Lurata

Lurata is an atypical antipsychotic developed by Dainippon Sumitomo Pharma. It was approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia on October 29, 2010 and is currently pending approval for the treatment of bipolar disorder in the United States. (Wikipedia)

Schizophrenia

Lurata is indicated for the treatment of patients with schizophrenia.

The efficacy of Lurata in schizophrenia was established in five 6-week controlled studies of adult patients with schizophrenia.

The effectiveness of Lurata 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 Lurata for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Depressive Episodes Associated with Bipolar I Disorder

Monotherapy: Lurata is indicated as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of Lurata was established in a 6-week monotherapy study in adult patients with bipolar depression.

Adjunctive Therapy with Lithium or Valproate: Lurata is indicated as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of Lurata as adjunctive therapy was established in a 6-week study in adult patients with bipolar depression who were treated with lithium or valproate.

The effectiveness of Lurata 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 Lurata for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

The efficacy of Lurata in the treatment of mania associated with bipolar disorder has not been established.

Lurata (Lurata) is an antipsychotic medicine. It works by changing the effects of chemicals in the brain.

Lurata is used to treat schizophrenia in adults.

Lurata is also used to treat episodes of depression in people with bipolar disorder (manic depression).

Schizophrenia

The recommended starting dose of Lurata is 40 mg once daily. Initial dose titration is not required. Lurata has been shown to be effective in a dose range of 40 mg per day to 160 mg per day. The maximum recommended dose is 160 mg per day.

Depressive Episodes Associated with Bipolar I Disorder

The recommended starting dose of Lurata is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. Lurata has been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate. The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day) [see Clinical Studies (14.2).

Administration Instructions

Lurata should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of Lurata. Administration with food increases the AUC approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies, Lurata was administered with food.

Dose Modifications in Special Populations

Renal Impairment

Dose adjustment is recommended in moderate (creatinine clearance: 30 to <50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min) patients. The recommended starting dose is 20 mg per day. The dose in these patients should not exceed 80 mg per day.

Hepatic Impairment

Dose adjustment is recommended in moderate (Child-Pugh Score = 7 to 9) and severe hepatic impairment (Child-Pugh Score = 10 to 15) patients. The recommended starting dose is 20 mg per day. The dose in moderate hepatic impairment patients should not exceed 80 mg per day and the dose in severe hepatic impairment patients should not exceed 40 mg/day.

Dose Modifications Due to Drug Interactions

Concomitant Use with CYP3A4 Inhibitors

Lurata should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.).

If Lurata is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the Lurata dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and Lurata is added to the therapy, the recommended starting dose of Lurata is 20 mg per day, and the maximum recommended dose of Lurata is 80 mg per day.

Grapefruit and grapefruit juice should be avoided in patients taking Lurata, since these may inhibit CYP3A4 and alter Lurata concentrations.

Concomitant Use with CYP3A4 Inducers

Lurata should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.). If Lurata is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the Lurata dose after chronic treatment (7 days or more) with the CYP3A4 inducer.

See also:
What is the most important information I should know about Lurata?

Lurata is not for use in psychotic conditions related to dementia. Lurata may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

You should not use this medication if you are allergic to Lurata, or if you are also using ketoconazole (Extina, Ketozole, Nizoral, Xolegal) or rifampin (Rifater, Rifadin, Rifamate).

Before you take Lurata, tell your doctor if you have liver disease, kidney disease, heart disease, high blood pressure, heart rhythm problems, a history of heart attack or stroke, high cholesterol or triglycerides, low white blood cell (WBC) counts, seizures, diabetes, Parkinson's disease, trouble swallowing, or a history of breast cancer or suicidal thoughts.

While you are taking Lurata, you may be more sensitive to temperature extremes such as very hot or cold conditions. Avoid getting too cold, or becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking Lurata.

Lurata may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Drinking alcohol can increase certain side effects of Lurata.

Stop using Lurata and call your doctor at once if you have very stiff (rigid) muscles, high fever, sweating, confusion, fast or pounding heartbeats, feeling like you might pass out, tremors, or twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs.

There are many other drugs that can interact with Lurata. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Use Lurata as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Lurata comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Lurata refilled.
• Take Lurata by mouth with food (at least 350 calories).
• Swallow Lurata whole. Do not split, crush, or chew before swallowing.
• Do not eat grapefruit or drink grapefruit juice while you use Lurata.
• Do not suddenly stop taking Lurata without checking with your doctor. You may have an increased risk of side effects. If you need to stop Lurata, your doctor may need to gradually lower your dose.
• Take Lurata on a regular schedule to get the most benefit from it. Taking Lurata at the same time each day will help you remember to take it.
• Continue to take Lurata even if you feel well. Do not miss any doses.
• If you miss a dose of Lurata, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once unless your doctor tells you to. If you are not sure what to do, call your doctor.

Ask your health care provider any questions you may have about how to use Lurata.

This medication is used to treat certain mental/mood disorders (such as schizophrenia, depression associated with bipolar disorder). Lurata helps you to think more clearly, feel less nervous, and take part in everyday life. It may also help to decrease hallucinations (hearing/seeing things that are not there). In addition, this medication may improve your mood, sleep, appetite, and energy level. Lurata is a psychiatric medication that belongs to the class of drugs called atypical antipsychotics. It works by helping to restore the balance of certain natural substances in the brain.

How to use Lurata

Read the Medication Guide provided by your pharmacist before you start taking Lurata and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with food as directed by your doctor, usually once daily. Dosage is based on your medical condition, kidney/liver function, other drugs you are taking, and your response to treatment.

Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

Continue taking this medication exactly as prescribed, even if you are feeling better and thinking more clearly. Do not increase your dose or take this drug more often than prescribed. Your symptoms will not improve any faster, and your risk of side effects will increase. Do not stop taking this medication without consulting your doctor.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so safely. Grapefruit can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.

Tell your doctor if your condition does not improve or if it worsens. It may take several weeks before you feel the full benefit of this medication.

See also:
What other drugs will affect Lurata?

Potential for Other Drugs to Affect Lurata

Lurata is predominantly metabolized by CYP3A4. Lurata should not be used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) or strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.). The Lurata dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 (e.g., diltiazem, atazanavir, erythromycin, fluconazole, verapamil, etc.). If Lurata is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the Lurata dose.

Lithium: It is not necessary to adjust the Lurata dose when used concomitantly with lithium (Figure 1).

Valproate: It is not necessary to adjust the Lurata dose when used concomitantly with valproate. A dedicated drug-drug interaction study has not been conducted with valproate and Lurata. Based on pharmacokinetic data from the bipolar depression studies valproate levels were not affected by Lurata, and Lurata concentrations were not affected by valproate.

Grapefruit: Grapefruit and grapefruit juice should be avoided in patients taking Lurata, since these may inhibit CYP3A4 and alter Lurata concentrations.

Figure 1: Impact of Other Drugs on Lurata Pharmacokinetics

Potential for Lurata to Affect Other Drugs

No dose adjustment is needed for lithium, substrates of P-gp, CYP3A4 (Figure 2) or valproate when coadministered with Lurata. ).

Figure 2: Impact of Lurata on Other Drugs

Drug Abuse And Dependence

Controlled Substance

Lurata is not a controlled substance.

Abuse

Lurata has not been systematically studied in humans for its potential for abuse or physical dependence or its ability to induce tolerance. While clinical studies with Lurata did not reveal any tendency for drug-seeking behavior, these observations were not systematic and 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 of Lurata misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

See also:
What are the possible side effects of Lurata?

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

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Suicidal Thoughts and Behaviors
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis
• Neuroleptic Malignant Syndrome
• Tardive Dyskinesia
• Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)
• Hyperprolactinemia
• Leukopenia, Neutropenia, and Agranulocytosis
• Orthostatic Hypotension and Syncope
• Seizures
• Potential for Cognitive and Motor Impairment
• Body Temperature Dysregulation
• Suicide
• Activation of Mania/Hypomania
• Dysphagia
• Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The information below is derived from an integrated clinical study database for Lurata consisting of 3799 patients exposed to one or more doses of Lurata for the treatment of schizophrenia and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250.9 patient-years. A total of 1106 Lurata-treated patients had at least 24 weeks and 371 Lurata-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.

Schizophrenia

The following findings are based on the short-term, placebo-controlled premarketing studies for schizophrenia in which Lurata was administered at daily doses ranging from 20 to 160 mg (n=1508).

Commonly Observed Adverse Reactions

The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with Lurata were somnolence, akathisia, extrapyramidal symptoms, and nausea.

Adverse Reactions Associated with Discontinuation of Treatment

A total of 9.5% (143/1508) Lurata-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with Lurata that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in Lurata-Treated Patients

Adverse reactions associated with the use of Lurata (incidence of 2% or greater, rounded to the nearest percent and Lurata incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 15.

Table 15: Adverse Reactions in 2% or More of Lurata-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Short-term Schizophrenia Studies

Dose-Related Adverse Reactions in the Schizophrenia Studies

Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for Lurata 20 mg, 10.7% for Lurata 40 mg, 12.3% for Lurata 80 mg, and 22.0% for Lurata 120 mg). Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for Lurata 20 mg, 11.5% for Lurata 40 mg, 11.9% for Lurata 80 mg, and 22.0% for Lurata 120 mg).

Bipolar Depression (Monotherapy)

The following findings are based on the short-term, placebo-controlled premarketing study for bipolar depression in which Lurata was administered at daily doses ranging from 20 to 120 mg (n=331).

Commonly Observed Adverse Reactions

The most common adverse reactions (incidence ≥ 5%, in either dose group, and at least twice the rate of placebo) in patients treated with Lurata were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety.

Adverse Reactions Associated with Discontinuation of Treatment

A total of 6.0% (20/331) Lurata-treated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with Lurata that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in Lurata-Treated Patients

Adverse reactions associated with the use of Lurata (incidence of 2% or greater, rounded to the nearest percent and Lurata incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 16.

Table 16: Adverse Reactions in 2% or More of Lurata-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in a Short-term Monotherapy Bipolar Depression Study

Dose-Related Adverse Reactions in the Monotherapy Study

In the short-term, placebo-controlled study (involving lower and higher Lurata dose ranges) the adverse reactions that occurred with a greater than 5% incidence in the patients treated with Lurata in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for Lurata 20 to 60 mg/day and Lurata 80 to 120 mg/day, respectively.

Bipolar Depression

Adjunctive Therapy with Lithium or Valproate

The following findings are based on two short-term, placebo-controlled premarketing studies for bipolar depression in which Lurata was administered at daily doses ranging from 20 to 120 mg as adjunctive therapy with lithium or valproate (n=360).

Commonly Observed Adverse Reactions

The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in subjects treated with Lurata were akathisia and somnolence.

Adverse Reactions Associated with Discontinuation of Treatment

A total of 5.8% (21/360) Lurata-treated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with Lurata that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in Lurata-Treated Patients

Adverse reactions associated with the use of Lurata (incidence of 2% or greater, rounded to the nearest percent and Lurata incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 17.

Table 17: Adverse Reactions in 2% or More of Lurata-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Short-term Adjunctive Therapy Bipolar Depression Studies

Extrapyramidal Symptoms

Schizophrenia

In the short-term, placebo-controlled schizophrenia studies, for Lurata-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% versus 5.8% for placebo-treated patients. The incidence of akathisia for Lurata-treated patients was 12.9% versus 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 18.

Table 18: Incidence of EPS Compared to Placebo in Schizophrenia Studies

Bipolar Depression

Monotherapy

In the short-term, placebo-controlled monotherapy bipolar depression study, for Lurata-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6.9% versus 2.4% for placebo-treated patients. The incidence of akathisia for Lurata-treated patients was 9.4% versus 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 19.

Table 19: Incidence of EPS Compared to Placebo in the Monotherapy Bipolar Depression Study

Adjunctive Therapy with Lithium or Valproate

In the short-term, placebo-controlled adjunctive therapy bipolar depression studies, for Lurata-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% versus 8.7% for placebo. The incidence of akathisia for Lurata-treated patients was 10.8% versus 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 20.

Table 20: Incidence of EPS Compared to Placebo in the Adjunctive Therapy Bipolar Depression Studies

In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias.

Schizophrenia

The mean change from baseline for Lurata-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (Lurata, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in Lurata-treated patients versus placebo for the BAS (Lurata, 14.4%; placebo, 7.1%), the SAS (Lurata, 5.0%; placebo, 2.3%) and the AIMS (Lurata, 7.4%; placebo, 5.8%).

Bipolar Depression

Monotherapy

The mean change from baseline for Lurata-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in Lurata-treated patients versus placebo for the BAS (Lurata, 8.4%; placebo, 5.6%), the SAS (Lurata, 3.7%; placebo, 1.9%) and the AIMS (Lurata, 3.4%; placebo, 1.2%).

Adjunctive Therapy with Lithium or Valproate

The mean change from baseline for Lurata-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in Lurata-treated patients versus placebo for the BAS (Lurata, 8.7%; placebo, 2.1%), the SAS (Lurata, 2.8%; placebo, 2.1%) and the AIMS (Lurata, 2.8%; placebo, 0.6%).

Dystonia

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.

Schizophrenia

In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2% of Lurata-treated subjects (0.0% Lurata 20 mg, 3.5% Lurata 40 mg, 4.5% Lurata 80 mg, 6.5% Lurata 120 mg and 2.5% Lurata 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events – four were receiving Lurata 80 mg/day and three were receiving Lurata 120 mg/day.

Bipolar Depression

Monotherapy

In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, dystonia occurred in 0.9% of Lurata-treated subjects (0.0% and 1.8% for Lurata 20 to 60 mg/day and Lurata 80 to 120 mg/day, respectively) compared to 0.0% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Adjunctive Therapy with Lithium or Valproate

In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1.1% of Lurata-treated subjects (20 to 120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Other Adverse Reactions Observed During the Premarketing Evaluation of Lurata

Following is a list of adverse reactions reported by patients treated with Lurata at multiple doses of ≥ 20 mg once daily within the premarketing database of 2905 patients with schizophrenia. 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 Table 15 or those that appear elsewhere in the Lurata label are not included. Although the reactions reported occurred during treatment with Lurata, they were not necessarily caused by it.

Reactions are further categorized by 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).

Blood and Lymphatic System Disorders: Infrequent: anemia

Cardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris, bradycardia

Ear and Labyrinth Disorders: Infrequent: vertigo

Eye Disorders: Frequent: blurred vision

Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis

General Disorders and Administrative Site Conditions: Rare: sudden death

Investigations: Frequent: CPK increased

Metabolism and Nutritional System Disorders: Frequent: decreased appetite

Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis

Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria

Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder

Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure

Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction

Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema

Vascular Disorders: Frequent: hypertension

Clinical Laboratory Changes

Schizophrenia

Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for Lurata-treated patients compared to +0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of Lurata-treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 21).

Table 21: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in Schizophrenia Studies

Bipolar Depression

Monotherapy

Serum Creatinine: In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for Lurata-treated patients compared to -0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 2.8% (9/322) of Lurata-treated patients and 0.6% (1/162) on placebo (Table 22).

Table 22: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in a Monotherapy Bipolar Depression Study

Adjunctive Therapy with Lithium or Valproate

Serum Creatinine: In short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for Lurata-treated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/360) of Lurata-treated patients and 1.6% (5/334) on placebo (Table 23).

Table 23: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adjunctive Therapy Bipolar Depression Studies