SPRAVATO® (esketamine) nasal spray, CIII

SPRAVATO® (esketamine) nasal spray, CIII

SPRAVATO® (esketamine) nasal spray, CIII

SPRAVATO® contains esketamine hydrochloride, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Esketamine is the S-enantiomer of racemic ketamine. The chemical name is (S)-2-(o-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride. Its molecular formula is C13H16ClNO.HCl and its molecular weight is 274.2.

Esketamine hydrochloride is a white or almost white crystalline powder that is freely soluble in water and in methanol, and soluble in ethanol.

SPRAVATO nasal spray is intended for nasal administration. Esketamine hydrochloride is contained as a solution in a stoppered glass vial within the nasal spray device. Each device delivers two sprays with a total of 32.3 mg of esketamine hydrochloride (equivalent to 28 mg of esketamine) in 0.2 mL of a clear, colorless aqueous solution with a pH of 4.5.

The inactive ingredients are citric acid monohydrate, edetate disodium, sodium hydroxide, and water for injection.

INDICATIONS AND USAGE

SPRAVATO® is indicated, in conjunction with an oral antidepressant, for the treatment of:

  • Treatment-resistant depression (TRD) in adults
  • Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior

Limitations of Use:

  • The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO.
  • SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established.

Mechanism of Action

Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The mechanism by which esketamine exerts its antidepressant effect is unknown. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity.

DOSAGE AND ADMINISTRATION

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.

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 Cmax) 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.

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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.

Treatment-Resistant Depression

Administer SPRAVATO in conjunction with an oral antidepressant (AD).

The recommended dosage of SPRAVATO for the treatment of TRD in adults 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

Induction Phase Maintenance Weeks 1 to 4: Administer twice per weekDay 1 starting dose: 56 mg
Subsequent doses: 56 mg or 84
Phase   Weeks 5 to 8: Administer once weekly
Week 9 and after: Administer every 2 weeks or once weekly*
mg 56 mg or 84 mg
56 mg or 84 mg

*Dosing frequency should be individualized to the least frequent dosing to maintain remission/response.

Depressive Symptoms in Patients with Major Depressive Disorder withAcute 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.

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.

SPRAVATO® (esketamine) nasal spray, CIII
SPRAVATO® (esketamine) nasal spray, CIII
SPRAVATO® (esketamine) nasal spray, CIII
SPRAVATO® (esketamine) nasal spray, CIII
SPRAVATO® (esketamine) nasal spray, CIII
SPRAVATO® (esketamine) nasal spray, CIII

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.

 Before 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.

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).

CONTRAINDICATIONS

SPRAVATO 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.

WARNINGS AND PRECAUTIONS

Sedation: 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 sessio.n, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting

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

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). 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.

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.

Increase in Blood Pressure: SPRAVATO causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after SPRAVATO administration and last approximately 4 hours.

Assess BP prior to administration of SPRAVATO. In patients whose BP is elevated prior to SPRAVATO administration (as a general guide: >140/90 mmHg) a decision to delay SPRAVATO therapy should take into account the balance of benefit and risk in individual patients.

Short-Term Cognitive Impairment: In a study in healthy volunteers, a single dose of SPRAVATO caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, SPRAVATO-treated subjects required a greater effort to complete cognitive tests at 40 minutes post-dose. Cognitive performance and mental effort were comparable between SPRAVATO and placebo at 2 hours post-dose. Sleepiness was comparable after 4 hours post-dose.

Impaired Ability to Drive and Operate Machinery: Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep. Patients will need to arrange transportation home following treatment with SPRAVATO.

Ulcerative or Interstitial Cystitis: Cases of ulcerative or interstitial cystitis have been reported in individuals with long-term off-label use or misuse/abuse of ketamine. In clinical studies with SPRAVATO nasal spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in SPRAVATO-treated patients than in placebo-treated patients. No cases of esketamine-related interstitial cystitis were observed in any of the studies, which included treatment for up to a year.

Monitor for urinary tract and bladder symptoms during the course of treatment with SPRAVATO, and refer to an appropriate healthcare provider as clinically warranted.

Embryo-fetal Toxicity: 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. Advise women of reproductive potential to consider pregnancy planning and prevention.

DRUG INTERACTIONS

Central Nervous System Depressants: Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation. Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants.

Psychostimulants: Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure. Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants.

Monoamine Oxidase Inhibitors (MAOIs): Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure. Closely monitor blood pressure with concomitant use of SPRAVATO with MAOIs.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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.

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.

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

Pediatric Use: The safety and effectiveness of SPRAVATO in pediatric patients have not been established. Clinical studies of SPRAVATO in pediatric patients have not been conducted.

Hepatic Impairment: The mean esketamine AUC and t1/2 values were higher in patients with moderate hepatic impairment compared to those with normal hepatic function. SPRAVATO-treated patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time.

SPRAVATO has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

SPRAVATO contains esketamine hydrochloride, the (S)-enantiomer of ketamine and a Schedule III controlled substance under the Controlled Substances Act.

Abuse

Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO. Abuse is the intentional, non-therapeutic use of a drug, even once, for its psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Careful consideration is advised prior to use of individuals with a history of substance use disorder, including alcohol.

SPRAVATO may produce a variety of symptoms including anxiety, dysphoria, disorientation, insomnia, flashback, hallucinations, and feelings of floating, detachment and to be “spaced out”. Monitoring for signs of abuse and misuse is recommended.

Management of Overdosage

There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of multiple drug involvement should be considered. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222 or www.poison.org).

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