Natalizumab

Natalizumab
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]

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Black Box Warning

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY See full prescribing information for complete Boxed Warning. Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include duration of therapy, prior use of immunosuppressants, and presence of anti-JCV antibodies. These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab. Healthcare professionals should monitor patients on natalizumab for any new sign or symptom that may be suggestive of PML. Natalizumab dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. Because of the risk of PML, natalizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH Prescribing Program.

Overview

Natalizumab is a monoclonal antibody that is FDA approved for the treatment of multiple sclerosis (MS) and Crohn's disease (CD). There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Multiple Sclerosis (MS)

• Is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis.
• Natalizumab increases the risk of PML.
• When initiating and continuing treatment with natalizumab, physicians should consider whether the expected benefit of natalizumab is sufficient to offset this risk.
• Dosage:

• 300 mg intravenous infusion over one hour every four weeks.

Crohn's Disease (CD)

• 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.
• Natalizumab should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α.
• Dosage:

• 300 mg intravenous infusion over one hour every four weeks

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Natalizumab in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Natalizumab in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Natalizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Natalizumab in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Natalizumab in pediatric patients.

Contraindications

• natalizumab is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML).
• natalizumab should not be administered to a patient who has had a hypersensitivity reaction to natalizumab. Observed reactions range from urticaria to anaphylaxis

Warnings

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY See full prescribing information for complete Boxed Warning. Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include duration of therapy, prior use of immunosuppressants, and presence of anti-JCV antibodies. These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab. Healthcare professionals should monitor patients on natalizumab for any new sign or symptom that may be suggestive of PML. Natalizumab dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. Because of the risk of PML, natalizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH Prescribing Program.

Progressive Multifocal Leukoencephalopathy

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 natalizumab.

Three factors that are known to increase the risk of PML in natalizumab-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 natalizumab 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 natalizumab.

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 exposure to the JC virus has 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. Anti-JCV antibody testing should not be performed for at least two weeks following plasma exchange due to the removal of antibodies from the serum.

There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of natalizumab will mitigate the disease. PML has been reported following discontinuation of natalizumab 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 natalizumab.

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 natalizumab.

Because of the risk of PML, natalizumab 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 natalizumab. 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 natalizumab therapy are uncommon.

Healthcare professionals should monitor patients on natalizumab for any new sign or symptom suggestive of PML. 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. The progression of deficits usually leads to death or severe disability over weeks or months. Withhold natalizumab dosing immediately at the first sign or symptom suggestive of PML.

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 natalizumab 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 natalizumab 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 natalizumab treated patients with PML, it has been used in such patients in the postmarketing setting to remove natalizumab more quickly from the circulation. Anti-JCV antibody testing should not be performed during or for at least two weeks following plasma exchange due to the removal of antibodies from the serum.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of natalizumab treated patients who developed PML and subsequently discontinued natalizumab. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating natalizumab. It presents as a clinical decline in the patient's condition after natalizumab 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. natalizumab has not been associated with IRIS in patients discontinuing treatment with natalizumab for reasons unrelated to PML. In natalizumab-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.

natalizumab TOUCH Prescribing Program

natalizumab 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 natalizumab, 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 natalizumab.
• Determine every six months whether patients should continue on treatment and, if so, authorize treatment for another six months.
• Submit to Biogen Idec the “natalizumab Patient Status Report and Reauthorization Questionnaire” six months after initiating treatment and every six months thereafter.
• Complete an “Initial Discontinuation Questionnaire” when natalizumab is discontinued and a “6-Month Discontinuation Questionnaire” following discontinuation of natalizumab.
• Report cases of PML, hospitalizations due to opportunistic infections, or deaths to Biogen Idec 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 natalizumab and complete and sign the Patient-Prescriber Enrollment Form.
• Pharmacies and infusion centers must be specially certified to dispense or infuse natalizumab.

Herpes Encephalitis and Meningitis

Natalizumab 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 natalizumab. Laboratory confirmation in those cases was based on positive PCR for viral DNA in the cerebrospinal fluid. The duration of treatment with natalizumab prior to onset ranged from a few months to several years. Monitor patients receiving natalizumab for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSBARI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered.

Hepatotoxicity

Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with natalizumab 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 natalizumab 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.

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

Hypersensitivity/Antibody Formation

Hypersensitivity reactions have occurred in patients receiving natalizumab, 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 natalizumab.

If a hypersensitivity reaction occurs, discontinue administration of natalizumab and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with natalizumab. Hypersensitivity reactions were more frequent in patients with antibodies to natalizumab compared to patients who did not develop antibodies to natalizumab in both MS and CD studies. Therefore, the possibility of antibodies to natalizumab 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 disappear with continued dosing. Repeat testing at three months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of natalizumab in a patient with persistent antibodies.

Experience with monoclonal antibodies, including natalizumab, suggests that patients who receive therapeutic monoclonal antibodies after an extended period without treatment may be at higher risk of hypersensitivity reactions than patients who received regularly scheduled treatment. Given that patients with persistent antibodies to natalizumab 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 natalizumab naïve patients.

Immunosuppression/Infections

The immune system effects of natalizumab 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 natalizumab-treated patients than in placebo-treated patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received natalizumab 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 natalizumab-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 natalizumab-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 natalizumab-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 natalizumab alone. The safety and efficacy of natalizumab 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 natalizumab. The risk of PML is also increased in patients who have been treated with an immunosuppressant prior to receiving natalizumab.

For patients with Crohn's disease who start natalizumab 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 natalizumab.

Laboratory Test Abnormalities

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

Immunizations

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

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared 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 natalizumab), 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 natalizumab, with a median duration of exposure of 28 months. A total of 1563 patients received natalizumab 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.

Multiple Sclerosis Clinical Studies

The most frequently reported serious adverse reactions in Study MS1 with natalizumab 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 naphylaxis/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 natalizumab (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 natalizumab-treated patients than was observed in placebo-treated patients.

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

Crohn's Disease Clinical Studies

The following serious adverse events in the induction Studies CD1 and CD2 were reported more commonly with natalizumab 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 events were seen in the maintenance Study CD3. TABLE 3 enumerates adverse drug reactions that occurred in Studies CD1 and CD2 (median exposure of 2.8 months). TABLE 4 enumerates adverse drug reactions that occurred in Study CD3 (median exposure of 11.0 months).

Infections

Progressive Multifocal Leukoencephalopathy (PML) occurred in three patients who received natalizumab 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 natalizumab 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 natalizumab-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 natalizumab-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 natalizumab-treated patients and placebo-treated patients. Most patients did not interrupt treatment with natalizumab 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 natalizumab-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 natalizumab-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 natalizumab therapy during infections and recovery occurred with appropriate treatment. Concurrent use of natalizumab 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 natalizumab 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 natalizumab-treated patients and placebo-treated patients. In Study CD3, the incidence of serious infection was approximately 3.3% in natalizumab-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 natalizumab-treated patients; some of these patients were receiving concurrent immunosuppressants. Two serious non-bacterial meningitides occurred in natalizumab-treated patients compared to none in placebo-treated patients.

Infusion-related Reactions

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 natalizumab-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 natalizumab compared to 7% of placebo-treated patients. Reactions more common in the natalizumab-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 natalizumab. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients. All patients recovered with treatment and/or discontinuation of the infusion.

Infusion-related reactions more common in CD patients receiving natalizumab 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 natalizumab-treated patients.

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

Postmarketing Experience

There is limited information regarding Natalizumab Postmarketing Experience in the drug label.

Drug Interactions

Because of the potential for increased risk of PML and other infections, Crohn's disease patients receiving natalizumab should not be treated with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α, and corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start natalizumab therapy. Ordinarily, MS patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with natalizumab.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C Natalizumab has been shown to reduce pup survival in guinea pigs when given in doses 7 times the human dose, and has been shown to have hematologic effects on the fetus in monkeys when given in doses 2.3 times the human dose. There are no adequate and well-controlled studies in pregnant women. natalizumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Natalizumab in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Natalizumab during labor and delivery.

Nursing Mothers

Natalizumab has been detected in human milk. The effects of this exposure on infants are unknown.

Pediatric Use

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

Geriatic Use

Clinical studies of natalizumab 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.

Gender

There is no FDA guidance on the use of Natalizumab with respect to specific gender populations.

Race

There is no FDA guidance on the use of Natalizumab with respect to specific racial populations.

Renal Impairment

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

Hepatic Impairment

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

Females of Reproductive Potential and Males

Natalizumab did not affect male fertility at doses up to 7-fold the clinical dose.

Immunocompromised Patients

There is no FDA guidance one the use of Natalizumab in patients who are immunocompromised.

Administration and Monitoring

Administration

Intravenous

Monitoring

There is limited information regarding Natalizumab Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Natalizumab and IV administrations.

Overdosage

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

Pharmacology

Natalizumab?
Therapeutic monoclonal antibody
Source	zu/o
Target	alpha-4 integrin
Identifiers
CAS number	189261-10-7
ATC code	L04AA23
PubChem	?
DrugBank	DB00108
Chemical data
Formula	?
Mol. mass	149 kDa
Pharmacokinetic data
Bioavailability	n/a
Metabolism	?
Half life	11 ± 4 days
Excretion	?
Therapeutic considerations
Licence data	EU, US
Pregnancy cat.	C(AU) C(US)
Legal status	Template:Unicode Prescription only
Routes	Intravenous infusion

Mechanism of Action

Natalizumab binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their counter-receptor(s). The receptors for the α4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. In vitro, anti-α4-integrin antibodies also block α4-mediated cell binding to ligands such as osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, natalizumab may further act to inhibit the interaction of α4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells.

The specific mechanism(s) by which natalizumab exerts its effects in multiple sclerosis and Crohn's disease have not been fully defined.

In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter-receptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction of α4β1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain. Data from an experimental autoimmune encephalitis animal model of multiple sclerosis demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical significance of these animal data is unknown.

In Crohn's disease, the interaction of the α4β7 integrin with the endothelial receptor MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of the disease. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to gut lymph tissue found in Peyer's patches. MAdCAM-1 expression has been found to be increased at active sites of inflammation in patients with CD, which suggests it may play a role in the recruitment of leukocytes to the mucosa and contribute to the inflammatory response characteristic of CD. The clinical effect of natalizumab in CD may therefore be secondary to blockade of the molecular interaction of the α4ß7-integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. VCAM-1 expression has been found to be upregulated on colonic endothelial cells in a mouse model of IBD and appears to play a role in leukocyte recruitment to sites of inflammation. The role of VCAM-1 in CD, however, is not clear.

Structure

Natalizumab is a recombinant humanized IgG4ϰ monoclonal antibody produced in murine myeloma cells. Natalizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to α4-integrin. The molecular weight of natalizumab is 149 kilodaltons

Pharmacodynamics

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

Pharmacokinetics

Multiple Sclerosis (MS) Patients

In patients with MS, following the repeat intravenous administration of a 300 mg dose of natalizumab, 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.

Crohn's Disease (CD) Patients

In patients with CD, following the repeat intravenous administration of a 300 mg dose of natalizumab, 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Reductions in female guinea pig fertility were observed in one study at dose levels of 30 mg/kg, but not at the 10 mg/kg dose level (2.3-fold the clinical dose). A 47% reduction in pregnancy rate was observed in guinea pigs receiving 30 mg/kg relative to control. Implantations were seen in only 36% of animals having corpora lutea in the 30 mg/kg group versus 66 to 72% in the other groups. Natalizumab did not affect male fertility at doses up to 7-fold the clinical dose.

Animal Toxicology and/or Pharmacology

In reproductive studies in monkeys and guinea pigs, there was no evidence of teratogenic effects at doses up to 30 mg/kg (7 times the human clinical dose based on a body weight comparison). In one study where female guinea pigs were exposed to natalizumab during the second half of pregnancy, a small reduction in pup survival was noted at post-natal day 14 with respect to control (3 pups/litter for the group treated with 30 mg/kg natalizumab and 4.3 pups/litter for the control group). In one of five studies that exposed monkeys or guinea pigs during pregnancy, the number of abortions in treated (30 mg/kg) monkeys was 33% versus 17% in controls. No effects on abortion rates were noted in any other study. natalizumab underwent trans-placental transfer and produced in utero exposure in developing guinea pigs and cynomolgus monkeys. When pregnant dams were exposed to natalizumab at approximately 7-fold the clinical dose, serum levels in fetal animals at delivery were approximately 35% of maternal serum natalizumab levels. A study in pregnant cynomolgus monkeys treated at 2.3-fold the clinical dose demonstrated natalizumab-related changes in the fetus. These changes included 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 offspring born to mothers treated with natalizumab at 7-fold the clinical dose, platelet counts were also reduced. This effect was reversed upon clearance of natalizumab. There was no evidence of anemia in these offspring. Offspring exposed in utero and via breast milk had no natalizumab-related changes in the lymphoid organs and had normal immune response to challenge with a T-cell dependent antigen.

Clinical Studies

Multiple Sclerosis

natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in patients with multiple sclerosis. Both studies enrolled patients who experienced at least one clinical relapse during the prior year and had a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0. Results for each study are shown in TABLE 5 and TABLE 6. Median time on study drug was 120 weeks in each study. In both studies, neurological evaluations were performed every 12 weeks and at times of suspected relapse. Magnetic resonance imaging evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.

Study MS1 enrolled patients who had not received any interferon-beta or glatiramer acetate for at least the previous 6 months; approximately 94% had never been treated with these agents. Median age was 37, with a median disease duration of 5 years. Patients were randomized in a 2:1 ratio to receive natalizumab 300 mg intravenous infusion (n=627) or placebo (n=315) every 4 weeks for up to 28 months (30 infusions).

Study MS2 enrolled patients who had experienced one or more relapses while on treatment with AVONEX® (Interferon beta-1a) 30 mcg intramuscularly (IM) once weekly during the year prior to study entry. Median age was 39, with a median disease duration of 7 years. Patients were evenly randomized to receive natalizumab 300 mg (n=589) or placebo (n=582) every 4 weeks for up to 28 months (30 infusions). All patients continued to receive AVONEX 30 mcg IM once weekly. The efficacy of natalizumab alone was not compared with the efficacy of natalizumab plus AVONEX.

The primary endpoint at 2 years was time to onset of sustained increase in disability, defined as an increase of at least 1 point on the EDSS from baseline EDSS ≥ 1.0 that was sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS=0 that was sustained for 12 weeks. Time to onset of sustained increase in disability was longer in natalizumab-treated patients than in placebo-treated patients in Studies MS1 (FIGURE 1) and MS2. The proportion of patients with increased disability and the annualized relapse rate were also lower in natalizumab-treated patients than in placebo-treated patients in Studies MS1 and MS2.

Crohn's Disease

The safety and efficacy of natalizumab were evaluated in three randomized, double-blind, placebo-controlled clinical trials in 1414 adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] ≥220 and ≤450). Concomitant inhibitors of TNF-α were not permitted. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunosuppressants (e.g., 6-mercatopurine, azathioprine, or methotrexate) were permitted, and 89% of patients continued to receive at least one of these medications. Although permitted in the clinical trials, combination therapy with immunosuppressants is not recommended. Overall, approximately two-thirds of patients were not taking concomitant immunosuppressants, and approximately one-third of patients were taking neither concomitant immunosuppressants nor concomitant corticosteroids.

Induction of clinical response (defined as ≥70-point decrease in CDAI from baseline) was evaluated in two studies. In Study CD1, 896 patients were randomized 4:1 to receive three monthly infusions of either 300 mg natalizumab or placebo. Clinical results were assessed at Week 10, and patients with incomplete information were considered as not having a clinical response. At Week 10, 56% of the 717 patients receiving natalizumab were in response compared to 49% of the 179 patients receiving placebo (treatment effect: 7%; 95% confidence interval (CI): [-1%, 16%]; p=0.067). In a post hoc analysis of the subset of 653 patients with elevated baseline C-reactive protein (CRP), indicative of active inflammation, 57% of natalizumab patients were in response compared to 45% of those receiving placebo (treatment effect: 12%; 95% CI: [3%, 22%]; nominal p=0.01).

In the second induction trial, Study CD2, only patients with elevated serum C-reactive Protein (CRP) were studied. A total of 509 patients were randomized 1:1 to receive three monthly infusions of either 300 mg natalizumab or placebo. In Study CD2, in contrast to Study CD1, clinical response and clinical remission (defined as CDAI score <150) were required to be met at both Weeks 8 and 12, rather than at a single time-point; patients with incomplete information were considered as not having a response.

In studies CD1 and CD2, for subgroups defined by prior use of, or by inadequate response to prior therapies (i.e., corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup of patients that were taking neither concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Patients with inadequate response to inhibitors of TNF-α appeared to have lower clinical response and lower clinical remission in both the treatment and placebo groups. For patients in Study CD2 with an inadequate response to prior treatment with inhibitors of TNF-α, clinical response at both Weeks 8 and 12 was seen in 38% of those randomized to natalizumab, and clinical remission at both Weeks 8 and 12 was seen in 17%.

Maintenance therapy was evaluated in Study CD3. In this study, 331 patients from Study CD1 that had had a clinical response to natalizumab at both Weeks 10 and 12 were re-randomized 1:1 to treatment with continuing monthly infusions of either 300 mg natalizumab or placebo.

Maintenance of response was assessed by the proportion of patients who did not lose clinical response at any study visit for an additional 6 and 12 months of treatment (i.e., Month 9 and Month 15 after initial treatment with natalizumab). The study also assessed the proportion of patients who did not lose clinical remission at any study visit within the subset of those who were in remission at study entry. Requiring maintenance of response or remission at each visit, as opposed to just at Month 9 or Month 15, may result in lower proportions meeting endpoint criteria, and may make a comparison of these results with those of other products used to treat Crohn's disease misleading.

For subgroups in study CD3 defined by prior use of, or by inadequate response to prior therapies (i.e., corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup of patients that were taking neither concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Patients with inadequate response to inhibitors of TNF-α appeared to have lower maintenance of clinical response and lower maintenance of clinical remission in both the treatment and placebo groups. For patients in study CD3 with an inadequate response to prior treatment with inhibitors of TNF-α, maintenance of clinical response through Month 9 was seen in 52% of those randomized to natalizumab, and maintenance of clinical remission through Month 9 was seen in 30%.

Given the requirement to discontinue chronic steroids it is important to note that in the subgroup of patients (n=65) who were receiving corticosteroid medication at baseline, responded to natalizumab in Study CD1, and were re-randomized to natalizumab in Study CD3, approximately two-thirds were able to discontinue steroids within 10 weeks of initiating a steroid taper.

How Supplied

• 300 mg natalizumab in 15 mL

• In a sterile single-use vial free of preservatives
• NDC 64406-008-01

Storage

• Must be refrigerated between 2 to 8°C (36° to 46°F)

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

General Counseling Information

Counsel patients to understand the risks and benefits of natalizumab 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 natuzimab to:

• Read the Medication Guide before starting natalizumab and before each natalizumab 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 natalizumab.
• 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 natalizumab.

Progressive Multifocal Leukoencephalopathy

Inform patients that Progressive Multifocal Leukoencephalopathy (PML) has occurred in patients who received natalizumab. 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 natalizumab.

natalizumab TOUCH Prescribing Program

Advise the patient that natalizumab 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 natalizumab is available only from certified pharmacies and infusion centers participating in the program.

Herpes Encephalitis/Meningitis

Inform patients that natalizumab increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Instruct patients to report immediately if they experience symptoms such as fever, headache and confusion.

Hepatotoxicity

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

Hypersensitivity Reactions

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 natalizumab.

Immunosuppression/Infections

Inform patients that natalizumab 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.

Precautions with Alcohol

Alcohol-Natalizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Tysabri

Look-Alike Drug Names

There is limited information regarding Natalizumab Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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