Dosage & Administration
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Spravato Prescribing Information
Sedation
- Patients are at risk for sedation after administration of SPRAVATO [see Warnings and Precautions (5.1)].
Dissociation
- Patients are at risk for dissociative or perceptual changes after administration of SPRAVATO [see Warnings and Precautions (5.2)].
Respiratory Depression
- Respiratory depression has been observed in postmarketing experience [see Warnings and Precautions (5.3)] .
Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored 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 Warnings and Precautions (5.1, 5.2, 5.3)] .
Abuse and Misuse
- SPRAVATO has the potential to be abused and misused. Consider the risks and benefits of prescribing SPRAVATO prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse [see Warnings and Precautions (5.4)] .
Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS [see Warnings and Precautions (5.5)] .
Suicidal Thoughts and Behaviors
Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients [see Warnings and Precautions (5.6)] .
SPRAVATO is indicated for the treatment of:
- 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
Limitations of Use
- The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated [see Clinical Studies (14.2)] . 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.
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)].
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.
| ||
| 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 weekly * | 56 mg or 84 mg | |
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.
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 Usebefore administration:
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 [see Warnings and Precautions (5.1, 5.2, 5.3, 5.7)] . 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 [see Warnings and Precautions (5.9)] .
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: 28 mg of esketamine per device. Each nasal spray device delivers two sprays containing a total of 28 mg esketamine.
Pregnancy
Pregnancy Exposure Registry
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 https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.
Risk Summary
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 (see Data) . 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 (see Clinical Considerations). 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 [see Use in Specific Populations (8.2)] .
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 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-Associated 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.
Data
Animal Data
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 6 to 18 at doses of 10, 30, and 100 mg/kg/day. The high dose was lowered from 100 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. The 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 19 in treatment groups as compared with PND 14 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.
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.
Females and Males of Reproductive Potential
Contraception
Based on published animal reproduction studies, SPRAVATO may cause embryo-fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.11)and Use in Specific Populations (8.1)]. However, it is not clear how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential during treatment with SPRAVATO.
Pediatric Use
The safety and effectiveness of SPRAVATO in pediatric patients have not been established.
Geriatric Use
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 maxand AUC values were higher in elderly patients compared with younger adult patients [see Clinical Pharmacology (12.3)] .
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 4 on the Montgomery-Åsberg Depression Rating Scale (MADRS).
Hepatic Impairment
The mean esketamine AUC and t 1/2values were higher in patients with moderate hepatic impairment compared to those with normal hepatic function [see Clinical Pharmacology (12.3)] . 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 [see Clinical Pharmacology (12.3)].
SPRAVATO is contraindicated in patients with:
- Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation [see Warnings and Precautions (5.7)]
- History of intracerebral hemorrhage [see Warnings and Precautions (5.7)]
- Hypersensitivity to esketamine, ketamine, or any of the excipients.