IMPORTANT SAFETY INFORMATION
WARNING: Progressive Multifocal Leukoencephalopathy (PML)
TYSABRI® (natalizumab) increases the risk of 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 TYSABRI.
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 including a
gadolinium-enhanced MRI scan of the brain and, when indicated,
cerebrospinal fluid analysis for JC viral DNA are recommended.
Because of the risk of PML, TYSABRI is available only through a
restricted program under a Risk Evaluation and Mitigation Strategy
(REMS) called the TOUCH Prescribing Program.
- Infection by the JC Virus (JCV) is required for the
development of PML.
- There are no known interventions that can reliably prevent
PML or that can adequately treat PML if it occurs. It is not known
whether early detection of PML and discontinuation of TYSABRI will
mitigate the disease.
- PML has been reported after discontinuation of TYSABRI 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
approximately 6 months after discontinuation of TYSABRI.
- Adverse events that 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 the majority of 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 a clinical decline in the
patient's condition after TYSABRI 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. 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.
- TYSABRI is contraindicated in patients who have or have had
- TYSABRI is contraindicated in patients who have had
a hypersensitivity reaction to TYSABRI.
TYSABRI TOUCH Prescribing Program
- Because of the risk of PML, TYSABRI is available only
through a restricted distribution program under a REMS called the TOUCH®
Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide,
understand the risks associated with TYSABRI and complete and sign the Patient-Prescriber Enrollment Form.
Herpes Encephalitis and Meningitis
- TYSABRI 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 TYSABRI.
- The duration of treatment with TYSABRI prior to onset
ranged from a few months to several years.
- Monitor patients receiving TYSABRI for signs and symptoms
of meningitis and encephalitis. If herpes encephalitis or
meningitis occurs, TYSABRI should be discontinued, and appropriate
treatment for herpes encephalitis/meningitis should be
- Clinically significant liver injury, including acute liver
failure requiring transplant, 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.
- TYSABRI should be discontinued in patients with jaundice or
other evidence of significant liver injury (e.g., laboratory
- Hypersensitivity reactions have occurred in patients
receiving TYSABRI, including serious systemic reactions (e.g.,
anaphylaxis) which occurred at an incidence of <1%.
- Reactions usually occur within 2 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.
- 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 with patients who did not
develop antibodies to TYSABRI in both MS and CD studies.
- Patients who receive TYSABRI after an extended period
without treatment may be at higher risk of hypersensitivity
- The immune system effects of TYSABRI may increase the risk
- 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 TYSABRI-treated
patients than in placebo-treated patients. One opportunistic
infection, a cryptosporidial gastroenteritis with a prolonged
course, was observed in a patient who received TYSABRI in Study
- 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.
- Concurrent use of antineoplastic, immunosuppressant, or
immunomodulating agents may further increase the risk of infections
over the risk observed with use of TYSABRI alone.
- In Studies MS1 and MS2, the rate of any type of infection
was approximately 1.5 per patient-year in both TYSABRI-treated
patients and placebo-treated patients.
- In Study MS1, the incidence of serious infections was
approximately 3% in TYSABRI-treated patients and in
placebo-treated patients. Most patients did not interrupt treatment
with TYSABRI during infections.
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 that are frequently transient.
- The most common adverse reactions reported at an incidence
of ≥10% with TYSABRI and ≥2% difference with placebo were
headache (38% vs 33%), fatigue (27% vs 21%),
infusion reactions (24% vs 18%), urinary tract infections (21%
vs 17%), arthralgia (19% vs 14%), depression (19% vs
16%), pain in extremity (16% vs 14%), rash (12% vs 9%),
gastroenteritis (11% vs 9%), and vaginitis (10% vs 6%).
- The most frequently reported serious adverse reactions in
Study MS1 were infections (3.2% vs 2.6% placebo), including urinary
tract infection (0.8% vs 0.3%) and pneumonia (0.6% vs 0%),
acute hypersensitivity reactions (1.1% vs 0.3%, including
anaphylaxis/anaphylactoid reaction [0.8% vs 0%]), depression
(1.0% vs 1.0%, including suicidal ideation or attempt
[0.6% vs 0.3%]), and cholelithiasis (1.0% vs 0.3%).
- Based on animal data, TYSABRI may cause fetal harm. TYSABRI
should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. If a woman becomes
pregnant while taking TYSABRI, consider enrolling her in the
TYSABRI Pregnancy Exposure Registry, by calling 1-800-456-2255.
Please see Full Prescribing Information,
including Boxed Warning.