Summary Basis of Decision for Latuda ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
LatudaTM
Lurasidone Hydrochloride (HCl), 40 mg, 80 mg, and 120 mg, Tablets, Oral
Sunovion Pharmaceuticals Canada Inc.
Submission control no: 145406
Date issued: 2012-10-15
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02387751 - 40 mg
- 02387778 - 80 mg
- 02387786 - 120 mg
Therapeutic Classification:
Non-medicinal ingredients:
The 80 mg tablet also contains: FD&C Blue No. 2 Aluminum Lake; and yellow ferric oxide
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On June 13, 2012, Health Canada issued a Notice of Compliance to Sunovion Pharmaceuticals Canada Inc., for the drug product Latuda.
Latuda contains the medicinal ingredient lurasidone hydrochloride (HCl) which is an antipsychotic agent.
Latuda (lurasidone HCl) is indicated for the acute treatment of patients with schizophrenia. In controlled clinical studies, Latuda was found to improve both positive and negative symptoms. The efficacy of Latuda was established in five short-term, 6-week controlled studies of adult patients. The efficacy of Latuda for long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled studies. It is thought that the mechanism of action of lurasidone in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy of Latuda for the treatment of schizophrenia was established in five multicenter, randomized, placebo-controlled studies in adult patients who met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for schizophrenia. An active control arm (olanzapine or extended-release quetiapine) was included in two studies to assess assay sensitivity. The primary endpoints were the mean change from baseline to Week 6 in the Brief Psychiatric Rating Scale (BPRS) total score in two Phase II studies; and the mean change in the Positive and Negative Syndrome Scale (PANSS) total score in three Phase III studies. The PANSS is a validated thirty item scale to assess a broad range of symptoms of schizophrenia. The BPRS is composed of eighteen items extracted from the PANSS. Doses in the range of 40 mg/day to 160 mg/day of Latuda were shown to be superior to placebo. The efficacy of Latuda for long-term use (>6 weeks), has not been systematically evaluated.
Latuda (40 mg, 80 mg, and 120 mg lurasidone HCl) is presented as film-coated tablets. The recommended starting dose of Latuda is 40 mg once daily. Latuda should be administered with food (at least 350 calories independent of fat content). In clinical studies, doses of 40, 80, 120 and 160 mg were shown to be effective. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 40 mg or 80 mg once daily for most patients. Doses above 80 mg may be considered for certain patients based on individual clinical judgement. Dosing guidelines are available in the Product Monograph.
Latuda is contraindicated in patients with a known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone. Latuda is also contraindicated with strong cytochrome P450 (CYP) 3A4 inhibitors [for example (e.g.), ketoconazole] and strong CYP3A4 inducers (e.g., rifampin).
Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo-controlled studies with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. These issues have been addressed through appropriate labelling (a Serious Warnings and Precautions box) in the Product Monograph.
Latuda should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Latuda are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Latuda is favourable for the acute treatment of patients with schizophrenia.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Lurasidone hydrochloride (HCl), the medicinal ingredient of Latuda is an antipsychotic agent. It is thought that the mechanism of action of lurasidone in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.
Manufacturing Process and Process Controls
The drug substance is synthetically derived.
Lurasidone HCl is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of lurasidone HCl has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
The sponsor has provided a summary of all drug-related impurities. Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH-established limits and/or were qualified from toxicological studies and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of lurasidone HCl are considered acceptable.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control. The level of impurities reported for the drug substance was found to be within the established limits.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated, long-term, and stress testing show that lurasidone HCl is a stable compound when packaged as proposed over the proposed storage period. The retest period for the drug substance is supported and is considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Latuda film-coated tablets are supplied in the following dosage strengths:
- 40 mg lurasidone HCl: White to off-white, round, debossed with "L40"
- 80 mg lurasidone HCl: Pale green, oval, debossed with "L80"
- 120 mg lurasidone HCl: White to off-white, oval, debossed with "L120"
The core tablets of the three product strengths are proportional in composition. Only the 80 mg tablet differs in overall composition by inclusion of small amounts of colorant in the film-coating.
Latuda contains the following non-medicinal ingredients: carnauba wax; croscarmellose sodium; hypromellose; magnesium stearate; mannitol; Opadry® (hypromellose, polyethylene glycol and titanium dioxide); and pregelatinized starch.
The 80 mg tablet also contains: FD&C Blue No. 2 Aluminum Lake; and yellow ferric oxide.
Latuda film-coated tablets are packaged in 30-, 90-, or 500-count high-density polyethylene (HDPE) bottles with polypropylene child-resistant closures with aluminum induction seal, or push-through aluminum/aluminum unit-dose blisters (7 or 10 cells per card). Only bottles for the 80 mg tablet strength will include a desiccant canister.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of lurasidone HCl with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Latuda, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of Latuda. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Manufacturing Process and Process Controls
Lurasidone tablets are manufactured using conventional pharmaceutical equipment and facilities. The manufacturing process is identical for the 40, 80, and 120 mg tablets. Colouring agents are included in the film-coat for the 80 mg tablets only.
The validated process is capable of consistently generating product that meets release specifications. All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Latuda is tested to verify that its identity, appearance, content uniformity, assay, dissolution, levels of degradation products, drug-related impurities, and microbial limits are within acceptance criteria. Validation results of the analytical method used for the determination of lurasidone HCl and the drug-related impurities are considered acceptable. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product. Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH-established limits and therefore, are considered to be acceptable.
Stability
Based on the long-term, accelerated, and stress stability data, as well as the photostability data submitted, the proposed 36-month shelf-life at 15 to 30°C for Latuda is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production of Latuda are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Latuda has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The nonclinical pharmacodynamic and safety pharmacology properties of lurasidone were characterized in a variety of in vitro and in vivo studies. Lurasidone appears to exert its effects by virtue of a high affinity for multiple neurotransmitter receptor families.
Lurasidone has the highest affinity for human dopamine, serotonin and α-adrenergic receptor families. In vitro receptor binding studies revealed that lurasidone is an antagonist with high affinity at dopamine D2 receptors [binding affinity (Ki) = 0.994 nM], the 5-hydroxytryptamine (5-HT, serotonin) receptors 5-HT2A (Ki = 0.47 nM), and 5-HT7 (Ki = 0.495 nM); is an antagonist with moderate affinity at α2C-adrenergic receptors (Ki = 10.8 nM), α2A adrenergic receptors (Ki = 40.7 nM), and α1-adrenergic receptors (Ki = 47.9 nM) and is a partial agonist with moderate affinity at serotonin 5-HT1A (Ki = 6.38 nM) receptors. Lurasidone exhibits little or no affinity for histamine H1 and muscarinic M1 receptors [half maximal inhibitory concentration (IC50) ≥1,000 nM and >1,000 nM, respectively].
The two major human metabolites studied (ID-20219 and ID-20220), showed no biologic affinity to any of the dopamine, serotonin or α-adrenergic receptor families in the tests conducted. Lurasidone is also metabolized into two non-major active metabolites (ID-14283 and ID-14326) which appear to be partial agonists for human 5-HT1A receptors and potent antagonists for human D2L and 5-HT7 receptors.
Primary pharmacological studies in non-clinical species demonstrate that lurasidone and some metabolites positively modulate behaviours in various methamphetamine- or tryptamine-induced animal models of schizophrenia; suggesting it has potent dopamine D2-blocking and serotonin 5-HT2-blocking actions. Furthermore, behaviour in various learning and memory impairment models improved following administration of lurasidone to rats.
Secondary pharmacodynamic studies assessing the extrapyramidal syndrome (EPS) and central nervous system (CNS) depressant properties of lurasidone in comparison to reference drugs suggested that the potential for drug-associated EPS and CNS depressive actions such as anesthesia potentiation, muscle relaxation, and inhibition of motor coordination is lower and/or comparable for lurasidone than to certain other related therapeutics.
In safety pharmacology studies, there were no effects on anterior pituitary, thyroid or sex hormones, but an increase in prolactin, adrenocorticotropic hormone (ACTH), and corticosterone were observed.
Potential cardiovascular effects were evaluated in in vitro and in vivo safety pharmacology and toxicology studies (toxicology studies are discussed in section 3.2.3 Toxicology below). In Human Embryonic Kidney 293 (HEK293) cells stably expressing the human Ether-à-go-go related gene (hERG) gene, lurasidone and its metabolites, ID-14326 and ID-14283, caused concentration-dependent suppression of hERG currents with IC50 values of 57 ng/mL, 357 ng/mL, and 434 ng/mL, respectively. There were no effects on action potential duration (APD) in guinea pig papillary muscle and on inotropic/chronotropic action in guinea pig atrium.
Conscious telemetered female dogs [total number (n) = 4/treatment] received single oral doses of vehicle, lurasidone 100 mg/kg, lurasidone 300 mg/kg, or sotalol according to Latin square crossover design. Lurasidone 100 mg/kg and 300 mg/kg caused statistically significant increases in heart rate. Lurasidone 300 mg/kg also caused a statistically significant increase in the QTc interval. Peak concentration (Cmax) values were reported to be 1.9 µg/mL for lurasidone 100 mg/kg and 2.8 µg/mL for lurasidone 300 mg/kg. In a 39-week, repeated oral doses toxicology study in dogs, lurasidone showed QTc prolongation in 1 out of 4 male dogs in the 100 mg/kg group and 2 out of 4 male dogs in the 200 mg/kg group. QT prolongation effect of lurasidone in dogs arises at 12- to 20-fold higher plasma levels than the plasma Cmax associated with the maximum dose evaluated in clinical trials.
3.2.2 Pharmacokinetics
The pharmacokinetics of lurasidone have been studied in mice, rats, dogs, rabbits, and monkeys.
Absorption
Lurasidone is rapidly absorbed with peak systemic exposure occurring within 5.3 hours of administration. The absolute bioavailability is low, <12%, in all species examined. Administration of lurasidone with food increases the extent of absorption two- to three-fold.
As food increases the bioavailability of lurasidone, the Product Monograph indicates that Latuda should be taken with food (at least 350 calories independent of fat content).
Distribution
Lurasidone binds extensively (>99% bound) to serum proteins including human serum albumin and α-glycoprotein. Binding of the two primary lurasidone metabolites, ID-14283 and ID-14326, in dog and human serum is also high, ≥98.8%. Distribution into red blood cells is moderate with blood/plasma ratios ranging from 0.57 to 0.80. Lurasidone distributes into most tissues, crosses the blood/brain and blood/testes barriers, and is retained by pigmented tissues including the eye. Elevated radioactivity levels were still observed in pigmented rats 3 months post-dose. Lurasidone also crosses into the foetus (particularly the foetal liver). A statement has been included in the Product Monograph indicating that lurasidone should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the foetus.
Studies in rats indicate that lurasidone also passes extensively into breast milk; radioactivity concentrations in milk were significantly higher compared with that observed in serum. It is not known whether lurasidone or its metabolites are excreted in human milk. The Product Monograph includes a statement recommending that women receiving Latuda not breastfeed.
Metabolism
Lurasidone is extensively metabolized. In general, the same metabolites are observed in all species examined, although the proportions may vary; no human specific metabolites were identified. Of the human metabolites identified, two (ID-20219 and ID-20220) were present systemically at concentrations >10% of the total radioactivity, thus, these two metabolites were defined as the ‘major’ human metabolites. The total systemic exposure [area under the curve (AUC)] in mice, rats, and dogs (pivotal toxicity study species) following repeated-dose administration of lurasidone was similar to, or greater than that observed in humans at steady state following administration of a 120 mg dose.
The primary metabolizing cytochrome P450 (CYP) isozyme in humans is CYP3A4. Specific metabolizing isozymes in nonclinical species have not been identified. In vitro studies conducted with human tissue preparations suggest that at clinically relevant concentrations lurasidone does not inhibit or induce CYP enzyme activity.
Elimination
The majority of [14C] lurasidone radioactivity was excreted in faeces as parent compound. Approximately 12 to 48% of the orally administered dose was absorbed. Unchanged parent compound is detected only at trace levels in bile and urine, indicating that the absorbed material is subject to extensive metabolism. Lurasidone is excreted into milk primarily as unchanged drug at concentrations that are greater than those in serum.
3.2.3 Toxicology
Single-Dose Toxicity
The acute oral toxicity of lurasidone was determined in single-dose studies in rats and monkeys. The highest dose administered in each study was 2,000 mg/kg. As there were no unscheduled deaths in either study, lurasidone had a low level of acute toxicity, with median lethal dose (LD50) values of >2,000 mg/kg. Clinical observations were consistent with the pharmacological activity or lurasidone and typical of other antipsychotics. In rats, clinical observations consisted of decreased spontaneous activity and ptosis in all animals, with ataxia observed in females at 2,000 mg/kg. In monkeys, clinical observations consisted of decreased spontaneous activity, closed eyelids, miosis, and tremors.
Mean body-weight gains were decreased in rats at both doses (1,000 and 2,000 mg/kg). Mean food consumption was decreased in monkeys at ≥250 mg/kg, but there was no effect on body weight. There were no treatment-related macroscopic findings in rats or monkeys. A histopathologic examination was not conducted in rats. In monkeys, there were slight prominent fat-storing cells in the liver and focus of atrophic hepatocytes; in the absence of changes in clinical chemistry parameters indicative of liver toxicity, the relationship to lurasidone treatment is unclear. However, it should be noted that no hepatotoxic effects were observed in longer-term toxicity studies in monkeys.
Repeat-Dose Toxicity
Repeat-dose toxicity studies were conducted in mice, rats, dogs, and monkeys. Clinical observations [such as (i.e.) decreased spontaneous activity, ptosis, miosis, and/or tremors] were consistent with the pharmacological activity of lurasidone. Increased serum prolactin concentrations (associated with dopamine D2 antagonism) were observed throughout each of the studies and may explain several of the major findings in these studies. There were no treatment-related unscheduled deaths in any of the repeat-dose toxicity studies.
Rat Study
The major treatment-related findings in a 6-month oral toxicity study in rats consisted of an elevation of serum prolactin, mammary hyperplasia in both males and females, and decreased bone density in females. In females there was a decrease in serum estradiol concentrations, a disruption of the estrus cycle, a decrease in corpora lutea, and uterine atrophy. The effect of lurasidone on bone density was determined only in females. Lurasidone reduced the density of trabecular bone.
An additional finding was the thickening of the adrenal zona glomerulosa observed in females. The no observable adverse effect level (NOAEL) for the 6-month rat toxicity study was 0.03 mg/kg/day, which provides no safety margin for these findings as Cmax values at this dose were below the Cmax determined in humans at a dose of 160 mg/day.
Dog Study
The main findings in a 39-week oral toxicity study in dogs (n = 4/treatment) consisted of an elevation of serum prolactin in all treated groups, cardiovascular effects, and effects on the reproductive system. Premature ventricular contractions were observed in two males at 200 mg/kg/day (high-dose group) and prolongation of the QT interval was observed in one male at 100 mg/kg/day and two males at 200 mg/kg/day. Both animals that exhibited premature ventricular contractions had high serum concentrations of lurasidone and a severe decrease in body weight. QT-interval prolongation was observed in these animals in the high-dose group; the one dog in the 100 mg/kg/day group with QT prolongation also had a severe decrease in body weight.
Slight to moderate atrophy of the prostate was observed in all treated groups. Slight to severe hypospermia in the epididymis was observed at ≥100 mg/kg/day and cellular debris in the lumen of the tubule and vacuolation of ductal epithelium was observed in 1 or 2 animals at 200 mg/kg/day. Histopathological findings in females consisted of a decrease in secondary follicles in the ovary in all treated groups; decreased number of animals with corpus lutea in all treated groups; mild atrophy of the uterus at 30 and 200 mg/kg/day; hydropic appearance of ductal epithelium of the mammary gland, diffuse lymphoid cell infiltration, and pigmentation were observed in all treated groups. A cholesterin granuloma in the mammary gland and dilated ducts containing cholesterin crystals was observed in one female at 200 mg/kg/day.
A slight decrease of trabecular bone density and an increase in fatty infiltration was observed in three males at doses from 100 to 200 mg/kg/day, while bone loss was not observed in any of the treated females.
Monkey Study
In a 52-week oral toxicity study in monkeys, serum prolactin concentrations were significantly increased in males and females in the high-dose group (50 mg/kg/day). Aside from the clinical observations apparent in all treated groups and the increase in prolactin levels, there were no treatment-related findings for any other parameters, including body weight. This indicates that the high dose administered did not achieve a maximally tolerated dose (MTD).
Genotoxicity and Mutagenicity
Lurasidone was negative in an in vitro bacterial reverse mutation test, an in vitro chromosomal aberration test in Chinese hamster lung cells, and an in vivo micronucleus test in mice treated orally with lurasidone at doses up to 2,000 mg/kg.
Carcinogenicity
Two oral carcinogenicity studies were conducted with lurasidone, one in mice and one in rats. Lurasidone was administered orally at doses of 30, 100, 300, or 650 mg/kg/day (the high dose was reduced from 1,200 mg/kg/day in males) to mice and 3, 12 or 36 mg/kg/day (high dose reduced from 50 mg/kg/day) to rats.
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) approximately equal to those in humans receiving the maximum dose evaluated in clinical studies (160 mg/day). No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 7- to 13-times those in humans receiving 160 mg/day dose.
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) 0.4-times those in humans receiving the 160 mg/day dose. Statistical evaluation revealed a significant positive trend in mammary carcinomas compared to the pooled control groups. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6-times those in humans receiving the 160 mg/day dose.
The neoplastic findings in these studies are considered to be treatment-related. Similar findings have been observed with other antipsychotics of this class and are thought to be prolactin-mediated.
Reproductive and Developmental Toxicity
Lurasidone was administered orally to female rats at doses of 0.1, 1.5, 15, or 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through Day 7 of gestation. Estrus cycle irregularities were seen at 1.5 mg/kg and above; the no-effect dose of 0.1 mg/kg is approximately 0.006-times the human 160 mg/day dose based on body surface area. Fertility was reduced only at the highest dose and this was shown to be reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is 0.9-times the human 160 mg/day dose based on body surface area.
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 (9-times the human 160 mg/day dose based on body surface area).
No teratogenic effects were seen in studies in which pregnant rats and rabbits were given lurasidone during the period of organogenesis at doses up to 25 and 50 mg/kg/day, respectively. These doses are 1.5- and 6-times the human 160 mg/day dose based on body surface area in rats and rabbits respectively.
No adverse developmental effects were seen in a study in which pregnant rats were given lurasidone during the period of organogenesis and continuing through weaning at doses up to 10 mg/kg/day; this dose is approximately half of the human 160 mg/day dose based on body surface area.
Special Toxicity Studies
Special toxicity studies for drug dependency and abuse, antigenicity, and phototoxicity did not demonstrate any notable effects for lurasidone.
3.2.4 Summary and Conclusion
The non-clinical pharmacological studies have demonstrated that lurasidone was effective in various animal models of schizophrenia induced by methamphetamine or tryptamine, and confirmed its potent dopamine D2-blocking and serotonin 5-HT2-blocking actions.
All of the findings in the non-clinical toxicity studies are related to the pharmacological activity of lurasidone. Dopamine D2 antagonism is associated with an increase in serum prolactin concentrations, which is responsible for the major findings in these studies. The target organs of toxicity were bone, adrenal gland, mammary gland, pituitary gland, and the reproductive system. Mammary gland tumors were observed in the mouse and rat carcinogenicity studies and pituitary tumors were observed in the mouse carcinogenicity study. The treatment-related findings with lurasidone have also been observed with other antipsychotics that block D2 receptors.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The mechanism of action of lurasidone, as with other drugs having efficacy in schizophrenia, is unknown. It has been suggested that the efficacy of lurasidone in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5-HT2A) receptor antagonism. Details of the pharmacodynamics of lurasidone from the non-clinical studies are found in Section 3.2.1 Pharmacodynamics.
Safety Pharmacology
The effects of Latuda on the QT/QTc interval were evaluated in a dedicated QT study. The trial involved Latuda doses of 120 and 600 mg once daily and ziprasidone (80 mg twice daily) as a positive control. The study was conducted in 87 clinically stable patients with schizophrenia. Electrocardiogram (ECG) data were collected over an 8 hour time period on the baseline day (Day 0) and on Day 11 of the double-blind treatment period. Statistically significant increases from baseline in the Fridericia corrected QT (QTcF) (n = 63) interval were observed from 1 to 8 hours post-dosing with lurasidone 120 mg, lurasidone 600 mg, and ziprasidone 160 mg. The maximum mean increases in QTcF from baseline were 11.6 msec [90% Confidence Interval (CI) 5.7, 17.4] for lurasidone 120 mg (n = 22), 9.9 msec (90% CI 4.1, 15.7) for lurasidone 600 mg (n = 18), and 21.1 msec (90% CI 16.9, 25.3) for ziprasidone (n = 23). There was no apparent dose (exposure)-response relationship in this study. A summary of the dedicated QTc study and recommendations for use have been included in the Warnings and Precautions section of the Product Monograph as a risk mitigation strategy for QT prolongation.
3.3.2 Pharmacokinetics
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. Following administration of 40 mg of Latuda, the mean elimination half-life was 18 hours.
Absorption
Lurasidone is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed.
In a food effect study, lurasidone mean Cmax and AUC were about 3-times and 2-times higher, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone exposure was not affected as meal size was increased from 350 to 1,000 calories and was independent of meal fat content.
Distribution
Following administration of 40 mg of Latuda, the mean apparent volume of distribution was 6,173 L. Lurasidone is highly bound (~99%) to serum proteins.
Metabolism
Lurasidone is metabolized mainly via the CYP3A4 enzyme. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. Lurasidone is metabolized into two active metabolites and two major non-active metabolites.
Excretion
Total excretion of radioactivity in urine and faeces combined was approximately 89%, with about 80% recovered in faeces and 9% recovered in urine, after a single dose of [14C]-labeled lurasidone.
Following administration of 40 mg of Latuda, the mean apparent clearance was 3,902 mL/min.
Comparative Bioavailability
Results from a pivotal bioavailability study demonstrated that the commercial formulation of Latuda meets Health Canada’s standards for comparative bioavailability with the Latuda formulation used in the pivotal safety and efficacy studies, when administered as a 120 mg dose.
In addition, this study demonstrated that both the peak serum lurasidone concentration (Cmax) and extent of exposure (AUCtau) are increased when lurasidone is administered with food, and this is consistent with the proposed labelling with regard to food. A separate study confirmed the finding that food significantly increases the rate and extent of lurasidone absorption into the systemic circulation.
Drug-Drug Interactions
Latuda is predominantly metabolized by CYP3A4; interaction of Latuda with strong and moderate inhibitors or inducers of this enzyme has been evaluated.
One study was conducted in healthy male subjects to evaluate the effect of repeated doses of the potent CYP3A4 inhibitor ketoconazole (400 mg/day for 5 days) on the pharmacokinetics of Latuda. Latuda was administered as a single 10 mg-dose following breakfast. The Cmax of lurasidone was increased 6.9-fold and AUC increased 9.0-fold following multiple administration of ketoconazole as compared to when Latuda was administered alone.
A second study in healthy male and female subjects evaluated the effect of repeated doses of the moderate CYP3A4 inhibitor diltiazem (240 mg once daily for 5 days) on the pharmacokinetics of Latuda. Latuda was administered as a single 20 mg dose after breakfast. Concomitant administration of Latuda and diltiazem resulted in a 2.1-fold increase in Cmax and a 2.2-fold increase in AUC of lurasidone relative to Latuda alone.
A third study in healthy adult male and female subjects evaluated the effect of repeated-dose administration (600 mg/day for 8 days) of the strong CYP3A4 inducer rifampin on the pharmacokinetics of Latuda. Latuda was administered as a single 40 mg dose. Concomitant administration of Latuda and rifampin resulted in a decrease in mean Cmax and AUC of lurasidone to 1/7th and 1/5th respectively, of the mean values observed following the administration of Latuda alone.
A statement has been added to the Product Monograph specifying the contraindication of lurasidone with strong CYP3A4 inhibitors (e.g., ketoconazole) and strong CYP3A4 inducers (e.g., rifampin). Latuda dose should not exceed 40 mg/day if co-administered with moderate CYP3A4 inhibitors.
Special Populations
Elderly
In elderly patients with psychosis (65 to 85), lurasidone concentrations following a 20 mg/day dose were, on average, similar to those in young subjects. No dose adjustment is necessary.
Hepatic impairment
One study evaluated the pharmacokinetics of lurasidone following a single 20 mg Latuda dose administered orally, following breakfast, to male and female adult subjects with moderate to severe hepatic impairment and to matched healthy controls. Lurasidone AUC0-last was 1.5-times, 1.7-times, and 3-times higher in subjects with mild, moderate and severe hepatic impairment, respectively compared to the values for healthy matched subjects. Mean Cmax was 1.3, 1.2, and 1.3-times higher for mild, moderate, and severe hepatically impaired patients, respectively, compared to the values for healthy matched subjects. It is recommended that the Latuda dose should not exceed 40 mg/day in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C).
Renal impairment
One study evaluated the pharmacokinetics of lurasidone and metabolites following a single 40 mg oral Latuda dose administered following breakfast in male or female adult subjects with mild, moderate and severe renal impairment and matched healthy controls.
The mean Cmax increased by 40%, 92%, and 54% and mean AUC(0-∞) increased by 53%, 91%, and 2-times in patients with mild, moderate, and severe renal impairment, respectively, compared to healthy matched subjects. It is recommended that the Latuda dose should not exceed 40 mg/day in patients with moderate and severe renal impairment [creatinine clearance (Clcr) ≥10 mL/min to <50 mL/min].
3.3.3 Clinical Efficacy
The efficacy of Latuda in the acute treatment of schizophrenia was demonstrated in five short-term (6-week), multicentre, randomized, placebo-controlled studies in adult patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of schizophrenia.
The primary endpoints were the mean change from baseline to Week 6 in the Brief Psychiatric Rating Scale (BPRS) total score in two Phase II studies; and the mean change in the Positive and Negative Syndrome Scale (PANSS) total score in three Phase III studies.
The PANSS is a validated 30-item scale to assess a broad range of symptoms of schizophrenia, and is composed of 3 subscales: Positive Syndrome Scale (items P1 to P7: delusions; conceptual disorganization; hallucinatory behavior; excitement; grandiosity; suspiciousness/persecution; and hostility); Negative Syndrome Scale (items N1 to N7: blunted affect; emotional withdrawal; poor rapport; passive apathetic social withdrawal; difficulty in abstract thinking; lack of spontaneity and flow of conversation; and a stereotyped thinking); and a General Psychopathology Index (items G1 to G16: somatic concern; anxiety; guilt feelings; tension; mannerisms and posturing; depression; motor retardation; uncooperativeness; unusual thought content; disorientation; poor attention; lack of judgment and insight; disturbance of volition; poor impulse control; preoccupation and active social avoidance).
The BPRS scale is composed of 18 items extracted from the PANSS scale.
The mean change in the Clinical Global Impression of Severity (CGI-S) was a secondary endpoint in the two Phase II studies, and it was a key secondary endpoint in the three Phase III studies (correction for multiplicity of testing was used).
Study D1050006 was a Phase II study conducted in the United States comparing doses of 40 mg/day and 120 mg/day of Latuda to placebo. Both the 40 mg and the 120 mg were superior to placebo for the primary and secondary endpoint.
Study D1050196 was a Phase II study conducted in the United States comparing a dose of 80 mg/day of Latuda to placebo. Latuda (80 mg) was superior to placebo for the primary and secondary endpoint.
Study D1050229 was a Phase III study conducted in the United States, Europe, and Asia comparing doses of 40 mg/day, 80 mg/day, and 120 mg/day of Latuda to placebo. The 80 mg group was superior to placebo for the primary endpoint and the key secondary endpoint. The 40 mg and the 120 mg groups were not superior to placebo.
Study D1050231 was a Phase III study conducted in the United States, Europe, South America and Asia comparing doses of 40 mg/day and 120 mg/day of Latuda to placebo; it also included olanzapine (15 mg/day) as an active comparator treatment group. Both the 40 mg and the 120 mg were superior to placebo for the primary endpoint and the key secondary endpoint. Olanzapine (15 mg) also was superior to placebo for the primary endpoint and key secondary endpoint.
Study D1050233 was a Phase III study conducted in the United States, Europe, South-America and Asia comparing doses of 80 mg/day and 160 mg/day of Latuda to placebo; it also included quetiapine XR (600 mg/day) as an active comparator treatment group. Both the 80 mg and the 160 mg were superior to placebo for the primary endpoint and the key secondary endpoint. Quetiapine XR (600 mg) was also superior to placebo for the primary endpoint and key secondary endpoint.
Consistent efficacy was demonstrated for the 80 mg/day Latuda dose which was superior to placebo in all three studies that evaluated this dose. The 40 mg/day and the 120 mg/day Latuda doses were superior to placebo in two of the three studies that evaluated these doses. The 120 mg/day dose performed slightly better than the 40 mg/day dose in one Phase II study, but did not perform better than the lower doses in the other two studies. The 160 mg dose of Latuda was superior to placebo in a single study that evaluated this dose. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 40 mg or 80 mg once daily for most patients. Doses above 80 mg may be considered for certain patients based on individual clinical judgement.
Additional Efficacy Data
Two additional short-term (6 weeks) studies (Studies D1050049 and D1001002) were conducted to evaluate the safety and efficacy of Latuda in patients with schizophrenia. In these studies, neither Latuda nor the active comparators showed superiority to placebo in the primary efficacy, and thus are considered as failed studies.
3.3.4 Clinical Safety
The clinical safety of Latuda was evaluated based on the data provided from the studies described in section 3.3.3 Clinical Efficacy as well as other data from all Phase II and III studies provided with the submission. A total of 2,905 patients with schizophrenia were exposed to one or more doses of Latuda. Of these patients, 1,508 participated in short-term, placebo-controlled studies (including the five pivotal studies) with doses ranging from 20 mg/day to 160 mg/day. A total of 769 patients had at least 24 weeks of exposure and 371 patients had at least 52 weeks of exposure.
The data submitted showed that the safety profile of Latuda is that expected for an atypical antipsychotic. The most common (≥5%) adverse events (AEs) in the short-term Phase II/III trials combined were, by decreasing incidence, EPS (24.7%, most frequently akathisia, 13%); somnolence (17%); insomnia (10%); headache (14.5%); nausea (10%); schizophrenia (6.8%); vomiting (8%); anxiety (5%); and dizziness (4%). Akathisia was the only AE that showed a dose-relationship in the 20 to 120 mg/day range and also in individual studies evaluating more than one fixed Latuda dose.
In the pooled short-term Phase II/III clinical studies, 9.5% of Latuda-treated patients and 9.3% of placebo-treated patients discontinued due to an AE. The most common events leading to discontinuation in Latuda-treated patients were: schizophrenia (3.4%) and akathisia (1.4%).
There were two deaths in the Latuda groups in the short-term studies. One patient died of sudden death on Day 46 of treatment which was considered to be related to Latuda. The second patient died of myocardial infarction 9 days after discontinuation. This death was not considered to be related to Latuda.
Most of the other serious events during the short-term studies were due to worsening of schizophrenia.
Ten other patients died in open-label, flexible Latuda dose studies: sudden death (two patients); completed suicide (four patients); septic shock (one patient); brain trauma due to car accident (one patient); accidental burns (one patient); and hypertensive heart disease (one patient). Of these deaths, three were considered related to Latuda: one sudden death; and two completed suicides.
Extrapyramidal Symptoms
In the short-term, placebo-controlled schizophrenia studies, the incidence of reported EPS-related events, excluding akathisia and restlessness, was 13.5% for Latuda-treated patients versus (vs.) 5.8% for placebo-treated patients. The incidence of akathisia for Latuda-treated patients was 12.9% vs. 3.0% for placebo-treated patients. A dose-relationship was observed in the 20 to 120 mg/day Latuda dose range.
EPS/movement disorders were also assessed by the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale (BAS) and the Simpson-Angus Rating Scale (SAS). The proportion of shifts from normal at baseline to any abnormal post-baseline assessment was higher in the Latuda groups compared to placebo in the SAS and the BAS scales and it was also dose-related in the 20 mg/day to 120 mg/day dose-range.
Hyperprolactinemia
Clinically significant increases in prolactin levels [≥5-times the upper limit of normal (ULN)] were seen frequently in all Phase II/III studies in both Latuda-treated (3%) and placebo-treated (1%) patients. Adverse events (AEs) possibly related to increased prolactin (e.g., amenorrhea, galactorrhea, and erectile dysfunction) were infrequent or rare in all pooled short-term Phase II/III clinical trials.
Weight Gain
In pooled short-term (6-week) clinical trials, the mean change in weight was a 0.43 kg increase for Latuda-treated patients compared to a 0.02 kg decrease for placebo-treated patients. The proportion of patients with a clinically significant (≥7%) increase in body weight (at endpoint) was 4.8% for Latuda-treated patients versus 3.3% for placebo-treated patients.
Metabolic Parameters - Blood Chemistry
In general, Latuda did not have a marked effect on blood glucose or lipids, although differences from placebo were noted in some studies for particular assessments.
QTc Prolongation
A dedicated QT/QTc study was conducted in patients with schizophrenia or schizoaffective disorder. For details of this study please refer to section 3.3.1 Pharmacodynamics - Safety Pharmacology. The Product Monograph for Latuda contains a warning on QT/QTc prolongation. The use of Latuda should be avoided in combination with drugs known to prolong QTc interval or cause electrolyte disturbances. Latuda 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.
Long-Term Safety Data
Limited safety data is available from open-label studies or extensions, and from one active comparator (risperidone) study. No new safety issues were raised.
Post-Marketing Data
Latuda was approved by the United States Food and Drug Administration (FDA) on October 28, 2010. With the current submission, the sponsor has provided United States Periodic Adverse Drug Experience Reports (PADERs) up to a cut-off date of October 27, 2011. No new safety issues were raised in these reports.
Summary
Overall, the safety profile of Latuda in the dose range evaluated is expected for an atypical antipsychotic. Extrapyramidal syndrome (EPS), hyperprolactinemia, weight gain, and changes in metabolic parameters (glucose, cholesterol and triglycerides) were observed more often in the Latuda treated groups as compared to placebo, and these effects were more or less pronounced in direct comparisons to other second-generation antipsychotics (SGA), depending on the parameter and specific SGA being compared.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The short-term (6-week) efficacy of Latuda in the treatment of patients with schizophrenia has been demonstrated in five multicentre, randomized, double-blind, placebo-controlled clinical studies. Doses in the range of 40 mg/day to 160 mg/day were shown to be superior to placebo on the primary outcome, the mean change from baseline in PANSS total score or in BPRS score (extracted from the PANSS), and in the secondary outcomes such as the CGI-S. The recommended starting dose of Latuda is 40 mg once daily. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 40 mg or 80 mg once daily for most patients. Doses above 80 mg may be considered for certain patients based on individual clinical judgement.
The data submitted showed that the safety profile of lurasidone is expected for an atypical antipsychotic.
The benefit/risk balance for Latuda in the treatment of schizophrenia is considered favourable at this time. The Latuda Product Monograph includes warnings and information for health professionals and consumers describing potential AEs with the use of Latuda, consistent with other drugs in this class, including but not restricted to orthostatic hypotension, QT/QTc prolongation, hyperglycaemia and diabetes mellitus, hyperprolactinaemia, weight gain, leukopaenia/neutropaenia/agranulocytosis, venous thromboembolism, neuroleptin malignant syndrome, and tardive dyskinesia. A Serious Warnings and Precautions Box is also included in the Product Monograph that describes the increased risk of mortality in elderly patients with dementia who use Latuda.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Latuda is favourable for the acute treatment of patients with schizophrenia. The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: LatudaTM
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2012-06-30 |
| Screening | |
| Screening Acceptance Letter issued: | 2011-08-19 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2012-05-11 |
| Quality Evaluation complete: | 2012-05-31 |
| Clinical Evaluation complete: | 2012-06-12 |
| Labelling Review complete: | 2012-06-12 |
| Notice of Compliance (NOC) issued by Director General: | 2012-06-13 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| LATUDA | 02387786 | SUMITOMO PHARMA CANADA, INC. | LURASIDONE HYDROCHLORIDE 120 MG |
| LATUDA | 02387778 | SUMITOMO PHARMA CANADA, INC. | LURASIDONE HYDROCHLORIDE 80 MG |
| LATUDA | 02387751 | SUMITOMO PHARMA CANADA, INC. | LURASIDONE HYDROCHLORIDE 40 MG |