Latuda

Some medicines are not suitable for people with certain conditions, and sometimes a medicine may only be used if extra care is taken. For these reasons, before you start taking lurasidone it is important that your doctor knows:

• If you are pregnant or breast-feeding.
• If you have a heart condition or blood vessel disease.
• If you have liver, kidney, or prostate problems.
• If you have any problems with your breathing.
• If you have any of the following: epilepsy, depression, Parkinson's disease, raised pressure in your eye (glaucoma) or a condition which causes muscle weakness, called myasthenia gravis.
• If you have ever had yellowing of your skin or the whites of your eyes (jaundice) or a blood disorder.
• If you have a tumour on your adrenal gland (a condition called phaeochromocytoma).
• If you have had an allergic reaction to a medicine.
• If you are taking or using any other medicines. This includes any medicines you are taking which are available to buy without a prescription, such as herbal and complementary medicines.

• You will need to have some tests from time to time as your treatment will require careful monitoring to make sure that you get the best possible benefit from lurasidone. Remember to keep your regular doctor's appointments so that your progress can be checked.
• Treatment with lurasidone is usually long-term unless you experience an adverse effect. Keep taking it unless your doctor tells you otherwise. Stopping lurasidone suddenly can cause problems so your doctor may want you to reduce your dose gradually if this becomes necessary.
• If you drink alcohol, ask your doctor for advice. Alcohol increases the risk of side-effects from lurasidone so it is best avoided.
• If you have diabetes you may need to check your blood glucose more frequently, as lurasidone may affect the levels of sugar in your blood. Your doctor will advise you about this.
• Some medicines similar to lurasidone can cause the skin to become more sensitive to sunlight than normal. It may be advisable to use a sunscreen in bright sunlight until you know how your skin reacts.
• A small number of people taking medicines for mood disorders can have thoughts about harming themselves or ending their lives, particularly when a new medicine is started. It is very important that you tell your doctor about this if it happens to you.
• If you are having an operation, tell the person carrying out the treatment which medicines you are taking. This is important because lurasidone may interfere with any anaesthetic you receive.
• If you buy or take any 'over-the-counter' medicines or herbal remedies, please check with a pharmacist that they are suitable for you to take with lurasidone. This is because lurasidone can interact with a number of other medicines, including a herbal remedy for depression, called St John's wort.

• Latuda^®

Dosage Forms & Strengths

tablet

• 20mg
• 40mg
• 80mg
• 120mg

Schizophrenia

40 mg PO qDay initially; may increase to 80 mg/day if needed; not to exceed 160 mg/day

Bipolar Depression

Indicated for major depressive episodes associated with bipolar I disorder; may be used as either monotherapy or adjunctive therapy with lithium or valproate

20 mg PO qDay initially; may increase dose if needed, not to exceed 120 mg/day

Efficacy of lurasidone in the treatment of mania associated with bipolar disorder has not been established

Dosage Modifications

CYP3A4 inhibitors or inducers

• Concomitant use with strong CYP3A4 inhibitor: Contraindicated; do not coadminister (see Contraindications)
• Concomitant use with strong CYP3A4 inducer: Contraindicated; do not coadminister (see Contraindications)
• Concomitant use with moderate CYP3A4 inhibitor (eg, diltiazem, atazanavir, erythromycin, fluconazole, verapamil): Reduce dose to 50% of original dose, not to exceed 80 mg/day; starting dose is 20 mg/day
• Concomitant use with moderate CYP3A4 inducer (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin): It may be necessary to increase lurasidone dose after chronic treatment (ie, ≥7 days) with the inducer
• Grapefruit and grapefruit juice: Avoid coadministration

Renal impairment

• Mild (CrCl ≥50 mL/min): Dosage adjustment not required
• Moderate-to-severe (CrCl <50 mL/min): 20 mg/day initially; not to exceed 80 mg/day

Hepatic impairment

• Mild (Child-Pugh class A): Dosage adjustment may not be necessary; use caution
• Moderate (Child-Pugh class B 7-9): 20 mg/day initially; not to exceed 80 mg/day
• Severe (Child-Pugh class C 10-15): 20 mg/day initially; not to exceed 40 mg/day

Dosing Considerations

Effectiveness for longer-term use (ie, >6 weeks) has not been established in controlled studies; therefore, the physician who elects to use lurasidone for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient

Dosage Forms & Strengths

tablet

• 20mg
• 40mg
• 80mg

Schizophrenia

Indicated for treatment of schizophrenia in adolescents aged 13-17 years

<13 years: Safety and efficacy not established

13-17 years

• Starting dose: 40 mg PO qDay; initial dose titration is not required
• Effective dosage rage: 40-80 mg/day; not to exceed 80 mg/day

Dosage Modifications

CYP3A4 inhibitors or inducers

• Concomitant use with strong CYP3A4 inhibitor: Contraindicated; do not coadminister (see Contraindications)
• Concomitant use with strong CYP3A4 inducer: Contraindicated; do not coadminister (see Contraindications)
• Concomitant use with moderate CYP3A4 inhibitor (eg, diltiazem, atazanavir, erythromycin, fluconazole, verapamil): Reduce dose to 50% of original dose, not to exceed 80 mg/day; starting dose is 20 mg/day
• Concomitant use with moderate CYP3A4 inducer (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin): It may be necessary to increase lurasidone dose after chronic treatment (ie, ≥7 days) with the inducer
• Grapefruit and grapefruit juice: Avoid coadministration

Renal impairment

• Mild (CrCl ≥50 mL/min): Dosage adjustment not required
• Moderate-to-severe (CrCl <50 mL/min): 20 mg/day initially; not to exceed 80 mg/day

Hepatic impairment

• Mild (Child-Pugh class A): Dosage adjustment may not be necessary; use caution
• Moderate (Child-Pugh class B 7-9): 20 mg/day initially; not to exceed 80 mg/day
• Severe (Child-Pugh class C 10-15): 20 mg/day initially; not to exceed 40 mg/day

Dosing Considerations

Effectiveness for longer-term use (ie, >6 weeks) has not been established in controlled studies; therefore, the physician who elects to use lurasidone for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient

Lurasidone is an antipsychotic medicine. It works by changing the effects of chemicals in the brain.

Lurasidone is used to treat schizophrenia in adults and teenagers who are at least 13 years old. Lurasidone is also used to treat episodes of depression in adults with bipolar disorder (manic depression).

Lurasidone may also be used for purposes not listed in this medication guide.

Schizophrenia

Acute treatment of schizophrenia in adults.1 2 4 5 8 88

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).28

Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.28 70 71 72

Bipolar Disorder

Treatment (alone or in combination with lithium or valproate) of major depressive episodes associated with bipolar I disorder (bipolar depression).1 86 87

Appears less likely to cause weight gain and to adversely affect metabolic parameters than some other atypical antipsychotic agents (e.g., olanzapine, quetiapine).1 96 97 Consider as alternative therapy in patients at higher risk of metabolic abnormalities (e.g., those with diabetes mellitus or hyperlipidemia).96

Manufacturer states that efficacy of lurasidone in the treatment of mania associated with bipolar disorder† has not been established.1

Metabolized principally by CYP3A4.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential pharmacokinetic interaction.1 Concomitant use contraindicated.1

Moderate CYP3A4 inhibitors: Potential pharmacokinetic interaction.1 Reduce lurasidone dosage to 50% of original dosage when a moderate CYP3A4 inhibitor is added to therapy.1 In patients receiving a moderate CYP3A4 inhibitor in whom lurasidone is initiated, recommended initial lurasidone hydrochloride dosage is 20 mg daily and maximum recommended dosage is 80 mg daily.1 85

Potent CYP3A4 inducers: Potential pharmacokinetic interaction.1 Concomitant use contraindicated.1

Moderate CYP3A4 inducers: Potential pharmacokinetic interaction.1 May need to increase lurasidone dosage after chronic therapy (i.e., ≥7 days) with the CYP3A4 inducer.1

Lurasidone is not a substrate of CYP isoenzymes 1A1, 1A2, 2A6, 4A11, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1; clinically important pharmacokinetic interactions with lurasidone and drugs that are inhibitors or inducers of these enzymes unlikely.1

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Alcohol	Possible additive CNS effects1	Avoid concomitant use1
Anticholinergic agents	Possible disruption of body temperature regulation1	Use with caution1
Atazanavir	Atazanavir (moderate CYP3A4 inhibitor) may increase lurasidone exposure1	When atazanavir is added to lurasidone therapy, reduce lurasidone dosage to 50% of original dosage1 In patients receiving atazanavir, recommended initial lurasidone hydrochloride dosage is 20 mg daily and maximum recommended dosage is 80 mg daily1
Carbamazepine	Carbamazepine (a strong CYP3A4 inducer) potentially can decrease peak serum concentrations and AUCs of lurasidone 1	Concomitant use contraindicated1
Clarithromycin	Clarithromycin (a strong CYP3A4 inhibitor) may substantially increase lurasidone exposure 1	Concomitant use contraindicated1
CNS agents	Possible additive CNS effects1	Use with caution1
Digoxin	Increased peak plasma concentrations and AUCs of digoxin by about 9 and 13%, respectively1 85	Digoxin dosage adjustment not required1 85
Diltiazem	Diltiazem (a moderate CYP3A4 inhibitor) increased peak serum concentrations and AUCs of lurasidone by about twofold1 85	When diltiazem is added to lurasidone therapy, reduce lurasidone dosage to 50% of original dosage1 In patients receiving diltiazem, recommended initial lurasidone hydrochloride dosage is 20 mg daily and maximum recommended dosage is 80 mg daily1 85
Erythromycin	Erythromycin (a moderate CYP3A4 inhibitor) may increase lurasidone exposure1	When erythromycin is added to lurasidone therapy, reduce lurasidone dosage to 50% of original dosage1 In patients receiving erythromycin, recommended initial lurasidone hydrochloride dosage is 20 mg daily and maximum recommended dosage is 80 mg daily1
Fluconazole	Fluconazole (a moderate CYP3A4 inhibitor) may increase lurasidone exposure1	When fluconazole is added to lurasidone therapy, reduce lurasidone dosage to 50% of original dosage1 In patients receiving fluconazole, recommended initial lurasidone hydrochloride dosage is 20 mg daily and maximum recommended dosage is 80 mg daily1
Grapefruit	Possible increased peak serum concentrations and AUCs of lurasidone1	Avoid concomitant use1
Hypotensive agents	Possible additive hypotensive effects; may result in orthostatic hypotension and syncope1	Consider use of lower initial lurasidone dosage and more gradual titration; monitor orthostatic vital signs1
Ketoconazole	Increased peak serum concentrations and AUCs of lurasidone by 6.8 and 9.3 times, respectively1 85	Concomitant use contraindicated1 85
Lithium	Decreased peak serum lurasidone concentrations by 8% and increased lurasidone AUCs by 7%;1 85 no evidence of additive CNS toxicity85 No clinically important change in lithium exposure1 85	Dosage adjustment of lurasidone and lithium not required1 85
Midazolam	Increased peak plasma concentrations and AUCs of midazolam by approximately 21 and 44%, respectively1 85	Midazolam dosage adjustment not required1
Oral contraceptives	Peak plasma concentrations and AUCs of oral contraceptives not substantially affected1 85 Sex hormone binding globulin concentrations not substantially affected1 85	Oral contraceptive dosage adjustment not required1
Phenytoin	Phenytoin (potent CYP3A4 inducer) potentially can decrease peak serum concentrations and AUCs of lurasidone 1	Concomitant use contraindicated1
Rifampin	Rifampin (potent CYP3A4 inducer) decreased peak serum concentrations and AUCs of lurasidone by approximately 85 and 82%, respectively1 85	Concomitant use contraindicated1
Ritonavir	Ritonavir (potent CYP3A4 inhibitor) may substantially increase lurasidone exposure 1	Concomitant use contraindicated1
Smoking	Lurasidone is not a substrate for CYP1A2 in vitro; smoking unlikely to alter lurasidone pharmacokinetics85
St. John's wort (Hypericum perforatum)	St. John's wort (potent CYP3A4 inducer) potentially can decrease peak serum concentrations and AUCs of lurasidone 1	Concomitant use contraindicated1
Valproate	No clinically important change in lurasidone or valproate serum concentrations1 85	Dosage adjustment of lurasidone and valproate not required1 85
Verapamil	Verapamil (moderate CYP3A4 inhibitor) may increase lurasidone exposure1	When verapamil is added to lurasidone therapy, reduce lurasidone dosage to 50% of original dosage1 In patients receiving verapamil, recommended initial lurasidone hydrochloride dosage is 20 mg daily and maximum recommended dosage is 80 mg daily1
Voriconazole	Voriconazole (potent CYP3A4 inhibitor) may substantially increase lurasidone exposure 1	Concomitant use contraindicated1

Take this medicine only as directed by your doctor even if you feel well. Do not take more of this medicine and do not take it more often than your doctor ordered. This medicine works best if there is a constant amount in the blood. To keep blood levels constant, take this medicine at the same time each day and do not miss any doses.

This medicine should come with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

You must take this medicine with food (containing at least 350 calories).

Do not eat grapefruit or drink grapefruit juice while you are using this medicine.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For schizophrenia:
    • Adults—At first, 40 milligrams (mg) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 160 mg per day.
    • Children 13 to 17 years of age—At first, 40 milligrams (mg) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 80 mg per day.
    • Children younger than 13 years of age—Use and dose must be determined by your doctor.
  • For depression:
    • Adults—At first, 20 milligrams (mg) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 120 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Lurasidone should not be used with certain medicines such as carbamazepine (Tegretol®), clarithromycin (Biaxin®), ketoconazole (Nizoral®), phenytoin (Dilantin®), rifampin (Rifadin®, Rimactane®), ritonavir (Norvir®), St. John's wort, or voriconazole (Vfend®). Using these medicines together may cause serious unwanted effects. Make sure your doctor knows all of the medicines you are taking.

Lurasidone may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies. If you or your caregiver notice any of these side effects, tell your doctor right away.

This medicine may increase risk of transient ischemic attack or stroke in elderly patients. Tell your doctor right away if you have confusion, double vision, headache, inability to move the arms, legs, or facial muscles, slow speech, or trouble speaking, thinking, or walking while using this medicine.

Check with your doctor right away if you have any of the following symptoms while using this medicine: convulsions (seizures), difficulty with breathing, a fast heartbeat, a high fever, high or low blood pressure, increased sweating, loss of bladder control, severe muscle stiffness, unusually pale skin, or tiredness. These could be symptoms of a serious condition called neuroleptic malignant syndrome (NMS).

This medicine may cause tardive dyskinesia (a movement disorder). Check with your doctor right away if you have lip smacking or puckering, puffing of the cheeks, rapid or worm-like movements of the tongue, uncontrolled chewing movements, or uncontrolled movements of the arms and legs while you are using this medicine.

This medicine may increase the amount of sugar in your blood. Check with your doctor right away if you have increased thirst or increased urination. If you have diabetes, you may notice a change in the results of your urine or blood sugar tests. If you have any questions, check with your doctor.

This medicine may increase your weight. Your doctor may need to check your weight on a regular basis while you are using this medicine. Talk to your doctor about ways to prevent weight gain.

Lurasidone can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. If you can, avoid people with infections. Check with your doctor right away if you think you are getting an infection, or if you have a fever or chills, a cough or hoarseness, lower back or side pain, or painful or difficult urination.

Dizziness, lightheadedness, or fainting may occur, especially when you get up suddenly from a lying or sitting position. Getting up slowly may help. If the problem continues or gets worse, check with your doctor.

This medicine may cause some people to become drowsy or dizzy, or to have trouble with thinking or controlling body movements, which may lead to falls, fractures or other injuries. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that requires you to be alert, well-coordinated, or able to think well.

Avoid activities involving high temperature or humidity. This medicine may reduce your body's ability to adjust to the heat.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds, sedatives, tranquilizers, or sleeping medicine, prescription pain medicines including other narcotics, medicine for seizures (eg, barbiturates), muscle relaxants, or anesthetics (numbing medicines), including some dental anesthetics. Check with your doctor before taking any of the above while you are using this medicine.

Before you have any medical tests, tell the medical doctor in charge that you are taking this medicine. The results of some tests may be affected by this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Absence of or decrease in body movement
• difficulty with swallowing
• drooling
• inability to sit still
• incremental or ratchet-like movement of the muscle
• loss of balance control
• mask-like face
• muscle discomfort
• muscle trembling, jerking, or stiffness
• need to keep moving
• restlessness
• rigid or stiff muscles
• shakiness in the legs, arms, hands, or feet
• shuffling walk
• slow movements
• slow reflexes
• slurred speech
• stiffness of the arms and legs
• tic-like (jerky) movements of the head, face, mouth, and neck
• trembling or shaking of the hands or feet
• twisting movements of the body
• uncontrolled movements, especially of the face, neck, and back

Less common

• Arm, back, or jaw pain
• blurred vision
• burning while urinating
• changes in patterns and rhythms of speech
• chest pain or discomfort
• chills
• cold sweats
• confusion
• convulsions
• difficult or painful urination
• difficulty opening the mouth
• difficulty with breathing
• dizziness
• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position
• fast, pounding, or irregular heartbeat or pulse
• fixed position of the eye
• headache
• high fever
• inability to move the eyes
• inability to speak
• increased blinking or spasms of the eyelid
• increased sweating
• lockjaw
• loss of bladder control
• muscle spasm, especially of the neck and back
• nervousness
• pale skin
• pounding in the ears
• seizures
• severe muscle stiffness
• severe or sudden headache
• slow or fast heartbeat
• slurred speech
• sticking out of the tongue
• sweating
• temporary blindness
• tiredness
• trouble with breathing, speaking, or swallowing
• troubled breathing with exertion
• uncontrolled twisting movements of the neck, trunk, arms, or legs
• unusual bleeding or bruising
• unusual facial expressions
• unusual tiredness or weakness
• unusually pale skin
• weakness in the arm or leg on one side of the body, sudden and severe

Rare

• Black, tarry stools
• bloody urine
• breast pain or swelling
• cough
• dark-colored urine
• decreased frequency or amount of urine
• fever
• increased thirst
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• lower back or side pain
• muscle cramps or spasms
• muscle pain or stiffness
• nausea
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swelling of the face, fingers, or lower legs
• swollen glands
• troubled breathing
• vomiting
• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Acid or sour stomach
• anxiety
• belching
• drowsiness
• dry mouth
• heartburn
• hyperventilation
• indigestion
• irritability
• relaxed and calm
• sleepiness or unusual drowsiness
• stomach discomfort, upset, or pain
• trouble sleeping
• unusually deep sleep
• unusually long duration of sleep

Less common

• Abnormal dreams
• anxiety
• back pain
• blurred vision
• burning feeling in the chest or stomach
• decreased appetite
• diarrhea
• feeling of constant movement of self or surroundings
• indigestion
• itching or skin rash
• sensation of spinning
• sweating
• tenderness in the stomach area
• watering of mouth and drooling

Rare

• Decreased interest in sexual intercourse
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance
• unexpected or excess milk flow from the breasts

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use Latuda as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take this medicine with food.
• Swallow whole. Do not chew, break, or crush.
• To gain the most benefit, do not miss doses.
• Keep taking Latuda (lurasidone) as you have been told by your doctor or other health care provider, even if you feel well.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.
• Do not stop taking this medicine all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop Latuda, you will want to slowly stop it as ordered by your doctor.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• If you are not sure what to do if you miss a dose, call your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. 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. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Latuda is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.

Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated
	Increases Compared to Placebo
<18	14 additional patients
18-24	5 additional patients
	Decreases Compared to Placebo
25-64	1 fewer patient
≥65	6 fewer patients

Latuda is not approved for use in pediatric patients with depression.

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Latuda, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. Latuda is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1)].

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including Latuda.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported.

Tardive Dyskinesia

Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, Latuda should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on Latuda, drug discontinuation should be considered. However, some patients may require treatment with Latuda despite the presence of the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because Latuda was not marketed at the time these studies were performed, it is not known if Latuda is associated with this increased risk.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 3.

Table 3: Change in Fasting Glucose in Adult Schizophrenia Studies

			Latuda
	Placebo	20 mg/day	40 mg/day	80 mg/day	120 mg/day	160 mg/day
Mean Change from Baseline (mg/dL)
	n=680	n=71	n=478	n=508	n=283	n=113
Serum Glucose	-0.0	-0.6	+2.6	-0.4	+2.5	+ 2.5
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose (≥ 126 mg/dL)	8.3% (52/628)	11.7% (7/60)	12.7% ( 57/449)	6.8% (32/472)	10.0% (26/260)	5.6% (6/108)

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), Latuda was associated with a mean change in glucose of +1.8 mg/dL at week 24 (n=355), +0.8 mg/dL at week 36 (n=299) and +2.3 mg/dL at week 52 (n=307).

Adolescents

In studies of adolescents and adults with schizophrenia, changes in fasting glucose were similar. In the short-term, placebo-controlled study of adolescents, fasting serum glucose mean values were -+1.3 for placebo (n=95), +0.1 for 40mg (n=90), and +1.8 for 80mg (n=92).

Bipolar Depression

Monotherapy

Data from the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4.

Table 4: Change in Fasting Glucose in the Adult Monotherapy Bipolar Depression Study

		Latuda
	Placebo	20 to 60 mg/day	80 to 120 mg/day
Mean Change from Baseline (mg/dL)
Patients were randomized to flexibly dosed Latuda 20 to 60 mg/day, Latuda 80 to 120 mg/day, or placebo
	n=148	n=140	n=143
Serum Glucose	+1.8	-0.8	+1.8
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose (≥ 126 mg/dL)	4.3% (6/141)	2.2% (3/138)	6.4% (9/141)

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Latuda as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129).

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.

Table 5: Change in Fasting Glucose in the Adult Adjunctive Therapy Bipolar Depression Studies

		Latuda
	Placebo	20 to 120 mg/day
Mean Change from Baseline (mg/dL)
Patients were randomized to flexibly dosed Latuda 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.
	n=302	n=319
Serum Glucose	-0.9	+1.2
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose (≥ 126 mg/dL)	1.0% (3/290)	1.3% (4/316)

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Latuda as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 6.

Table 6: Change in Fasting Lipids in Adult Schizophrenia Studies

			Latuda
	Placebo	20 mg/day	40 mg/day	80 mg/day	120 mg/day	160 mg/day
Mean Change from Baseline (mg/dL)
	n=660	n=71	n=466	n=499	n=268	n=115
Total Cholesterol	-5.8	-12.3	-5.7	-6.2	-3.8	-6.9
Triglycerides	-13.4	-29.1	-5.1	-13.0	-3.1	-10.6
Proportion of Patients with Shifts
Total Cholesterol (≥ 240 mg/dL)	5.3% (30/571)	13.8% (8/58)	6.2% (25/402)	5.3% (23/434)	3.8% (9/238)	4.0% (4/101)
Triglycerides (≥ 200 mg/dL)	10.1% (53/526)	14.3% (7/49)	10.8% (41/379)	6.3% (25/400)	10.5% (22/209)	7.0% (7/100)

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), Latuda was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356) and -15.1 (n=357) mg/dL at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dL at week 36 and -2.5 (n=307) and -6.9 (n=307) mg/dL at week 52, respectively.

Adolescents

In the adolescent short-term, placebo-controlled study, fasting serum cholesterol mean values were -9.6 for placebo (n=95), -4.4 for 40mg (n=89), and +1.6 for 80mg (n=92), and fasting serum triglyceride mean values were +0.1 for placebo (n=95), -0.6 for 40mg (n=89), and +8.5 for 80mg (n=92).

Bipolar Depression

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 7.

Table 7: Change in Fasting Lipids in the Adult Monotherapy Bipolar Depression Study

		Latuda
	Placebo	20 to 60 mg/day	80 to 120 mg/day
Mean Change from Baseline (mg/dL)
Patients were randomized to flexibly dosed Latuda 20 to 60 mg/day, Latuda 80 to 120 mg/day, or placebo
	n=147	n=140		n=144
Total cholesterol	-3.2	+1.2		-4.6
Triglycerides	+6.0	+5.6		+0.4
Proportion of Patients with Shifts
Total cholesterol (≥ 240 mg/dL)	4.2% (5/118)	4.4% (5/113)		4.4% (5/114)
Triglycerides (≥ 200 mg/dL)	4.8% (6/126)	10.1% (12/119)		9.8% (12/122)

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Latuda as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 (n=130) and -1.0 (n=130) mg/dL at week 24, respectively.

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8.

Table 8: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression Studies

		Latuda
	Placebo	20 to 120 mg/day
Mean Change from Baseline (mg/dL)
Patients were randomized to flexibly dosed Latuda 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.
	n=303	n=321
Total cholesterol	-2.9	-3.1
Triglycerides	-4.6	+4.6
Proportion of Patients with Shifts
Total cholesterol (≥ 240 mg/dL)	5.7% (15/263)	5.4% (15/276)
Triglycerides (≥ 200 mg/dL)	8.6% (21/243)	10.8% (28/260)

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Latuda, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dL at week 24, respectively.

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 9. The mean weight gain was +0.43 kg for Latuda-treated patients compared to -0.02 kg for placebo-treated patients. Change in weight from baseline for olanzapine was +4.15 kg and for quetiapine extended-release was +2.09 kg in Studies 3 and 5 [see Clinical Studies (14.1)], respectively. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.8% for Latuda-treated patients versus 3.3% for placebo-treated patients.

Table 9: Mean Change in Weight (kg) from Baseline in Adult Schizophrenia Studies

			Latuda
	Placebo (n=696)	20 mg/day (n=71)	40 mg/day (n=484)	80 mg/day (n=526)	120 mg/day (n=291)	160 mg/day (n=114)
All Patients	-0.02	-0.15	+0.22	+0.54	+0.68	+0.60

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), Latuda was associated with a mean change in weight of -0.69 kg at week 24 (n=755), -0.59 kg at week 36 (n=443) and -0.73 kg at week 52 (n=377).

Adolescents

Data from the short-term, placebo-controlled adolescent schizophrenia study are presented in Table 10. The mean weight gain was +0.5 kg for Latuda-treated patients compared to +0.2 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 3.3% for Latuda-treated patients versus 4.5% for placebo-treated patients.

Table 10: Mean Change in Weight (kg) from Baseline in the Adolescent Schizophrenia Study

	Placebo (n=111)	Latuda
		40 mg/day (n=109)	80 mg/day (n=104)
All Patients	+0.2	+0.3	+0.7

Bipolar Depression

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 11. The mean weight gain was +0.29 kg for Latuda-treated patients compared to -0.04 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 2.4% for Latuda-treated patients versus 0.7% for placebo-treated patients.

Table 11: Mean Change in Weight (kg) from Baseline in the Adult Monotherapy Bipolar Depression Study

		Latuda
	Placebo (n=151)	20 to 60 mg/day (n=143)	80 to 120 mg/day (n=147)
Patients were randomized to flexibly dosed Latuda 20 to 60 mg/day, Latuda 80 to 120 mg/day, or placebo
All Patients	-0.04	+0.56		+0.02

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Latuda as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 12. The mean weight gain was +0.11 kg for Latuda-treated patients compared to +0.16 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 3.1% for Latuda-treated patients versus 0.3% for placebo-treated patients.

Table 12: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies

		Latuda
	Placebo (n=307)	20 to 120 mg/day (n=327)
Patients were randomized to flexibly dosed Latuda 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.
All Patients	+0.16	+0.11

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with Latuda, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86).

Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, Latuda elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients [see Adverse Reactions (6)].

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a carcinogenicity study conducted with lurasidone in rats and mice [see Nonclinical Toxicology (13)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

Schizophrenia

Adults

In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for Latuda-treated patients was +0.4 ng/mL and was -1.9 ng/mL in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/mL and for females was -0.2 ng/mL. Median changes for prolactin by dose are shown in Table 13.

Table 13: Median Change in Prolactin (ng/mL) from Baseline in Adult Schizophrenia Studies

			Latuda
	Placebo	20 mg/day	40 mg/day	80 mg/day	120 mg/day	160 mg/day
All Patients	-1.9 (n=672)	-1.1 (n=70)	-1.4 (n=476)	-0.2 (n=495)	+3.3 (n=284)	+3.3 (n=115)
Females	-5.1 (n=200)	-0.7 (n=19)	-4.0 (n=149)	-0.2 (n=150)	+6.7 (n=70)	+7.1 (n=36)
Males	-1.3 (n=472)	-1.2 (n=51)	-0.7 (n=327)	-0.2 (n=345)	+3.1 (n=214)	+2.4 (n=79)

The proportion of patients with prolactin elevations ≥5× upper limit of normal (ULN) was 2.8% for Latuda-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 5.7% for Latuda-treated patients versus 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 1.6% versus 0.6% for placebo-treated male patients.

In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), Latuda was associated with a median change in prolactin of -0.9 ng/mL at week 24 (n=357), -5.3ng/mL at week 36 (n=190) and -2.2 ng/mL at week 52 (n=307).

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, the median change from baseline to endpoint in prolactin levels for Latuda-treated patients was +1.1 ng/mL and was +0.1 ng/mL for placebo-treated patients. For Latuda-treated patients, the median change from baseline to endpoint for males was +1.0 ng/mL and for females was +2.6 ng/mL. Median changes for prolactin by dose are shown in Table 14.

Table 14: Median Change in Prolactin (ng/mL) from Baseline in the Adolescent Schizophrenia Study

	Placebo	Latuda 40 mg/day	Latuda 80 mg/day
All Patients	+0.10 (n=103)	+0.75 (n=102)	+1.20 (n=99)
Females	+0.70 (n=39)	+0.60 (n=42)	+4.40 (n=33)
Males	0.00 (n=64)	+0.75 (n=60)	+1.00 (n=66)

The proportion of patients with prolactin elevations ≥5x ULN was 0.5% for Latuda-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 1.3% for Latuda-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% versus 1.6% for placebo-treated male patients.

Bipolar Depression

Monotherapy

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with Latuda 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 15.

Table 15: Median Change in Prolactin (ng/mL) from Baseline in the Adult Monotherapy Bipolar Depression Study

		Latuda
	Placebo	20 to 60 mg/day	80 to 120 mg/day
Patients were randomized to flexibly dosed Latuda 20 to 60 mg/day, Latuda 80 to 120 mg/day, or placebo
All Patients	+0.3 (n=147)	+1.7 (n=140)		+3.5 (n=144)
Females	0.0 (n=82)	+1.8 (n=78)		+5.3 (n=88)
Males	+0.4 (n=65)	+1.2 (n=62)		+1.9 (n=56)

The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0.4% for Latuda-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0.6% for Latuda-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% versus 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with Latuda as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of -1.15 ng/mL at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with Latuda 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes for prolactin across the dose range are shown in Table 16.

Table 16: Median Change in Prolactin (ng/mL) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies

		Latuda
	Placebo	20 to 120 mg/day
Patients were randomized to flexibly dosed Latuda 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.
All Patients	0.0 (n=301)	+2.8 (n=321)
Females	+0.4 (n=156)	+3.2 (n=162)
Males	-0.1 (n=145)	+2.4 (n=159)

The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0.0% for Latuda-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0% for Latuda-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% versus 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with Latuda, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88).

Leukopenia, Neutropenia and Agranulocytosis

Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and Latuda should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue Latuda and have their WBC followed until recovery.

Orthostatic Hypotension and Syncope

Latuda may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs.

Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥ 20 mm Hg decrease in systolic blood pressure and ≥10 bpm increase in pulse from sitting to standing or supine to standing position.

Schizophrenia

Adults

The incidence of orthostatic hypotension and syncope reported as adverse events from short-term, placebo-controlled schizophrenia studies was (Latuda incidence, placebo incidence): orthostatic hypotension [0.3% (5/1508), 0.1% (1/708)] and syncope [0.1% (2/1508), 0% (0/708)].

In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.8% with Latuda 40 mg, 2.1% with Latuda 80 mg, 1.7% with Latuda 120 mg and 0.8% with Latuda 160 mg compared to 0.7% with placebo.

Adolescents

The incidence of orthostatic hypotension reported as adverse events from the short-term, placebo-controlled adolescent schizophrenia study was 0.5% (1/214) in Latuda-treated patients and 0% (0/112) in placebo-treated patients. No syncope event was reported.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0% with Latuda 40 mg and 2.9% with Latuda 80 mg, compared to 1.8% with placebo.

Bipolar Depression

Monotherapy

In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with Latuda 20 to 60 mg and 0.6% with Latuda 80 to 120 mg compared to 0% with placebo.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with Latuda 20 to 120 mg compared to 0.9% with placebo.

Seizures

As with other antipsychotic drugs, Latuda should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Schizophrenia

In adult short-term, placebo-controlled schizophrenia studies, seizures/convulsions occurred in 0.1% (2/1508) of patients treated with Latuda compared to 0.1% (1/708) placebo-treated patients.

Bipolar Depression

Monotherapy

In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, no patient experienced seizures/convulsions.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions.

Potential for Cognitive and Motor Impairment

Latuda, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with Latuda does not affect them adversely.

In clinical studies with Latuda, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.

Schizophrenia

Adults

In short-term, placebo-controlled schizophrenia studies, somnolence was reported by 17.0% (256/1508) of patients treated with Latuda (15.5% Latuda 20 mg, 15.6% Latuda 40 mg, 15.2% Latuda 80 mg, 26.5% Latuda 120 mg and 8.3% Latuda 160 mg/day) compared to 7.1% (50/708) of placebo patients.

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, somnolence was reported by 14.5% (31/214) of patients treated with Latuda (15.5% Latuda 40 mg and 13.5% Latuda 80 mg,/day) compared to 7.1% (8/112) of placebo patients.

Bipolar Depression

Monotherapy

In the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with Latuda 20 to 60 mg and 80 to120 mg, respectively compared to 6.5% (11/168) of placebo patients.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies, somnolence was reported by 11.4% (41/360) of patients treated with Latuda 20-120 mg compared to 5.1% (17/334) of placebo patients.

Body Temperature Dysregulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Latuda for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Activation of Mania/Hypomania

Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes.

In the bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the Latuda and placebo groups developed manic or hypomanic episodes.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Latuda and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies

Patients with Parkinson's Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

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

Latuda is used to treat schizophrenia in adults and teenagers who are at least 13 years old.

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

You should not use Latuda if you are allergic to lurasidone.

Some medicines can interact with lurasidone and should not be used at the same time. Your doctor may need to change your treatment plan if you use certain other medicines, including:

• antifungal medicine such as ketoconazole or voriconazole;

• an antibiotic such as clarithromycin or rifampin;

• an antiviral such as ritonavir;

• St. John's wort; or

• seizure medicine such as carbamazepine or phenytoin.

Latuda is not approved for use in psychotic conditions related to dementia. Latuda may increase the risk of death in older adults with dementia-related conditions.

To make sure this medicine is safe for you, tell your doctor if you have ever had:

• heart disease, high or low blood pressure;

• high cholesterol or triglycerides (a type of fat in the blood);

• diabetes or high blood sugar (in you or your family);

• a seizure;

• liver or kidney disease;

• low white blood cell (WBC) counts;

• abnormal hormone function tests (thyroid, pituitary gland);

• breast cancer; or

• suicidal thoughts or actions.

Some young people have thoughts about suicide when first taking medicine to treat depression. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Taking antipsychotic medication during the last 3 months of pregnancy may cause problems in the newborn, such as withdrawal symptoms, breathing problems, feeding problems, fussiness, tremors, and limp or stiff muscles. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you become pregnant while taking Latuda, do not stop taking it without your doctor's advice.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of lurasidone on the baby.

It is not known whether lurasidone passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding.

Latuda is not approved for schizophrenia in anyone younger than 13 years old. Latuda is not approved for depression in anyone younger than 18 years old.

It is easier to become dangerously overheated and dehydrated while you are taking Latuda. Drink plenty of fluids, especially in hot weather and during exercise. You may also be more sensitive to temperature extremes (hot or cold).

Grapefruit and grapefruit juice may interact with lurasidone and lead to unwanted side effects. Avoid the use of grapefruit products while taking Latuda.

Latuda may impair your thinking or reactions. Avoid driving or operating machinery until you know how this medicine will affect you. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Dizziness or severe drowsiness can cause falls, fractures, or other injuries.

Avoid drinking alcohol. Dangerous side effects could occur.

Taking Latuda with other drugs that make you sleepy or slow your breathing can cause dangerous or life-threatening side effects. Ask your doctor before taking a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression, or seizures.

Many drugs can interact with lurasidone. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially medicines to treat:

• depression or psychotic episodes;

• sleep problems (insomnia);

• high blood pressure or a heart rhythm disorder;

• swelling or inflammation;

• seizures; or

• Parkinson's disease.

This list is not complete and many other drugs can interact with lurasidone. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.