SPRAVATO® Efficacy | SPRAVATO® (esketamine) HCP

TRD=treatment-resistant depression in adults.

MDSI=depressive symptoms in adults with MDD with acute suicidal ideation or behavior.

SPRAVATO® (esketamine) plus oral AD demonstrated superior improvement in depression symptoms compared to placebo plus oral AD at Week 4 for adults with TRD^1,2

Most of the treatment difference between SPRAVATO® and placebo was observed at 24 hours
Between 24 hours and Day 28, both SPRAVATO® and placebo groups continued to improve
The difference between the groups generally remained the same but did not appear to increase over time through Day 28

AD=antidepressant.

LS=least-squares.

MADRS=Montgomery-Åsberg Depression Rating Scale.

TRD Study 1 (Short-term) Study Design^1,2

Demonstrated superior improvement in depression symptoms at Week 4 for adults with TRD^1,2

Primary Endpoint

Change from baseline (Day 1) to endpoint (Day 28) in Montgomery-Åsberg Depression Rating Scale (MADRS) score

Flexible Dosing

Patients (aged 18-64 years) were randomized to receive twice-weekly doses of SPRAVATO® (flexible dose; 56 mg or 84 mg) plus a newly initiated oral AD or intranasal placebo plus newly initiated oral AD
Dosages could be titrated to 84 mg or maintained on 56 mg, and were adjusted on Day 4, 8, 11, or 15
Dosages remained stable after Day 15

Oral Antidepressant

A newly initiated open-label oral AD (SSRIs: escitalopram, sertraline; SNRIs: duloxetine, venlafaxine extended-release) was initiated on Day 1
The selection of the newly initiated oral AD was determined by the investigator based on patient’s prior history

Demographics and Baseline Characteristics

Median age 47 years; 62% female; 93% Caucasian; 5% Black

Secondary descriptive endpoints: TRD response and remission rates at Week 4^1,2

Response was defined as an improvement of at least 50% from baseline in total MADRS score
Remission was defined as a MADRS total score of ≤12

*All subjects taking SPRAVATO® started on 56 mg on Day 1. Dose adjustment was made on prespecified days based on clinical judgment.

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission^1,3

SPRAVATO® plus oral AD significantly delayed time to relapse compared to placebo plus oral AD in a long-term maintenance trial in patients with stable remission^1,3*

Stable remission was defined as a MADRS total score of ≤12 in at least 3 of the last 4 weeks of the optimization phase

*Relapse was defined as a MADRS total score of ≥22 for 2 consecutive weeks and/or hospitalization for worsening depression, or any other clinically relevant event determined per clinical judgment to be suggestive of a relapse of depressive illness.

AD=antidepressant.

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission^1,3

In a long-term maintenance trial in patients with TRD with stable response, SPRAVATO® plus oral AD significantly delayed time to relapse compared to placebo^1,3*

Stable response was defined as a MADRS total score reduction of ≥50% from baseline in each of the last 2 weeks of the optimization phase but does not meet criteria for stable remission

TRD Study 2 (Long-term) Study Design^1,3

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission^1,3

Primary Endpoint

Time to relapse (cumulative distribution) during the maintenance phase among patients in stable remission
- Relapse was defined as one of the following:
  - MADRS total score of ≥22 for 2 consecutive weeks
  - Hospitalization for worsening depression, or any other clinically relevant event determined per clinical judgment to be suggestive of a relapse of depressive illness

Secondary Endpoint

Time to relapse (cumulative distribution) during the maintenance phase among patients in stable response

Enrollment

437 patients (aged 18-64 years) were directly enrolled
- Patients who were directly enrolled received SPRAVATO® (56 mg or 84 mg twice/week) plus a new oral AD in a 4-week open-label induction phase before entering a 12-week optimization phase
268 patients (aged 18-64 years) were transferred from short-term studies

Demographics and Baseline Characteristics

Median age 48 years (range 19-64 years); 66% female; 90% Caucasian, 4% Black

Next: Safety and tolerability

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References:

1. SPRAVATO® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. July 2020.

2. Popova V, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study [published online May 21, 2019]. Am J Psychiatry. 2019;176(6):428-438. doi:10.1176/appi.ajp.2019.19020172

3. Daly EJ, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial [published online June 5, 2019]. JAMA Psychiatry. 2019;76(9):893-903. doi:10.1001/jamapsychiatry.2019.1189

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

See full prescribing information for complete boxed warning

Risk for sedation and dissociation after administration. Monitor patients for at least two hours after administration (5.1, 5.2).
Potential for abuse and misuse. Consider the risks and benefits of using SPRAVATO^® prior to use in patients at higher risk of abuse. Monitor for signs and symptoms of abuse and misuse (5.3).
SPRAVATO^® is only available through a restricted program called the SPRAVATO^® REMS (5.4).
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 (5.5).

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: In clinical trials, 48% to 61% of SPRAVATO^®-treated patients developed sedation and 0.3% to 0.4% of SPRAVATO^®-treated patients experienced loss of consciousness.

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.

Closely monitor for sedation with concomitant use of SPRAVATO^® with CNS depressants (e.g., benzodiazepines, opioids, alcohol).

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). 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 and monitor all patients for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy. 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.

SPRAVATO^® Risk Evaluation and Mitigation Strategy (REMS): SPRAVATO^® is available only through a restricted program called the SPRAVATO^® REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse.

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^®.
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.

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 adult and pediatric patients, the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater than in placebo-treated patients. SPRAVATO^® is not approved in pediatric (<18 years of age) 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.

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.

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.

Approximately 8% to 19% of SPRAVATO^®-treated patients experienced an increase of more than 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. SPRAVATO^® is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage). Before prescribing SPRAVATO^®, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO^® outweigh its risk.

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.

BP should be monitored for at least 2 hours after SPRAVATO^® administration. Measure blood pressure around 40 minutes post-dose and subsequently as clinically warranted until values decline. If BP remains high, promptly seek assistance from practitioners experienced in BP management. Refer patients experiencing symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness, or focal neurological deficits) immediately for emergency care.

Closely monitor blood pressure with concomitant use of SPRAVATO^® with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) or monoamine oxidase inhibitors (MAOIs).

In patients with a history of hypertensive encephalopathy, more intensive monitoring, including more frequent blood pressure and symptom assessment, is warranted because these patients are at increased risk for developing encephalopathy with even small increases in blood pressure.

Cognitive Impairment

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 the 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.

Long-Term Cognitive Impairment: Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse. No adverse effects of SPRAVATO^® nasal spray on cognitive functioning were observed in a one-year open-label safety study; however, the long-term cognitive effects of SPRAVATO^® have not been evaluated beyond one year.

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 involved 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.

PREGNANCY, EMBRYO-FETAL TOXICITY, AND LACTATION

SPRAVATO^® is not recommended during pregnancy. 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.

There are risks to the mother associated with untreated depression in pregnancy. If a woman becomes pregnant while being treated with SPRAVATO^®, treatment with SPRAVATO^® should be discontinued and the patient should be counseled about the potential risk to the fetus.

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/.

SPRAVATO^® is present in human milk. Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment with SPRAVATO^®.

SELECT USE IN SPECIFIC POPULATIONS

Geriatric Use: 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. At the end of a 4-week, randomized, double-blind study, there was no statistically significant difference between groups on the primary efficacy endpoint.

Hepatic Impairment: 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.

ADVERSE REACTIONS

The most common adverse reactions with SPRAVATO^® plus oral antidepressant (incidence ≥5% and at least twice that of placebo nasal spray plus oral antidepressant) were:

TRD: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.

Treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior: dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo.

Please see full Prescribing Information, including Boxed WARNINGS, and Medication Guide for SPRAVATO^®.

cp-170362v2

Efficacy

With SPRAVATO® (esketamine) your adult patients with TRD may find the efficacy they've been seeking

SPRAVATO® (esketamine) plus oral AD demonstrated superior improvement in depression symptoms compared to placebo plus oral AD at Week 4 for adults with TRD^1,2

TRD Study 1 (Short-term) Study Design^1,2

Secondary descriptive endpoints: TRD response and remission rates at Week 4^1,2

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission^1,3

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission^1,3

TRD Study 2 (Long-term) Study Design^1,3

You are leaving the SPRAVATO® (esketamine) CIII website

Efficacy

With SPRAVATO® (esketamine) your adult patients with TRD may find the efficacy they've been seeking

SPRAVATO® (esketamine) plus oral AD demonstrated superior improvement in depression symptoms compared to placebo plus oral AD at Week 4 for adults with TRD1,2

TRD Study 1 (Short-term) Study Design1,2

Secondary descriptive endpoints: TRD response and remission rates at Week 41,2

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission1,3

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission1,3

TRD Study 2 (Long-term) Study Design1,3

You are leaving the SPRAVATO® (esketamine) CIII website

SPRAVATO® (esketamine) plus oral AD demonstrated superior improvement in depression symptoms compared to placebo plus oral AD at Week 4 for adults with TRD^1,2

TRD Study 1 (Short-term) Study Design^1,2

Secondary descriptive endpoints: TRD response and remission rates at Week 4^1,2

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission^1,3

Significantly delayed time to relapse in a long-term maintenance trial in adults with TRD with stable remission^1,3

TRD Study 2 (Long-term) Study Design^1,3