Generic Name
Asenapine
Brand Names
Saphris, Secuado
FDA approval date: September 30, 2013
Classification: Atypical Antipsychotic
Form: Tablet, Film
What is Saphris (Asenapine)?
AN D USAGE SAPHRIS is indicated for: Schizophrenia in adults [see Clinical Studies ( 1.
Approved To Treat
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Brand Information
SAPHRIS (Asenapine Maleate)
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
1INDICATIONS AND USAGE
SAPHRIS is indicated for:
- Schizophrenia in adults
- Bipolar I disorder
2DOSAGEFORMS ANDSTRENGTHS
- SAPHRIS 2.5 mg tablets, black cherry flavor, are round, white to off-white sublingual tablets, with a hexagon on one side.
- SAPHRIS 5 mg tablets, black cherry flavor, are round, white to off-white sublingual tablets, with “5” on one side within a circle.
- SAPHRIS 10 mg tablets, black cherry flavor, are round, white to off-white sublingual tablets, with “10” on one side within a circle.
3CONTRAINDICATIONS
SAPHRIS is contraindicated in patients with:
- Severe hepatic impairment (Child-Pugh C)
- A history of hypersensitivity reactions to asenapine. Reactions have included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash
4ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Use in Elderly Patients with Dementia-Related Psychosis
- Neuroleptic Malignant Syndrome
- Tardive Dyskinesia
- Metabolic Changes
- Hypersensitivity Reactions
- Orthostatic Hypotension, Syncope, and other Hemodynamic Effects
- Falls
- Leukopenia, Neutropenia, and Agranulocytosis
- QT Interval Prolongation
- Hyperprolactinemia
- Seizures
- Potential for Cognitive and Motor Impairment
- Body Temperature Regulation
- Dysphagia
The most common adverse reactions (≥5% and at least twice the rate of placebo) reported with acute treatment in adults with schizophrenia were akathisia, oral hypoesthesia, and somnolence. The safety profile of SAPHRIS in the maintenance treatment of schizophrenia in adults was similar to that seen with acute treatment.
The most common adverse reactions (≥5% and at least twice the rate of placebo) reported with acute monotherapy treatment of manic or mixed episodes associated with bipolar I disorder in adults were somnolence, oral hypoesthesia dizziness, extrapyramidal symptoms (excluding akathisia) and akathisia; and during the adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia. The rates were lower at the 5mg twice daily dose than the 10mg twice daily dose for all of these most common adverse reactions. The safety profile of SAPHRIS in the maintenance treatment of manic or mixed episodes associated with bipolar I disorder in adults was similar to that seen with acute treatment.
The adult information below is derived from a clinical trial database for SAPHRIS consisting of over 5355 patients and/or healthy subjects exposed to one or more sublingual doses of SAPHRIS.
In a 3-week monotherapy trial, the most common adverse reactions (≥5% and at least twice the rate of placebo) reported in pediatric patients with bipolar I disorder treated with SAPHRIS were somnolence, dizziness, dysgeusia, oral hypoesthesia, nausea, increased appetite, fatigue, and increased weight. No new major safety findings were reported from a 50-week, open-label, uncontrolled safety trial.
A total of 651 pediatric patients were treated with SAPHRIS. Of these patients, 352 pediatric patients were treated with SAPHRIS for at least 180 days and 58 pediatric patients treated with SAPHRIS had at least 1 year of exposure. The safety of SAPHRIS was evaluated in 403 pediatric patients with bipolar I disorder who participated in a 3-week, placebo-controlled, double-blind trial, of whom 302 patients received SAPHRIS at fixed doses ranging from 2.5 mg to 10 mg twice daily.
The stated frequencies of adverse reactions represent the proportion of individuals who experienced a treatment-emergent adverse event of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
4.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adult Patients with Schizophrenia: The following findings are based on the short-term placebo-controlled pre-marketing trials for schizophrenia (a pool of three 6-week fixed-dose trials and one 6-week flexible-dose trial) in which sublingual SAPHRIS was administered in doses ranging from 5 to 10 mg twice daily.
Adverse Reactions Associated with Discontinuation of Treatment:A total of 9% of SAPHRIS-treated patients and 10% of placebo-treated patients discontinued due to adverse reactions. There were no drug-related adverse reactions associated with discontinuation in patients treated with SAPHRIS at the rate of at least 1% and at least twice the placebo rate.
Adverse Reactions Occurring at an Incidence of 2% or More in SAPHRIS-Treated Patients with Schizophrenia: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 8.
* Akathisia includes: akathisia and hyperkinesia.
†Extrapyramidal symptoms included dystonia, oculogyration, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, tremor, and extrapyramidal disorder (excluding akathisia).
‡Somnolence includes the following events: somnolence, sedation, and hypersomnia.
§Also includes the Flexible-dose trial (N=90).
Dose-Related Adverse Reactions:In the short term schizophrenia trials the incidence of akathisia appeared to be dose-related (see Table 8).
Monotherapy in Adult Patients with Bipolar Mania: The following findings are based on the short-term placebo-controlled trials for bipolar mania (a pool of two 3-week flexible-dose trials and one 3-week fixed-dose trial) in which sublingual SAPHRIS was administered in doses of 5 mg or 10 mg twice daily.
Adverse Reactions Associated with Discontinuation of Treatment:Approximately 10% (61/620) of SAPHRIS-treated patients in short-term, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with about 7% (22/329) on placebo. There were no adverse reactions associated with discontinuation in patients treated with SAPHRIS at the rate of at least 1% and at least twice the placebo rate
Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated (Monotherapy) patients with Bipolar I Disorder:Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute monotherapy (up to 3-weeks in patients with bipolar mania) are shown in Table 9.
a Includes fixed and flexible dose trials
bSAPHRIS 5 mg to 10 mg twice daily with fixed and flexible dosing.
c Oral Hypoesthesia includes the preferred terms: oral hypoesthesia, oral paresthesia, and oral dysaesthesia.
d Abdominal pain includes the preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
eFatigue includes the preferred terms: fatigue and lethargy.
fSomnolence includes the preferred terms: somnolence, sedation, and hypersomnia.
gExtrapyramidal symptoms (excluding akathisia) includes the preferred terms: dyskinesia, dystonia, resting tremor, tremor, oromandibular dystonia, myoclonus, muscle spasms, muscle rigidity, musculoskeletal stiffness, muscle contractions involuntary, blepharospasm, tongue disorder, and Parkinsonism.
hDyspepsia includes the preferred terms: dyspepsia and gastroesophageal reflux disease.
i Nasopharyngitis includes the preferred terms: nasopharyngitis and upper respiratory tract infection.
j Bipolar Disorder/Mania includes the preferred terms: bipolar disorder, bipolar I disorder and mania.
Monotherapy in Pediatric Patients with Bipolar Mania:The following findings are based on a 3-week , placebo-controlled trial for bipolar mania in which SAPHRIS was administered at doses of 2.5 mg, 5 mg, or 10 mg twice daily.
Adverse Reactions Leading to Discontinuation of Treatment:A total of 6.7% (7/104) of patients treated with SAPHRIS 2.5 mg twice daily, 5.1% (5/99) of patients treated with SAPHRIS 5 mg twice daily, and 5.1% (5/99) of patients treated with SAPHRIS 10 mg twice daily discontinued treatment due to adverse reactions compared to 4% (4/101) on placebo. The most common adverse reactions that led to discontinuation in pediatric patients treated with SAPHRIS (rates at least 2% in any SAPHRIS arm and at least twice the placebo rate) were somnolence (3% in the 2.5mg twice daily group, 1% in the 5mg twice daily group, and 2% in the 10mg twice daily group), abdominal pain (2% in the 10mg twice daily group), and nausea (2% in the 10mg twice daily group) No placebo-treated patients dropped out for these events.
Adverse Reactions Occurring with SAPHRIS at an Incidence of 2% or More in SAPHRIS-treated Bipolar I Patients: Adverse reactions associated with the use of SAPHRIS (incidence of ≥2% in any SAPHRIS dose group and greater than placebo) that occurred during acute therapy are shown in Table 10.
1 Includes the preferred terms tachycardia and heart rate increased.
2 Includes the preferred terms oral hypoesthesia, oral paresthesia, and oral dysesthesia.
3 Includes the preferred terms abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
4 Includes the preferred terms fatigue and lethargy.
5 Includes the preferred terms hyperinsulinemia and blood insulin increased.
6 Includes the preferred terms somnolence, sedation, and hypersomnia.
Dose-Related Adverse Reactions:In the short term pediatric bipolar I trial the incidence of fatigue appeared to be dose-related (see Table 10).
Adjunctive Therapy in Adult Patients with Bipolar Mania:The following findings are based on a 12 week placebo-controlled trial (with a 3 week efficacy endpoint) in adult patients with bipolar mania in which sublingual SAPHRIS was administered in doses of 5 mg or 10 mg twice daily as adjunctive therapy with lithium or valproate.
Adverse Reactions Associated with Discontinuation of Treatment:Approximately 16% (25/158) of SAPHRIS-treated patients discontinued treatment due to an adverse reaction, compared with about 11% (18/166) on placebo. The most common adverse reactions associated with discontinuation in subjects treated with SAPHRIS (rates at least 1% and at least twice the placebo rate) were depression (2.5%), suicidal ideation (2.5%), bipolar I disorder (1.9%), insomnia (1.9%) and depressive symptoms (1.3%).
Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated (Adjunctive) Bipolar I Patients:Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute adjunctive therapy at 3 weeks, a time when most of the patients were still participating in the trial, are shown in Table 11.
* SAPHRIS 5 mg to 10 mg twice daily with flexible dosing.
† Extrapyramidal symptoms included: dystonia, parkinsonism, oculogyration, and tremor (excluding akathisia).
‡ Somnolence includes the following events: somnolence and sedation.
Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups [see Dosage and Administration (2.3), Use in Specific Populations (8.4), and Clinical Pharmacology (12.3)].
Extrapyramidal Symptoms: In the short-term, placebo-controlled schizophrenia and bipolar mania adult trials, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Assessments of Involuntary Movement Scales (for dyskinesias). The mean change from baseline for the all-SAPHRIS 5 mg or 10 mg twice daily treated group was comparable to placebo in each of the rating scale scores.
In the short-term, placebo-controlled schizophrenia adult trials, the incidence of reported EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 10% versus 7% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 6% versus 3% for placebo. In short-term placebo-controlled bipolar mania adult trials, the incidence of EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 8% versus 4% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 7% versus 3% for placebo. The incidence rates of all EPS events (including akathisia) were lower at the 5mg twice daily dose (11% of N=122) than the 10mg twice daily dose (25% of N=119) in a fixed-dose study.
In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the incidences of EPS-related events, excluding events related to akathisia, were 4%, 3%, and 5% for patients treated with SAPHRIS 2.5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 3% for placebo-treated patients. EPS-related events include: bradykinesia, dyskinesia, dystonia, oromandibular dystonia, muscle contractions involuntary, muscle twitching, musculoskeletal stiffness, parkinsonism, protrusion tongue, resting tremor, and tremor.
For events of akathisia, incidences were 2%, 2%, and 1% for pediatric patients treated with SAPHRIS 2.5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 0% for placebo-treated patients.
Other Findings: Oral hypoesthesia and/or oral paresthesia may occur directly after administration of SAPHRIS and usually resolves within 1 hour.
Laboratory Test Abnormalities:
Transaminases:Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania adult trials were more common in treated patients. In short-term, placebo-controlled schizophrenia adult trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 1.6 units/L compared to a decrease of 0.4 units/L for placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times ULN (at Endpoint) was 0.9% for SAPHRIS-treated patients versus 1.3% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 6.1 units/L compared to a decrease of 3.9 units/L in placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times upper limit of normal (ULN) (at Endpoint) was 2.1% for SAPHRIS-treated patients versus 0.7% for placebo-treated patients. The incidence rate of transaminase elevations ≥3 times ULN is 3% of N=95 for 10 mg twice daily dose, and 0% of N=108 for the 5 mg twice daily dose and 0% of N=115 for placebo in a fixed-dose study.
In a 52-week, double-blind, comparator-controlled trial that included primarily adult patients with schizophrenia, the mean increase from baseline of ALT was 1.7 units/L.
In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, transient elevations in serum transaminases (primarily ALT) were more common in treated patients. The proportion of pediatric patients with ALT elevations ≥3 times upper limit of normal (ULN) was 2.4% for patients treated with SAPHRIS 10 mg twice daily versus none for the other SAPHRIS dose groups and placebo-treated patients.
Prolactin: In short-term, placebo-controlled adult schizophrenia trials, the mean decreases in prolactin levels were 6.5 ng/mL for SAPHRIS-treated patients compared to 10.7 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.6% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in prolactin levels was 6.7 ng/mL for SAPHRIS-treated patients compared to a decrease of 1.0 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.0% for SAPHRIS-treated patients versus 0.8% for placebo-treated patients.
In a long-term (52-week), double-blind, comparator-controlled adult trial that included primarily patients with schizophrenia, the mean decrease in prolactin from baseline for SAPHRIS-treated patients was 26.9 ng/mL.
In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the mean increases (at Endpoint) in prolactin levels were 3.2 ng/mL for patients treated with SAPHRIS 2.5 mg twice daily, 2.1 ng/mL for patients treated with SAPHRIS 5 mg twice daily, and 6.4 ng/mL for patients treated with SAPHRIS 10 mg twice daily compared to an increase of 2.5 ng/mL for placebo-treated patients. There were no reports of prolactin elevations ≥4 times ULN (at Endpoint) for patients treated with SAPHRIS or placebo. Galactorrhea or dysmenorrhea were reported in 0% of patients treated with SAPHRIS 2.5 mg twice daily, 2% of patients treated with SAPHRIS 5 mg twice daily, and 1% of patients treated with SAPHRIS 10 mg twice daily compared to 1% of placebo-treated patients. There were no reports of gynecomastia in this trial.
Creatine Kinase (CK): The proportion of adult patients with CK elevations >3 times ULN at any time were 6.4% and 11.1% for patients treated with SAPHRIS 5 mg twice daily and 10 mg twice daily, respectively, as compared to 6.7% for placebo-treated patients in pre-marketing short-term, fixed-dose trials in schizophrenia and bipolar mania. The clinical relevance of this finding is unknown.
The proportion of patients with CK elevations ≥3 times ULN during a 3-week trial in pediatric bipolar I disorder at any time were 1%, 0%, and 1% for patients treated with SAPHRIS 2.5 mg, 5 mg, and 10 mg twice daily, respectively, versus 3% for placebo-treated patients.
Other Adverse Reactions Observed During the Premarketing Evaluation of SAPHRIS:Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with sublingual SAPHRIS at multiple doses of ≥5 mg twice daily during any phase of a trial within the database of adult patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions already listed for either adults or pediatric patients in other parts of Adverse Reactions (6), or those considered in Contraindications (4),Warnings and Precautions(5) or Overdosage (10) are not included. Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).
Blood and lymphatic disorders:infrequent: anemia; rare: thrombocytopenia
Cardiac disorders:infrequent: temporary bundle branch block
Eye disorders:infrequent: accommodation disorder
Gastrointestinal disorders:infrequent:swollen tongue
General disorders:rare: idiosyncratic drug reaction
Investigations:infrequent: hyponatremia
Nervous system disorders:infrequent: dysarthria
Following is a list of MedDRA terms not already listed either for adults or pediatric patients in other parts of
Eye disorders: infrequent: diplopia, vision blurred
Gastrointestinal disorders: infrequent: gastroesophageal reflux disease
Injury, Poisoning, and Procedural Complications:infrequent: fall
Skin and subcutaneous tissue disorders:infrequent: photosensitivity reaction
Renal and urinary disorders: infrequent:enuresis
4.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of SAPHRIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure. In many cases, the occurrence of these adverse reactions led to discontinuation of therapy.
- Application site reactions, primarily in the sublingual area, have been reported. These application site reactions included oral ulcers, blisters, peeling/sloughing, and inflammation.
- Choking has been reported by patients, some of whom may have also experienced oropharyngeal muscular dysfunction or hypoesthesia.
5OVERDOSAGE
Human Experience: In adult pre-marketing clinical studies involving more than 3350 patients and/or healthy subjects, accidental or intentional acute overdosage of SAPHRIS was identified in 3 patients. Among these few reported cases of overdose, the highest estimated ingestion of SAPHRIS was 400 mg. Reported adverse reactions at the highest dosage included agitation and confusion.
Management of Overdosage: There is no specific antidote to SAPHRIS. The possibility of multiple drug involvement should be considered. An electrocardiogram should be obtained and management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Consult with a Certified Poison Control Center for up-to-date guidance and advice on the management of overdosage (1-800-222-1222.)
Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of SAPHRIS-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
6DESCRIPTION
SAPHRIS contains asenapine maleate which is an atypical antipsychotic that is available for sublingual administration. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical designation is (3a
![SAPHRIS contains asenapine maleate which is an atypical antipsychotic that is available for sublingual administration. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical designation is (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1). Its molecular formula is C17H16ClNOC4H4O4 and its molecular weight is 401.84 (free base: 285.8). The chemical structure is:](https://dailymed.nlm.nih.gov/dailymed/image.cfm?name=saphris-01.jpg&setid=5429f134-839f-4ffc-9944-55f51238def8)
Asenapine maleate is a white to off-white powder.
SAPHRIS, black cherry flavor, is supplied for sublingual administration in tablets containing 2.5 mg, 5 mg or 10 mg asenapine; inactive ingredients include gelatin, mannitol, sucralose, and black cherry flavor.
7CLINICAL STUDIES
Efficacy of SAPHRIS was established in the following trials:
- Two fixed-dose, short-term trials and one flexible-dose, maintenance trial in adult patients with schizophrenia as monotherapy
- One fixed-dose and two flexible-dose, short-term trials of monotherapy in adults with manic or mixed episodes associated with bipolar I disorder
- One flexible-dose, maintenance trial of monotherapy in adults with bipolar I disorder
- One fixed-dose, short term trial of monotherapy in children (10 to 17 years) with manic or mixed episodes associated with bipolar I disorder
- One flexible-dose, short-term trial in adult patients with manic or mixed episode associated with bipolar I disorder as adjunctive treatment to lithium or valproate
7.1Schizophrenia
The efficacy of SAPHRIS in the treatment of schizophrenia in adults was evaluated in three fixed-dose, short-term (6 week), randomized, double-blind, placebo-controlled, and active-controlled (haloperidol, risperidone, and olanzapine) trials of adult patients who met DSM-IV criteria for schizophrenia and were having an acute exacerbation of their schizophrenic illness. In two of the three trials SAPHRIS demonstrated superior efficacy to placebo. In a third trial, SAPHRIS could not be distinguished from placebo; however, an active control in that trial was superior to placebo.
In the two positive trials for SAPHRIS, the primary efficacy rating scale was the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The primary endpoint was change from baseline to endpoint on the PANSS total score. The results of the SAPHRIS trials in schizophrenia follow:
In trial 1, a 6-week trial (n=174), comparing SAPHRIS (5 mg twice daily) to placebo, SAPHRIS 5 mg twice daily was statistically superior to placebo on the PANSS total score (Trial 1 in Table 13).
In trial 2, a 6-week trial (n=448), comparing two fixed doses of SAPHRIS (5 mg and 10 mg twice daily) to placebo, SAPHRIS 5 mg twice daily was statistically superior to placebo on the PANSS total score. SAPHRIS 10 mg twice daily showed no added benefit compared to 5 mg twice daily and was not significantly different from placebo (Trial 2 in Table 13).
An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex or race.
Maintenance of efficacy has been demonstrated in a placebo-controlled, double-blind, multicenter, flexible dose (5 mg or 10 mg twice daily based on tolerability) clinical trial with a randomized withdrawal design. All patients were initially administered 5 mg twice daily for 1 week and then titrated up to 10 mg twice daily. A total of 700 patients entered open-label treatment with SAPHRIS for a period of 26 weeks. Of these, a total of 386 patients who met pre-specified criteria for continued stability (mean length of stabilization was 22 weeks) were randomized to a double-blind, placebo-controlled, randomized withdrawal phase. SAPHRIS was statistically superior to placebo in time to relapse or impending relapse defined as increase in PANSS ≥20% from baseline and a Clinical Global Impression–Severity of Illness (CGI-S) score ≥4 (at least 2 days within 1 week) or PANSS score ≥5 on “hostility” or “uncooperativeness” items and CGI-S score ≥4 (≥2 days within a week), or PANSS score ≥5 on any two of the following items: “unusual thought content,” “conceptual disorganization,” or “hallucinatory behavior” items, and CGI-S score ≥4 (≥2 days within 1 week) or investigator judgment of worsening symptoms or increased risk of violence to self (including suicide) or other persons. The Kaplan-Meier curves of the time to relapse or impending relapse during the double-blind, placebo-controlled, randomized withdrawal phase of this trial for SAPHRIS and placebo are shown in Figure 4.
Figure 4: Kaplan-Meier Estimation of Percent Relapse/Impending Relapse for SAPHRIS and placebo
7.2Bipolar I Disorder
Monotherapy
Adults:The efficacy of SAPHRIS in the treatment of acute mania was established in two similarly designed 3-week, randomized, double-blind, placebo-controlled, and active-controlled (olanzapine) trials of adult patients who met DSM-IV criteria for Bipolar I Disorder with an acute manic or mixed episode with or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). Patients were also assessed on the Clinical Global Impression – Bipolar (CGI-BP) scale. In both trials, all patients randomized to SAPHRIS were initially administered 10 mg twice daily, and the dose could be adjusted within the dose range of 5 to 10 mg twice daily from Day 2 onward based on efficacy and tolerability. Ninety percent of patients remained on the 10 mg twice daily dose. SAPHRIS was statistically superior to placebo on the YMRS total score and the CGI-BP Severity of Illness score (mania) in both studies (Trials 1 and 2 in Table 14).
In another 3-week, randomized, double-blind, placebo-controlled trial (n=359), comparing two fixed doses of SAPHRIS (5 mg and 10 mg twice daily) to placebo, both doses were statistically superior to placebo on the YMRS total score and CGI-BP Severity of Illness overall score. (Trial 3 in Table 14).
An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, or race.
Maintenance of efficacy has been demonstrated in a placebo-controlled, double-blind, multicenter, flexible dose (5 mg or 10 mg twice daily based on tolerability) clinical trial with a randomized withdrawal design. All patients were initially administered 5 or 10 mg twice daily, and the option to titrate down to 5 mg twice daily was provided based on tolerability. A total of 549 patients entered open-label treatment with SAPHRIS for a period of 12 to 16 weeks. Of these, a total of 252 patients who met pre-specified criteria for continued stability were randomized to and treated in a double-blind, placebo-controlled, randomized withdrawal phase. SAPHRIS was statistically superior to placebo in time to relapse defined as 1) YMRS or MADRS score ≥ 16; 2) requirement or initiation of any non-study medication to treat mixed, manic, or depressive symptoms, including an antipsychotic, antidepressant, or mood-stabilizing agent; 3) requirement or initiation of psychiatric hospitalization; 4) investigator judgment to discontinue the study due to a mood event. The Kaplan-Meier curves of the time to relapse during the double-blind, placebo-controlled, randomized withdrawal phase of this trial for SAPHRIS and placebo are shown in Figure 5.
Figure 5: Kaplan-Meier Estimation of Percent Relapse for SAPHRIS and Placebo
Time (days) represents the number of days from randomization in the double-blind period to the first date of achieving relapse status.
The product limit estimators are based on the Kaplan-Meier distribution with censoring at last contact date.
Pediatric patients: The efficacy of SAPHRIS in the treatment of acute mania was established in a single, 3-week, placebo-controlled, double-blind trial of 403 pediatric patients 10 to 17 years of age, of whom 302 patients received SAPHRIS at fixed doses of 2.5 mg, 5 mg and 10 mg twice daily. All patients were started on 2.5 mg twice daily. For those assigned to 5 mg twice daily, the dose was increased to 5 mg twice daily after 3 days. For those assigned to 10 mg twice daily, the dose was increased from 2.5 to 5 mg twice daily after 3 days, and then to 10 mg twice daily after 3 additional days.
SAPHRIS was statistically superior to placebo in improving YMRS total score and the CGI-BP Severity of Illness overall score as measured by the change from baseline to week 3 (Trial 3 Pediatric in Table 14). An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, and race.
Adjunctive Therapy: The efficacy of SAPHRIS as an adjunctive therapy in acute mania was established in a 12-week, placebo-controlled trial with a 3-week primary efficacy endpoint involving 326 adult patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially responsive to lithium or valproate monotherapy after at least 2 weeks of treatment. All patients randomized to SAPHRIS were initially administered 5 mg twice daily, and the dose could be adjusted within the dose range of 5 to 10 mg twice daily from Day 2 onward based on efficacy and tolerability. SAPHRIS was statistically superior to placebo in the reduction of manic symptoms (measured by the YMRS total score) as an adjunctive therapy to lithium or valproate monotherapy at Week 3 (Trial 5 Adjunctive in Table 14).
8HOW SUPPLIED/STORAGE AND HANDLING
SAPHRIS (asenapine) sublingual tablets are supplied as:
2.5mg Tablets, black cherry flavor
Round, white to off-white sublingual tablets, with a hexagon on one side.
Child-resistant packaging
Box of 60 6 blisters with 10 tablets NDC 0456-2402-60
Hospital Unit Dose
Box of 100 10 blisters with 10 tablets NDC 0456-2402-63
5mg Tablets, black cherry flavor
Round, white to off-white sublingual tablets, with “5” on one side within a circle.
Child-resistant packaging
Box of 60 6 blisters with 10 tablets NDC 0456-2405-60
Hospital Unit Dose
Box of 100 10 blisters with 10 tablets NDC 0456-2405-63
10mg Tablets, black cherry flavor
Round, white to off-white sublingual tablets, with “10” on one side within a circle.
Child-resistant packaging
Box of 60 6 blisters with 10 tablets NDC 0456-2410-60
Hospital Unit Dose
Box of 100 10 blisters with 10 tablets NDC 0456-2410-63
Storage
Store at 20ºC to 25ºC(68ºF to 77ºF); excursions permitted between 15ºCand 30ºC (59ºFand 86ºF) [seeUSP Controlled Room Temperature].
9PATIENT COUNSELING INFORMATION
Dosage and Administration
Counsel patients on proper sublingual administration of SAPHRIS and advise them to read the FDA-approved patient labeling (
Hypersensitivity Reactions
Counsel patients on the signs and symptoms of a serious allergic reaction (e.g., difficulty breathing, itching, swelling of the face, tongue or throat, feeling lightheaded etc.) and to seek immediate emergency assistance if they develop any of these signs and symptoms
Application Site Reactions
Inform patients that application site reactions, primarily in the sublingual area, including oral ulcers, blisters, peeling/sloughing and inflammation have been reported. Instruct patients to monitor for these reactions
Neuroleptic Malignant Syndrome
Counsel patients about a potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Patients should contact their health care provider or report to the emergency room if they experience the following signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia)
Tardive Dyskinesia
Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur
Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)
Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight
Orthostatic Hypotension
Educate patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing) especially early in treatment, and also at times of re-initiating treatment or increases in dose
Leukopenia/Neutropenia
Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking SAPHRIS
Hyperprolactinemia
Counsel patients on the signs and symptoms of hyperprolactinemia and to contact their health care provider if these abnormalities occur
Interference with Cognitive and Motor Performance
Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that SAPHRIS therapy does not affect them adversely
Heat Exposure and Dehydration
Counsel patients regarding appropriate care in avoiding overheating and dehydration
Concomitant Medications
Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or over-the-counter medications since there is a potential for interactions
Pregnancy
Advise patients that SAPHRIS may cause fetal harm as well as extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy
Pregnancy Registry
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SAPHRIS during pregnancy
Distributed by:
© 2025 N. V. Organon; used by AbbVie under license.
The trademarks SAPHRIS, SAPHRIS & Star Design, and Star Design are used by AbbVie under license from N. V. Organon.
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NDC 0456-2402-06
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NDC 0456-2405-60
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