6 ADVERSE REACTIONS

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

Progressive Multifocal Leukoencephalopathy (PML) [see Warnings and Precautions (5.1)]
Herpes Infections [see Warnings and Precautions (5.3)]
Hepatotoxicity [see Warnings and Precautions (5.4)]
Hypersensitivity/Antibody Formation [see Warnings and Precautions (5.5 )]
Immunosuppression/Infections [see Warnings and Precautions (5.6 )]
Thrombocytopenia [see Warnings and Precautions (5.8 )]

6.1 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 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 (5.5)].

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.

Multiple Sclerosis Clinical Studies

The most common 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).

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 TYSABRI-treated patients than was observed in placebo-treated patients.

Table 2: Adverse Reactions in Study MS1 (Monotherapy Study)
Adverse Reactions (Preferred Term)	TYSABRI n=627 %	Placebo n=312 %
*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.
General
Headache	38	33
Fatigue	27	21
Arthralgia	19	14
Chest discomfort	5	3
Other hypersensitivity reactions**	5	2
Acute hypersensitivity reactions**	4	<1
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 Muscle cramp Joint swelling	16 5 2	14 3 1
Gastrointestinal Abdominal discomfort Diarrhea NOS Abnormal liver function test	11 10 5	10 9 4

Skin Rash Dermatitis Pruritus Night sweats	12 7 4 1	9 4 2 0

Menstrual Disorders* Irregular menstruation Dysmenorrhea Amenorrhea Ovarian cyst	5 3 2 2	4 <1 1 <1

Neurologic Disorders Vertigo Somnolence	6 2	5 <1

Renal and Urinary Disorders Urinary urgency/frequency Urinary incontinence	9 4	7 3

Injury Limb injury NOS Skin laceration Thermal burn	3 2 1	2 <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 reactions 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 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)
Adverse Reactions*	TYSABRI n=983 %	Placebo n=431 %
* Occurred at an incidence of at least 1% higher in TYSABRI-treated patients than placebo-treated patients.
** Percentage based on female patients only.
General Headache Fatigue Arthralgia Influenza-like illness Acute hypersensitivity reactions Tremor	32 10 8 5 2 1	23 8 6 4 <1 <1

Infection Upper respiratory tract infection Vaginal infections** Viral infection Urinary tract infection	22 4 3 3	16 2 2 1

Respiratory Pharyngolaryngeal pain Cough	6 3	4 <1

Gastrointestinal Nausea Dyspepsia Constipation Flatulence Aphthous stomatitis	17 5 4 3 2	15 3 2 2 <1

Skin Rash Dry skin	6 1	4 0

Menstrual Disorder Dysmenorrhea**	2	<1

Table 4: Adverse Reactions in Study CD3 (Maintenance Study)
Adverse Reactions*	TYSABRI n=214 %	Placebo n=214 %
* Occurred at an incidence of at least 2% higher in TYSABRI-treated patients than placebo-treated patients.
** Percentage based on female patients only.
General Headache Influenza-like illness Peripheral edema Toothache	37 11 6 4	31 6 3 <1

Infection Influenza Sinusitis Vaginal infections** Viral infection	12 8 8 7	5 4 <1 3

Respiratory Cough	7	5

Gastrointestinal Lower abdominal pain	4	2

Musculoskeletal and Connective Tissue Back pain	12	8

Menstrual Disorder Dysmenorrhea**	6	3

Infections

Progressive Multifocal Leukoencephalopathy (PML) occurred in three patients who received TYSABRI in clinical trials [see Warnings and Precautions (5.1)]. 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 TYSABRI in addition to interferon beta-1a [see Warnings and Precautions (5.1)]. 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 TYSABRI-treated multiple sclerosis and Crohn's disease patients who were not receiving concomitant immunomodulatory therapy.

In Studies MS1 and MS2 [see Clinical Studies (14.1)], the rate of any type of infection was approximately 1.5 per patient-year in both TYSABRI-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 TYSABRI-treated patients and placebo-treated patients. Most patients did not interrupt treatment with TYSABRI 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 [see Clinical Studies (14.2)], the rate of any type of infection was 1.7 per patient-year in TYSABRI-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 TYSABRI-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 TYSABRI therapy during infections, and recovery occurred with appropriate treatment. Concurrent use of TYSABRI 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 TYSABRI 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 TYSABRI-treated patients and placebo-treated patients. In Study CD3, the incidence of serious infection was approximately 3.3% in TYSABRI-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 TYSABRI-treated patients; some of these patients were receiving concurrent immunosuppressants [see Warnings and Precautions (5.6)]. Two serious non-bacterial meningitides occurred in TYSABRI-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 TYSABRI-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 TYSABRI compared to 7% of placebo-treated patients. Reactions more common in the TYSABRI-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 TYSABRI. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients [see Warnings and Precautions (5.5)]. All patients recovered with treatment and/or discontinuation of the infusion.

Infusion-related reactions that were more common in CD patients receiving TYSABRI 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 TYSABRI-treated patients.

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

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to natalizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Patients in Study MS1 [see Clinical Studies (14.1)] 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 TYSABRI 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 TYSABRI. The risk of increased disability and the annualized relapse rate were similar in persistently antibody-positive TYSABRI-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 [see Clinical Studies (14.2)] 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 anti-natalizumab 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 TYSABRI and the effects of low to moderate levels of antibody to natalizumab are unknown [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of TYSABRI. 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, thrombocytopenia (including immune thrombocytopenic purpura).