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Medications: Saphris® – asenapine

MEDICATIONS

Saphris® – asenapine (View the FDA label)

Administration Instructions

SAPHRIS is a sublingual tablet. To ensure optimal absorption, patients should be instructed to place the tablet under the tongue and allow it to dissolve completely. The tablet will dissolve in saliva within seconds. SAPHRIS sublingual tablets should not be split, crushed, chewed, or swallowed [see Clinical Pharmacology (12.3)]. Patients should be instructed to not eat or drink for 10 minutes after administration [see Clinical Pharmacology (12.3) and Patient Counseling Information (17)].

Schizophrenia

The recommended dose of SAPHRIS is 5 mg given twice daily. In short term controlled trials, there was no suggestion of added benefit with a 10 mg twice daily dose, but there was a clear increase in certain adverse reactions. If tolerated, daily dosage can be increased to 10 mg twice daily after one week. The safety of doses above 10 mg twice daily has not been evaluated in clinical studies [see Clinical Studies (14.1)].

Bipolar I Disorder

Acute Treatment of Manic or Mixed Episodes:

Monotherapy in Adults: The recommended starting dose of SAPHRIS is 10 mg twice daily. The dose can be decreased to 5 mg twice daily if warranted by adverse effects. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials [see Clinical Studies (14.2)].

Monotherapy in Pediatric Patients: The recommended dose of SAPHRIS is 2.5 mg to 10 mg twice daily in pediatric patients 10 to 17 years of age, and dose may be adjusted for individual response and tolerability. The starting dose of SAPHRIS is 2.5 mg twice daily. After 3 days, the dose can be increased to 5 mg twice daily, and from 5 mg to 10 mg twice daily after 3 additional days. Pediatric patients aged 10 to 17 years appear to be more sensitive to dystonia with initial dosing with SAPHRIS when the recommended escalation schedule is not followed [see Use in Specific Populations (8.4)]. The safety of doses greater than 10 mg twice daily has not been evaluated in clinical trials [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].

Adjunctive Therapy in Adults: The recommended starting dose of SAPHRIS is 5 mg twice daily when administered as adjunctive therapy with either lithium or valproate. Depending on the clinical response and tolerability in the individual patient, the dose can be increased to 10 mg twice daily. The safety of doses above 10 mg twice daily as adjunctive therapy with lithium or valproate has not been evaluated in clinical trials.

If SAPHRIS is used for extended periods in bipolar disorder, the health care provider should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Use in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1 and 5.2)]
  • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)]
  • Tardive Dyskinesia [see Warnings and Precautions (5.4)]
  • Metabolic Changes [see Warnings and Precautions (5.5)]
  • Hypersensitivity Reactions [see Contraindications, Warnings and Precautions (5.6) and Patient Counseling Information (17)]
  • Application site reactions including oral ulcers, blisters, peeling/sloughing and inflammation [see Adverse Reactions (6.2)]
  • Orthostatic Hypotension, Syncope, and other Hemodynamic Effects [see Warnings and Precautions (5.7)]
  • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
  • QT Interval Prolongation [see Warnings and Precautions (5.9)]
  • Hyperprolactinemia [see Warnings and Precautions (5.10)]
  • Seizures [see Warnings and Precautions (5.11)]
  • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)]
  • Body Temperature Regulation [see Warnings and Precautions (5.13)]
  • Suicide [see Warnings and Precautions (5.14)]
  • Dysphagia [see Warnings and Precautions (5.15)]
  • Use in Patients with Concomitant Illness [see Warnings and Precautions (5.16)]

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, dizziness, extrapyramidal symptoms other than akathisia, and increased weight and during the adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia.

The adult information below is derived from a clinical trial database for SAPHRIS consisting of over 4565 patients and/or healthy subjects exposed to one or more sublingual doses of SAPHRIS. A total of 1314 SAPHRIS-treated patients were treated for at least 24 weeks and 785 SAPHRIS-treated patients had at least 52 weeks of exposure at therapeutic doses.

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 paresthesia, 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, placebocontrolled, 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 treatmentemergent 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.

Clinical 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 premarketing 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.

Table 8: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 6-Week Schizophrenia Trials

System Organ Class/Preferred Term Placebo
N=378
%
SAPHRIS 5 mg twice daily
N= 274
%
SAPHRIS 10 mg twice daily
N=208
%
All SAPHRIS§ 5 mg or 10 mg twice daily
N=572
%
Constipation 6 7 4 5
Dry mouth 1 3 1 2
Oral hypoesthesia 1 6 7 5
Salivary hypersecretion 0 <1 4 2
Stomach discomfort 1 <1 3 2
Vomiting 5 4 7 5
General disorders
Fatigue 3 4 3 3
Irritability <1 2 1 2
Investigations
Increased weight <1 3 0 2
Metabolism disorders
Increased appetite <1 3 0 2
Nervous system disorders
Akathisia* 3 4 11 6
Dizziness 4 7 3 5
Extrapyramidal symptoms (excluding akathisia) 7 9 12 10
Somnolence 7 15 13 13
Psychiatric disorders
Insomnia 13 16 15 15
Vascular disorders
Hypertension 2 2 3 2

* 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) 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% (38/379) of SAPHRIS-treated patients in short-term, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with about 6% (12/203) on placebo. The most common adverse reactions associated with discontinuation in patients treated with SAPHRIS (rates at least 1% and at least twice the placebo rate) were anxiety (1.1%) and oral hypoesthesia (1.1%) compared to placebo (0%).

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.

Table 9: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 3-Week Bipolar Mania Trials

System Organ Class/Preferred Term Placebo
N=203
%
SAPHRIS
5 mg or 10 mg twice daily*
N=379
%
Gastrointestinal disorders
Dry mouth 1 3
Dyspepsia 2 4
Oral hypoesthesia <1 4
Toothache 2 3
General disorders
Fatigue 2 4
Investigations
Increased weight <1 5
Metabolism disorders
Increased appetite 1 4
Musculoskeletal and connective tissue disorders
Arthralgia 1 3
Pain in extremity <1 2
Nervous system disorders
Akathisia 2 4
Dizziness 3 11
Dysgeusia <1 3
Headaache 11 12
Other extrapyramidal symptoms (exclusing akathisia) 2 7
Somnolence 6 24
Psychiatric disorders
Anxiety 2 4
Depression 1 2
Insomnia 5 6

* SAPHRIS 5 mg to 10 mg twice daily with flexible dosing.
Extrapyramidal symptoms included: dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, gait disturbance, masked facies, and tremor (excluding akathisia).
Somnolence includes the following events: somnolence, sedation, and hypersomnia.

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 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.

Table 10: Adverse Reactions Reported in 2% or More of Pediatric Patients (Ages 10 to 17 Years) in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in a 3-Week Bipolar Mania Trial

System Organ Class/AE Preferred Term Placebo SAPHRIS 2.5 mg twice daily SAPHRIS 5 mg twice daily SAPHRIS 10 mg twice daily All SAPHRIS 2.5, 5, and 10 mg
N=101
Placebo
N=104
2.5 mg
N=99
5 mg
N=99
10 mg
N=101
%
N=104
%
N=99
%
N=99
%
N=302
%
Cardiac Disorders
Tachycardia1 0 3 0 1 1
Gastrointestinal Disorders
Oral paraesthesia2 4 25 25 30 27
Nausea 3 6 6 6 6
Vomiting 3
Abdominal pain3 7 9 3 5 6
Glossodynia 0 0 2 0 1
General Disorders and Administrative Site Disorders
Fatigue4 5 4 8 14 9
Irritability 1 1 1 2 1
Injury, Poisoning, and Procedural Complications
Muscle strain 0 0 0 2 1
Investigations
Increased weight 0 6 2 2 3
Hyperinsulinemia5 0 1 3 1 2
ALT increased 0 0 0 2 1
AST increased 0 0 0 2 1
Metabolism and Nutrition Disorders
Increased appetite 2 10 9 6 8
Dehydration 1 0 2 0 1
Muscoskeletal and Connective Tissue Disorders
Myalgia 0 0 2 1 1
Nervous System Disorders
Somnolence6 12 46 53 49 49
Headache 6 8 11 9 9
Dizziness 3 6 10 5 7
Dysgeusia 2 4 5 9 6
Akathisia 0 2 2 1 2
Parkinsonism 0 1 0 2 1
Psychiatric Disorders
Insomnia 3 3 4 3 3
Suicidal Ideation 1 4 1 3 3
Anger 0 0 0 2 1
Reproductive System and Breast Disorders
Dysmenorrhea 1 0 2 0 1
Respiratory, Thoracic, and Mediastinal Disorders
Oropharyngeal pain 2 0 3 1 1
Nasal congestion 1 0 2 0 1
Dyspnea 0 0 2 0 1
Skin and Subcutaneous Tissue Disorders
Rash 1 0 1 2 1

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 trials 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 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.

Table 11: Adverse Reactions Reported in 2% or More of Adult Patients In Any SAPHRIS-Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks in Adjunctive Bipolar Mania Trials

System Organ Class/Preferred Term Placebo
N=166
%
SAPHRIS 5 mg or 10 mg twice daily*
N=158
%
Gastrointestinal disorders
Dyspepsia 2 3
Oral hypoesthesia 0 5
General disorders</strong
Fatigue 2 4
Edema peripheral <1 3
Investigations
Increased weight 0 3
Nervous system disorders
Dizziness 2 4
Other extrapyramidal symptoms (excluding akathisia) 5 6
Somnolence 10 22
Psychiatric disorders
Insomnia 8 10
Vascular disorders
Hypertension <1 3

* 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 7% versus 2% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 4% versus 2% for placebo.

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 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, placebocontrolled bipolar adult mania trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 8.9 units/L compared to a decrease of 4.9 units/L in placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times upper limit of normal (ULN) (at Endpoint) was 2.5% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients.

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 placebotreated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in prolactin levels was 4.9 ng/mL for SAPHRIS-treated patients compared to a decrease of 0.2 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.3% for SAPHRIS-treated patients versus 0.7% 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 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 Adverse Reactions (6), or those considered in Contraindications (4), Warnings and Precautions (5) or Overdosage (10) that reflect adverse reactions reported by pediatric patients (Ages 10 to 17 years) treated with sublingual SAPHRIS at doses of 2.5 mg, 5 mg, or 10 mg twice daily during any phase of a trial within the database of pediatric patients.

  • 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

Postmarketing 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.
  • Cerebrovascular Adverse Events: An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs. (5.2)
  • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3)
  • Tardive Dyskinesia: Discontinue if clinically appropriate. (5.4)
  • Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.5)
  • Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with, and at risk for diabetes. (5.5)
  • Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. (5.5)
  • Weight Gain: Patients should receive regular monitoring of weight. (5.5)
  • Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed. (5.6)
  • Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects: Dizziness, tachycardia or bradycardia, and syncope may occur, especially early in treatment. Use with caution in patients with known cardiovascular or cerebrovascular disease, and in antipsychotic-naïve patients. (5.7)
  • Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotics. Patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and SAPHRIS should be discontinued at the first sign of a decline in WBC in the absence of other causative factors. (5.8)
  • QT Prolongation: Increases in QT interval; avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. (5.9)
  • Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.11)Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.12)
  • Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients. (5.14)

Drugs Having Clinically Important Drug Interactions with SAPHRIS

Table 12: Clinically Important Drug Interactions with SAPHRIS

Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Antihypertensive Drugs Because of its α1 -adrenergic antagonism with potential for inducing hypotension, SAPHRIS may enhance the effects of certain antihypertensive agents [see Warnings and Precautions (5.7)]. Monitor blood pressure and adjust dosage of antihypertensive drug accordingly.
Strong CYP1A2 Inhibitors  (e.g., Fluvoxamine) SAPHRIS is metabolized by CYP1A2. Marginal increase of asenapine exposure was observed when SAPHRIS is used with fluvoxamine at 25 mg administered twice daily [see Clinical Pharmacology (12.3)]. However, the tested fluvoxamine dose was suboptimal. Full therapeutic dose of fluvoxamine is expected to cause a greater increase in asenapine exposure. Dosage reduction for SAPHRIS based on clinical response may be necessary.
CYP2D6 substrates and inhibitors (e.g., paroxetine) SAPHRIS may enhance the inhibitory effects of paroxetine on its own metabolism. Concomitant use of paroxetine with SARPHIS increased the paroxetine exposure by 2-fold as compared to use paroxetine alone [see Clinical Pharmacology (12.3)]. Reduce paroxetine dose by half when paroxetine is used in combination with SAPHRIS.

Drugs Having No Clinically Important Interactions with SAPHRIS

No dosage adjustment of SAPHRIS is necessary when administered concomitantly with paroxetine (see Table 9 in Drug Interactions (7.1) for paroxetine dosage adjustment), imipramine, cimetidine, valporate, lithium, or a CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampin).

In addition, valproic acid and lithium pre-dose serum concentrations collected from an adjunctive therapy study were comparable between asenapine-treated patients and placebo-treated patients indicating a lack of effect of asenapine on valproic and lithium plasma levels.

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.

Uses

Administration Instructions

SAPHRIS is a sublingual tablet. To ensure optimal absorption, patients should be instructed to place the tablet under the tongue and allow it to dissolve completely. The tablet will dissolve in saliva within seconds. SAPHRIS sublingual tablets should not be split, crushed, chewed, or swallowed [see Clinical Pharmacology (12.3)]. Patients should be instructed to not eat or drink for 10 minutes after administration [see Clinical Pharmacology (12.3) and Patient Counseling Information (17)].

Schizophrenia

The recommended dose of SAPHRIS is 5 mg given twice daily. In short term controlled trials, there was no suggestion of added benefit with a 10 mg twice daily dose, but there was a clear increase in certain adverse reactions. If tolerated, daily dosage can be increased to 10 mg twice daily after one week. The safety of doses above 10 mg twice daily has not been evaluated in clinical studies [see Clinical Studies (14.1)].

Bipolar I Disorder

Acute Treatment of Manic or Mixed Episodes:

Monotherapy in Adults: The recommended starting dose of SAPHRIS is 10 mg twice daily. The dose can be decreased to 5 mg twice daily if warranted by adverse effects. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials [see Clinical Studies (14.2)].

Monotherapy in Pediatric Patients: The recommended dose of SAPHRIS is 2.5 mg to 10 mg twice daily in pediatric patients 10 to 17 years of age, and dose may be adjusted for individual response and tolerability. The starting dose of SAPHRIS is 2.5 mg twice daily. After 3 days, the dose can be increased to 5 mg twice daily, and from 5 mg to 10 mg twice daily after 3 additional days. Pediatric patients aged 10 to 17 years appear to be more sensitive to dystonia with initial dosing with SAPHRIS when the recommended escalation schedule is not followed [see Use in Specific Populations (8.4)]. The safety of doses greater than 10 mg twice daily has not been evaluated in clinical trials [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].

Adjunctive Therapy in Adults: The recommended starting dose of SAPHRIS is 5 mg twice daily when administered as adjunctive therapy with either lithium or valproate. Depending on the clinical response and tolerability in the individual patient, the dose can be increased to 10 mg twice daily. The safety of doses above 10 mg twice daily as adjunctive therapy with lithium or valproate has not been evaluated in clinical trials.

If SAPHRIS is used for extended periods in bipolar disorder, the health care provider should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Side Effects

The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Use in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1 and 5.2)]
  • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)]
  • Tardive Dyskinesia [see Warnings and Precautions (5.4)]
  • Metabolic Changes [see Warnings and Precautions (5.5)]
  • Hypersensitivity Reactions [see Contraindications, Warnings and Precautions (5.6) and Patient Counseling Information (17)]
  • Application site reactions including oral ulcers, blisters, peeling/sloughing and inflammation [see Adverse Reactions (6.2)]
  • Orthostatic Hypotension, Syncope, and other Hemodynamic Effects [see Warnings and Precautions (5.7)]
  • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
  • QT Interval Prolongation [see Warnings and Precautions (5.9)]
  • Hyperprolactinemia [see Warnings and Precautions (5.10)]
  • Seizures [see Warnings and Precautions (5.11)]
  • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)]
  • Body Temperature Regulation [see Warnings and Precautions (5.13)]
  • Suicide [see Warnings and Precautions (5.14)]
  • Dysphagia [see Warnings and Precautions (5.15)]
  • Use in Patients with Concomitant Illness [see Warnings and Precautions (5.16)]

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, dizziness, extrapyramidal symptoms other than akathisia, and increased weight and during the adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia.

The adult information below is derived from a clinical trial database for SAPHRIS consisting of over 4565 patients and/or healthy subjects exposed to one or more sublingual doses of SAPHRIS. A total of 1314 SAPHRIS-treated patients were treated for at least 24 weeks and 785 SAPHRIS-treated patients had at least 52 weeks of exposure at therapeutic doses.

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 paresthesia, 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, placebocontrolled, 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 treatmentemergent 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.

Clinical 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 premarketing 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.

Table 8: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 6-Week Schizophrenia Trials

System Organ Class/Preferred Term Placebo
N=378
%
SAPHRIS 5 mg twice daily
N= 274
%
SAPHRIS 10 mg twice daily
N=208
%
All SAPHRIS§ 5 mg or 10 mg twice daily
N=572
%
Constipation 6 7 4 5
Dry mouth 1 3 1 2
Oral hypoesthesia 1 6 7 5
Salivary hypersecretion 0 <1 4 2
Stomach discomfort 1 <1 3 2
Vomiting 5 4 7 5
General disorders
Fatigue 3 4 3 3
Irritability <1 2 1 2
Investigations
Increased weight <1 3 0 2
Metabolism disorders
Increased appetite <1 3 0 2
Nervous system disorders
Akathisia* 3 4 11 6
Dizziness 4 7 3 5
Extrapyramidal symptoms (excluding akathisia) 7 9 12 10
Somnolence 7 15 13 13
Psychiatric disorders
Insomnia 13 16 15 15
Vascular disorders
Hypertension 2 2 3 2

* 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) 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% (38/379) of SAPHRIS-treated patients in short-term, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with about 6% (12/203) on placebo. The most common adverse reactions associated with discontinuation in patients treated with SAPHRIS (rates at least 1% and at least twice the placebo rate) were anxiety (1.1%) and oral hypoesthesia (1.1%) compared to placebo (0%).

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.

Table 9: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 3-Week Bipolar Mania Trials

System Organ Class/Preferred Term Placebo
N=203
%
SAPHRIS
5 mg or 10 mg twice daily*
N=379
%
Gastrointestinal disorders
Dry mouth 1 3
Dyspepsia 2 4
Oral hypoesthesia <1 4
Toothache 2 3
General disorders
Fatigue 2 4
Investigations
Increased weight <1 5
Metabolism disorders
Increased appetite 1 4
Musculoskeletal and connective tissue disorders
Arthralgia 1 3
Pain in extremity <1 2
Nervous system disorders
Akathisia 2 4
Dizziness 3 11
Dysgeusia <1 3
Headaache 11 12
Other extrapyramidal symptoms (exclusing akathisia) 2 7
Somnolence 6 24
Psychiatric disorders
Anxiety 2 4
Depression 1 2
Insomnia 5 6

* SAPHRIS 5 mg to 10 mg twice daily with flexible dosing.
Extrapyramidal symptoms included: dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, gait disturbance, masked facies, and tremor (excluding akathisia).
Somnolence includes the following events: somnolence, sedation, and hypersomnia.

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 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.

Table 10: Adverse Reactions Reported in 2% or More of Pediatric Patients (Ages 10 to 17 Years) in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in a 3-Week Bipolar Mania Trial

System Organ Class/AE Preferred Term Placebo SAPHRIS 2.5 mg twice daily SAPHRIS 5 mg twice daily SAPHRIS 10 mg twice daily All SAPHRIS 2.5, 5, and 10 mg
N=101
Placebo
N=104
2.5 mg
N=99
5 mg
N=99
10 mg
N=101
%
N=104
%
N=99
%
N=99
%
N=302
%
Cardiac Disorders
Tachycardia1 0 3 0 1 1
Gastrointestinal Disorders
Oral paraesthesia2 4 25 25 30 27
Nausea 3 6 6 6 6
Vomiting 3
Abdominal pain3 7 9 3 5 6
Glossodynia 0 0 2 0 1
General Disorders and Administrative Site Disorders
Fatigue4 5 4 8 14 9
Irritability 1 1 1 2 1
Injury, Poisoning, and Procedural Complications
Muscle strain 0 0 0 2 1
Investigations
Increased weight 0 6 2 2 3
Hyperinsulinemia5 0 1 3 1 2
ALT increased 0 0 0 2 1
AST increased 0 0 0 2 1
Metabolism and Nutrition Disorders
Increased appetite 2 10 9 6 8
Dehydration 1 0 2 0 1
Muscoskeletal and Connective Tissue Disorders
Myalgia 0 0 2 1 1
Nervous System Disorders
Somnolence6 12 46 53 49 49
Headache 6 8 11 9 9
Dizziness 3 6 10 5 7
Dysgeusia 2 4 5 9 6
Akathisia 0 2 2 1 2
Parkinsonism 0 1 0 2 1
Psychiatric Disorders
Insomnia 3 3 4 3 3
Suicidal Ideation 1 4 1 3 3
Anger 0 0 0 2 1
Reproductive System and Breast Disorders
Dysmenorrhea 1 0 2 0 1
Respiratory, Thoracic, and Mediastinal Disorders
Oropharyngeal pain 2 0 3 1 1
Nasal congestion 1 0 2 0 1
Dyspnea 0 0 2 0 1
Skin and Subcutaneous Tissue Disorders
Rash 1 0 1 2 1

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 trials 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 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.

Table 11: Adverse Reactions Reported in 2% or More of Adult Patients In Any SAPHRIS-Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks in Adjunctive Bipolar Mania Trials

System Organ Class/Preferred Term Placebo
N=166
%
SAPHRIS 5 mg or 10 mg twice daily*
N=158
%
Gastrointestinal disorders
Dyspepsia 2 3
Oral hypoesthesia 0 5
General disorders</strong
Fatigue 2 4
Edema peripheral <1 3
Investigations
Increased weight 0 3
Nervous system disorders
Dizziness 2 4
Other extrapyramidal symptoms (excluding akathisia) 5 6
Somnolence 10 22
Psychiatric disorders
Insomnia 8 10
Vascular disorders
Hypertension <1 3

* 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 7% versus 2% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 4% versus 2% for placebo.

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 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, placebocontrolled bipolar adult mania trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 8.9 units/L compared to a decrease of 4.9 units/L in placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times upper limit of normal (ULN) (at Endpoint) was 2.5% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients.

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 placebotreated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in prolactin levels was 4.9 ng/mL for SAPHRIS-treated patients compared to a decrease of 0.2 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.3% for SAPHRIS-treated patients versus 0.7% 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 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 Adverse Reactions (6), or those considered in Contraindications (4), Warnings and Precautions (5) or Overdosage (10) that reflect adverse reactions reported by pediatric patients (Ages 10 to 17 years) treated with sublingual SAPHRIS at doses of 2.5 mg, 5 mg, or 10 mg twice daily during any phase of a trial within the database of pediatric patients.

  • 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

Postmarketing 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.
Precautions
  • Cerebrovascular Adverse Events: An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs. (5.2)
  • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3)
  • Tardive Dyskinesia: Discontinue if clinically appropriate. (5.4)
  • Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.5)
  • Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with, and at risk for diabetes. (5.5)
  • Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. (5.5)
  • Weight Gain: Patients should receive regular monitoring of weight. (5.5)
  • Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed. (5.6)
  • Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects: Dizziness, tachycardia or bradycardia, and syncope may occur, especially early in treatment. Use with caution in patients with known cardiovascular or cerebrovascular disease, and in antipsychotic-naïve patients. (5.7)
  • Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotics. Patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and SAPHRIS should be discontinued at the first sign of a decline in WBC in the absence of other causative factors. (5.8)
  • QT Prolongation: Increases in QT interval; avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. (5.9)
  • Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.11)Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.12)
  • Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients. (5.14)
Interactions

Drugs Having Clinically Important Drug Interactions with SAPHRIS

Table 12: Clinically Important Drug Interactions with SAPHRIS

Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Antihypertensive Drugs Because of its α1 -adrenergic antagonism with potential for inducing hypotension, SAPHRIS may enhance the effects of certain antihypertensive agents [see Warnings and Precautions (5.7)]. Monitor blood pressure and adjust dosage of antihypertensive drug accordingly.
Strong CYP1A2 Inhibitors  (e.g., Fluvoxamine) SAPHRIS is metabolized by CYP1A2. Marginal increase of asenapine exposure was observed when SAPHRIS is used with fluvoxamine at 25 mg administered twice daily [see Clinical Pharmacology (12.3)]. However, the tested fluvoxamine dose was suboptimal. Full therapeutic dose of fluvoxamine is expected to cause a greater increase in asenapine exposure. Dosage reduction for SAPHRIS based on clinical response may be necessary.
CYP2D6 substrates and inhibitors (e.g., paroxetine) SAPHRIS may enhance the inhibitory effects of paroxetine on its own metabolism. Concomitant use of paroxetine with SARPHIS increased the paroxetine exposure by 2-fold as compared to use paroxetine alone [see Clinical Pharmacology (12.3)]. Reduce paroxetine dose by half when paroxetine is used in combination with SAPHRIS.

Drugs Having No Clinically Important Interactions with SAPHRIS

No dosage adjustment of SAPHRIS is necessary when administered concomitantly with paroxetine (see Table 9 in Drug Interactions (7.1) for paroxetine dosage adjustment), imipramine, cimetidine, valporate, lithium, or a CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampin).

In addition, valproic acid and lithium pre-dose serum concentrations collected from an adjunctive therapy study were comparable between asenapine-treated patients and placebo-treated patients indicating a lack of effect of asenapine on valproic and lithium plasma levels.

Overdose

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.

Interpreting the GeneSight® Test:
Gene-Drug Interaction Chart

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