Approved Drug Label (PDF)
6
Adverse Reactions
6.3 Postmarketing Experience
Additions and/or
revisions underlined:
The following
adverse reactions have been identified during post-approval use of SPINRAZA. 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.
Serious infections associated with lumbar puncture, such as meningitis,
have been reported. Hydrocephalus, aseptic meningitis, hypersensitivity reactions (e.g.
angioedema, urticaria, rash), and arachnoiditis have also
been reported.
Approved Drug Label (PDF)
6
Adverse Reactions
Clinical Trials Experience
(Additions and/or
revisions underlined)
In clinical studies, 346 patients (47% male, 76% Caucasian) were treated with
SPINRAZA, including 314 exposed for at least 6 months,
258 exposed for at least 1 year, and 138 exposed for at
least 2 years. The safety
of SPINRAZA was studied in presymptomatic infants with SMA; pediatric patients (approximately 3 days to 16 years of age at first dose)
with symptomatic SMA; in a sham-controlled
trial in infants with symptomatic SMA (Study 1; n=80 for SPINRAZA, n=41 for
control); in a sham-controlled trial in children with symptomatic SMA (Study 2; n=84 for SPINRAZA,
n=42 for control); in an open-label study in presymptomatic
infants (Study 3, n=25) and other studies in symptomatic
infants (n=54) and later-onset patients (n=103).
In Study 1, 58 patients were exposed
for at least 6 months and 28
patients were exposed for at least 12
months.
Immunogenicity
(Additions and/or
revisions underlined)
The immunogenic response to nusinersen
was evaluated in 294
patients with post-baseline plasma samples for anti-drug
antibodies (ADAs). Seventeen patients (6%) developed treatment- emergent
ADAs, of which 5 were transient, 12 were
considered to be persistent.
Approved Drug Label (PDF)
6
Adverse Reactions
6.3 Postmarketing Experience
(Additions
and/or revisions underlined)
The
following adverse reactions have been identified during post-approval use of
SPINRAZA. 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.
Serious
infections associated with lumbar puncture, such as meningitis, have
been observed. Hydrocephalus, aseptic meningitis, and hypersensitivity
reactions (e.g. angioedema, urticaria, rash) have also been reported.
Approved Drug Label (PDF)
Boxed Warning
6.3 Postmarketing Experience
(Additions
and/or revisions underlined)
The
following adverse reactions have been identified during post-approval use of
SPINRAZA. 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.
Serious
infections associated with lumbar puncture, such as meningitis, have
been observed. Hydrocephalus, aseptic meningitis, and hypersensitivity
reactions (e.g. angioedema, urticaria, rash) have also been reported.
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
(additions
underlined)
Risk Summary
There are no adequate data on the developmental risk
associated with the use of SPINRAZA in pregnant women. When nusinersen
was administered by subcutaneous injection to mice throughout pregnancy
and lactation, developmental toxicity (long-term neurobehavioral impairment)
was observed at all doses tested (see
Data).
…
When nusinersen (1.4, 5.8, or 17.2 mg/kg) was
administered to pregnant female mice by subcutaneous injection every other day
throughout organogenesis and continuing once every six days throughout the
lactation period, adverse
neurobehavioral effects (alterations in locomotor activity, learning and memory
deficits) were observed when offspring were tested after weaning or as
adults. A no-effect level for
neurobehavioral impairment was not established.
8.2 Lactation
(additions underlined)
Risk Summary
There are no data on the presence of nusinersen in human
milk, the effects on the breastfed infant, or the effects of the drug on milk
production.Nusinersen was detected in the milk of lactating mice when
administered by subcutaneous injection. The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical
need for SPINRAZA and any potential adverse effects on the breastfed infant
from SPINRAZA or from the underlying maternal condition.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Thrombocytopenia and Coagulation Abnormalities
(additions
underlined)
Coagulation
abnormalities and thrombocytopenia, including acute severe thrombocytopenia,
have been observed after administration of some antisense oligonucleotides.
In sham-controlled studies for patients with
infantile-onset and later-onset SMA, 24 of 146
(16%) SPINRAZA-treated patients with high, normal, or unknown platelet count
at baseline developed a platelet level below the lower limit of normal,
compared to 10 of 72 (14%) sham- controlled patients.
In the sham-controlled study in patients with
later-onset SMA (Study 2), two SPINRAZA-treated patients developed
platelet counts less than 50,000 cells per microliter, with a lowest level
of 10,000 cells per microliter recorded on day 28.
Because of the risk of thrombocytopenia and coagulation abnormalities from SPINRAZA,
patients may be at increased risk of bleeding complications.
Perform a platelet count and coagulation laboratory
testing at baseline and prior to each administration of SPINRAZA and as
clinically needed.
5.2 Renal Toxicity
(additions
underlined)
Renal toxicity, including potentially fatal
glomerulonephritis, has been observed after administration of some antisense
oligonucleotides.
SPINRAZA is present in and excreted by the kidney. In the
sham-controlled studies for patients with infantile-onset and later-onset SMA,
71 of 123 (58%) of SPINRAZA-treated patients had elevated urine
protein, compared to 22 of 65 (34%) sham- controlled patients. Conduct quantitative spot urine protein
testing (preferably using a first morning urine specimen) at baseline and prior
to each dose of SPINRAZA. For urinary protein concentration greater than 0.2
g/L, consider repeat testing and further evaluation.
6
Adverse Reactions
6.1 Clinical Trials Experience
(additions
and revisions, please refer to label)
6.2 Immunogenicity
(additions
underlined)
As with all oligonucleotides, there is
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 nusinersen in the studies described below with the
incidence of antibodies in other studies or to other products may be
misleading.
The immunogenic response to nusinersen was
determined in 249 patients with post-baseline plasma samples evaluated for
anti-drug antibodies (ADAs). Sixteen patients (6%) developed treatment-emergent
ADAs, of which 3 were transient,13 were considered to be persistent.
Persistent was defined as having one positive
test followed by another one more than 100 days after the first positive test.
In addition, “persistent” is also defined as having one or more positive
samples and no sample more than 100 days after the first positive sample.
Transient was defined as having one or more positive results and not confirmed
to be persistent. There are insufficient
data to evaluate an effect of ADAs on clinical response, adverse events, or the
pharmacokinetic profile of nusinersen.
Approved Drug Label (PDF)
6
Adverse Reactions
6.3 Postmarketing Experience
(additions underlined)
The
following adverse reactions have been identified during post-approval use of SPINRAZA.
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.
Serious infections (including
meningitis) and hydrocephalus have occurred in patients treated with
SPINRAZA via lumbar puncture.
Approved Drug Label (PDF)
6
Adverse Reactions
6.3 Postmarketing Experience
(Newly added subsection)
The following adverse reactions have
been identified during post-approval use of SPINRAZA. 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.
Serious infections, including
meningitis, have occurred as complications of lumbar puncture in patients
treated with SPINRAZA.