Spravato

WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS

• Risk for sedation, dissociation, and respiratory depression after administration. Monitor patients for at least two hours after administration. (
  
  

  5.1 Sedation

  SPRAVATO may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing. In clinical trials, 48% to 61% of SPRAVATO-treated patients developed sedation based on the Modified Observer's Assessment of Alertness/Sedation scale (MOAA/S)

  [see Adverse Reactions (6.1)]

  , and 0.3% to 0.4% of SPRAVATO-treated patients experienced loss of consciousness (MOAA/S score of 0).

  Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting

  [see Dosage and Administration (2.5)]

  .

  Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants

  [see Drug Interactions (7.1)]

  .

  SPRAVATO is available only through a restricted program under a REMS

  [see Warnings and Precautions (5.5)]

  .

  ,
  
  

  5.2 Dissociation

  The most common psychological effects of SPRAVATO were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO-treated patients developed dissociative or perceptual changes based on the Clinician-Administered Dissociative States Scale)

  [see Adverse Reactions (6.1)]

  . Given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO; treatment should be initiated only if the benefit outweighs the risk.

  Because of the risks of dissociation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting

  [see Dosage and Administration (2.5)]

  .

  SPRAVATO is available only through a restricted program under a REMS

  [see Warnings and Precautions (5.5)]

  .

  ,
  
  

  5.3 Respiratory Depression

  In post marketing experience, respiratory depression was observed with the use of SPRAVATO. In addition, there were rare reports of respiratory arrest

  [see Adverse Reactions (6.2)]

  .

  Because of the risks of respiratory depression, patients must be monitored for changes in respiratory status by a healthcare provider for at least 2 hours (including pulse oximetry) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting

  [see Dosage and Administration (2.5)]

  .

  SPRAVATO is available only through a restricted program under a REMS

  [see Warnings and Precautions (5.5)]

  .

  )
  
  
• Potential for abuse and misuse. Consider the risks and benefits of prescribing SPRAVATO prior to using in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse. (
  
  

  5.4 Abuse and Misuse

  SPRAVATO contains esketamine, a Schedule III controlled substance (CIII), and may be subject to abuse and diversion. Assess each patient's risk for abuse or misuse prior to prescribing SPRAVATO and monitor all patients receiving SPRAVATO for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of SPRAVATO. Individuals with a history of drug abuse or dependence are at greater risk; therefore, use careful consideration prior to treatment of individuals with a history of substance use disorder and monitor for signs of abuse or dependence

  [see Drug Abuse and Dependence (9)]

  .

  SPRAVATO is available only through a restricted program under a REMS

  [see Warnings and Precautions (5.5)]

  .

  )
  
  
• SPRAVATO is only available through a restricted program called the SPRAVATO REMS. (
  
  

  5.5 SPRAVATO Risk Evaluation and Mitigation Strategy (REMS)

  SPRAVATO is available only through a restricted program under a REMS called the SPRAVATO REMS because of the risks of serious adverse outcomes from sedation, dissociation, respiratory depression, abuse and misuse

  [see Boxed Warningand Warnings and Precautions (5.1, 5.2, 5.3, 5.4)].

  Important requirements of the SPRAVATO REMS include the following:

  • Healthcare settings must be certified in the program and ensure that SPRAVATO is:
    • – Only dispensed and administered in healthcare settings.
    • – Patients treated in outpatient settings (e.g. medical offices and clinics) must be enrolled in the program.
    • – Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO
      [see Dosage and Administration (2.5)].
  • Pharmacies must be certified in the REMS and must only dispense SPRAVATO to healthcare settings that are certified in the program.

  Further information, including a list of certified pharmacies is available at www.SPRAVATOrems.com or 1-855-382-6022.

  )
  
  
• Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients. (
  
  

  5.6 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

  In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients (SPRAVATO is not approved in pediatric patients), the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with major depressive disorder (MDD). The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

  Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in PediatricSPRAVATO is not approved in pediatric patients.and Adult Patients

  Age Range (Years)	Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated
  	Increases Compared to Placebo
  <18	14 additional patients
  18–24	5 additional patients
  	Decreases Compared to Placebo
  25–64	1 fewer patient
  ≥65	6 fewer patients

  It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

  Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing SPRAVATO and/or the concomitant oral antidepressant, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

  )
  
  

• Treatment-resistant depression (TRD) in adults as monotherapy or in conjunction with an oral antidepressant
• Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant

• Administer SPRAVATO intranasally under the supervision of a healthcare provider. (
  
  
  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.

  Respiratory Status Assessment During Treatment

  • Monitor patients for changes in respiratory status for at least 2 hours (including pulse oximetry) at each treatment session
    [see Warnings and Precautions (5.3)]
    .

  Blood Pressure Assessment Before and After Treatment

  • Assess blood pressure prior to dosing with SPRAVATO
    [see Warnings and Precautions (5.7)]
    .
  • 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
    [see Warnings and Precautions (5.7)].
    Do not administer SPRAVATO if an increase in blood pressure or intracranial pressure poses a serious risk
    [see Contraindications (4)]
    .
  • 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
    [see Warnings and Precautions (5.7)].

  Food and Liquid Intake Recommendations Prior to Administration

  Because some patients may experience nausea and vomiting after administration of SPRAVATO

  [see Adverse Reactions (6.1)],

  advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration.

  Nasal Corticosteroid or Nasal Decongestant

  Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should administer these medications at least 1 hour before SPRAVATO

  [see Clinical Pharmacology (12.3)].
  )
  
• Assess blood pressure prior to and after administration. (
  
  
  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.

  Respiratory Status Assessment During Treatment

  • Monitor patients for changes in respiratory status for at least 2 hours (including pulse oximetry) at each treatment session
    [see Warnings and Precautions (5.3)]
    .

  Blood Pressure Assessment Before and After Treatment

  • Assess blood pressure prior to dosing with SPRAVATO
    [see Warnings and Precautions (5.7)]
    .
  • 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
    [see Warnings and Precautions (5.7)].
    Do not administer SPRAVATO if an increase in blood pressure or intracranial pressure poses a serious risk
    [see Contraindications (4)]
    .
  • 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
    [see Warnings and Precautions (5.7)].

  Food and Liquid Intake Recommendations Prior to Administration

  Because some patients may experience nausea and vomiting after administration of SPRAVATO

  [see Adverse Reactions (6.1)],

  advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration.

  Nasal Corticosteroid or Nasal Decongestant

  Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should administer these medications at least 1 hour before SPRAVATO

  [see Clinical Pharmacology (12.3)].
  )
  
• TRD:
  Evidence of therapeutic benefit should be evaluated at the end of the 4-week induction phase to determine need for continued treatment. (
  
  
  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 1 to 4:
  	Administer twice per week	56 mg or 84 mg
  Maintenance Phase	Weeks 5 to 8 :
  	Administer once weekly	56 mg or 84 mg
  	Week 9 and after :
  	Administer every 2 weeks or once weeklyDosing frequency should be individualized to the least frequent dosing to maintain remission/response.	56 mg or 84 mg
  )
  
• 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. (
  
  
  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.
  )
  
• See Full Prescribing Information for recommended dosage. (
  
  
  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 1 to 4:
  	Administer twice per week	56 mg or 84 mg
  Maintenance Phase	Weeks 5 to 8 :
  	Administer once weekly	56 mg or 84 mg
  	Week 9 and after :
  	Administer every 2 weeks or once weeklyDosing 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.
  )
  
• See Full Prescribing Information for important administration instructions. (
  
  
  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:

  

  

  

  

  

  

  

  

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  )
  

Nasal Spray: 28 mg of esketamine per device. Each nasal spray device delivers two sprays containing a total of 28 mg esketamine.

• Lactation: Breastfeeding not recommended. (
  
  
  8.2 Lactation

  Risk Summary

  Esketamine is present in human milk. There are no data on the effects of SPRAVATO on the breastfed infant or on milk production. Published studies in juvenile animals report neurotoxicity

  (see Data)

  . Because of the potential for neurotoxicity, advise patients that breast-feeding is not recommended during treatment with SPRAVATO.

  Data

  Published juvenile animal studies demonstrate that the administration of drugs that block NMDA receptors, such as ketamine, during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but this window may extend out to approximately 3 years of age in humans.
  )