Drug Safety-related Labeling Changes (SrLC)

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SPINRAZA (NDA-209531)

(NUSINERSEN SODIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/16/2020 (SUPPL-10)

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.

06/17/2019 (SUPPL-7)

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.


06/17/2019 (SUPPL-8)

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.

10/10/2018 (SUPPL-5)

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.

05/14/2018 (SUPPL-3)

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.

05/14/2018 (SUPPL-4)

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.

11/21/2017 (SUPPL-2)

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.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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