SPINRAZA

An antisense oligonucleotide that induces survival motor neuron (SMN) protein expression, it was approved by the U.S. FDA in December, 2016 as Spinraza for the treatment of children and adults with spinal muscular atrophy (SMA).

It is adminstrated as direct intrathecal injection.

Indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.

Autopsy samples from patients (n=3) had higher levels of SMN2 messenger ribonucleic acid (mRNA) containing exon in the thoracic spinal cord compared to untreated SMA infants.

In 121 patients with spinal muscular atrophy who received either nusinersen or sham-control, QTcF values >500 ms and change from baseline values >60 ms were observed in 5% of patients receiving nusinersen.

Compared to the sham-control, there was no increase in the incidence of cardiac adverse reactions associated with delayed ventricular repolarization in patients treated with nusinersen.

Intrathecal injection of nusinersen into the cerebrospinal fluid (CSF) allows it to be distributed from the CSF to the target central nervous system (CNS) tissues.

Following intrathecal administration, trough plasma concentrations of nusinersen were relatively low, compared to the trough CSF concentration.

Median plasma

Tmax values ranged from 1.7-6.0 hours.

Mean plasma Cmax and

AUC values increased approximately dose-proportionally up to a dose of 12 mg.

Nusinersen is metabolized via exonuclease (3' - and 5')-mediated hydrolysis primarily at the 3' end of the oligonucleotide.

It is not a substrate for, or inhibitor or inducer of CYP450 enzymes.

N-1 metabolites of the drug can be detected in the cerebrospinal fluid while N-1,2,3 metabolites can be predominantly detected in the plasma 2.

Excreted by the kidney as chain-shortened oligonucleotides, which are not considered pharmacologically active.

The mean terminal elimination half-life is estimated to be 135-177 days in CSF, and 63-87 days in plasma Label.

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Single injection to adult monkeys produced apparent acute neurological impairment.

is administered intrathecally Recommended Dosage The recommended dosage is one of two options: Low Dose Regimen: Administer one 12 mg loading dose every 14 days for three doses; then a fourth 12 mg loading dose 30 days after the third dose; then administer a 12 mg maintenance dose once every 4 months thereafter.

Administer one 50 mg loading dose followed by a second 50 mg loading dose 14 days later; then administer a 28 mg maintenance dose once every 4 months thereafter.

Important Preparation and Administration Instructions

Allow to warm to room temperature prior to administration Administer within 4 hours of removal from vial Prior to administration, remove 5 mL of cerebrospinal fluid Administer as intrathecal bolus injection over to 3 minutes Laboratory Testing and Monitoring to Assess Safety At baseline and prior to each dose, obtain a platelet count, coagulation laboratory testing, and quantitative spot urine protein testing 2.1 Recommended Dosage SPINRAZA is administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures.

Two dosing regimen options for

SPINRAZA, which consist of loading followed by maintenance dosages, are presented in Table 1.

Table 1: Recommended Dosage for SPINRAZA Loading Dosages Maintenance Dosage Low Dose Regimen (Low dose with four loading doses) Administer a total of four loading doses as follows: one 12 mg dose every 14 days for three doses, then a fourth 12 mg dose 30 days after the third dose.

Administer 12 mg once every 4 months starting 4 months after the last loading dose.

Regimen (High dose with two loading doses) Administer a total of two loading doses as follows: one 50 mg dose followed by a second 50 mg dose 14 days later.

Administer 28 mg once every 4 months starting 4 months after the last loading dose. 2.2 Missed Doses Missed Dose of Low Dose Regimen Missed Loading Dose If a 12 mg loading dose (any of the 4 loading doses) is missed, administer the missed loading dose as soon as possible; adjust the date for the subsequent doses to maintain the recommended interval between doses.

Less than 8 months from last maintenance dose Administer the missed 12 mg maintenance dose as soon as possible; then administer the next maintenance dose per the originally scheduled date, as long as these two doses are administered at least 14 days apart.

At least 8 months but less than 16 months from last maintenance dose Administer the missed 12 mg maintenance dose as soon as possible, followed by one additional dose 14 days later, and then administer the next maintenance dose 4 months thereafter.

At least 16 months but less than 40 months from last maintenance dose Administer the missed 12 mg maintenance dose as soon as possible, followed by two additional doses 14 days apart, and then administer the next maintenance dose 4 months thereafter.

At least 40 months from last dose Restart Low Dose Regimen with 12 mg loading dosesas described in Recommended Dosage.

Missed Dose of High Dose Regimen Missed Second 50 mg Loading Dose Administer the missed 50 mg loading dose as soon as possible; then administer 28 mg maintenance doses every 4 months thereafter.

Missed 28 mg Maintenance Dose Less than 8 months from last maintenance dose Administer the missed 28 mg maintenance dose as soon as possible; administer the next 28 mg maintenance dose per the originally scheduled date, as long as these two doses are administered at least 14 days apart; then administer 28 mg every 4 months thereafter.

At least 8 months to less than 40 months from last maintenance dose Administer a 50 mg loading dose as soon as possible; then administer 28 mg maintenance doses every 4 months thereafter.

At least 40 months from last maintenance dose Restart High Dose Regimen with two 50 mg loading doses as described in Recommended Dosage. 2.3 Important Preparation and Administration Instructions SPINRAZA is for intrathecal use only.

Prepare and use

SPINRAZA according to the following steps using aseptic technique.

Each vial is intended for single dose only.

Use the vial strength that corresponds to the prescribed dose.

Do not combine

SPINRAZA vials of different strengths and concentrations or use partial vials to achieve the prescribed dose.

SPINRAZA in the carton in a refrigerator until time of use.

Allow the

SPINRAZA vial to warm to room temperature (25 o C/77 o F) prior to administration.

Do not use external heat sources.

Inspect the

SPINRAZA vial for particulate matter and discoloration prior to administration.

Do not administer

SPINRAZA if visible particulates are observed or if the liquid in the vial is discolored.

The use of external filters is not required.

Withdraw 5 mL of SPINRAZA from the single-dose vial into a syringe and discard unused contents of the vial.

SPINRAZA within 4 hours of removal from vial.

Consider sedation as indicated by the clinical condition of the patient.

Consider ultrasound or other imaging techniques to guide intrathecal administration of SPINRAZA, particularly in younger patients.

Prior to administration, remove 5 mL of cerebrospinal fluid.

SPINRAZA as an intrathecal bolus injection over to 3 minutes using a spinal anesthesia needle.

SPINRAZA in areas of the skin where there are signs of infection or inflammation. 2.4 Laboratory Testing and Monitoring to Assess Safety Conduct the following laboratory tests at baseline and prior to each dose of SPINRAZA and as clinically needed: Platelet count Prothrombin time; activated partial thromboplastin time Quantitative spot urine protein testing 2.5 Transition Between SPINRAZA Dose Regimens If transitioning from SPINRAZA Low Dose Regimen to High Dose Regimen, administer a single 50 mg bolus dose at least four months (+/ - 14 days) after the last 12 mg maintenance dose, followed by a 28 mg maintenance dose once every 4 months thereafter.

Additional clinical benefit in patients who transition from the Low Dose Regimen to the High Dose Regimen has not been established in a controlled study.

SPINRAZA injection is a sterile, clear and colorless, preservative-free solution in single-dose glass vials supplied as one vial per carton in the following strengths: 12 mg/5 mL (2.4 mg/mL) (NDC 64406-058-01) 28 mg/5 mL (5.6 mg/mL) (NDC 64406-036-01) 50 mg/5 mL (10 mg/mL) (NDC 64406-037-01) 16.2 Storage and Handling Store in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

SPINRAZA should be protected from light and kept in the original carton until time of use.

If no refrigeration is available, SPINRAZA may be stored in its original carton, protected from light at or below 30 o C (86 o F) for up to 14 days.

Prior to administration, unopened vials of SPINRAZA can be removed from and returned to the refrigerator, if necessary.

If removed from the original carton, the total combined time out of refrigeration should not exceed 30 hours at a temperature that does not exceed 25 o C (77 o F).

Store in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

SPINRAZA should be protected from light and kept in the original carton until time of use.

If no refrigeration is available, SPINRAZA may be stored in its original carton, protected from light at or below 30 o C (86 o F) for up to 14 days.

Prior to administration, unopened vials of SPINRAZA can be removed from and returned to the refrigerator, if necessary.

If removed from the original carton, the total combined time out of refrigeration should not exceed 30 hours at a temperature that does not exceed 25 o C (77 o F).

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.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

When nusinersen (0, 3, 10, or 25 mg/kg) was administered subcutaneously to male and female mice every other day prior to and during mating and continuing in females throughout organogenesis, no adverse effects on embryofetal development were observed.

Subcutaneous administration of nusinersen (0, 6, 12.6, or 25 mg/kg) to pregnant rabbits every other day throughout organogenesis produced no evidence of embryofetal developmental toxicity.

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.

The safety and effectiveness of

SPINRAZA in pediatric patients from newborn to 17 years have been established.

In intrathecal toxicity studies in juvenile monkeys, administration of nusinersen (0, 0.3, 1, or 3 mg/dose for 14 weeks and 0, 0.3, 1, or 4 mg/dose for 53 weeks) resulted in brain histopathology (neuronal vacuolation and necrosis/cellular debris in the hippocampus) at the mid and high doses and acute, transient deficits in lower spinal reflexes at the high dose in each study.

In addition, possible neurobehavioral deficits were observed on a learning and memory test at the high dose in the 53-week monkey study.

In a combined and 13 week toxicity study in juvenile monkeys, intrathecal administration of nusinersen at higher doses (0, 5, 10, or 15 mg/dose) resulted in additional acute, transient effects, including limited use of limbs at the mid and high dose and uncoordinated movement at the high dose.

The no-effect dose for neurohistopathology in monkeys (0.3 mg/dose) is approximately equivalent to and lower than the recommended clinical maintenance doses of and 28 mg, respectively, when calculated on annual dose basis and corrected for species differences in CSF volume.

Clinical studies of

SPINRAZA did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.