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Saphris

Saphris

SIDE EFFECTS

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
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%
* 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: 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
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%
* 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.

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
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%
* 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

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]. 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

Read the Saphris (asenapine sublingual tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

The risks of using SAPHRIS in combination with other drugs have not been extensively evaluated. Given the primary CNS effects of SAPHRIS, caution should be used when it is taken in combination with other centrally acting drugs or alcohol.

Because of its α1-adrenergic antagonism with potential for inducing hypotension, SAPHRIS may enhance the effects of certain antihypertensive agents.

Potential for Other Drugs to Affect SAPHRIS

Asenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). The potential effects of inhibitors of several of these enzyme pathways on asenapine clearance were studied.

Table 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers

Coadministered drug (Postulated effect on CYP450/UGT) Dose schedules Effect on asenapine pharmacokinetics Recommendation
Coadministered drug Asenapine Cmax AUC0-∞
Fluvoxamine (CYP1A2 inhibitor) 25 mg twice daily for 8 days 5-mg Single Dose 13% 29% Coadminister with caution*
Paroxetine (CYP2D6 inhibitor) 20 mg once daily for 9 days 5-mg Single Dose –13% –9% No SAPHRIS dose adjustment required [see DRUG INTERACTIONS]
Imipramine (CYP1A2/2C19/3A4 inhibitor) 75-mg Single Dose 5-mg Single Dose 17% 10% No SAPHRIS dose adjustment required
Cimetidine (CYP3A4/2D6/1A2 inhibitor) 800 mg twice daily for 8 days 5-mg Single Dose –13% 1% No SAPHRIS dose adjustment required
Carbamazepine (CYP3A4 inducer) 400 mg twice daily for 15 days 5-mg Single Dose –16% –16% No SAPHRIS dose adjustment required
Valproate (UGT1A4 inhibitor) 500 mg twice daily for 9 days 5-mg Single Dose 2% –1% No SAPHRIS dose adjustment required
* The full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.

A population pharmacokinetic analysis indicated that the concomitant administration of lithium had no effect on the pharmacokinetics of asenapine.

Potential for SAPHRIS to Affect Other Drugs

Coadministration with CYP2D6 Substrates

In vitro studies indicate that asenapine weakly inhibits CYP2D6.

Following coadministration of dextromethorphan and SAPHRIS in healthy subjects, the ratio of dextrorphan/dextromethorphan (DX/DM) as a marker of CYP2D6 activity was measured. Indicative of CYP2D6 inhibition, treatment with SAPHRIS 5 mg twice daily decreased the DX/DM ratio to 0.43. In the same study, treatment with paroxetine 20 mg daily decreased the DX/DM ratio to 0.032. In a separate study, coadministration of a single 75-mg dose of imipramine with a single 5-mg dose of SAPHRIS did not affect the plasma concentrations of the metabolite desipramine (a CYP2D6 substrate). Thus, in vivo, SAPHRIS appears to be at most a weak inhibitor of CYP2D6. Coadministration of a single 20-mg dose of paroxetine (a CYP2D6 substrate and inhibitor) during treatment with 5 mg SAPHRIS twice daily in 15 healthy male subjects resulted in an almost 2-fold increase in paroxetine exposure. Asenapine may enhance the inhibitory effects of paroxetine on its own metabolism.

SAPHRIS should be coadministered cautiously with drugs that are both substrates and inhibitors for CYP2D6.

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.

Drug Abuse And Dependence

Controlled Substance

SAPHRIS is not a controlled substance.

Abuse

SAPHRIS has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance or physical dependence. Thus, it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs that they are misusing or abusing SAPHRIS (e.g., drug-seeking behavior, increases in dose).

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

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