Consumer medicine information

Latuda

Lurasidone hydrochloride

BRAND INFORMATION

Brand name

Latuda

Active ingredient

Lurasidone hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Latuda.

SUMMARY CMI

LATUDA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using LATUDA?

LATUDA contains the active ingredient lurasidone hydrochloride. LATUDA is used to treat adults and adolescents (aged 13 years and over) with schizophrenia. It is only available with a doctor's prescription. For more information, see Section 1. Why am I using LATUDA? in the full CMI.

2. What should I know before I use LATUDA?

Do not use if you have ever had an allergic reaction to LATUDA or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. LATUDA is not approved for treatment of elderly patients with dementia-related psychosis or behavioural disorders. For more information, see Section 2. What should I know before I use LATUDA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with LATUDA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use LATUDA?

Your doctor or pharmacist will tell you how many tablets you will need to take each day. This depends on your condition and whether or not you are taking any other medicines. Unless your doctor gives you other directions, you should take LATUDA only once a day. Take LATUDA during or immediately after food, consider evening meal. More instructions can be found in Section 4. How do I use LATUDA? in the full CMI. Continue taking the tablets for as long as your doctor tells you.

5. What should I know while using LATUDA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using LATUDA.
Things you should not do
  • Do not stop taking LATUDA, or lower the dosage, even if you are feeling better, without checking with your doctor.
  • Do not take any other medications, whether they require a prescription or not, without telling your doctor you are taking LATUDA as sometimes the action of one medicine may interfere with another.
  • Avoid grapefruit and grapefruit juice while taking LATUDA.
Driving or using machines
  • Do not drive or operate machinery until you know how LATUDA affects you. Speak with your doctor about when you can resume these activities.
Drinking alcohol
  • Talk to your doctor about how much alcohol you drink. People who drink excessive quantities of alcohol should not take LATUDA.
Looking after your medicine
  • Keep your tablets in the pack until it is time to take them. Keep them in a cool dry place where the temperature stays below 30°C. Keep it where children cannot reach them.

For more information, see Section 5. What should I know while using LATUDA? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. Severe allergic reactions and other severe reactions such as nervous system or musculoskeletal related disorders have rarely been reported. Medical attention or hospitalisation may then be required and should be sought urgently from a doctor or Accident and Emergency at the nearest hospital. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

LATUDA®

Active ingredient(s): Lurasidone Hydrochloride (pronounced lu-ra-si-done hy-dro-chl-ride)

Consumer Medicine Information (CMI)

This leaflet provides important information about using LATUDA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using LATUDA.

Where to find information in this leaflet:

1. Why am I using LATUDA?
2. What should I know before I use LATUDA?
3. What if I am taking other medicines?
4. How do I use LATUDA?
5. What should I know while using LATUDA?
6. Are there any side effects?
7. Product details

1. Why am I using LATUDA?

  • LATUDA contains the active ingredient lurasidone hydrochloride.

LATUDA belongs to a group of medicines called atypical antipsychotics. It helps to correct chemical imbalances in the brain, which may cause mental illness.

  • LATUDA is used to treat adults and adolescents (aged 13 years over with schizophrenia).

Schizophrenia is a mental illness with disturbances in thinking, feelings and behaviour.

Your doctor may have prescribed LATUDA for another reason.

Ask your doctor if you have any questions about why LATUDA has been prescribed for you.

LATUDA is not addictive or habit forming.

LATUDA is available only with a doctor's prescription.

LATUDA is not recommended for use in children or adolescents under 13 years of age, as safety and effectiveness have not been established in this age group.

LATUDA is not approved for the treatment of elderly patients with dementia-related psychosis or behavioural disorders. Medicines like LATUDA can increase the risk of death in elderly people who have memory loss (dementia).

2. What should I know before I use LATUDA?

There are some people who shouldn't take LATUDA. Please read the list below. If you think any of these situations apply to you or you have any questions, please see your doctor.

Warnings

Do not use LATUDA if:

  • you are allergic to lurasidone hydrochloride, or any of the ingredients listed at the end of this leaflet.
  • always check the ingredients to make sure you can use this medicine.
  • you are taking medicines that can affect how your body processes LATUDA such as:
    - ketoconazole or voriconazole, used to treat certain fungal infections
    - ritonavir, used to treat HIV infection
    - carbamazepine, used to treat convulsions (fits)
    - phenytoin, used to treat convulsions (fits) and some heart conditions
    - rifampicin or clarithromycin, used to treat bacterial infections
    - herbal medicines derived from St. John's wort, used to treat depression
  • the packaging is torn or shows signs of tampering
  • the expiry date (EXP) printed in the pack has passed
  • If you are not sure whether you should start taking LATUDA, talk to your doctor or pharmacist.

Before you start to take it

Tell your doctor if you have allergies to:

  • Any other medicines
  • Any other substances, such as foods, preservatives or dyes

Talk to your doctor about how much alcohol you drink. People who drink excessive quantities of alcohol should not take LATUDA.

  • If you have any doubts or questions about taking LATUDA consult your doctor.

Check with your doctor if you have or have had:

  • dementia-related psychosis (particularly in the elderly)
  • neuroleptic malignant syndrome, a reaction to some medicines with a sudden increase in body temperature, extremely high blood pressure and severe convulsions (fits)
  • tardive dyskinesia, a reaction to some medicines with worm-like movements of the tongue, or other uncontrolled movements of the mouth, tongue, cheeks or jaws which may progress to the arms and legs
  • diseases of the blood with a reduced number of white blood cells (e.g. leukopenia or neutropenia) which may result in fever or other signs of infection.
  • diabetes, increased blood sugar (also known as hyperglycaemia), or have a family history of diabetes or high blood sugar.
  • seizures
  • suicidal thoughts or behaviour
  • cardiovascular disease (e.g. heart failure, history of heart attack, ischemia, conduction abnormalities, or have a condition known as QT prolongation)
  • changed levels of lipids such as cholesterol, triglycerides etc. in the blood (also known as dyslipidemia)
  • high blood pressure (also known as hypertension) or low blood pressure (also known as hypotension) or fainting
  • venous thromboembolism (e.g. blockage of a blood vessel by a blood clot formed elsewhere in the body)
  • cerebrovascular disease (e.g. stroke, dehydration, low blood pressure), particularly in the elderly
  • liver or kidney problems
  • breast cancer, pituitary tumours (e.g. tumours at the base of the brain)
  • high prolactin levels (which may present as breast swelling, unusual secretions of breast milk, missed or irregular menstrual periods, breast enlargement in men or impotence)
  • difficulty swallowing
  • weight gain
  • sleep apnoea (temporarily stopping breathing while sleeping)

Tell your doctor if you are participating in activities that may contribute to an elevation in core body temperature (e.g. exercising strenuously, exposure to extreme heat) or subject you to dehydration.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

  • Tell your doctor if you are pregnant or intend to become pregnant.

Like most atypical antipsychotic medicines, LATUDA is not recommended for use during pregnancy. However, if you need to take LATUDA during your pregnancy, your doctor will discuss with you the benefits and risks of taking it.

Newborn babies exposed to antipsychotic medicines (including LATUDA) during the third trimester of pregnancy are at risk of experiencing unusual movements of trembling and/or withdrawal symptoms following delivery including breathing problems, difficulty in feeding, spasms, restlessness, drowsiness.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is recommended that you do not breast-feed while taking LATUDA, as it may pass into breast milk and therefore there is a possibility that the breast-fed baby may be affected. Be sure you have discussed with your doctor the risks and benefits of using this medicine while breast-feeding.

  • If you have not told your doctor or pharmacist about any of the above, tell them before you start taking LATUDA.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

  • Some medicines may interfere with LATUDA and affect how it works. Medicines that can affect how your body processes LATUDA include:
  • ketoconazole or voriconazole, used to treat certain fungal infections
  • ritonavir, used to treat HIV infection
  • carbamazepine, used to treat convulsions (fits)
  • phenytoin, used to treat convulsions (fits) and some heart conditions
  • rifampicin or clarithromycin, used to treat bacterial infections
  • herbal medicines derived from St. John's wort, used to treat depression

These medicines may be affected by LATUDA or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

  • Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect LATUDA.

4. How do I use LATUDA?

How much to take

  • Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

Your doctor or pharmacist will tell you how many tablets you will need to take each day. This depends on your condition and whether or not you are taking any other medicines.

  • If you do not understand the instructions on the box, ask your doctor or pharmacist for help.
  • Do not change your dose without the advice of your doctor even if you feel better.

Follow the instructions provided and take LATUDA until your doctor tells you to stop.

When to take LATUDA

  • Swallow LATUDA whole with a glass of water. Do not chew the tablets.
  • LATUDA should be taken during or immediately after food, consider evening meal.
  • Unless your doctor gives you other directions, you should take LATUDA only once a day.

How to take LATUDA

  • Continue taking the tablets for as long as your doctor tells you.

LATUDA helps control your condition but does not cure it. Therefore you must take LATUDA every day.

  • Do not stop taking it unless your doctor tells you to – even if you feel better.

If you forget to take LATUDA

LATUDA should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then go back to taking your medicine as you would normally.

  • If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.
  • Do not take a double dose to make up for the dose you missed.

This may increase the chance of you getting an unwanted side effect.

  • If you are not sure what to do, ask your doctor or pharmacist.
  • If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much LATUDA

  • It is important that you do not take more LATUDA tablets than your doctor has prescribed.

If you think that you have used too much LATUDA, you may need urgent medical attention.

If you take too much, you may experience:

  • fast, slow or irregular heartbeat
  • low blood pressure (i.e. dizziness, light-headedness)
  • reduced alertness
  • seizures (i.e. fits)
  • uncontrolled muscle spasms affecting the head and neck

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

If anyone accidentally swallows any of your LATUDA tablets, call your nearest Poisons Information Centre for advice (Australian telephone: 13 11 26), or go to Accident and Emergency at your nearest hospital. Keep the telephone number for those places handy whilst taking any medications.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using LATUDA?

Things you should do

Tell any other doctors, dentists and pharmacists who are treating you that you are taking LATUDA if:

  • you are about to be started on any new medicines
  • you plan to have surgery that needs a general anaesthetic
  • you become pregnant while taking LATUDA
  • you need to have any medical tests while you are taking LATUDA
  • you have signs of frequent infections such as fever, chills, sore throat or mouth ulcers
  • you have hyperglycaemia (high blood sugar)
  • you have a sudden increase in body temperature, sweating, fast heartbeat, muscle stiffness, high blood pressure and convulsions (these symptoms may be associated with a condition called ‘neuroleptic malignant syndrome’)
  • dizziness on standing up, especially when getting up from a sitting or lying position (orthostatic hypotension) or fainting
  • high blood prolactin levels (which may present as breast swelling, unusual secretion of breast milk, missed or irregular menstrual periods, breast enlargement in men or impotence)

LATUDA may affect the results of some tests.

Do not take any other medications, whether they require a prescription or not, without first telling your doctor that you are taking LATUDA as sometimes the action of one medicine may interfere with another.

  • Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel the tablets are not helping your condition.

Avoid eating grapefruit or drinking grapefruit juice during treatment with LATUDA. Grapefruit and grapefruit juice may affect the amount of LATUDA in your blood.

  • Keep all your doctor's appointments so that your progress can be checked.

Call your doctor straight away if you:

  • If you have any thoughts about suicide or doing harm to yourself, call your doctor immediately and also contact someone you trust.

All thoughts or talk about suicide or violence towards others or yourself are serious.

If you or someone you know is showing any of the following common warning signs, either contact your doctor or healthcare professional or go to the nearest hospital for treatment:

  • worsening symptoms of depression or anxiety
  • thoughts or talk about death or suicide
  • thoughts or talk about self-harm or doing harm to others
  • any recent attempts of self-harm
  • an increase in aggressive behaviour, irritability or agitation

If someone you know shows any of these symptoms, suggest they urgently contact a healthcare professional.

In addition to talking to your doctor, confidential support and counselling services are available (in Australia) from LifeLine by calling 13 11 14.

Remind any doctor, dentist or pharmacist you visit that you are using LATUDA.

Things you should not do

  • Do not stop taking LATUDA, or lower the dosage, even if you are feeling better, without checking with your doctor.

If you stop taking LATUDA suddenly, your condition may worsen or your chance of getting an unwanted side effect may increase.

To prevent this, your doctor may gradually reduce the amount of LATUDA you take each day before stopping completely.

  • Do not take LATUDA to treat any other complaints unless your doctor tells you to.
  • Do not take any medicines that cause drowsiness while you are taking LATUDA, unless recommended by your doctor.
  • You should not take LATUDA together with certain medications (see also under “Do not use LATUDA if”) as they can affect how your body processes LATUDA.

Do not give LATUDA to anyone else, even if their symptoms seem similar or they have the same condition as you.

Things to be careful of

  • Grapefruit and grapefruit juice should be avoided while taking LATUDA.

Grapefruit juice contains one or more components that alter the metabolism of some medicines including LATUDA. This may lead to higher and unpredictable levels of LATUDA in the blood.

Do not become too hot or dehydrated while taking LATUDA as your body's ability to reduce core body temperature may be affected.

Driving or using machines

  • Be careful before you drive or use any machines or tools until you know how LATUDA affects you. Speak with your doctor about when you can resume these activities.

As with other antipsychotic medicines, LATUDA has the potential to impair judgement, thinking or motor skills in some people. Make sure you know how you react to LATUDA before you drive a car, operate machinery, or do anything else that could be dangerous if you are affected by LATUDA.

Drinking alcohol

  • Tell your doctor if you drink alcohol. Talk to you doctor about how much alcohol you drink.

People who drink excessive quantities of alcohol should not take LATUDA.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.
  • Keep it where young children cannot reach it.

When to discard your medicine (as relevant)

Discard the medicine when the expiry date (EXP) printed on the pack has passed.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

  • Serious side effects
  • What to do
Severe allergic reaction exists with any medication. The following are general signs and symptoms of an allergic reaction:
  • skin rash, itching or hives
  • swelling of the face, lips, tongue or other parts of the body
  • shortness of breath, wheezing or difficulty breathing
Musculoskeletal and connective tissue disorders:
  • temporary paralysis, weakness of muscles or muscle pain
  • severe spasms in the muscles of the shoulders, neck and upper body
Nervous system disorders:
  • worm-like movements of the tongue, or other uncontrolled movements of the tongue, mouth, cheeks, or jaw which may progress to the arms and legs
  • Neuroleptic malignant syndrome (NMS) a serious condition that can lead to death. Symptoms include: sudden increase in body temperature, confusion, sweating, fast heartbeat, muscle stiffness, high blood pressure
  • seizures
Psychiatric disorders:
  • suicidal thoughts or behaviour
Vascular disorders:
  • stroke (cerebrovascular problems) in elderly people with dementia‐related psychosis that can lead to death
  • sudden severe headache, loss of vision, loss of coordination, slurred speech, shortness of breath, chest pain, numbness, heat or swelling in the arms and legs (these symptoms may be associated with a blockage in the blood vessels)
Blood and Lymphatic System Disorders:
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Less serious side effects

  • Less serious side effects
  • What to do
Psychiatric disorders:
  • restlessness, agitation, anxiety
  • extrapyramidal symptoms including Parkinsonism (e.g. unusual movements, including trembling and shaking of the hands and fingers, twisting movements of the body, rigid posture, stiffness of the arms and legs, slow movements and a shuffling, unbalanced walk)
Nervous system disorders:
  • dizziness
  • sleepiness (somnolence), difficulty sleeping (insomnia)
Gastrointestinal disorders:
  • feeling sick (nausea), vomiting,
  • diarrhoea, abdominal pain, indigestion, decreased appetite, increased saliva, difficulty swallowing
Reproductive system and breast disorders:
  • breast swelling, unusual secretion of breast milk, missed or irregular menstrual periods. Breast enlargement or impotence in men
Eye disorders
  • blurred vision
Musculoskeletal and connective tissue disorders:
  • back pain
Vascular disorders:
  • high or low blood pressure
Injury, Poisoning and Procedural Complications:
  • falls
Investigations:
  • weight gain
  • Speak to your doctor if you have any of these less serious side effects and they worry you.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What LATUDA contains

Active ingredient
(main ingredient)		lurasidone hydrochloride
Other ingredients
(inactive ingredients)		carnauba wax, croscarmellose sodium, hypromellose, magnesium stearate, mannitol, Opadry complete film coating system 03F48969 white, pregelatinised maize starch, colourings: indigo carmine and iron oxide yellow (80 mg tablet only)
Potential allergensLATUDA does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes

Do not take this medicine if you are allergic to any of these ingredients.

What LATUDA looks like

LATUDA is registered on the Australian register of Therapeutic Goods and has the Australia Register numbers:

  • AUST R 206650 – 40 mg tablets
  • AUST R 206651 – 80 mg tablets

LATUDA 40 mg tablets are round, white to off-white and debossed on one side with “L40”.

LATUDA 80 mg tablets are oval-shaped, pale green and debossed on one side with “L80”.

LATUDA tablets come in a blister strip. Each box contains 30 tablets.

Who distributes LATUDA

LATUDA is supplied in Australia by:
Servier Laboratories (Aust.) Pty. Ltd.
Level 4, Building 9,
588A Swan Street
Burnley, 3121, Victoria
Telephone: 1800 153 590
Internet: www.servier.com.au

This leaflet was prepared in August 2023.

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Latuda

Active ingredient

Lurasidone hydrochloride

Schedule

S4

 

1 Name of Medicine

Lurasidone hydrochloride.

2 Qualitative and Quantitative Composition

Each Latuda tablet contains 20 mg, 40 mg, or 80 mg of lurasidone hydrochloride.
Lurasidone hydrochloride (HCl) is chemically identified as (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl) piperazin-1-ylmethyl]cyclohexylmethyl} hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Lurasidone is an atypical antipsychotic belonging to the chemical class of benzisothiazol derivatives. It has antagonist activity on the dopamine 2 (D2) and serotonin (5HT)2A receptors. Lurasidone HCl (active entity) is a white to off white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCl, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene, very slightly soluble in acetone and has a pKa of 7.6.
Latuda tablets contain 20 mg lurasidone hydrochloride (equivalent to 18.62 mg of lurasidone), 40 mg (equivalent to 37.24 mg lurasidone), or 80 mg (equivalent to 74.49 mg lurasidone).
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Film-coated tablet.

Latuda 20 mg*.

White to off-white, round, strength specific one-sided debossing "L20".

Latuda 40 mg.

White to off-white, round, strength specific one-sided debossing "L40".

Latuda 80 mg.

Pale green, oval, strength specific one-sided debossing "L80".
* The 20 mg tablet is not currently available in Australia.

4 Clinical Particulars

4.1 Therapeutic Indications

Latuda is indicated for the treatment of schizophrenia in adults and adolescents (aged 13 to 17 years).

4.2 Dose and Method of Administration

Latuda film-coated tablets are intended for oral administration only.
The efficacy of Latuda has been established at doses of 40, 80, 120 and 160 mg/day. The recommended starting dose is 40 mg once daily. Initial dose titration is not required. 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. Dose increase should be based on physician judgement and observed clinical response. In the six week controlled trials, there was no suggestion of added benefit with the 120 mg/day dose compared to 40 and 80 mg/day. In the pooled analyses, added benefit occurred at 160 mg/day compared to lower doses. Doses above 80 mg may be considered for certain patients based on individual clinical judgment. The maximum recommended dose is 160 mg/day. Latuda should be taken with food.

Children and adolescents.

The recommended starting dose of lurasidone in adolescent patients 13 to 17 years of age with schizophrenia is 40 mg/day. The maximum recommended dose in adolescent patients is 80 mg/day. Lurasidone was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 40 mg and 80 mg. The safety and efficacy of Latuda in children aged less than 13 years have not been established (see Section 4.4).
Due to difficulties associated with diagnosing schizophrenia in adolescents, diagnosis of schizophrenia in adolescents should be made by practitioners experienced in the diagnosis and management of adolescent psychiatric disorders.
The effectiveness of Latuda has not been established in controlled studies for treatment duration of more than 6 weeks in adolescents. Therefore, if Latuda is to be used for more than 6 weeks, the treating physician should periodically re-evaluate the long-term use of Latuda for the individual patient.

Patients with renal impairment.

There are limited clinical data in patients with renal impairment. No dose adjustment for Latuda is required in patients with mild (CrCL: 50 to 80 mL/min) renal impairment.
In patients with moderate (CrCl: 30 to < 50 mL/min) or severe (CrCL: < 30 mL/min) renal impairment, the recommended starting dose is 20 mg and the maximum dose should not exceed 80 mg once daily. As the 20 mg tablet is not available in Australia, Latuda should not be started in patients with moderate or severe renal impairment.

Patients with hepatic impairment.

There are limited clinical data in patients with hepatic impairment.
No dose adjustment for Latuda is required in patients with mild hepatic impairment.
Dose adjustment is recommended in patients with moderate (Child-Pugh Class B) hepatic impairment. The recommended starting dose is 20 mg. The dose in patients with moderate hepatic impairment should not exceed 80 mg. As the 20 mg tablet is not available in Australia, Latuda should not be started in patients with moderate (Child-Pugh Class B) hepatic impairment.
Latuda is not recommended in patients with severe (Child-Pugh Class C) hepatic impairment.

Elderly patients.

No dose adjustment is necessary in elderly patients. Clinical studies of Latuda in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In elderly patients with psychosis (65 to 85), Latuda concentrations (20 mg/day) were similar to those in young subjects.
Dosing recommendations for older patients with normal renal function (CrCl ≥ 80 mL/min) are the same as for adults with normal renal function. However, as older patients may have diminished renal function, dose adjustments may be required according to their renal function status (see Section 4.2). Renal function and cardiovascular status should be assessed prior to commencing treatment with Latuda.

Dose adjustment due to interactions.

If Latuda is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem) is added to therapy, the Latuda dose should be reduced to half of the original dose level.
Similarly, if a moderate CYP3A4 inhibitor is being prescribed and Latuda is added to the therapy, the recommended starting dose of Latuda is 20 mg per day, and the maximum dose of Latuda is 80 mg per day. As the 20 mg tablet is not available in Australia, Latuda should not be used in combination with moderate CYP3A4 inhibitors.
Latuda is contraindicated for use in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir, and voriconazole) and strong CYP3A4 inducers (e.g. rifampin, St. John's wort, phenytoin, and carbamazepine).
Grapefruit and grapefruit juice should be avoided in patients taking Latuda, as these may inhibit CYP3A4 and alter Latuda concentrations.

Switching between antipsychotic medicinal products.

Due to different pharmacodynamic and pharmacokinetic profiles among antipsychotic medicinal products, supervision by a clinician is needed when switching to another antipsychotic product is considered medically appropriate.

Abuse.

Latuda has not been systematically studied in humans for its potential for abuse or physical dependence or its ability to induce tolerance. While clinical studies with Latuda did not reveal any tendency for drug seeking behaviour, these observations were not systematic and it is not possible to predict the extent to which a CNS active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of Latuda misuse or abuse (e.g. development of tolerance, drug seeking behaviour, increases in dose).

4.3 Contraindications

Latuda (lurasidone HCl) is contraindicated in any patient with a known hypersensitivity to lurasidone HCl or any components in the formulation.
Latuda is contraindicated with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir, and voriconazole) and strong CYP3A4 inducers (e.g. rifampin, St. John's wort, phenytoin, and carbamazepine) (see Section 4.4).

4.4 Special Warnings and Precautions for Use

Increased mortality in elderly patients with dementia related psychosis.

In placebo controlled trials with similar atypical antipsychotics in elderly subjects with dementia related psychosis, there was a higher incidence of fatalities, compared to placebo treated subjects. Elderly patients with dementia related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo. A meta-analysis of seventeen placebo controlled trials with dementia related behavioural disorders showed a risk of death in the drug treated patients of approximately 1.6 to 1.7 times that seen in placebo treated patients. The clinical trials included in the meta-analysis were undertaken with olanzapine, aripiprazole, risperidone and quetiapine. Over the course of these trials averaging about 10 weeks in duration, the rate of death in drug treated patients was about 4.5%, compared to a rate of approximately 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. Latuda is not approved for the treatment of elderly patients with dementia related psychosis or behavioural disorders.

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.

Neuroleptic malignant syndrome.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported in association with administration of antipsychotic medicines, including Latuda. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including Latuda, must be discontinued.
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.

Seizures.

As with other antipsychotic medicines, 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.

Suicide.

The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high risk patients should accompany treatment with an antipsychotic medicine. Prescriptions for Latuda should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

Weight gain.

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Pooled data from short-term, placebo controlled schizophrenia studies are presented in Table 1. The mean weight gain was 0.43 kg for Latuda treated patients compared to -0.02 kg for placebo treated patients. The proportion of patients with a ≥ 7% increase in bodyweight (at endpoint) was 4.8% for Latuda treated patients versus 3.3% for placebo treated patients.
In long-term controlled studies, for patients who had normal BMI status at baseline (18.5 to < 25.0), the rate of clinically significant weight gain (≥ 7% increase in BMI) at month 12 was 12.4%, 34.5% and 5.6% and to study endpoint (LOCF) was 9.6%, 17.7% and 8.3% of the Latuda, risperidone and quetiapine XR groups, respectively. For those who were overweight at baseline (BMI 25.0 to < 30.0), the rate of clinically significant weight gain at study endpoint was 6.3%, 14.1% and 9.5%, in patients given Latuda, risperidone and quetiapine XR, respectively.

Orthostatic hypotension, syncope and cardiovascular disease.

Latuda may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. Latuda should be used with caution in patients with known cardiovascular disease (e.g. heart failure, history of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g. dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
Caution should be exercised when Latuda is prescribed in patients with known cardiovascular disease or family history of QT prolongation, hypokalaemia, and in concomitant use with other medicinal products thought to prolong the QT interval. Latuda has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials. Due to the risk of orthostatic hypotension with Latuda, caution should be observed in patients with known cardiovascular disease.
Electrocardiogram (ECG) measurements were taken at various time points during the Latuda clinical trial program. No postbaseline QT prolongations exceeding 500 msec were reported in patients treated with Latuda. Within a subset of patients defined as having an increased cardiac risk, no potentially important changes in ECG parameters were observed. No cases of torsade de pointes or other severe cardiac arrhythmias were observed in the premarketing clinical program.
The effects of Latuda on the QT/QTc interval were evaluated in a dedicated QT study involving 87 clinically stable patients with schizophrenia or schizoaffective disorder, who were treated with Latuda doses of 120 mg daily, 600 mg daily, or ziprasidone 160 mg daily. Holter monitor derived electrocardiographic assessments were obtained over an eight hour period at baseline and steady state. The maximum mean (upper 1 sided, 95% CI) increases of baseline adjusted QTc intervals based on individual correction method (QTcI) were 0.36 (1.40) ms for Latuda 120 mg and 1.69 (6.51) ms for Latuda 600 mg. No patients treated with Latuda experienced QTc increases > 60 msec from baseline, nor did any patient experience a QTc of > 500 msec.

Tardive dyskinesia.

Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic medicines, including lurasidone. 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 medicines differ in their potential to cause tardive dyskinesia is unknown.
The risk of development of tardive dyskinesia may be reduced by using the lowest effective dose. Latuda should not be continued in patients who have not responded to treatment. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic medicines, 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, discontinuation of Latuda should be considered.

Venous thromboembolism.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Latuda and preventive measures undertaken.

Hyperprolactinemia.

As with other medicines 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. Premenopausal women who develop secondary amenorrhoea of greater than six months duration should receive appropriate preventative therapy to avoid hypooestrogenic bone loss.
In short-term, placebo controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for Latuda treated patients was +0.4 nanogram/mL and was -1.9 nanogram/mL in the placebo treated patients. The median change from baseline to endpoint for males was +0.5 nanogram/mL and for females was -0.2 nanogram/mL. Median changes for prolactin by dose are shown in Table 2.
The proportion of patients with prolactin elevations ≥ 5 x 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 ≥ 5 x ULN was 5.7% for Latuda treated patients versus 2.0% for placebo treated female patients. The proportion of male patients with prolactin elevations ≥ 5 x ULN was 1.6% versus 0.6% for placebo treated male patients.

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.

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. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients 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. Pooled data from short-term, placebo controlled schizophrenia studies are presented in Table 3.

Dyslipidemia.

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from short-term, placebo controlled schizophrenia studies are presented in Table 4.
In long-term controlled studies the rate of markedly abnormal metabolic parameters was similar between Latuda, risperidone and quetiapine XR. For patients given any dose of Latuda the rate of shift from normal to high total cholesterol was 2.2% and triglycerides was 6.2%.

Body temperature regulation.

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.

Dysphagia.

Oesophageal dysmotility and aspiration have been associated with the use antipsychotic medicines. 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 medicines should be used cautiously in patients at risk for aspiration pneumonia.

Sleep apnoea.

Sleep apnoea and related disorders have been reported in patients treated with antipsychotic medicines, with or without prior history of sleep apnoea, and with or without concomitant weight-gain. In patients who have a history of or are at risk for sleep apnoea, or who are concomitantly using central nervous system depressants, antipsychotic medicines including lurasidone should be used with caution.

Use in the elderly.

Clinical studies with Latuda did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In elderly patients with psychosis (65 to 85), Latuda concentrations (20 mg/day) were similar to those in young subjects. It is unknown whether dose adjustment is necessary on the basis of age alone.
Elderly patients with schizophrenia may have reduced renal function and coexisting cardiovascular disease. In these patients, the starting dose should be reduced (see Section 4.2).
Elderly patients with dementia related psychosis treated with Latuda are at an increased risk of death compared to placebo. Latuda is not approved for the treatment of patients with dementia related psychosis.

Paediatric use.

The safety and efficacy of Latuda has been established in adolescents aged 13 to 17 years. The safety and efficacy of Latuda in children aged less than 13 years have not yet been established. Latuda is not recommended in children aged less than 13 years.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Given the primary central nervous system effects of lurasidone (see Section 4.8), Latuda should be used with caution in combination with other centrally acting medicines and alcohol.

Effects on Latuda.

Based on in vitro studies, lurasidone is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. This suggests that an interaction of lurasidone with medicines that are inhibitors or inducers of these enzymes is unlikely.
Grapefruit and grapefruit juice inhibits CYP3A4 and may increase the serum levels of Latuda. It should not be taken with Latuda.
Lurasidone is predominantly metabolized by CYP3A4; interaction of Latuda with strong and moderate inhibitors or inducers of this enzyme has been observed (Table 5). Latuda should not be used in combination with strong inhibitors or inducers of this enzyme.

Effects on coadministered medicines.

Digoxin (P-gp substrate).

Coadministration of Latuda (120 mg/day) at steady state with a single dose of digoxin (0.25 mg) increased Cmax and AUC(0-24) for digoxin by approximately 9% and 13%, respectively relative to digoxin alone. Digoxin dose adjustment is not required when coadministered with Latuda.

Lithium.

Coadministration of Latuda (120 mg/day) and lithium (1200 mg/day) at steady state resulted in comparable mean lithium Cmax values on Day 4 (0.65 mmol/L) and Day 8 (0.75 mmol/L) and maintenance of the therapeutic range for lithium (0.6 to 1.2 mmol/L). No adjustment of lithium dose is required when coadministered with Latuda.

Midazolam (CYP3A4 substrate).

Coadministration of Latuda (120 mg/day) at steady state with a single dose of 5 mg midazolam increased midazolam Cmax and AUC(0-24) by approximately 21% and 44%, respectively relative to midazolam alone. Midazolam dose adjustment is not required when coadministered with Latuda.

Oral contraceptive (estrogen/ progesterone).

Coadministration of Latuda (40 mg/day) at steady state with an oral contraceptive (OC) containing ethinyl estradiol and norelgestimate resulted in equivalent AUC(0-24) and Cmax of ethinyl estradiol and norelgestromin relative to OC administration alone. Also, sex hormone binding globulin levels were not meaningfully affected by coadministration of Latuda and OC. Dose adjustment of OC dose is not required when coadministered with Latuda.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There was no effect on mating performance or fertility in male rats treated with lurasidone prior to and during mating at oral doses up to 150 mg/kg/day, corresponding to about 9 times the maximum recommended human dose (MRHD) based on body surface area.
In female rats given lurasidone prior to and during mating and in early pregnancy, oestrus was prolonged and mating was delayed at oral doses of 1.5-150 mg/kg/day (0.1-9 times the MRHD based on body surface area); the no-effect dose was 0.1 mg/kg/day. At the 150 mg/kg/day dose, reductions were observed in the proportion of females mating, fertility and the number of corpora lutea, implantations and live fetuses per dam. These changes were reversed after a 14 day treatment free period. The no-effect dose for reduced fertility was 15 mg/kg/day (approximately the MRHD based on body surface area).
(Category B1)
There are no adequate and well controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with Latuda. Latuda should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human data.

Neonates exposed to antipsychotic medicines during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Animal data.

No teratogenic or other adverse effects on fetuses were observed in studies in which lurasidone was administered during the period of organogenesis to rats and rabbits at respective oral doses up to 25 and 50 mg/kg/day, corresponding to 1.5 and 5 times, respectively, the MRHD based on body surface area. No effects on delivery or pup development were observed in rats given lurasidone from early gestation to weaning at oral doses up to 10 mg/kg/day (about half the MRHD based on body surface area).
 Lurasidone and/or other metabolites were excreted in milk of rats during lactation and the same would be expected for human milk. Women receiving Latuda should not breastfeed.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
The following findings are derived from a clinical study database for Latuda consisting of 2,905 patients with schizophrenia exposed to one or more doses with a total experience of 985.3 patient years. Of these patients, 1,508 participated in short-term, placebo controlled schizophrenia studies with doses of 20 mg, 40 mg, 80 mg, 120 mg or 160 mg once daily. A total of 769 Latuda treated patients had at least 24 weeks and 371 Latuda treated patients had at least 52 weeks of exposure.
The most common adverse events (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with Latuda were somnolence, akathisia, nausea and parkinsonism.
Adverse events reported with the use of Latuda (incidence of 2% or greater, rounded to the nearest percent and Latuda incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 6.

Dose related adverse events.

Akathisia and extrapyramidal symptoms were dose related in adults with schizophrenia. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for Latuda 20 mg, 10.7% for Latuda 40 mg, 12.3% for Latuda 80 mg, and 22.0% for Latuda 120 mg). Akathisia was reported by 7.4% (9/121) of adult patients receiving 160 mg/day. Akathisia occurred in 3.0% of adult subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for Latuda 20 mg, 11.5% for Latuda 40 mg, 11.9% for Latuda 80 mg, and 22.0% for Latuda 120 mg).
Due to the observed dose related adverse effects, the recommended starting dose of Latuda in adults (40 or 80 mg/day) should be utilized for initial treatment based on clinical evaluation. Dose increases should be based on physician judgment and observed clinical response.

Extrapyramidal symptoms.

In the short-term, placebo controlled schizophrenia studies, for Latuda treated adult patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% versus 5.8% for placebo treated patients. The incidence of akathisia for Latuda treated adult patients was 12.9% versus 3.0% for placebo treated adult patients. Incidence of EPS by dose is provided in Table 7.

Other adverse reactions observed during the premarketing evaluation of Latuda.

Following is a list of other adverse reactions and laboratory investigations reported by adult patients treated with Latuda at multiple doses of ≥ 20 mg once daily during any phase of a study within the database of 3,202 patients. The reactions listed are those that could be of clinical relevance, as well as reactions that are plausibly drug related on pharmacologic or other grounds. Reactions listed in Table 6 or those that appear elsewhere in Section 4.8 Adverse Effects (Undesirable Effects) are not included. Although the reactions reported occurred during treatment with Latuda, they were not necessarily caused by it.
The following adverse reactions are classified by system organ class and are according to the following definitions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Blood and lymphatic system disorders.

Uncommon: anaemia. Rare: leukopenia, neutropenia.

Cardiac disorders.

Common: tachycardia. Uncommon: angina pectoris, bradycardia. Rare: A-V block 1st degree.

Ear and labyrinth disorders.

Uncommon: vertigo.

Eye disorders.

Common: vision blurred.

Gastrointestinal disorders.

Common: abdominal pain, diarrhoea. Uncommon: dysphagia, gastritis.

General disorders and administrative site conditions.

Rare: sudden death.

Investigations.

Common: creatinine phosphokinase increased.

Metabolism and nutritional system disorders.

Common: decreased appetite. Uncommon: hyponatraemia.

Musculoskeletal and connective tissue disorders.

Rare: rhabdomyolysis.

Nervous system disorders.

Uncommon: dysarthria, cerebrovascular accident, syncope, tardive dyskinesia. Rare: neuroleptic malignant syndrome, seizure.

Psychiatric disorders.

Uncommon: abnormal dreams, panic attack, sleep disorder. Rare: suicidal behaviour.

Renal and urinary disorders.

Uncommon: dysuria. Rare: renal failure.

Reproductive system and breast disorders.

Uncommon: amenorrhea, dysmenorrhoea, erectile dysfunction. Rare: breast pain, galactorrhoea, breast enlargement.

Skin and subcutaneous tissue disorders.

Common: rash, pruritus. Rare: angioedema.

Vascular disorders.

Common: hypertension. Uncommon: orthostatic hypotension.

Paediatric population.

The following findings are based on the short-term, placebo-controlled pre-marketing study for schizophrenia in which lurasidone was administered at daily doses ranging from 40 to 80 mg (n = 326). The most common adverse events reported (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with lurasidone were somnolence, nausea, akathisia, and vomiting.
Adverse events reported with the use of lurasidone (incidence of 2% or greater, rounded to the nearest percent and lurasidone incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in adolescent patients with schizophrenia) are shown in Table 8.

Clinical laboratory changes.

Serum creatinine.

In short-term, placebo controlled trials in adults, the mean change from baseline in serum creatinine was +0.05 mg/dL for Latuda treated patients compared to +0.02 mg/dL for placebo treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1,453) of Latuda treated patients and 1.6% (11/681) on placebo (Table 9). The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study. See Table 10.

Adverse reactions observed postmarketing.

As these reactions are reported voluntarily from a population of uncertain size, the incidence rate of these adverse reactions cannot be estimated (frequency unknown).
The following adverse reactions, classified by system organ class and frequency, have been identified with Latuda in the postmarketing period.

Immune system disorders.

Frequency unknown: hypersensitivity (hypersensitivity may include symptoms such as throat swelling, tongue swelling, urticaria, or symptoms of angioedema. Hypersensitivity may also include symptoms of severe cutaneous reactions such as dermatitis bullous, rash maculopapular, rash pustular, skin eruption and skin exfoliation).

Metabolism and nutritional system disorders.

Frequency unknown: hyponatraemia.
The following adverse reactions, classified by system organ class and frequency, have been identified with atypical antipsychotic medicines including Latuda in the post-marketing period:

Psychiatric disorders.

Frequency unknown: somnambulism (sleepwalking) and related behaviours including sleep-related eating disorder.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
There is no specific antidote to lurasidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers.
Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT prolonging effects when administered in patients with an acute overdose of Latuda. Similarly the alpha-blocking properties of bretylium might be additive to those of Latuda, resulting in problematic hypotension.
Hypotension and circulatory collapse should be treated with appropriate measures. Adrenaline and dopamine should not be used or other sympathomimetics with beta agonist activity, since beta stimulation may worsen hypotension in the setting of Latuda induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Administration of activated charcoal together with a laxative should be considered.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism of action of lurasidone, as with other medicines having efficacy in schizophrenia, is not fully understood. However, based on its receptor pharmacology, it is believed that the efficacy of Latuda is mediated mainly through antagonist activity at dopamine D2 and 5-hydroxytryptamine (5HT, serotonin) 5HT2A receptors.
In vitro receptor binding studies revealed that Latuda binds with high affinity at human D2 receptors (Ki = 0.994 nanoM) and 5HT2A (Ki = 0.47 nanoM) and 5HT7 (Ki = 0.495 nanoM) receptors, with moderate affinity at human α2C adrenergic receptors (Ki = 10.8 nanoM), D3 receptors (Ki = 15.7 nanoM) and 5HT1A (Ki = 6.38 nanoM) receptors, and with weak affinity at human D4.4 (Ki = 29.7 nanoM) and α2A (Ki = 40.7 nanoM) and α1A (Ki = 35.7 nanoM) adrenergic receptors. Latuda exhibits little or no affinity for human histamine H1 and muscarinic M1 receptors (IC50 > 1,000 nanoM). Latuda is a partial agonist at 5HT1A receptors but is believed to act as an antagonist at all the other receptors.
Latuda doses ranging from 10 to 80 mg administered to healthy subjects produced a dose dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, in the caudate, putamen and ventral striatum detected by positron emission tomography.
After single administration at doses of 20 and 40 mg in a quantitative electroencephalographic evaluation, Latuda decreased the threshold of flicker discrimination in the flicker test without affecting GFP value in any frequency band in electroencephalography.

Clinical trials.

The efficacy of Latuda in the treatment of adults with schizophrenia was established in five short-term (6 week), placebo controlled, studies in adult patients (mean age of 38.4 years, range 18-72) who met DSM-IV criteria for schizophrenia. An active control arm (olanzapine or quetiapine XR) was included in two studies to assess assay sensitivity.
Several instruments were used for assessing psychiatric signs and symptoms in these studies.
1. Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210.
2. Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. BPRSd scores may range from 18 to 126.
3. The Clinical Global Impression severity scale (CGI-S) is a validated clinician rated scale that measures the subject's current illness state on a 1 to 7 point scale.
The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the Latuda and control groups.
The results of the studies follow (Table 11).
1. In a 6 week, placebo controlled trial (N = 145) involving two fixed doses of Latuda (40 or 120 mg/day), both doses of Latuda at endpoint were superior to placebo on the BPRSd total score, and the CGI-S.
2. In a 6 week, placebo controlled trial (N = 180) involving a fixed dose of Latuda (80 mg/day), Latuda at endpoint was superior to placebo on the BPRSd total score, and the CGI-S.
3. In a 6 week, placebo and active controlled trial (N = 473) involving two fixed doses of Latuda (40 or 120 mg/day) and an active control (olanzapine), both Latuda doses and the active control at endpoint were superior to placebo on the PANSS total score, and the CGI-S.
4. In a 6 week, placebo controlled trial (N = 489) involving three fixed doses of Latuda (40, 80 or 120 mg/day), only the 80 mg/day dose of Latuda at endpoint was superior to placebo on the PANSS total score, and the CGI-S.
5. In a 6 week, placebo and active controlled trial (N = 482) involving two fixed doses of Latuda (80 or 160 mg/day) and an active control (quetiapine XR), both Latuda doses and the active control at endpoint were superior to placebo on the PANSS total score, and the CGI-S.
Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness.
An analysis of adult patients with a ≥ 30% reduction from baseline PANSS score (clinical response analysis) was performed in three of these studies. The placebo response rate was around 35% across the studies and the response rates for Latuda 40 mg, 80 mg and 120 mg were all around 50%, giving a 15% difference in response rates from placebo and a NNT of 6.7 for one patient to achieve a clinically significant improvement. One study assessed efficacy of the 160 mg dose and 120 patients were given this dose. The response rate for 160 mg Latuda was 63%, a NNT of approximately 3.6. There was limited evidence of dose response for doses between 40 mg and 80 mg.

Adolescents.

The efficacy of lurasidone in the treatment of schizophrenia in adolescent patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled study of patients (N=327) who met DSM-IV criteria for schizophrenia [D1050301]. Both the 80 mg and 40 mg doses of lurasidone demonstrated superiority over placebo on the PANSS total score after 6 weeks of double-blind treatment (Table 12).

Maintenance of effect.

A double-blind study compared flexibly dosed Latuda (40 to 160 mg daily) with flexibly dosed quetiapine XR (200 to 600 mg daily) for up to 12 months in adult patients with schizophrenia who had shown a clinical response to Latuda in a short-term study. The mean daily dose of Latuda was 125.5 mg and of quetiapine XR was 629.6 mg. Relapses were reported in 21% of subjects given Latuda and in 27% given quetiapine XR. The probability of relapse by month 12 was 23.7% and 33.6% for Latuda and quetiapine, respectively. The relapse hazard ratio of Latuda versus quetiapine XR was 0.728 (95% CI: 0.41, 1.29).

5.2 Pharmacokinetic Properties

The activity of Latuda is primarily due to the parent drug. The pharmacokinetics of Latuda is dose proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of lurasidone are reached within 7 days of starting lurasidone. Following administration of 40 mg the mean (%CV) elimination half-life was 18 (7) hours.

Absorption.

Latuda is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed. In a food effect study, Latuda mean Cmax and AUC were about 3 times and 2 times, respectively, when administered with food compared to the levels observed under fasting conditions. Latuda exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content (see Section 4.2).

Distribution.

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

Metabolism.

Latuda is metabolised mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. Latuda is metabolised into two nonmajor active metabolites (ID-14283 and ID-14326) and two major nonactive metabolites (ID-20219 and ID-20220). Latuda and its metabolites ID-14283, ID-14326, ID-20219 and ID-20220 correspond to approximately 11.4, 4.1, 0.4, 24 and 11% respectively, of serum radioactivity respectively. Latuda is a single isomer form, which does not appear to undergo conversion to other enantiomers on metabolism.

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

Special populations.

Renal impairment.

After administration of a single dose of 40 mg Latuda to 27 patients with mild (n = 9; CrCL: 50 to 80 mL/min), moderate (n = 9; CrCL: 30 to < 50 mL/min) and severe (n = 9; CrCL: < 30 mL/min) renal impairment, mean Cmax increased by 1.4, 1.9 and 1.5-fold, respectively, and mean AUC(0-∞) increased by 1.5, 1.9 and 2.0-fold, respectively, compared to healthy matched subjects (n = 9).

Hepatic impairment.

The exposure to lurasidone is increased in patients with Child-Pugh Class A and B hepatic impairment with mean Cmax increased by 1.3 and 1.2-fold, respectively and mean AUC(0-∞) increased by 1.5 and 1.7-fold, respectively compared to healthy matched subjects. The pharmacokinetics of Latuda has not been adequately established in patients with severe hepatic impairment and Latuda is not recommended in these patients.

Elderly.

Limited data have been collected in patients ≥ 65 years. Of the data collected, similar exposure was obtained compared with subjects < 65 years.

Paediatrics.

The pharmacokinetics of lurasidone, in paediatric patients 6-17 years of age was similar to those in adults. There were no clinically relevant differences between genders in the pharmacokinetics of lurasidone in patients with schizophrenia.

5.3 Preclinical Safety Data

Genotoxicity.

Lurasidone was not genotoxic in the bacterial reverse mutation (Ames) test, the in vitro chromosomal aberration test in Chinese hamster lung cells, or the in vivo mouse bone marrow micronucleus test.

Carcinogenicity.

Lurasidone was administered orally for 24 months at doses of 30, 100, 300, or 650 (the high dose was reduced from 1,200 in males) mg/kg/day to ICR mice and 3, 12, or 36 (high dose reduced from 50) mg/kg/day to Sprague-Dawley rats.
In the mouse study, there were increased incidences of malignant mammary gland tumours and pituitary gland adenomas in females at all doses; the lowest dose tested produced plasma levels (AUC in females) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 160 mg/day. No increases in tumours were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14 times those in humans receiving the MRHD.
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 MRHD. No increases in tumours were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6 times those in human receiving the MRHD.
Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic medicines and are considered to be prolactin mediated. The relevance of this increased incidence of prolactin-mediated pituitary or mammary gland tumours in rodents in terms of human risk is unknown.
To date, neither clinical studies nor epidemiological studies have shown an association between chronic administration of these medicines and mammary tumorigenesis. However, since tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, Latuda should be used cautiously in patients with previously detected breast cancer or in patients with pituitary tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Croscarmellose sodium, hypromellose, magnesium stearate, mannitol, pregelatinised maize starch.

Film-coating (20 mg and 40 mg tablets).

Carnauba wax, Opadry complete film coating system 03F48969 white.

Film-coating (80 mg tablets).

Carnauba wax, Opadry complete film coating system 03F48969 white, indigo carmine, iron oxide yellow.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

Latuda 40 mg and 80 mg.

4 years.

Latuda 20 mg*.

3 years.
* The 20 mg tablet is not currently available in Australia.

6.4 Special Precautions for Storage

Latuda 40 mg and 80 mg.

Store below 30°C.

Latuda 20 mg*.

Store below 25°C.
* The 20 mg tablet is not currently available in Australia.

6.5 Nature and Contents of Container

While Latuda tablets are supplied in Aluminium/Aluminium blisters in cartons of 7, 10, 14, 28, 30, 56, 60, 90, 98 or 100 tablets, only the 10 and 30 tablet pack sizes are currently marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

367514-88-3.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes