Saphris Information
Saphris ()
Saphris () Contraindications
Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed in patients treated with asenapine. Therefore, Saphris () is contraindicated in patients with a known hypersensitivity to the product .
Saphris () Warnings And Precautions
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Saphris () is not approved for the treatment of patients with dementia-related psychosis .
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including Saphris () . Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
A syndrome of potentially irreversible, involuntary, dyskinetic movements can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause Tardive Dyskinesia (TD) is unknown.
The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, Saphris () should be prescribed in a manner that is most likely to minimize the occurrence of TD. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of TD appear in a patient on Saphris () , drug discontinuation should be considered. However, some patients may require treatment with Saphris () despite the presence of the syndrome.
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Because Saphris () was not marketed at the time these studies were performed, it is not known if Saphris () is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the antipsychotic drug.
Increases in weight have been observed in pre-marketing clinical trials with Saphris () . Patients receiving Saphris () should receive regular monitoring of weight .
In short-term schizophrenia and bipolar mania trials, there were differences in mean weight gain between Saphris () -treated and placebo-treated patients. In short-term, placebo-controlled schizophrenia trials, the mean weight gain was 1.1 kg for Saphris () -treated patients compared to 0.1 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.9% for Saphris () -treated patients versus 2% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the mean weight gain for Saphris () -treated patients was 1.3 kg compared to 0.2 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 5.8% for Saphris () -treated patients versus 0.5% for placebo-treated patients.
In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia or schizoaffective disorder, the mean weight gain from baseline was 0.9 kg. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 14.7%. provides the mean weight change from baseline and the proportion of patients with a weight gain of ≥7% categorized by Body Mass Index (BMI) at baseline:
Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed in patients treated with asenapine. In several cases, these reactions occurred after the first dose. These hypersensitivity reactions included: anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.
Saphris () may induce orthostatic hypotension and syncope in some patients, especially early in treatment, because of its α1-adrenergic antagonist activity. In short-term schizophrenia trials, syncope was reported in 0.2% (1/572) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of Saphris () , compared to 0.3% (1/378) of patients treated with placebo. In short-term bipolar mania trials, syncope was reported in 0.3% (1/379) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of Saphris () , compared to 0% (0/203) of patients treated with placebo. During pre-marketing clinical trials with Saphris () , including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1953) of patients treated with Saphris () .
Four normal volunteers in clinical pharmacology studies treated with either intravenous, oral, or sublingual Saphris () experienced hypotension, bradycardia, and sinus pauses. These spontaneously resolved in 3 cases, but the fourth subject received external cardiac massage. The risk of this sequence of hypotension, bradycardia, and sinus pause might be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.
Patients should be instructed about nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). Saphris () should be used with caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications); and (2) in the elderly. Saphris () should be used cautiously when treating patients who receive treatment with other drugs that can induce hypotension, bradycardia, respiratory or central nervous system depression . Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs.
In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including Saphris () . Agranulocytosis (including fatal cases) has been reported with other agents in the class.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced 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 decline in WBC in the absence of other causative factors.
Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count
The effects of Saphris () on the QT/QTc interval were evaluated in a dedicated QT study. This trial involved Saphris () doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily, and placebo, and was conducted in 151 clinically stable patients with schizophrenia, with electrocardiographic assessments throughout the dosing interval at baseline and steady state. At these doses, Saphris () was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with Saphris () experienced QTc increases ≥60 msec from baseline measurements, nor did any patient experience a QTc of ≥500 msec.
Electrocardiogram (ECG) measurements were taken at various time points during the Saphris () clinical trial program (5-mg or 10-mg twice daily doses). Post-baseline QT prolongations exceeding 500 msec were reported at comparable rates for Saphris () and placebo in these short-term trials. There were no reports of Torsade de Pointes or any other adverse reactions associated with delayed ventricular repolarization.
The use of Saphris () should be avoided in combination with other drugs known to prolong QTc including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and antibiotics (e.g., gatifloxacin, moxifloxacin). Saphris () should also be avoided in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including bradycardia; hypokalemia or hypomagnesemia; and presence of congenital prolongation of the QT interval.
Like other drugs that antagonize dopamine D receptors, Saphris () can elevate prolactin levels, and the elevation can persist during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. In Saphris () clinical trials, the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo .
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent , a factor of potential importance if the prescription of these drugs is considered in a patient with previously-detected breast cancer. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
Somnolence was reported in patients treated with Saphris () . It was usually transient with the highest incidence reported during the first week of treatment. In short-term, fixed-dose, placebo-controlled schizophrenia trials, somnolence was reported in 15% (41/274) of patients on Saphris () 5 mg twice daily and in 13% (26/208) of patients on Saphris () 10 mg twice daily compared to 7% (26/378) of placebo patients. In short-term, placebo-controlled bipolar mania trials of therapeutic doses (5–10 mg twice daily), somnolence was reported in 24% (90/379) of patients on Saphris () compared to 6% (13/203) of placebo patients. During pre-marketing clinical trials with Saphris () , including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1953) of patients treated with Saphris () . Somnolence (including sedation) led to discontinuation in 0.6% (12/1953) of patients in short-term, placebo-controlled trials.
Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that Saphris () therapy does not affect them adversely.
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia was reported in 0.2% and 0% (1/572, 0/379) of patients treated with therapeutic doses (5–10 mg twice daily) of Saphris () as compared to 0% (0/378, 0/203) of patients treated with placebo in short-term schizophrenia and bipolar mania trials, respectively. During pre-marketing clinical trials with Saphris () , including long-term trials without comparison to placebo, dysphagia was reported in 0.1% (2/1953) of patients treated with Saphris () .
Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Saphris () is not indicated for the treatment of dementia-related psychosis, and should not be used in patients at risk for aspiration pneumonia .
Clinical experience with Saphris () in patients with certain concomitant systemic illnesses is limited .
Saphris () has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from pre-marketing clinical trials. Because of the risk of orthostatic hypotension with Saphris () , caution should be observed in cardiac patients .
Saphris () Adverse Reactions
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.
Saphris () 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.
Saphris () Use In Specific Populations
Clinical studies of Saphris () in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Of the approximately 2250 patients in pre-marketing clinical studies of Saphris () , 1.1% (25) were 65 years of age or over. Multiple factors that might increase the pharmacodynamic response to Saphris () , causing poorer tolerance or orthostasis, could be present in elderly patients, and these patients should be monitored carefully.
In elderly patients with psychosis, asenapine exposure (AUC) was on average 40% higher compared to younger adult patients .
Elderly patients with dementia-related psychosis treated with Saphris () are at an increased risk of death compared to placebo. Saphris () is not approved for the treatment of patients with dementia-related psychosis .
Saphris () Overdosage
Human Experience:
Management of Overdosage:
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.
Saphris () Description
Saphris () is a psychotropic agent that is available for sublingual administration. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical designation is (3a,12b)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1dibenzo[2,3:6,7]oxepino[4,5-]pyrrole (2)-2-butenedioate (1:1). Its molecular formula is CHClNO•CHO and its molecular weight is 401.84 (free base: 285.8). The chemical structure is:
Asenapine is a white to off-white powder.
Saphris () is supplied for sublingual administration in tablets containing 5-mg or 10-mg asenapine; inactive ingredients include gelatin and mannitol.
Saphris () , black cherry flavor, is supplied for sublingual administration in tablets containing 5-mg or 10-mg asenapine; inactive ingredients include gelatin, mannitol, sucralose, and black cherry flavor.
Saphris () Clinical Studies
The efficacy of Saphris () in the treatment of schizophrenia in adults was evaluated in three fixed-dose, short-term (6 week), randomized, double-blind, placebo-controlled, and active-controlled (haloperidol, risperidone, and olanzapine) trials of adult patients who met DSM-IV criteria for schizophrenia and were having an acute exacerbation of their schizophrenic illness. In two of the three trials Saphris () demonstrated superior efficacy to placebo. In a third trial, Saphris () could not be distinguished from placebo; however, an active control in that trial was superior to placebo.
In the two positive trials for Saphris () the primary efficacy rating scale was the Positive and Negative Syndrome Scale (PANSS), which assesses the symptoms of schizophrenia. The primary endpoint was change from baseline to endpoint on the PANSS total score. The results of the Saphris () trials in schizophrenia follow:
In trial 1, a 6-week trial (n=174), comparing Saphris () (5 mg twice daily) to placebo, Saphris () 5 mg twice daily was statistically superior to placebo on the PANSS total score.
In trial 2, a 6-week trial (n=448), comparing two fixed doses of Saphris () (5 mg and 10 mg twice daily) to placebo, Saphris () 5 mg twice daily was statistically superior to placebo on the PANSS total score. Saphris () 10 mg twice daily showed no added benefit compared to 5 mg twice daily and was not significantly different from placebo.
An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender or race.
Maintenance of efficacy has been demonstrated in a placebo-controlled, double-blind, multicenter, flexible dose (5 mg or 10 mg twice daily based on tolerability) clinical trial with a randomized withdrawal design. A total of 700 patients entered open-label treatment with Saphris () for a period of 26 weeks. Of these, a total of 386 patients who met pre-specified criteria for continued stability (mean length of stabilization was 22 weeks) were randomized to a double-blind, placebo-controlled, randomized withdrawal phase. Saphris () was statistically superior to placebo in time to relapse or impending relapse defined as increase in PANSS ≥20% from baseline and a Clinical Global Impression–Severity of Illness (CGI-S) score ≥4 (at least 2 days within 1 week) or PANSS score ≥5 on "hostility" or "uncooperativeness" items and CGI-S score >4 (>2 days within a week), or PANSS score ≥5 on any two of the following items: "unusual thought content," "conceptual disorganization," or "hallucinatory behavior" items, and CGI-S score ≥4 (≥2 days within 1 week) or investigator judgment of worsening symptoms or increased risk of violence to self (including suicide) or other persons. The Kaplan-Meier curves of the time to relapse or impending relapse during the double-blind, placebo-controlled, randomized withdrawal phase of this trial for Saphris () and placebo are shown in Figure 1.
Saphris () How Supplied/storage And Handling
Saphris () (asenapine) sublingual tablets are supplied as:
Round, white to off-white sublingual tablets, with "5" on one side.
Round, white to off-white sublingual tablets, with "10" on one side.
Round, white to off-white sublingual tablets, with "5" on one side within a circle.
Round, white to off-white sublingual tablets, with "10" on one side within a circle.
Saphris () Patient Counseling Information
IMPORTANT:
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