Latuda Information
Latuda (Lurasidone) . Indications And Usage
Latuda (Lurasidone) is indicated for the treatment of patients with schizophrenia.
The efficacy of Latuda (Lurasidone) in schizophrenia was established in four 6-week controlled studies of adult patients with schizophrenia
The effectiveness of Latuda (Lurasidone) for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use Latuda (Lurasidone) for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient .
Latuda (Lurasidone) . Dosage And Administration
Dosage adjustments are not recommended on the basis of age, gender, and race
Dose adjustment is recommended in moderate and severe renal impairment patients. The dose in these patients should not exceed 40 mg/day
Dose adjustment is recommended in moderate and severe hepatic impairment patients. The dose in these patients should not exceed 40 mg/day
Latuda (Lurasidone) . Dosage Forms And Strengths
Latuda (Lurasidone) tablets are available in the following shape and color () with respective one-sided debossing: 20 mg (white to off-white, round, “L20”), 40 mg (white to off-white, round, “L40”), or 80 mg (pale green, oval, “L80”).
Latuda (Lurasidone) . Contraindications
Latuda (Lurasidone) is contraindicated in any patient with a known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone [].
Latuda (Lurasidone) is contraindicated with strong CYP3A4 inhibitors (e.g., ketoconazole) and strong CYP3A4 inducers (e.g., rifampin) [].
Latuda (Lurasidone) . Warnings And Precautions
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Latuda (Lurasidone) is not approved for the treatment of dementia-related psychosis [
see
].
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including Latuda (Lurasidone) .
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 creatinine 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. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported.
Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that 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 is unknown.
The risk of developing tardive dyskinesia 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 tardive dyskinesia, 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, Latuda (Lurasidone) should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. 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 tardive dyskinesia appear in a patient on Latuda (Lurasidone) , drug discontinuation should be considered. However, some patients may require treatment with Latuda (Lurasidone) despite the presence of the syndrome.
As with other drugs that antagonize dopamine D receptors, Latuda (Lurasidone) elevates prolactin levels.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin 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 with prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients .
In short-term, placebo-controlled studies, the median change from baseline to endpoint in prolactin levels for Latuda (Lurasidone) -treated patients was 1.1 ng/mL and was - 0.6 ng/mL in the placebo-treated patients. The increase in prolactin was greater in female patients; the median change from baseline to endpoint for females was 1.5 ng/mL and was 1.1 ng/mL in males. The increase in prolactin concentrations was dose-dependent ().
The proportion of patients with prolactin elevations ≥ 5× ULN was 3.6% for Latuda (Lurasidone) -treated patients versus 0.7% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 8.3% for Latuda (Lurasidone) -treated patients versus 1% for placebo-treated female patients. The proportion of male patients with prolactin elevations > 5x ULN was 1.9% versus 0.6% for placebo-treated male patients.
In the uncontrolled longer-term studies (primarily open-label extension studies), Latuda (Lurasidone) was associated with a median change in prolactin of -1.9 ng/mL at week 24 (n=188), -5.4 ng/mL at week 36 (n=189) and -3.3 ng/mL at week 52 (n=243).
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. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a Latuda (Lurasidone) carcinogenicity study conducted in rats and mice 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.
Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. 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 Latuda (Lurasidone) 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
Latuda (Lurasidone) may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension and syncope events from short-term, placebo-controlled studies was (Latuda (Lurasidone) incidence, placebo incidence): orthostatic hypotension [0.4% (4/1004), 0.2% (1/455)] and syncope [
Latuda (Lurasidone) should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
As with other antipsychotic drugs, Latuda (Lurasidone) should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.
In short-term, placebo-controlled trials, seizures/convulsions occurred in
Latuda (Lurasidone) , like other antipsychotics, has the potential to impair judgment, thinking or motor skills.
In short-term, placebo-controlled trials, somnolence was reported in 22.3% (224/1004) of patients treated with Latuda (Lurasidone) compared to 9.9% (45/455) of placebo patients, respectively. The frequency of somnolence increases with dose; somnolence was reported in 26.5% (77/291) of patients receiving Latuda (Lurasidone) 120 mg/day. In these short-term trials, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.
Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with Latuda (Lurasidone) does not affect them adversely.
The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for Latuda (Lurasidone) should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
In short-term, placebo-controlled studies in patients with schizophrenia, the incidence of treatment-emergent suicidal ideation was 0.6% (6/1004) for Latuda (Lurasidone) -treated patients compared to 0.4% (2/455) on placebo. No suicide attempts or completed suicides were reported in these studies.
Latuda (Lurasidone) . Adverse Reactions
The following adverse reactions are discussed in more detail in other sections of the labeling:
The information below is derived from a clinical study database for Latuda (Lurasidone) consisting of over 2096 patients with schizophrenia exposed to one or more doses with a total experience of 624 patient-years. Of these patients, 1004 participated in short-term, placebo-controlled schizophrenia studies with doses of 20 mg, 40 mg, 80 mg or 120 mg once daily. A total of 533 Latuda (Lurasidone) -treated patients had at least 24 weeks and 238 Latuda (Lurasidone) -treated patients had at least 52 weeks of exposure.
Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
The stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event of the type listed. Treatment-emergent adverse events were defined as adverse experiences, which started or worsened on or after the date of the first dose through seven days after study medication discontinuation. There was no attempt to use investigator causality assessments; i.e., all events meeting the defined criteria, regardless of investigator causality are included. It is important to emphasize that, although the reactions occurred during treatment with Latuda (Lurasidone) , they were not necessarily caused by it. The label should be read in its entirety to gain an understanding of the safety profile of Latuda (Lurasidone) .
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 studies. 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.
In the short-term, placebo-controlled schizophrenia studies, for Latuda (Lurasidone) -treated patients, the incidence of reported EPS-related events, excluding akathisia and restlessness, was 14.7% versus 5.1% for placebo-treated patients; and the incidence of akathisia for Latuda (Lurasidone) -treated patients was 15.0% versus 3.3% for placebo-treated patients. Akathisia appeared to be dose-related and the greatest frequency of parkinsonism and dystonia occurred with the highest dose of Latuda (Lurasidone) , 120 mg/day ().
In the short-term, placebo-controlled schizophrenia studies, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Abnormal Involuntary Movement Scale (for dyskinesias). The mean change from baseline for Latuda (Lurasidone) -treated patients was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (Latuda (Lurasidone) , 0.2; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in Latuda (Lurasidone) -treated patients versus placebo for the BAS (Latuda (Lurasidone) , 16.0%; placebo, 7.6%) and the SAS (Latuda (Lurasidone) , 5.3%; placebo, 2.5%).
Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with Latuda (Lurasidone) at multiple doses of ≥ 20 mg once daily during any phase of a study within the database of 2096 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 listed in are not included. Although the reactions reported occurred during treatment with Latuda (Lurasidone) , 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 (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).
Latuda (Lurasidone) . Drug Interactions
Given the primary CNS effects of Latuda (Lurasidone) , caution should be used when it is taken in combination with other centrally acting drugs and alcohol.
Latuda (Lurasidone) is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. This suggests that an interaction of Latuda (Lurasidone) with drugs that are inhibitors or inducers of these enzymes is unlikely.
Latuda (Lurasidone) is predominantly metabolized by CYP3A4; interaction of Latuda (Lurasidone) with strong and moderate inhibitors or inducers of this enzyme has been observed (). Latuda (Lurasidone) should not be used in combination with strong inhibitors or inducers of this enzyme
Latuda (Lurasidone) . Use In Specific Populations
Clinical studies of Latuda (Lurasidone) in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In elderly patients with psychosis (65 to 85), lurasidone concentrations (20 mg/day) were similar to those in young subjects . No dose adjustment is necessary in elderly patients.
Elderly patients with dementia-related psychosis treated with Latuda (Lurasidone) are at an increased risk of death compared to placebo. Latuda (Lurasidone) is not approved for the treatment of patients with dementia-related psychosis .
It is recommended that Latuda (Lurasidone) dose should not exceed 40 mg/day in patients with moderate and severe renal impairment (Cl ≥ 10 mL/min to
After administration of a single dose of 40 mg Latuda (Lurasidone) to patients with mild, moderate and severe renal impairment, mean C increased by 40%, 92% and 54%, respectively and mean AUC increased by 53%, 91% and 2-times, respectively compared to healthy matched subjects.
Latuda (Lurasidone) . Overdosage
Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific antidote to Latuda (Lurasidone) , therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers.
Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of Latuda (Lurasidone) . Similarly, the alpha-blocking properties of bretylium might be additive to those of Latuda (Lurasidone) , resulting in problematic hypotension.
Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of Latuda (Lurasidone) -induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
Latuda (Lurasidone) . Description
Latuda (Lurasidone) is a psychotropic agent belonging to the chemical class of benzoisothiazol derivatives.
Its chemical name is (3a,4,7,7a)-2-{(1,2)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2-isoindole-1,3-dione hydrochloride. Its molecular formula is CHNOS·HCl and its molecular weight is 529.14.
The chemical structure is:
Lurasidone hydrochloride is a white to off-white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCl, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone.
Latuda (Lurasidone) tablets are intended for oral administration only. Each tablet contains 20 mg, 40 mg, or 80 mg of lurasidone hydrochloride.
Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No.2 Aluminum Lake.
Latuda (Lurasidone) . Clinical Pharmacology
In vitro
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The activity of lurasidone is primarily due to the parent drug. The pharmacokinetics of lurasidone is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of lurasidone are reached within 7 days of starting Latuda (Lurasidone) .
Following administration of 40 mg of Latuda (Lurasidone) , the mean (%CV) elimination half-life was 18 (7) hours.
Latuda (Lurasidone) . Nonclinical Toxicology
Carcinogenesis:
In the mouse study, there were increased incidences of malignant mammary gland tumors and pituitary gland adenomas in females at all doses; the lowest dose tested produced plasma levels (AUC) 2 times those in humans receiving the maximum recommended human dose (MRHD) of 80 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 15-25 times those in humans receiving the MRHD.
In rats, an increased incidence of mammary gland carcinomas was seen in females at the two higher doses; the no-effect dose of 3 mg/kg produced plasma levels (AUC) 0.7 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to highest dose tested, which produced plasma levels (AUC) 10 times those in humans receiving the MRHD.
Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin mediated. The relevance of this increased incidence of prolactin-mediated pituitary or mammary gland tumors in rodents in terms of human risk is unknown
Mutagenesis:
in vitro
in vivo
Impairment of Fertility:
Fertility was not affected in male rats treated orally with lurasidone for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (12 times the MRHD based on body surface area).
Latuda (Lurasidone) . How Supplied/storage And Handling
Latuda (Lurasidone) tablets are white to off-white, round (20 mg or 40 mg), or pale green, oval (80 mg) and identified with strength-specific one-sided debossing, “L20” (20 mg), “L40” (40 mg), or “L80” (80 mg). Tablets are supplied in the following strengths and package configurations ():
Latuda (Lurasidone) . Patient Counseling Information
Physicians are advised to discuss with patients for whom they prescribe Latuda (Lurasidone) all relevant safety information including, but not limited to, the following:
Patients should be advised regarding appropriate care in avoiding overheating and dehydration
SUNOVION
Manufactured for:Sunovion Pharmaceuticals Inc.Marlborough, MA 01752 USA
For Customer Service, call 1-888-394-7377.For Medical Information, call 1-800-739-0565.To report suspected adverse reactions, call 1-877-737-7226.
Revised: December 2011901456R03
Latuda (Lurasidone) is a registered trademark of Dainippon Sumitomo Pharma Co. Ltd. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Dainippon Sumitomo Pharma Co. Ltd.
© 2010, 2012 Sunovion Pharmaceuticals Inc.
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