SPRAVATO

Major depressive disorder (MDD) is a significant cause of disability worldwide and the most common illness preceding suicide. 5, 3 On March 5, 2019, the nasal spray drug, esketamine, also known as Spravato (by Janssen Pharmaceuticals), was approved by the FDA for treatment-resistant major depression.

Esketamine is the s-enantiomer of

Ketamine is a mixture of two enantiomers (mirror image molecules).

This is the first time that the FDA has approved esketamine for any use.

FDA approved ketamine (Ketalar) in 1970.

Esketamine may prove to be a promising treatment for patients diagnosed with major depressive disorder who have not experienced an improvement in symptoms despite treatment with various medications and therapies.

The intranasal route of administration for this drug allows for easy administration and a fast onset of action, which sets it apart from many other antidepressant agents that may take several weeks to take effect.

Esketamine is indicated in combination with an oral antidepressant or as a monotherapy for the treatment of treatment-resistant depression in adults.

It is also indicated for the treatment of depressive symptoms in adults with major depressive disorder experiencing acute suicidal ideation or behaviour.

General effects

Esketamine is considered a central nervous system (CNS) depressant agent.

It may cause sedation, dizziness, and lethargy, among other symptoms.

This drug has dissociative and antidepressant properties.

Acutely, esketamine may impair attention, judgment, thinking, reaction speed, and motor skills.

Two placebo-controlled studies were performed to evaluate the effects of ketamine on the ability to drive.

The effects of esketamine 84 mg were comparable to placebo at 6 hours and 18 hours post-ingestion.

Effects on cardiac electrophysiology

The effect of esketamine (84 mg nasal spray and 0.8 mg/kg esketamine Intravenous infused over 40 minutes) on the QTc interval was studied in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy volunteers.

A marked increase in heart rate (higher than 10 bpm) was measured in subjects receiving intranasal and intravenous esketamine.

Summative evidence from both nonclinical and clinical data suggests a lack of clinically relevant QTc prolongation at the normal therapeutic dose of esketamine.

Effects on blood pressure

Eskestamine causes increases in systolic and/or diastolic blood pressure at all therapeutic doses.

Peak blood pressure elevation after esketamine administration occurs about 40 minutes after administration and lasts approximately 4 hours.

Cognitive effects

In a study of healthy volunteers, one dose of this agent caused decline in cognitive performance 40 minutes after administration.

Compared to subjects ingesting a placebo, esketamine-treated subjects required a higher level of effort to complete assigned cognitive tests at 40 minutes after administration.

Cognitive performance and mental effort were found to be similar between esketamine and placebo at 2 hours after administration.

Reports of long-term memory or cognitive impairment have been made following repeated ketamine misuse or abuse.

No adverse effects of esketamine nasal spray on cognitive function were seen in a one-year open-label safety study.

The long-term cognitive effects of esketamine have not been studied for more than a 1 year period, therefore, the risk of cognitive decline with long-term use is not yet confirmed.

receptor Antagonist Glutamate receptor ionotropic, NMDA 2B Antagonist Neurotrophic factor BDNF precursor form Agonist.

Due to the fact that this drug is administered via nasal spray, absorption is rapid.

The mean absolute bioavailability is approximately 48% after esketamine nasal spray administration.

The time to achieve peak esketamine plasma concentration is 20-40 minutes after the last nasal spray of esketamine.

Inter-subject variability of esketamine ranges from 27% to 66% for Cmax (maximum concentration) and 18% to 45% for AUC (area under the curve).

The intra-subject variability of esketamine is about 15% for Cmax and 10% for AUC.

The average steady-state volume of distribution of esketamine administered by the intravenous route is 709 L.

Esketamine is mainly metabolized to the noresketamine metabolite by cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A4, and to a lesser extent, CYP2C9 and CYP2C19.

Noresketamine is metabolized by cytochrome-dependent metabolic pathways followed by subsequent glucuronidation of metabolites.

Hover over products below to view reaction partners Esketamine Noresketamine.

Less than 1% of a dose of nasal esketamine is measured as unchanged drug, excreted in the urine.

Following intravenous (Intravenous) or oral (Oral) administration, esketamine-derived metabolites were mainly recovered in urine (≥ 78% of a radiolabeled dose), and a smaller percentage was measured in the feces (≤ 2% of a radiolabeled dose).

The mean terminal half-life (t1/2) ranges from 7-12 hours.

The average clearance of esketamine is approximately 89 L/hour following intravenous administration.

Elimination of the major esketamine metabolite, noresketamine, from plasma is slower than esketamine.

The decrease of noresketamine plasma concentrations occurs in a biphasic fashion, with a more rapid decline for the first 4 hours post-administration, and an average terminal t1/2 of approximately 8 hours.

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Ketamine hydrochloride

LD50: 447 mg/kg, Rat (oral) MSDS Neurotoxicity In a one-dose neuronal toxicity study with esketamine intranasal administration to adult female rats, no finding of neuronal vacuolation in the brain occurred with doses up to the equivalent of the maximum recommended human dose of 84 mg/day.

Neuronal vacuolation was not evaluated in this study.

The relevance of these findings in humans is unknown at this time.

A note on dependence and tolerance

Reports of physical dependence have been made following prolonged use of ketamine.

Withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of a drug is a common manifestation of drug dependence.

There were no withdrawal symptoms observed up to 4 weeks in subjects after stopping esketamine treatment.

Withdrawal symptoms have been observed after the discontinuation of frequently used (more than weekly) high doses of ketamine for a longer duration.

These symptoms of withdrawal have a higher chance of occurring if esketamine was similarly abused.

Symptoms of withdrawal reported to be associated with daily intake of high ketamine doses include craving, fatigue, poor appetite, and anxiety.

Therefore, monitor esketamine-treated patients for symptoms and signs of physical dependence upon the discontinuation of the drug.

Tolerance has been reported with prolonged use of ketamine.

Tolerance is characterized by a decreased response to a drug following repeated doses (i.e., a higher dose of a drug is required to produce the same effect that was previously achieved at a lower dose).

Comparable tolerance would be expected to occur with long-term use of esketamine.

Use in pregnancy

This drug may cause fetal harm, based on the findings of animal studies.

Pregnancy planning and prevention in females of reproductive potential should occur before the initiation of esketamine treatment.

There is a pregnancy registry for women who exposed to esketamine during pregnancy.

The goal of the registry is to gather data about the health of women and infants exposed to esketamine.

Use in lactation

Esketamine is present in human milk.

No safety data on the effects of esketamine on the breastfed infant or on milk production are available.

Studies in young animals report neurotoxicity.

Due to the risk of neurotoxicity, advise patients that breastfeeding is not recommended during treatment with this drug.

is contraindicated in patients with: Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation History of intracerebral hemorrhage Hypersensitivity to esketamine, ketamine, or any of the excipients.

Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.

Intracerebral hemorrhage.

Hypersensitivity to esketamine, ketamine, or any of the excipients.

SPRAVATO intranasally under the supervision of a healthcare provider.

Assess blood pressure prior to and after administration.

Evidence of therapeutic benefit should be evaluated at the end of the 4-week induction phase to determine need for continued treatment.

Depressive symptoms in MDD with acute suicidal ideation or behavior: Evidence of therapeutic benefit should be evaluated after 4 weeks to determine need for continued treatment.

Treatment beyond 4 weeks has not been systematically evaluated.

Information for recommended dosage.

Information for important administration instructions. 2.1 Important Considerations Prior to Initiating and During Therapy SPRAVATO must be administered under the direct supervision of a healthcare provider.

A treatment session consists of nasal administration of SPRAVATO and post-administration observation under supervision.

Monitor patients for changes in respiratory status for at least 2 hours (including pulse oximetry) at each treatment session.

Blood Pressure Assessment Before and After Treatment Assess blood pressure prior to dosing with SPRAVATO.

If baseline blood pressure is elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), consider the risks of short term increases in blood pressure and benefit of SPRAVATO treatment.

Do not administer

SPRAVATO if an increase in blood pressure or intracranial pressure poses a serious risk.

After dosing with

SPRAVATO, reassess blood pressure at approximately 40 minutes (which corresponds with the C max ) and subsequently as clinically warranted.

If blood pressure is decreasing and the patient appears clinically stable for at least two hours, the patient may be discharged at the end of the post-dose monitoring period; if not, continue to monitor.

Food and Liquid Intake Recommendations Prior to Administration Because some patients may experience nausea and vomiting after administration of SPRAVATO, advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration.

Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should administer these medications at least 1 hour before SPRAVATO. 2.2 Treatment-Resistant Depression The recommended dosage of SPRAVATO for the treatment of TRD in adults as monotherapy or in conjunction with an oral antidepressant is shown in Table 1.

Dosage adjustments should be made based on efficacy and tolerability.

Evidence of therapeutic benefit should be evaluated at the end of the induction phase to determine need for continued treatment.

Table 1: Recommended Dosage for SPRAVATO for TRD Adults Induction Phase Weeks to 4: Administer twice per week 56 mg or 84 mg Maintenance Phase Weeks to 8: Administer once weekly 56 mg or 84 mg Week and after: Administer every 2 weeks or once weekly Dosing frequency should be individualized to the least frequent dosing to maintain remission/response. 56 mg or 84 mg 2.3 Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior Administer SPRAVATO in conjunction with an oral antidepressant (AD).

The recommended dosage of

SPRAVATO for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior is 84 mg twice per week for 4 weeks.

Dosage may be reduced to 56 mg twice per week based on tolerability.

After 4 weeks of treatment with SPRAVATO, evidence of therapeutic benefit should be evaluated to determine need for continued treatment.

The use of

SPRAVATO, in conjunction with an oral antidepressant, beyond 4 weeks has not been systematically evaluated in the treatment of depressive symptoms in patients with MDD with acute suicidal ideation or behavior. 2.4 Administration Instructions SPRAVATO is for nasal use only.

The nasal spray device delivers a total of 28 mg of esketamine.

To prevent loss of medication, do not prime the device before use.

Use 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device.

Follow these administration instructions and read the Instructions for Use before administration: Figure Figure Figure Figure Figure Figure Figure Figure 2.5 Post-Administration Observation During and after SPRAVATO administration at each treatment session, observe the patient for at least 2 hours until the patient is safe to leave.

SPRAVATO administration, instruct patients not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery, until the next day after a restful sleep. 2.6 Missed Treatment Session(s) If a patient misses treatment session(s), provided there is no worsening of their depressive symptoms, the patient should continue the current dosing schedule.

For patients who miss treatment session(s) during maintenance treatment and have worsening of depression symptoms, per clinical judgement, consider returning to the previous dosing schedule (e.g., if doses missed during weekly dosing, revert to twice weekly dosing).

® nasal spray is available as an aqueous solution of esketamine hydrochloride in a stoppered glass vial within a nasal spray device.

Each nasal spray device delivers two sprays containing a total of 28 mg of esketamine (supplied as 32.3 mg of esketamine hydrochloride).

SPRAVATO is available in the following presentations: 56 mg Dose Kit: Unit-dose carton containing two 28 mg nasal spray devices (56 mg total dose) (NDC 50458-028-02). 84 mg Dose Kit: Unit-dose carton containing three 28 mg nasal spray devices (84 mg total dose) (NDC 50458-028-03).

Within each kit, each 28 mg device is individually packaged in a sealed blister (NDC 50458-028-00).

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) .

SPRAVATO nasal spray devices must be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) .

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO, during pregnancy.

Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at.

SPRAVATO is not recommended during pregnancy.

There are insufficient data on

SPRAVATO use in pregnant women to draw conclusions about any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Based on published findings from pregnant animals treated with ketamine, the racemic mixture of arketamine and esketamine, SPRAVATO may cause fetal harm when administered to pregnant women.

Advise pregnant women of the potential risk to an infant exposed to SPRAVATO in utero.

There are risks to the mother associated with untreated depression in pregnancy.

If a woman becomes pregnant while being treated with SPRAVATO, treatment with esketamine should be discontinued and the patient should be counseled about the potential risk to the fetus.

Published studies in pregnant primates demonstrate that the administration of drugs that block N -methyl.

• D -aspartate (NMDA) receptors during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted at maternally toxic doses when ketamine was intranasally administered with a No Observed Adverse Effect Level (NOAEL) at estimated esketamine exposures 0.3 times the exposures at the maximum recommended human dose (MRHD) of 84 mg/day. In addition, intranasal administration of esketamine to pregnant rats during pregnancy and lactation at exposures that were similar to those at the MRHD resulted in a delay in sensorimotor development in pups during the preweaning period and a decrease in motor activity in the post-weaning period.

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

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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.

Maternal and/or Embryo-Fetal Risk A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy.

The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants.

Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Based on published data, when female monkeys were treated intravenously with racemic ketamine at anesthetic dose levels in the third trimester of pregnancy, neuronal cell death was observed in the brains of their fetuses.

This period of brain development translates into the third trimester of human pregnancy.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.

Racemic ketamine was administered intranasally to pregnant rats during the period of organogenesis at doses of 15, 50, and 150 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) for embryo-fetal toxicity in rats was the highest dose of 150 mg/kg/day. Estimating 50% of the exposure to be from esketamine, the NOAEL associated with esketamine plasma exposure (AUC) is 12-times the AUC exposure at the MRHD of 84 mg/day. In pregnant rabbits, racemic ketamine was administered intranasally from gestational day to 18 at doses of 10, 30, and 100 mg/kg/day. The high dose was lowered from to 50 mg/kg after 5 days of dosing due to excessive mortality in the pregnant rabbits.

Skeletal malformations were observed at doses ≥ 30 mg/kg/day, which were maternally toxic.

NOAEL for skeletal malformations was associated with a plasma esketamine exposure (AUC) that was 0.3 times the AUC exposure at MRHD of 84 mg/day. Administration of esketamine to pregnant rats during pregnancy and lactation at intranasal doses equivalent to 4.5, 15, and 45 mg/kg/day (based on a 200-gram rat) produced AUC exposures 0.07, 0.5, and 0.7 times the MRHD of 84 mg/day, respectively.

Maternal toxicity was observed at doses ≥ 15 mg/kg/day. In addition, a dose-dependent delay in the age of attainment of Preyer response reflex was observed in pups at all doses during the preweaning period.

This sensory/motor developmental measure was tested starting on postnatal day (PND) 9, and the effect normalized by PND in treatment groups as compared with PND for the majority of the control animals.

There is no

NOAEL for this delay in sensory/motor response observed in pups during the preweaning period.

During the postweaning period, a decrease in motor activity was observed at doses ≥ 15 mg/kg which is 0.5-times the human exposure at the MRHD of 84 mg/day. The NOAEL for maternal toxicity and decreased motor activity during the postweaning period was 4.5 mg/kg/day which was associated with a plasma exposure (AUC) that was 0.07-times the AUC exposure at MRHD of 84 mg/day.

The safety and effectiveness of

SPRAVATO in pediatric patients have not been established.

Of the total number of patients in randomized, double-blind, placebo-controlled short-term clinical studies exposed to SPRAVATO, (N=2064), 238 (12%) were 65 years of age and older, and 29 (1%) were 75 years of age and older.

No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age.

The mean esketamine C max and

AUC values were higher in elderly patients compared with younger adult patients.

The efficacy of SPRAVATO for the treatment of TRD in geriatric patients was evaluated in a 4-week, randomized, double-blind study comparing flexibly-dosed intranasal SPRAVATO plus a newly initiated oral antidepressant compared to intranasal placebo plus a newly initiated oral antidepressant in patients ≥ 65 years of age.

SPRAVATO was initiated at 28 mg twice weekly and could be titrated to 56 mg or 84 mg administered twice weekly.

At the end of four weeks, there was no statistically significant difference between groups on the primary efficacy endpoint of change from baseline to Week on the Montgomery-Åsberg Depression Rating Scale (MADRS).