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Saphris Side Effects

Generic Name: asenapine

Please note - some side effects for Saphris may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Saphris - for the Consumer

Saphris

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Saphris:

Decreased feeling around the mouth; dizziness; drowsiness; dry mouth; headache; increased appetite; increased saliva production; indigestion; joint aches; restlessness; taste changes; tiredness; trouble sleeping; upset stomach; vomiting; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur when using Saphris:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness; wheezing); change in the amount of urine produced; chest pain; fainting or loss of consciousness; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; muscle pain, weakness, or stiffness; new or worsening mental or mood changes (eg, aggression, agitation, depression, severe anxiety); seizures; severe or persistent dizziness or light-headedness; shortness of breath; suicidal thoughts or actions; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; confusion; flushing; rapid breathing; fruit-like breath odor; weakness); symptoms of high prolactin levels (eg, enlarged breast size, decreased sexual ability, missed menstrual period, nipple discharge); trouble swallowing; uncontrolled muscle movements (eg, of the arms, legs, tongue, jaw, or cheeks; tremors; twitching); unusual sweating.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Saphris Side Effects - for the Professional

Saphris

Overall Adverse Reactions Profile

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

The most common adverse reactions (≥5% and at least twice the rate of placebo) reported with acute treatment in schizophrenia were akathisia, oral hypoesthesia, and somnolence. The safety profile of Saphris in the maintenance treatment of schizophrenia 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 were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and weight increased and during the adjunctive therapy trial in bipolar disorder were somnolence and oral hypoesthesia.

The information below is derived from a clinical trial database for Saphris consisting of over 4565 patients and/or normal 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.

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.

The figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses, and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

Clinical Studies Experience

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 subjects and 10% of placebo subjects discontinued due to adverse reactions. There were no drug-related adverse reactions associated with discontinuation in subjects 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 Schizophrenic 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 therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 2.

TABLE 2: Adverse Reactions Reported in 2% or More of Subjects in One of the Saphris Dose Groups 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
*
Also includes the Flexible-dose trial (N=90).
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.
Gastrointestinal disorders
  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
  Weight increased <1% 2% 2% 3%
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%

Dose-Related Adverse Reactions: Of all the adverse reactions listed in Table 2, the only apparent dose-related adverse reaction was akathisia.

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 subjects 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) 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 monotherapy (up to 3-weeks in patients with bipolar mania) are shown in Table 3.

TABLE 3: Adverse Reactions Reported in 2% or More of Subjects in One of the Saphris Dose Groups 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
*
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.
Gastrointestinal disorders
  Dry mouth 1% 3%
  Dyspepsia 2% 4%
  Oral hypoesthesia <1% 4%
  Toothache 2% 3%
General disorders
  Fatigue 2% 4%
Investigations
  Weight increased <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%
  Headache 11% 12%
  Other extrapyramidal symptoms (excluding akathisia) 2% 7%
  Somnolence 6% 24%
Psychiatric disorders
  Anxiety 2% 4%
  Depression 1% 2%
  Insomnia 5% 6%

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 1 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 4.

TABLE 4: Adverse Reactions Reported in 2% or More Among Saphris-Treated (Adjunctive) Bipolar Mania Patients and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks
System Organ Class/Preferred Term Placebo
N=166
Saphris
5 mg or 10 mg twice daily*
N=158
*
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.
Gastrointestinal disorders
  Dyspepsia 2% 3%
  Oral hypoesthesia 0% 5%
General disorders
  Fatigue 2% 4%
  Edema peripheral <1% 3%
Investigations
  Weight increased 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%

Dystonia: Antipsychotic Class Effect: 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.

Extrapyramidal Symptoms: In the short-term, placebo-controlled schizophrenia and bipolar mania 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 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 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.

Other Findings: Oral hypoesthesia and/or oral paraesthesia may occur directly after administration of asenapine and usually resolves within 1 hour.

Laboratory Test Abnormalities:

Glucose: The effects on fasting serum glucose levels in the short-term schizophrenia and bipolar mania trials revealed no clinically relevant mean changes [see also Warnings and Precautions (5.5)]. In the short-term placebo-controlled schizophrenia trials, the mean increase in fasting glucose levels for Saphris-treated patients was 3.2 mg/dL compared to a decrease of 1.6 mg/dL for placebo-treated patients. The proportion of patients with fasting glucose elevations ≥126 mg/dL (at Endpoint), was 7.4% for Saphris-treated patients versus 6% for placebo-treated patients. In the short-term, placebo-controlled bipolar mania trials, the mean decreases in fasting glucose levels for both Saphris-treated and placebo-treated patients were 0.6 mg/dL. The proportion of patients with fasting glucose elevations ≥126 mg/dL (at Endpoint), was 4.9% for Saphris-treated patients versus 2.2% for placebo-treated patients.

In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the mean increase from baseline of fasting glucose was 2.4 mg/dL.

Lipids: The effects on total cholesterol and fasting triglycerides in the short-term schizophrenia and bipolar mania trials revealed no clinically relevant mean changes. In short-term, placebo-controlled schizophrenia trials, the mean increase in total cholesterol levels for Saphris-treated patients was 0.4 mg/dL compared to a decrease of 3.6 mg/dL for placebo-treated patients. The proportion of patients with total cholesterol elevations ≥240 mg/dL (at Endpoint) was 8.3% for Saphris-treated patients versus 7% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the mean increase in total cholesterol levels for Saphris-treated patients was 1.1 mg/dL compared to a decrease of 1.5 mg/dL in placebo-treated patients. The proportion of patients with total cholesterol elevations ≥240 mg/dL (at Endpoint) was 8.7% for Saphris-treated patients versus 8.6% for placebo-treated patients. In short-term, placebo-controlled schizophrenia trials, the mean increase in triglyceride levels for Saphris-treated patients was 3.8 mg/dL compared to a decrease of 13.5 mg/dL for placebo-treated patients. The proportion of patients with elevations in triglycerides ≥200 mg/dL (at Endpoint) was 13.2% for Saphris-treated patients versus 10.5% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the mean decrease in triglyceride levels for Saphris-treated patients was 3.5 mg/dL versus 17.9 mg/dL for placebo-treated subjects. The proportion of patients with elevations in triglycerides ≥200 mg/dL (at Endpoint) was 15.2% for Saphris-treated patients versus 11.4% for placebo-treated patients.

In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the mean decrease from baseline of total cholesterol was 6 mg/dL and the mean decrease from baseline of fasting triglycerides was 9.8 mg/dL.

Transaminases: Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania trials were more common in treated patients but mean changes were not clinically relevant. In short-term, placebo-controlled schizophrenia 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 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. No cases of more severe liver injury were seen.

In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the mean increase from baseline of ALT was 1.7 units/L.

Prolactin: The effects on prolactin levels in the short-term schizophrenia and bipolar mania trials revealed no clinically relevant mean changes in baseline. In short-term, placebo-controlled 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 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 trial of patients with schizophrenia and schizoaffective disorder, the mean decrease in prolactin from baseline for Saphris-treated patients was 26.9 ng/mL.

Creatine Kinase (CK): The proportion of patients with CK elevations >3 times ULN at any time were 6.4% and 11.1% for patients treated with Saphris 5 mg bid and 10 mg bid, 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.

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 in other parts of Adverse Reactions (6), or those considered in Warnings and Precautions (5) or Overdosage (10) are not included. Although the reactions reported occurred during treatment with Saphris, they were not necessarily caused by it. 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 (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; and those occurring in fewer than 1/1000 patients.

Blood and lymphatic disorders: <1/1000 patients: thrombocytopenia; ≥1/1000 patients and <1/100 patients: anemia

Cardiac disorders: ≥1/1000 patients and <1/100 patients: tachycardia, temporary bundle branch block

Eye disorders: ≥1/1000 patients and <1/100 patients: accommodation disorder

Gastrointestinal disorders: ≥1/1000 patients and <1/100 patients: oral paraesthesia, glossodynia, swollen tongue

General disorders: <1/1000 patients: idiosyncratic drug reaction

Investigations: ≥1/1000 patients and <1/100 patients: hyponatremia

Nervous system disorders: ≥1/1000 patients and <1/100 patients: dysarthria

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 reliably estimate their frequency or establish a causal relationship to drug exposure: oral mucosal lesions (including ulcerations, blistering, and inflammation).

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Side Effects by Body System - for Healthcare Professionals

Nervous system

Nervous system side effects including somnolence (up to 24%), extrapyramidal symptoms excluding akathisia (up to 12%), headache (up to 12%), dizziness (up to 11%), dysgeusia (up to 3%), neuroleptic malignant syndrome, and dysarthria have been reported.

Symptoms of dystonia 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. There is an elevated risk of acute dystonia in males and younger age groups.

Psychiatric

Psychiatric side effects including insomnia (up to 16%), anxiety (up to 4%), and depression (up to 2%) have been reported.

Gastrointestinal

Gastrointestinal side effects including constipation (up to 7%), oral hypoesthesia (up to 7%), vomiting (up to 7%), salivary hypersecretion (up to 4%), dyspepsia (up to 4%), stomach discomfort (up to 3%), dry mouth (up to 3%), toothache (3%), oral paraesthesia, glossodynia, and swollen tongue have been reported.

General

General side effects including increased weight (up to 5%), fatigue (up to 4%), and irritability (up to 2%) have been reported.

Metabolic

Metabolic side effects including increased appetite (up to 4%) and hyponatremia have been reported.

Hyperglycemia, in some cases extreme and associated with ketoacidosis, or hyperosmolar coma, or death has been reported in patients treated with atypical antipsychotics. In clinical trials of asenapine, the occurrence of any adverse reaction related to glucose metabolism was less than 1% in both the asenapine and placebo treatment groups.

Musculoskeletal

Musculoskeletal side effects including arthralgia (up to 3%) and pain in extremity ( up to 2%) have been reported.

Hepatic

Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania trials were more common in treated patients but mean changes were not clinically relevant. In short-term, placebo-controlled schizophrenia trials, the mean increase in transaminase levels for asenapine 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 three or more times the ULN (at the endpoint) was 0.9% for asenapine treated patients versus 1.3% for placebo treated patients. In short-term, placebo-controlled bipolar mania trials, the mean increase in transaminase levels for asenapine 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 three or more times the ULN (at the endpoint) was 2.5% for asenapine treated patients versus 0.6% for placebo treated patients. No cases of more severe liver injury were seen. In a 52 week, double-blind, comparator controlled trial of patients with schizophrenia and schizoaffective disorder, the mean increase from baseline of ALT was 1.7 units/L.

Hepatic side effects including transient elevations in serum transaminase have been reported.

Hematologic

Hematologic side effects including thrombocytopenia and anemia have been reported.

Cardiovascular

Cardiovascular side effects including tachycardia and temporary bundle branch block have been reported.

Four normal volunteers in clinical studies treated with asenapine experienced hypotension, bradycardia, and sinus pauses.

Ocular

Ocular side effects including accommodation disorder have been reported.

Hypersensitivity

Hypersensitivity side effects including idiosyncratic drug reaction have been reported. Post marketing reports have included anaphylaxis and angioedema. In several cases, these reactions occurred after the first dose. These hypersensitivity reactions included: hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.

Other

Other side effects have included oral hypoesthesia and/or oral paraesthesia.

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