Latuda

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of LATUDA in the treatment of schizophrenia and bipolar depression is unknown. However, its efficacy in schizophrenia and bipolar depression could be mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

Pharmacodynamics

LATUDA is an antagonist with high affinity binding at the dopamine D2 receptors (Ki=1 nM) and the 5-hydroxytryptamine (5-HT, serotonin) receptors 5-HT2A (Ki=0.5 nM) and 5-HT7 (Ki=0.5 nM) receptors. It also binds with moderate affinity to the human α2C adrenergic receptors (Ki=11 nM), is a partial agonist at serotonin 5-HT1A (Ki=6.4 nM) receptors, and is an antagonist at the α2A adrenergic receptors (Ki=41 nM). LATUDA exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 > 1,000 nM).

ECG Changes

The effects of LATUDA on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with schizophrenia or schizoaffective disorder, who were treated with LATUDA doses of 120 mg daily, 600 mg daily and completed the study. The maximum mean (upper 1-sided, 95% CI) increase in baseline-adjusted QTc intervals based on individual correction method (QTcI) was 7.5 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship.

In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with LATUDA or placebo.

Pharmacokinetics

The activity of LATUDA is primarily due to the parent drug. The pharmacokinetics of LATUDA is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of LATUDA are reached within 7 days of starting LATUDA.

Following administration of 40 mg of LATUDA, the mean (%CV) elimination half-life was 18 (7) hours.

Absorption and Distribution

LATUDA is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed.

Following administration of 40 mg of LATUDA, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. LATUDA is highly bound (~99%) to serum proteins.

In a food effect study, LATUDA mean Cmax and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. LATUDA exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content [see DOSAGE AND ADMINISTRATION].

In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food [see DOSAGE AND ADMINISTRATION].

Metabolism and Elimination

LATUDA is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. LATUDA is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220). Based on in vitro studies, LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because LATUDA is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of LATUDA.

Total excretion of radioactivity in urine and feces combined was approximately 89%, with about 80% recovered in feces and 9% recovered in urine, after a single dose of [14C]-labeled LATUDA.

Following administration of 40 mg of LATUDA, the mean (%CV) apparent clearance was 3902 (18.0) mL/min.

Clinical Studies

Schizophrenia

The efficacy of LATUDA for the treatment of schizophrenia was established in five short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.4 years, range 18-72) who met DSM-IV criteria for schizophrenia. An active-control arm (olanzapine or quetiapine extended-release) was included in two studies to assess assay sensitivity.

Several instruments were used for assessing psychiatric signs and symptoms in these studies:

  1. Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210.
  2. Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. The BPRSd consists of 18 items rated on a scale of 1 (not present) to 7 (severe). BPRSd scores may range from 18 to 126.
  3. The Clinical Global Impression severity scale (CGI-S) is a clinician-rated scale that measures the subject's current illness state on a 1- to 7-point scale.
  4. The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the drug and control groups.

The results of the studies follow:

  1. Study 1: In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of LATUDA (40 or 120 mg/day), both doses of LATUDA at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S.
  2. Study 2: In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of LATUDA (80 mg/day), LATUDA at Endpoint was superior to placebo on the BPRSd total score, and the CGI-S.
  3. Study 3: In a 6-week, placebo- and active-controlled trial (N=473) involving two fixed doses of LATUDA (40 or 120 mg/day) and an active control (olanzapine), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
  4. Study 4: In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of LATUDA (40, 80 or 120 mg/day), only the 80 mg/day dose of LATUDA at Endpoint was superior to placebo on the PANSS total score, and the CGI-S.
  5. Study 5: In a 6-week, placebo- and active-controlled trial (N=482) involving two fixed doses of LATUDA (80 or 160 mg/day) and an active control (quetiapine extended-release), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.

Thus, the efficacy of LATUDA at doses of 40, 80, 120 and 160 mg/day has been established (Table 24).

Table 24: Primary Efficacy Results for Studies in Schizophrenia (BPRSd or PANSS Scores)

Study Treatment Group Mean Baseline Score LS Mean Change (SD) Primary Efficacy Measure: BPRSd from Baseline (SE) Placebo-subtracted Differencea (95% CI)
1 LATUDA (40 mg/day)* 54.2 (8.8) -9.4 (1.6) -5.6 (-9.8, -1.4)
LATUDA (120 mg/day)* 52.7 (7.6) -11.0 (1.6) -6.7 (-11.0, -2.5)
Placebo 54.7 (8.1) -3.8 (1.6) --
2 LATUDA (80 mg/day)* 55.1 (6.0) -8.9 (1.3) -4.7 (-8.3,-1.1)
Placebo 56.1 (6.8) -4.2 (1.4) --
  Primary Efficacy Measure: PANSS
3 LATUDA (40 mg/day)* 96.6 (10.7) -25.7 (2.0) -9.7 (-15.3, -4.1)
LATUDA (120 mg/day)* 97.9 (11.3) -23.6 (2.1) -7.5 (-13.4, -1.7)
Olanzapine (15 mg/day )*b 96.3 (12.2) -28.7 (1.9) -12.6 (-18.2, -7.9)
Placebo 95.8 (10.8) -16.0 (2.1) --
4 LATUDA (40 mg/day) 96.5 (11.5) -19.2 (1.7) -2.1 (-7.0, 2.8)
LATUDA (80 mg/day)* 96.0 (10.8) -23.4 (1.8) -6.4 (-11.3, -1.5)
LATUDA (120 mg/day) 96.0 (9.7) -20.5 (1.8) -3.5 (-8.4, 1.4)
Placebo 96.8 (11.1) -17.0 (1.8) --
5 LATUDA (80 mg/day)* 97.7 (9.7) -22.2 (1.8) -11.9 (-16.9, -6.9)
LATUDA (160 mg/day)* 97.5 (11.8) -26.5 (1.8) -16.2 (-21.2, -11.2)
Quetiapine Extended-release (600 mg/day)*b 97.7 (10.2) -27.8 (1.8) -17.5 (-22.5, -12.4)
Placebo 96.6 (10.2) -10.3 (1.8) --
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons.
aDifference (drug minus placebo) in least-squares mean change from baseline.
bIncluded for assay sensitivity.
* Doses statistically significantly superior to placebo.

Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness. Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness.

Depressive Episodes Associated with Bipolar I Disorder

Monotherapy

The efficacy of LATUDA, as monotherapy, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.5 years, range 18 to 74) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=485). Patients were randomized to one of two flexible-dose ranges of LATUDA (20 to 60 mg/day, or 80 to 120 mg/day) or placebo.

The primary rating instrument used to assess depressive symptoms in this study was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the subject's current illness state on a 7-point scale, where a higher score is associated with greater illness severity.

For both dose groups, LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The primary efficacy results are provided in Table 25. The high dose range (80 to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 to 60 mg per day).

Adjunctive Therapy with Lithium or Valproate

The efficacy of LATUDA, as an adjunctive therapy with lithium or valproate, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.7 years, range 18 to 72) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=340). Patients who remained symptomatic after treatment with lithium or valproate were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo.

The primary rating instrument used to assess depressive symptoms in this study was the MADRS. The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the CGI-BP-S scale.

LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6, as an adjunctive therapy with lithium or valproate (Table 25).

Table 25: Primary Efficacy Results for Studies in Depressive Episodes Associated with Bipolar I Disorder (MADRS Scores)

Study Treatment Group Primary Efficacy Measure: MADRS
Mean Baseline Score(SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI)
Monotherapy study LATUDA (20-60 mg/day)* 30.3 (5.0) -15.4 (0.8) -4.6 (-6.9, -2.3)
LATUDA (80-120 mg/day)* 30.6 (4.9) -15.4 (0.8) -4.6 (-6.9, -2.3)
Placebo 30.5 (5.0) -10.7 (0.8) --
Adjunctive Therapy study LATUDA (20-120 mg/day)* + lithium or valproate 30.6 (5.3) -17.1 (0.9) -3.6 (-6.0, -1.1)
Placebo + lithium or valproate 30.8 (4.8) -13.5 (0.9) --
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons.
aDifference (drug minus placebo) in least-squares mean change from baseline.
* Treatment group statistically significantly superior to placebo.

Last reviewed on RxList: 7/26/2013
This monograph has been modified to include the generic and brand name in many instances.

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