri. Patients presenting with eye symptoms, including decreased visual acuity, redness, or eye pain, should be referred for retinal screening for ARN. Some ARN cases occurred in patients with central nervous system (CNS) herpes infections (e.g., herpes meningitis or encephalitis). Serious cases of ARN led to blindness of one or both eyes in some patients. Following clinical diagnosis of ARN, consider discontinuation of Tizabri. The treatment reported in ARN cases included anti-viral therapy and, in some cases, surgery.

Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with Tizabri in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses. In some patients, liver injury recurred upon rechallenge, providing evidence that Tizabri caused the injury. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients.

Tizabri should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).

Hypersensitivity reactions have occurred in patients receiving Tizabri, including serious systemic reactions (e.g., anaphylaxis), which occurred at an incidence of <1%. These reactions usually occur within two hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain. Generally, these reactions are associated with antibodies to Tizabri.

If a hypersensitivity reaction occurs, discontinue administration of Tizabri, and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with Tizabri. Hypersensitivity reactions were more frequent in patients with antibodies to Tizabri compared to patients who did not develop antibodies to Tizabri in both MS and CD studies. Therefore, the possibility of antibodies to Tizabri should be considered in patients who have hypersensitivity reactions.

Antibody testing: If the presence of persistent antibodies is suspected, antibody testing should be performed. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected early in the treatment course (e.g., within the first six months) may be transient and may disappear with continued dosing. It is recommended that testing be repeated three months after an initial positive result to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of Tizabri in a patient with persistent antibodies.

Patients who receive Tizabri for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment. Given that patients with persistent antibodies to Tizabri experience reduced efficacy, and that hypersensitivity reactions are more common in such patients, consideration should be given to testing for the presence of antibodies in patients who wish to recommence therapy following a dose interruption. Following a period of dose interruption, patients testing negative for antibodies prior to re-dosing have a risk of antibody development with re-treatment that is similar to Tizabri naïve patients.

The immune system effects of Tizabri may increase the risk for infections. In Study MS1 , certain types of infections, including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections, occurred more often in Tizabri-treated patients than in placebo-treated patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received Tizabri in Study MS1.

In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in Tizabri-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids.

In CD clinical studies, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of Tizabri-treated patients; some of these patients were receiving concurrent immunosuppressants.

In Studies CD1 and CD2, an increase in infections was seen in patients concurrently receiving corticosteroids. However, the increase in infections was similar in placebo-treated and Tizabri-treated patients who received steroids.

Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections, including PML and other opportunistic infections, over the risk observed with use of Tizabri alone. The safety and efficacy of Tizabri in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established. Patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not ordinarily be treated with Tizabri. The risk of PML is also increased in patients who have been treated with an immunosuppressant prior to receiving Tizabri.

For patients with Crohn's disease who start Tizabri while on chronic corticosteroids, commence steroid withdrawal as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within six months, discontinue Tizabri.

In clinical trials, Tizabri was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during Tizabri exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. Tizabri induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dL) that are frequently transient.

No data are available on the effects of vaccination in patients receiving Tizabri. No data are available on the secondary transmission of infection by live vaccines in patients receiving Tizabri.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Counsel patients to understand the risks and benefits of Tizabri before an initial prescription is written. The patient may be educated by either the enrolled prescriber or a healthcare provider under that prescriber's direction. INSTRUCT PATIENTS USING Tizabri TO:

• Read the Medication Guide before starting Tizabri and before each Tizabri infusion.
• Promptly report any new or continuously worsening symptoms that persist over several days to their prescriber.
• Inform all of their physicians that they are receiving Tizabri.
• Plan to see their prescriber three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing Tizabri.

Inform patients that Progressive Multifocal Leukoencephalopathy (PML) has occurred in patients who received Tizabri. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Instruct the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. Instruct the patient that the progression of deficits usually leads to death or severe disability over weeks or months.

Instruct patients to continue to look for new signs and symptoms suggestive of PML for approximately 6 months following discontinuation of Tizabri.

Advise the patient that Tizabri is only available through a restricted program called the TOUCH® Prescribing Program. Inform the patient of the following requirements:

Patients must read the Medication Guide and sign the Patient Prescriber Enrollment Form. Advise patients that Tizabri is available only from certified pharmacies and infusion centers participating in the program.

Inform patients that Tizabri increases the risk of developing encephalitis, and meningitis, which could be fatal, and acute retinal necrosis, which could lead to blindness, caused by the family of herpes viruses (e.g., herpes simplex and varicella zoster viruses). Instruct patients to immediately report any possible symptoms of encephalitis and meningitis (such as fever, headache, and confusion) or acute retinal necrosis (such as decreased visual acuity, eye redness, or eye pain).

Inform patients that Tizabri may cause liver injury. Instruct patients treated with Tizabri to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.

Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction (e.g., urticaria with or without associated symptoms) during or following an infusion of Tizabri.

Inform patients that Tizabri may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection.

No clastogenic or mutagenic effects of natalizumab were observed in the Ames test or in vitro chromosomal aberration assay in human lymphocytes. Natalizumab showed no effects in in vitro assays of α4-integrin positive human tumor line proliferation/cytotoxicity. Xenograft transplantation models in SCID and nude mice with two α4-integrin positive human tumor lines (leukemia, melanoma) demonstrated no increase in tumor growth rates or metastasis resulting from natalizumab treatment.

In male guinea pigs administered natalizumab (0, 3, 10, or 30 mg/kg) by intravenous (IV) infusion on alternate days from 28 days prior to and continuing throughout mating (to untreated females), no effects on fertility were observed. The highest dose tested is 6 times the recommended human dose (RHD) (300 mg) on a body weight (mg/kg) basis.

In a separate study in female guinea pigs (mated with untreated males), natalizumab (0, 3, 10, or 30 mg/kg), administered by IV infusion on alternate days from gestation day (GD) 30 of the first pregnancy through GD 30 of the second pregnancy, resulted in a decrease in pregnancy rate and number of implantations at 30 mg/kg. (Fertility parameters were assessed for the second pregnancy.) The no-effect dose for effects on female fertility (10 mg/kg) is 2 times the RHD on a body weight basis.

There are no adequate data on the developmental risk associated with the use of Tizabri in pregnant women. In animal studies, administration of natalizumab during pregnancy produced fetal immunologic and hematologic effects in monkeys at doses similar to the human dose and reduced offspring survival in guinea pigs at doses greater than the human dose. These doses were not maternally toxic but produced the expected pharmacological effects in maternal animals.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Animal Data

In developmental toxicity studies conducted in guinea pigs and monkeys, at natalizumab doses up to 30 mg/kg (7 times the recommended human dose based on body weight [mg/kg]), transplacental transfer and in utero exposure of the embryo/fetus was demonstrated in both species.

In a study in which pregnant guinea pigs were administered natalizumab (0, 3, 10, or 30 mg/kg) by intravenous (IV) infusion on alternate days throughout organogenesis (gestation days [GD] 430), no effects on embryofetal development were observed.

When pregnant monkeys were administered natalizumab (0, 3, 10, or 30 mg/kg) by IV infusion on alternative days throughout organogenesis (GDs 20-70), serum levels in fetuses at delivery were approximately 35% of maternal serum natalizumab levels. There were no effects on embryofetal development; however, natalizumab-related immunological and hematologic changes were observed in the fetuses at the two highest doses. These changes included decreases in lymphocytes (CD3+ and CD20+), changes in lymphocyte subpopulation percentages, mild anemia, reduced platelet count, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis.

In a study in which monkeys were exposed to natalizumab during pregnancy (IV infusion of 30 mg/kg) on alternate days from GD20 to GD70 or GD20 to term, abortions were increased approximately 2-fold compared to controls. In offspring born to mothers administered natalizumab on alternate days from GD20 until delivery, hematologic effects (decreased lymphocyte and platelet counts) were also observed. These effects were reversed upon clearance of natalizumab. There was no evidence of anemia in these offspring. Offspring exposed in utero and during lactation had a normal immune response to challenge with a T-cell dependent antigen.

In a study in which pregnant guinea pigs were exposed to natalizumab (30 mg/kg IV) on alternate dates during GDs 30-64, a reduction in pup survival was observed.

Natalizumab has been detected in human milk. There are no data on the effects of this exposure on the breastfed infant or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Tizabri and any potential adverse effects on the breastfed infant from Tizabri or from the underlying maternal condition.

Safety and effectiveness in pediatric patients with multiple sclerosis or Crohn's disease below the age of 18 years have not been established. Tizabri is not indicated for use in pediatric patients.

Clinical studies of Tizabri did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Dosage (Posology) and method of administration

Only prescribers registered in the MS TOUCH® Prescribing Program may prescribe Tizabri for multiple sclerosis. The recommended dose of Tizabri for multiple sclerosis is 300 mg intravenous infusion over one hour every four weeks.

Only prescribers registered in the CD TOUCH® Prescribing Program may prescribe Tizabri for Crohn's disease.

The recommended dose of Tizabri for Crohn's disease is 300 mg intravenous infusion over one hour every four weeks. Tizabri should not be used with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or concomitant inhibitors of TNF-α. Aminosalicylates may be continued during treatment with Tizabri.

If the patient with Crohn's disease has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue Tizabri. For patients with Crohn's disease who start Tizabri while on chronic oral corticosteroids, commence steroid tapering as soon as a therapeutic benefit of Tizabri has occurred; if the patient with Crohn's disease cannot be tapered off of oral corticosteroids within six months of starting Tizabri, discontinue Tizabri. Other than the initial six-month taper, prescribers should consider discontinuing Tizabri for patients who require additional steroid use that exceeds three months in a calendar year to control their Crohn's disease.

1. Use aseptic technique when preparing Tizabri solution for intravenous infusion. Each vial is intended for single use only.
2. Tizabri is a colorless, clear to slightly opalescent concentrate. Inspect the Tizabri vial for particulate material and discoloration prior to dilution and administration. If visible particulates are observed and/or the liquid in the vial is discolored, the vial must not be used.
3. To prepare the solution, withdraw 15 mL of Tizabri concentrate from the vial using a sterile needle and syringe. Inject the concentrate into 100 mL of 0.9% Sodium Chloride Injection, USP. No other IV diluents may be used to prepare the Tizabri solution.
4. Gently invert the Tizabri solution to mix completely. Do not shake. Inspect the solution visually for particulate material prior to administration.
5. The final dosage solution has a concentration of 2.6 mg/mL.
6. Following dilution, infuse Tizabri solution immediately, or refrigerate solution at 2°C to 8°C, and use within 8 hours. If stored at 2°C to 8°C, allow the solution to warm to room temperature prior to infusion. DO NOT FREEZE.

• Infuse Tizabri 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP, over approximately one hour (infusion rate approximately 5 mg per minute). Do not administer Tizabri as an intravenous push or bolus injection. After the infusion is complete, flush with 0.9% Sodium Chloride Injection, USP.
• Observe patients during the infusion and for one hour after the infusion is complete. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction.
• Use of filtration devices during administration has not been evaluated. Other medications should not be injected into infusion set side ports or mixed with Tizabri.