Latuda®- New dose, new do's and don'ts?

Wayne is a 36 year-old patient with schizophrenia admitted for an exacerbation of auditory hallucinations and bizarre behavior. You are consulted for medication management. His past treatment history includes haloperidol (QT prolongation), aripiprazole (ineffective), and olanzapine (hypersomnolence and weight gain) with frequent hospitalizations attributed to non-adherence. He is particularly sensitive to sedating effects of medications which affect his ability to complete ADLs. Wayne has been successfully adherent to lurasidone 80 mg daily, which has kept him well for the past 9 months until his recent presentation. Is increasing his lurasidone a potential evidence-based treatment strategy?

In October of 2010, the second-generation antipsychotic lurasidone (Latuda®) was approved for treatment of schizophrenia in 40mg and 80 mg tablets dosed once daily with food (≥ 350 calories).¹ Early approval studies demonstrated that doses above 80 mg daily did not provide significant benefit but had a greater incidence of side effects.²³ In April of 2012, the labeling was updated to include a maximum daily dose of 160 mg.⁴ The 160 mg dose of lurasidone demonstrated benefit in efficacy, and dosing at bedtime appeared to help mitigate dose-dependent side effects seen in prior studies where lurasidone was dosed in the morning.⁵

Similar to other second-generation antipsychotics, lurasidone is an antagonist at dopamine D2 and serotonin 5HT2A receptors, and also has a high binding affinity (antagonist) for the serotonin 5HT7 receptor.¹ For a complete review of lurasidone, please refer to the article “New Drug Review: Lurasidone (Latuda®) - The New Antipsychotic on the Block” in the December 2011 issue of the Mental Health Clinician. Efficacy was originally established within the dose range of 40–120 mg/d with four 6-week, randomized, controlled trials.²³

In 2012 the FDA approved an expanded dose range for lurasidone increasing the maximum daily dose from 80 mg daily to 160 mg daily based in part on data from a 6-week placebo and active-controlled trial involving two fixed doses of lurasidone.⁴ This newly expanded dose range for lurasidone (20–160 mg daily) includes approval of the 120 mg day and 160 mg daily doses, as well as a new 120 mg tablet.⁴ This dose range reflects the positive results from short-term studies that evaluated the safety and efficacy of lurasidone, where once daily doses of 40 mg, 80 mg, 120 mg, and 160 mg were shown to be safe and effective.³ A recent review of short term clinical trial data comparing efficacy versus side effects calculated number needed to treat (NNT) and number needed to harm (NNH).³ Differences in PANSS total scores from baseline were superior to placebo for lurasidone 40 mg (2 of 3 studies), lurasidone 80 mg (3 of 3 studies), lurasidone 120 mg (2 of 3 studies), and lurasidone 160 mg (single study).³ NNT for PANSS reductions >30% were calculated to be 6 (40 mg), 6 (80 mg), 7 (120 mg), and 4 (160 mg).³ NNH versus placebo ranged from 6 (akathisia with lurasidone 120 mg) to 30 (parkinsonism with lurasidone 80 mg).³ NNH did not statistically separate from placebo for the lurasidone 160 mg dosage trial that utilized once daily dosing in the evening, contrasting dosing in previous trials.³

The PEARL 3 study was the pivotal trial that evaluated the safety and efficacy of lurasidone 160 mg in hospitalized patients with an acute exacerbation of schizophrenia.⁵ Subjects were enrolled in a 6-week, double-blind, randomized control trial with treatment arms including lurasidone 80 mg, lurasidone 160 mg, quetiapine XR 600 mg, and placebo.⁵ Unlike previous lurasidone trials, all medications were dosed once daily in the evening.³⁵ The 160 mg lurasidone treatment arm included a 3-day lurasidone 120 mg initial titration. ⁵ Significant differences in PANSS total scores were observed in both 80 mg (−22.2) and 160 mg (−26.5) doses of lurasidone and 600 mg quetiapine XR (−27.8) versus placebo (−10.3).⁵ Statistical significance in PANSS total score between lurasidone and placebo was reached at treatment day 4, and was sustained through study completion.⁵ Lurasidone 160 mg was not associated with dose-related increases in side effects or event-related discontinuations versus lurasidone 80 mg. It appears that altering the dosage schedule from morning to evening mitigates dose-related side effects of lurasidone, thus enhancing tolerability of increased doses. Mean increases in weight were not statistically significant from placebo, although the 6-week duration of PEARL 3 makes it difficult to project long-term propensity for metabolic side effects. The most common side effects observed are summarized below in Table 1.

Table 1. Number of Patients and rate (%) for Common Adverse Events-Pooled Data (Safety Population)

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PEARL 3 was the first study to assess secondary endpoints on the effect of lurasidone on cognitive performance with the Performance-based Skills Assessment, Brief (UPSA-B), a scale that assesses the capacity for functioning.⁵ Lurasidone 160 mg was superior to placebo (p<0.05, d=0.25) and quetiapine XR 600 mg (p<0.05, d=0.28) on the composite cognitive functioning measure.⁵ Lurasidone 80 mg did not differ from placebo or quetiapine on cognitive assessments.⁵ UPSA-B assessments of all study medications were superior to placebo.⁵

HOW DOES THE 160MG DOSE COMPARE TO OTHERS WITH RESPECT TO SIDE EFFECTS³?

From the above data³, lurasidone 160 mg daily appears to be better tolerated than lurasidone 40, 80, and 120 mg daily with respect to akathisia, nausea, parkinsonism, headache, sedation, somnolence, insomnia, dyspepsia, and anxiety. However, it is important to consider that data regarding lurasidone 160 mg daily came from a study where it was administered in the evening as compared to the other studies where medication was given in the morning.⁶ The most consistently common adverse effects in studies to date include akathisia, nausea, sedation, somnolence, and parkinsonism, as highlighted above. Short-term use of lurasidone is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, or the ECG QT interval.⁴ This data is listed in Table 2.

Table 2. Mean Change from Baseline for Common Metabolic Adverse Effects

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HOW IS LURASIDONE DOSED AND MONITORED?

The newly approved 120 mg and 160 mg lurasidone dose is administered once daily, preferably in the evening with at least 350 calories of food in order to optimize bioavailability.⁴ Lurasidone is primarily metabolized in the liver through the CYP3A4 enzyme system, and coadministration with drugs that are strong inhibitors of CYP3A4 (e.g., ketoconazole) or strong inducers (e.g., rifampin) is contraindicated.⁴ Co-administration with moderate inhibitors of CYP 3A4 (e.g., diltiazem) limits the maximum daily dose to 80 mg daily.⁶ Dose adjustments for hepatic and renal impairment have also been updated, with an initial recommended dose of 20 mg daily and a maximum daily dose of 80 mg daily for those with moderate to severe renal impairment and moderate hepatic impairment.⁶ The maximum daily dose for severe hepatic impairment is 40 mg daily.⁴

Lurasidone is associated with minimal weight gain and does not appear to cause clinically significant alterations in glucose, lipids, or the QT interval. The proportion of patients with a ≥ 7% increase in body weight (at study endpoint) was 5.6% for lurasidone-treated patients versus 4.0% for placebo-treated patients.² Maintenance monitoring continues to include fasting blood glucose at baseline, week 12, and annually in all patients (monitor more closely if family history of diabetes); CBC with differential; blood pressure at baseline, week 12, and annually thereafter (monitor more closely if risk factors for hypertension); waist circumference at baseline and annually thereafter; weight and BMI at baseline, week 4, week 8, week 12, following initiation/change in therapy, and quarterly thereafter; and monitoring for signs of tardive dyskinesia (e.g., AIMS) prior to treatment and annually thereafter or every 6 months in patients with higher risk (e.g., elderly, those who have experienced acute dystonic reactions, akathisia, or EPS).⁷

WHAT IS THE COST AND WHAT DOSAGE FORMS ARE AVAILABLE?

See Table 3.

Table 3. RED BOOK Pricing information⁸(September 2012)

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WHAT PLACE DOES HIGH DOSE LURASIDONE HAVE IN THE TREATMENT OF SCHIZOPHRENIA?

If we revert back to the original case presented in this article, it highlights a patient with sensitivity to ECG changes, hypersomnolence from olanzapine, and past difficulties with adherence. He has tolerated doses up to 80 mg lurasidone daily but his current mental state warrants a change in therapy. This patient may be a candidate for an increase in dose to 120 mg lurasidone dosed at bedtime (AWP $32.20 each dose or $966 monthly). Monitor for common adverse effects listed in Table 1 above. Further dose increase to lurasidone 160 mg daily at bedtime may be warranted if symptoms remain, although this would increase the cost of each dose if the patient needs two 80 mg tablets (AWP $40.26 each dose for two 80 mg tablets or $1207.80 monthly) and may affect adherence. Evening dosing with meals is recommended to mitigate some common side effects seen in clinical studies and enhance bioavailability.⁶

Although lurasidone 160 mg daily appears to be better tolerated as described in the PEARL 3 study, it is difficult to determine if the enhanced tolerability is secondary to the dosing schedule switch to the evening or is a dose-related effect. There are no current studies directly comparing lurasidone 120 mg daily in the evening to lurasidone 160 mg daily in the evening. Higher doses of lurasidone may be appropriate for individuals who are seeking a relatively metabolically neutral, once daily treatment option for schizophrenia who have tolerated lower doses of lurasidone well. Dosing in the evening versus in the morning may be considered to mitigate side effects, particularly if the patient experiences somnolence. Lurasidone may be less appropriate for individuals with sensitivity to akathisia, nausea, sedation, excessive somnolence, and parkinsonism.⁴