Tysabri

natalizumab

Dosage Form: injection
FULL PRESCRIBING INFORMATION

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Cases of PML have been reported in patients taking Tysabri who were recently or concomitantly treated with immunomodulators or immunosuppressants, as well as in patients receiving Tysabri as monotherapy [seeWarnings and Precautions (5.1)].

• Because of the risk of PML, Tysabri is available only through a special restricted distribution program called the TOUCH® Prescribing Program. Under the TOUCH® Prescribing Program, only prescribers, infusion centers, and pharmacies associated with infusion centers registered with the program are able to prescribe, distribute, or infuse the product. In addition, Tysabri must be administered only to patients who are enrolled in and meet all the conditions of the TOUCH® Prescribing Program [see Warnings and Precautions (5.1, 5.2)].


• Healthcare professionals should monitor patients on Tysabri for any new sign or symptom that may be suggestive of PML. Tysabri 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 [see Contraindications (4), Warnings and Precautions (5.1)].

Indications and Usage for Tysabri

Multiple Sclerosis (MS)

 Tysabri is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. The efficacy of Tysabri beyond two years is unknown.

Because Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability, Tysabri is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate multiple sclerosis therapy [see Boxed Warning, Warnings and Precautions (5.1)].

Safety and efficacy in patients with chronic progressive multiple sclerosis have not been studied.

Crohn's Disease (CD)

Tysabri 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. Tysabri should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α [see Boxed Warning, Warnings and Precautions (5.1)].

Tysabri Dosage and Administration

Multiple Sclerosis (MS)

Only prescribers registered in the MS TOUCH® Prescribing Program may prescribe Tysabri for multiple sclerosis [see Boxed Warning, Warnings and Precautions (5.2)]. The recommended dose of Tysabri for multiple sclerosis is 300 mg intravenous infusion over one hour every four weeks.

Crohn's Disease (CD)

Only prescribers registered in the CD TOUCH® Prescribing Program may prescribe Tysabri for Crohn's disease [see Boxed Warning, Warnings and Precautions (5.1)].

The recommended dose of Tysabri for Crohn's disease is 300 mg intravenous infusion over one hour every four weeks. Tysabri 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 Tysabri.

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

Dilution Instructions

1. Use aseptic technique when preparing Tysabri solution for intravenous infusion. Each vial is intended for single use only.


2. Tysabri is a colorless, clear to slightly opalescent concentrate. Inspect the Tysabri 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 Tysabri concentrate from the vial using a sterile needle and syringe. Inject the concentrate into 100 mL 0.9% Sodium Chloride Injection, USP. No other IV diluents may be used to prepare the Tysabri solution.


4. Gently invert the Tysabri 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 Tysabri solution immediately, or refrigerate solution at 2 to 8°C, and use within 8 hours. If stored at 2 to 8°C, allow the solution to warm to room temperature prior to infusion. DO NOT FREEZE.

Administration Instructions

• Infuse Tysabri 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 Tysabri 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 [see Warnings and Precautions (5.3)].


• Use of filtration devices during administration has not been evaluated. Other medications should not be injected into infusion set side ports or mixed with Tysabri.

Dosage Forms and Strengths

Tysabri is a concentrated solution that must be diluted prior to intravenous infusion. Tysabri injection is supplied as 300 mg natalizumab in 15 mL (20 mg/mL) in a sterile, single-use vial free of preservatives.

Contraindications

• Tysabri is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML) [see Boxed Warning, Warnings and Precautions (5.1)].


• Tysabri should not be administered to a patient who has had a hypersensitivity reaction to Tysabri. Observed reactions range from urticaria to anaphylaxis [see Warnings and Precautions (5.3)].

Warnings and Precautions

Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC virus, that typically only occurs in patients who are immunocompromised, developed in three patients who received Tysabri in clinical trials [see Boxed Warning]. Two cases of PML were observed among 1869 patients with multiple sclerosis treated for a median of 120 weeks. The third case occurred among 1043 patients with Crohn's disease after the patient received eight doses. Both multiple sclerosis patients were receiving concomitant immunomodulatory therapy and the Crohn's disease patient had been treated in the past with immunosuppressive therapy.

 In the postmarketing setting, additional cases of PML have been reported in multiple sclerosis patients who were receiving no concomitant immunomodulatory therapy. In patients treated with Tysabri, the risk of developing PML increases with longer treatment duration, and for patients treated for 24 to 36 months is generally similar to the rates seen in clinical trials. There is limited experience beyond 3 years of treatment. 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 Tysabri will mitigate the disease.

 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 Tysabri.

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

In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy withTysabri. This MRI may be helpful in differentiating subsequent multiple sclerosis symptomsfrom PML.

In Crohn's disease patients, a baseline brain MRI may also be helpful to distinguish preexistentlesions from newly developed lesions, but brain lesions at baseline that could causediagnostic difficulty while on Tysabri therapy are uncommon.

Healthcare professionals should monitor patients on Tysabri for any new sign orsymptom suggestive of PML. Typical symptoms associated with PML are diverse, progress overdays 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 andpersonality changes. The progression of deficits usually leads to death or severe disability overweeks or months. Withhold Tysabri dosing immediately at the first sign or symptom suggestiveof 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. 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 Tysabri 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 Tysabri treated patients with PML, it has been used in such patients in the postmarketing setting to remove Tysabri more quickly from the circulation.

 Immune reconstitution inflammatory syndrome (IRIS) has been reported in Tysabri treated patients who developed PML and subsequently discontinued Tysabri. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating Tysabri. It presents as an unanticipated clinical decline in the patient's condition after return of immune function (and in some cases after apparent clinical improvement) and, in the case of PML, is often followed by characteristic changes in the MRI. Tysabri has not been associated with IRIS in patients discontinuing treatment with Tysabri for reasons unrelated to PML. In Tysabri 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.

Distribution Program for Tysabri

Tysabri is available only under a special restricted distribution program called the TOUCH® Prescribing Program. Under the TOUCH® Prescribing Program, only prescribers, infusion centers, and pharmacies associated with infusion centers registered with the program are able to prescribe, distribute, or infuse the product. 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). Tysabri must be administered only to patients who are enrolled in and meet all the conditions of the MS or CD TOUCH® Prescribing Program. Contact the TOUCH® Prescribing Program at 1-800-456-2255 [see Boxed Warning].

To enroll in the TOUCH® Prescribing Program, prescribers and patients are required to understand the risks of treatment with Tysabri, including PML and other opportunistic infections. Prescribers are required to understand the information in the Prescribing Information and to be able to:

• Educate patients on the benefits and risks of treatment with Tysabri, ensure that the patient receives the Medication Guide, instruct them to read it, and encourage them to ask questions when considering Tysabri. Patients may be educated by the enrolled prescriber or a healthcare provider under that prescriber's direction.


• Review the TOUCH® Prescriber/Patient Enrollment form for Tysabri with the patient and answer all questions.


• As part of the initial prescription process for Tysabri, obtain the patient's signature and initials on the TOUCH® program enrollment form, sign it, place the original signed form in the patient's medical record, send a copy to Biogen Idec, and give a copy to the patient.


• Report serious opportunistic and atypical infections with Tysabri to Biogen Idec or Elan at 1-800-456-2255 and to the Food and Drug Administration's MedWatch Program at 1-800-FDA-1088.


• Evaluate the patient three months after the first infusion, six months after the first infusion, and every six months thereafter.


• Determine every six months whether patients should continue on treatment and if so reauthorize treatment every six months.


• Submit to Biogen Idec the Tysabri Patient Status Report and Reauthorization Questionnaire six months after initiating treatment and every six months thereafter.

Hypersensitivity/Antibody Formation

Hypersensitivity reactions have occurred in patients receiving Tysabri, 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 Tysabri.

If a hypersensitivity reaction occurs, discontinue administration of Tysabri and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with Tysabri. Hypersensitivity reactions were more frequent in patients with antibodies to Tysabri compared to patients who did not develop antibodies to Tysabri in both MS and CD studies. Therefore, the possibility of antibodies to Tysabri should be considered in patients who have hypersensitivity reactions [see Adverse Reactions (6.2)].

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 Tysabri in a patient with persistent antibodies.

Experience with monoclonal antibodies, including Tysabri, 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 Tysabri 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 Tysabri naïve patients [see Adverse Reactions (6.2)].

Immunosuppression/Infections

The immune system effects of Tysabri may increase the risk for infections. In Study MS1 [see Clinical Studies (14.1)], 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 Tysabri-treated patients than in placebo-treated patients [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received Tysabri 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 Tysabri-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 Tysabri-treated patients; some of these patients were receiving concurrent immunosuppressants [see Boxed Warning, Warnings and Precautions (5.1, 5.4), Adverse Reactions (6.1)].

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 Tysabri-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 Tysabri alone [see Boxed Warning, Warnings and Precautions (5.1), Adverse Reactions (6.1)]. The safety and efficacy of Tysabri 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 Tysabri.

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

Hepatotoxicity

Clinically significant liver injury has been reported in patients treated with Tysabri 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 Tysabri 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.

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

Laboratory Test Abnormalities

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

Immunizations

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

Adverse Reactions

Clinical Trials Experience

The most serious adverse reactions were [see Warnings and Precautions (5)]:

• Progressive Multifocal Leukoencephalopathy (PML)


• Hypersensitivity


• Immunosuppression/Infections

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 Tysabri), 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%) [see Warnings and Precautions (5.3)].

A total of 1617 multiple sclerosis patients in controlled studies received Tysabri, with a median duration of exposure of 28 months. A total of 1563 patients received Tysabri 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.

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of Tysabri cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reaction information does, however, provide a basis for identifying the adverse events that appear to be related to drug use and a basis for approximating rates.

Multiple Sclerosis Clinical Studies

The most frequently reported serious adverse reactions in Study MS1 [see Clinical Studies (14.1)] with Tysabri 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 Tysabri (0.8% versus 0.2% in placebo) [see Warnings and Precautions (5.4), Adverse Reactions - Infections].

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

Table 1. Adverse Reactions in Study MS1 (Monotherapy Study)

*Percentage based on female patients only.
**Acute versus other hypersensitivity reactions are defined as occurring within 2 hours post-infusion versus more than 2 hours.
Adverse Reactions (Preferred Term)	Tysabri n=627 Percentage	Placebo n=312 Percentage
General
Headache	38%	33%
Fatigue	27%	21%
Arthralgia	19%	14%
Chest discomfort	5%	3%
Acute hypersensitivity reactions**	4%	<1%
Other hypersensitivity reactions**	5%	2%
Seasonal allergy	3%	2%
Rigors	3%	<1%
Weight increased	2%	<1%
Weight decreased	2%	<1%
Infection
Urinary tract infection	21%	17%
Lower respiratory tract infection	17%	16%
Gastroenteritis	11%	9%
Vaginitis*	10%	6%
Tooth infections	9%	7%
Herpes	8%	7%
Tonsillitis	7%	5%
Psychiatric
Depression	19%	16%
Musculoskeletal/Connective Tissue Disorders
Pain in extremity	16%	14%
Muscle cramp	5%	3%
Joint swelling	2%	1%
Gastrointestinal
Abdominal discomfort	11%	10%
Diarrhea NOS	10%	9%
Abnormal liver function test	5%	4%
Skin
Rash	12%	9%
Dermatitis	7%	4%
Pruritus	4%	2%
Night sweats	1%	0%
Menstrual Disorders*
Irregular menstruation	5%	4%
Dysmenorrhea	3%	<1%
Amenorrhea	2%	1%
Ovarian cyst	2%	<1%
Neurologic Disorders
Somnolence	2%	<1%
Vertigo	6%	5%
Renal and Urinary Disorders
Urinary incontinence	4%	3%
Urinary urgency/frequency	9%	7%
Injury
Limb injury NOS	3%	2%
Skin laceration	2%	<1%
Thermal burn	1%	<1%

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

Crohn's Disease Clinical Studies

The following serious adverse events in the induction Studies CD1 and CD2 [see Clinical Studies (14.2)] were reported more commonly with Tysabri 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 2 enumerates adverse drug reactions that occurred in Studies CD1 and CD2 (median exposure of 2.8 months). Table 3 enumerates adverse drug reactions that occurred in Study CD3 (median exposure of 11.0 months).

Table 2. Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

*Occurred at an incidence of at least 1% higher in Tysabri-treated patients than placebo-treated patients.
**Percentage based on female patients only.
Adverse Reactions*	Tysabri n=983 Percentage	Placebo n=431 Percentage
General
Headache	32%	23%
Fatigue	10%	8%
Arthralgia	8%	6%
Influenza-like illness	5%	4%
Acute hypersensitivity reactions	2%	<1%
Tremor	1%	<1%
Infection
Upper respiratory tract infection	22%	16%
Vaginal infections**	4%	2%
Viral infection	3%	2%
Urinary tract infection	3%	1%
Respiratory
Pharyngolaryngeal pain	6%	4%
Cough	3%	<1%
Gastrointestinal
Nausea	17%	15%
Dyspepsia	5%	3%
Constipation	4%	2%
Flatulence	3%	2%
Aphthous stomatitis	2%	<1%
Skin
Rash	6%	4%
Dry skin	1%	0%
Menstrual Disorder
Dysmenorrhea**	2%	<1%

Table 3. Adverse Reactions in Study CD3 (Maintenance Study)

*Occurred at an incidence of at least 2% higher in Tysabri-treated patients than placebo-treated patients.
**Percentage based on female patients only.
Adverse Reactions*	Tysabri n=214 Percentage	Placebo n=214 Percentage
General
Headache	37%	31%
Influenza-like illness	11%	6%
Toothache	4%	<1%
Peripheral edema	6%	3%
Infection
Influenza	12%	5%
Sinusitis	8%	4%
Viral infection	7%	3%
Vaginal infections**	8%	<1%
Respiratory