TYSABRI (Page 3 of 7)

5.7 Laboratory Test Abnormalities

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

5.8 Thrombocytopenia

Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported with the use of TYSABRI in the postmarketing setting. Symptoms of thrombocytopenia may include easy bruising, abnormal bleeding, and petechiae. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, TYSABRI should be discontinued.

5.9 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.

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)	TYSABRIn=627%	Placebon=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	1652	1431
Gastrointestinal Abdominal discomfort Diarrhea NOS Abnormal liver function test	11105	1094
Skin Rash Dermatitis Pruritus Night sweats	12741	9420
Menstrual Disorders* Irregular menstruation Dysmenorrhea Amenorrhea Ovarian cyst	5322	4<11<1
Neurologic Disorders Vertigo Somnolence	62	5<1
Renal and Urinary Disorders Urinary urgency/frequency Urinary incontinence	94	73
Injury Limb injury NOS Skin laceration Thermal burn	321	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*	TYSABRIn=983%	Placebon=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	32108521	23864<1<1
Infection Upper respiratory tract infection Vaginal infections** Viral infection Urinary tract infection	22433	16221
Respiratory Pharyngolaryngeal pain Cough	63	4<1
Gastrointestinal Nausea Dyspepsia Constipation Flatulence Aphthous stomatitis	175432	15322<1
Skin Rash Dry skin	61	40
Menstrual Disorder Dysmenorrhea**	2	<1

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

Adverse Reactions*	TYSABRIn=214%	Placebon=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	371164	3163<1
Infection Influenza Sinusitis Vaginal infections** Viral infection	12887	54<13
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.