Consumer medicine information

Saphris

Asenapine

BRAND INFORMATION

Brand name

Saphris

Active ingredient

Asenapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Saphris.

SUMMARY CMI

SAPHRIS®

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 SAPHRIS?

SAPHRIS contains the active ingredient asenapine. SAPHRIS is used to treat Schizophrenia and Bipolar 1 Disorder in adults.

For more information, see Section 1. Why am I using SAPHRIS? in the full CMI.

2. What should I know before I use SAPHRIS?

Do not use if you have ever had an allergic reaction to SAPHRIS 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.

For more information, see Section 2. What should I know before I use SAPHRIS? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SAPHRIS 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 SAPHRIS?

  • Your doctor will tell you how many wafers you will need to take each day and how long you need to take it.
  • Place the wafer under your tongue and allow to completely dissolve. Do not chew or swallow the wafer.

More instructions can be found in Section 4. How do I use SAPHRIS? in the full CMI.

5. What should I know while using SAPHRIS?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using SAPHRIS.
  • Tell your doctor immediately if you become pregnant while taking SAPHRIS,
  • Tell your doctor immediately if you have thoughts about harming or killing yourself
Things you should not do
  • Do not stop using taking SAPHRIS, or change the dosage, unless your doctor tells you to, even if you feel better.
  • Do not give SAPHRIS to anyone else, even if they have the same condition as you.
  • Do not take SAPHRIS to treat any other complaints, unless your doctor tells you to
Driving or using machines
  • Be careful driving or operating machinery until you know how SAPHRIS affects you.
  • SAPHRIS may cause dizziness, and tiredness, in some people.
Drinking alcohol
  • Be careful when drinking alcohol while taking SAPHRIS.
  • Combining SAPHRIS and alcohol can make you more sleepy or dizzy.
Looking after your medicine
  • Keep your wafers in the original packaging until it is time to take them. Protect from light.
  • Keep your wafers in a cool dry place where the temperature stays below 30°C
  • Keep it where children cannot reach it.

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

6. Are there any side effects?

Common side effects include nausea, dry mouth, constipation, tiredness, sleepiness, dizziness, weight increase, restlessness, change in taste and increased appetite. Serious side effects may include signs of frequent infections, extremely high body temperature, uncontrolled movements of the mouth and body, muscle spasms, and signs of an allergic reaction (such as, skin rash, itching or hives, shortness of breath etc.).

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

SAPHRIS®

Active ingredient(s): asenapine

Consumer Medicine Information (CMI)

This leaflet provides important information about using SAPHRIS. 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 SAPHRIS.

Where to find information in this leaflet:

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

1. Why am I using SAPHRIS?

SAPHRIS contains the active ingredient asenapine.

SAPHRIS belongs to a group of medicines called antipsychotics. It helps to correct chemical imbalances in the brain, which may cause certain mental illnesses.

SAPHRIS is used to treat the mental illnesses:

  • Schizophrenia - an illness with disturbances in thinking, feelings and behaviour.
  • Bipolar 1 disorder - an illness in which there are sustained mood swings either up (mania) or down (low moods). During mania, patients experience episodes of overactivity, elation or irritability. During low moods, patients may feel depressed or guilty, lack energy, lose their appetite and have trouble sleeping.

SAPHRIS is not addictive.

2. What should I know before I use SAPHRIS?

Warnings

Do not use SAPHRIS if:

  • you are allergic to asenapine, or any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction to SAPHRIS may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin or you may feel faint.
  • the packaging is torn or shows signs of tampering

Check with your doctor if you:

  • have any other medical conditions, especially the following:
    - Dementia (in elderly patients) or dementia with Lewy Bodies
    - Parkinson's disease
    - heart disease / low blood pressure
    - liver disease
    - diabetes or family history of diabetes
    - difficulty in swallowing
    - epilepsy (seizures)
    - higher levels of the hormone, prolactin, in your blood
    - neuroleptic malignant syndrome - a reaction to some medicines with a sudden increase in body temperature, extremely high blood pressure and severe convulsions
    - 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
  • take any medicines for any other condition
  • have allergies to any other medicines, any other substances, such as foods, preservatives or dyes.
  • have diabetes or risk factors for diabetes, such as being overweight or a family history of diabetes. Your blood sugar should be tested at the beginning of and throughout treatment with SAPHRIS. Complications of diabetes can be serious and even life-threatening. Tell your doctor if you have blood sugar problems or signs of diabetes, such as being thirsty all the time, going to the bathroom a lot, or feeling weak or hungry.

Tell your doctor or mental health professional if you have any mental/mood changes or suicidal thoughts.

  • Depression and other mental illnesses can lead to suicide. It is important to discuss all the risks of treating depression and mental illness as well as the risks of not treating it. You should discuss all treatment choices with your doctor, not just the use of anti-depressants.
  • Patients (and caregivers of patients) need to monitor for any worsening of their condition and/or the emergence of thoughts of suicide or suicidal behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.
  • The long-term safety and effectiveness of SAPHRIS beyond 12 weeks has not been assessed in Bipolar disorder.

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

Do not take SAPHRIS if you are pregnant or breastfeeding unless your doctor tells you to. Ask your doctor about the risks and benefits involved.

It is not known if it is safe for you to take SAPHRIS while you are pregnant. However, if you need to take SAPHRIS during your pregnancy, the doctor will discuss the risks and benefits of taking it with you.

The following symptoms may occur in newborn babies, of mothers that have used antipsychotics in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these symptoms contact your doctor.

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

It is recommended that you do not breast-feed while taking SAPHRIS.

Risk of Falls

Asenapine may cause sleepiness, sudden drops in blood pressure when you stand up, dizziness and changes in your ability to move and balance, which may lead to falls and, consequently, fractures or other injuries. Patients at risk for fall should be evaluated prior to prescribing asenapine.

Use in Children

SAPHRIS is not recommended for use in children below 18 years of age.

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 SAPHRIS and affect how it works. These may include:

  • blood pressure lowering medicines
  • antidepressant drugs (e.g. paroxetine, fluvoxamine or fluoxetine)

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

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

4. How do I use SAPHRIS?

How much to take

  • The dose of SAPHRIS is one wafer to be taken twice a day
  • Your doctor will tell you how many wafers you will need to take each day. This depends on your condition and whether or not you are taking any other medicines.
    Continue taking the wafers for as long as your doctor tells you. SAPHRIS helps control your condition, but does not cure it. Therefore, you must take SAPHRIS every day
  • Do not stop taking SAPHRIS unless your doctor tells you to, even if you feel better.

How to take SAPHRIS

  • Do not remove the wafer from the blister until ready to take
  • Use dry hands when handling the wafer
  • Do not push the wafer through the blister. Do not cut or tear the blister. Peel back the coloured tab.

  • Gently remove the wafer from the blister. Do not crush the wafer.

  • Place the wafer under your tongue and allow it to completely dissolve.

  • Do not chew or swallow the wafer.
  • Do not eat or drink for 10 minutes after taking the wafer.
    Otherwise SAPHRIS will not be absorbed completely, and it may not work as effectively.

If you forget to use SAPHRIS

SAPHRIS 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.

  • 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 SAPHRIS (overdose)

If you take too much SAPHRIS, you may feel restless, confused, drowsy, dizzy, sleepy or have a fast heartbeat.

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

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.

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

5. What should I know while using SAPHRIS?

Things you should do

  • If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking SAPHRIS.
  • If you are about to have any blood tests, tell your doctor that you are taking SAPHRIS.
    SAPHRIS may interfere with the results of some tests.
  • Be sure to keep all of your doctor's appointments so that your progress can be checked.
    Your doctor will check your progress and may want to take some blood tests from time to time. This helps to reduce unwanted side effects.
  • Make sure you keep cool in hot weather and keep warm in cool weather.
    SAPHRIS may affect the way your body reacts to temperature changes.

Contact your doctor or mental health professional immediately or go to the nearest hospital for treatment if you or someone you know is demonstrating any of the following warning signs of suicide while taking SAPHRIS:

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

Occasionally, the symptoms of depression may include thoughts of suicide or self-harm. These symptoms may continue or get worse during the early stages of treatment until the effect of the medicine becomes apparent. All mentions of suicide or violence must be taken seriously.

Call your doctor straight away if you:

  • become pregnant while taking SAPHRIS.

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

Things you should not do

  • Do not give SAPHRIS to anyone else, even if they have the same condition as you.
  • Do not take SAPHRIS to treat any other complaints unless your doctor tells you to.
  • Do not stop taking SAPHRIS, or change the dosage, even if you are feeling better, without checking with your doctor.
    If you stop taking SAPHRIS 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 SAPHRIS you take each day before stopping completely.
  • Do not take any medicines that cause drowsiness while you are taking SAPHRIS, unless recommended by your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SAPHRIS affects you.

SAPHRIS may cause dizziness, and tiredness, in some people. Make sure you know how you react to SAPHRIS before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or sleepy.

If SAPHRIS makes you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Drinking alcohol

Be careful when drinking alcohol while taking SAPHRIS.

Combining SAPHRIS and alcohol can make you more sleepy or dizzy.

Your doctor may suggest you avoid alcohol while you are being treated with SAPHRIS.

Looking after your medicine

  • Keep your wafers in the original packaging until it is time to take them to protect them from light and moisture.
    If you take the wafers out of their packaging, they will not keep well.
  • Keep your wafers in a cool dry place away from moisture, heat or sunlight where the temperature stays below 30°C.

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 SAPHRIS:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking SAPHRIS or the wafers have passed their expiry date, ask your pharmacist what to do with any that are left over.

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.

Less serious side effects

Less serious side effectsWhat to do
  • sleepiness
  • increased appetite, weight gain
  • drowsiness
  • tremor
  • sensation of numbness in the mouth
  • dizziness
  • change in taste
  • fatigue
  • dry mouth
  • mouth ulcers and pain in the mouth
  • increased saliva (drooling)
  • nausea
  • constipation
  • restlessness, agitation, anxiety, excitement or difficulty concentrating
  • an overwhelming urge to move such as feeling the need to pace, swing the legs while seated or rock from foot to foot
  • difficulty sleeping
  • headache
  • hot, dry skin
  • increased or decreased sweating
  • signs of increased blood sugar levels such as excessive thirst, hunger, weakness, urination or onset or worsening of diabetes.
  • falls may occur as a result of one or more adverse events such as: sleepiness, sudden drops in blood pressure when you stand up, dizziness and changes in your ability to move and balance.
These side effects are usually mild. Some of these side effects may go away after a while. Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • signs of frequent infections such as fever, chills, sore throat or mouth ulcers
  • extremely high body temperature
  • worm-like movements of the tongue, or other uncontrolled movements of the tongue, mouth, cheeks, or jaw which may progress to arms and legs
  • sudden onset of uncontrollable muscle spasms affecting the eyes, head, neck and body
  • fainting
  • convulsions, fits or seizures
  • severe spasms in the muscles of the shoulders, neck and upper body
  • sudden increase in body temperature, with sweating, fast heartbeat, muscle stiffness and fluctuating blood pressure which may lead to coma
  • abnormal electrocardiogram (prolongation of the QT interval)
  • sudden signs of allergy such as skin rash, itching or hives, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty breathing
These are very serious side effects. You may need urgent medical attention or hospitalisation. 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.

Occasionally, SAPHRIS may be associated with changes in liver function or blood such as cholesterol or triglyceride levels.

These can only be found when your doctor does tests from time to time to check your progress.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

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 SAPHRIS contains

Active ingredient
(main ingredient)		SAPHRIS wafers come in two strengths:
  • 5 mg asenapine
  • 10 mg asenapine
Other ingredients
(inactive ingredients)
  • Gelatin
  • Mannitol

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

What SAPHRIS looks like

SAPHRIS 5 mg - white to off-white round wafer with a "5" marking on one side (Aust R 166562).

SAPHRIS 10 mg - white to off-white round wafer with a "10" marking on one side (Aust R 166561).

SAPHRIS is available in Al/Al blister packs of 20, 60 and 100 wafers*.

*Not all pack sizes may be available.

Who distributes SAPHRIS

Organon Pharma Pty Ltd
Level 5, 66 King St
Sydney NSW 2000
Australia

This leaflet was prepared in February 2025.

S-CCPPI-MK8274-SB-T-102017

RCN000006067/ RCN000005108

Published by MIMS April 2025

BRAND INFORMATION

Brand name

Saphris

Active ingredient

Asenapine

Schedule

S4

 

1 Name of Medicine

Asenapine (as maleate).

2 Qualitative and Quantitative Composition

Saphris is available as 5 mg and 10 mg wafers containing 5 mg asenapine (7.03 mg asenapine maleate) and 10 mg asenapine (14.06 mg asenapine maleate), respectively.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Saphris 5 mg contains 5 mg of asenapine as maleate. It is a round wafer, white to off-white in colour with "5" debossed on one side.
Saphris 10 mg contains 10 mg of asenapine as maleate. It is a round wafer, white to off-white in colour with "10" debossed on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Saphris is indicated in the:
treatment of schizophrenia in adults;
treatment of acute manic or mixed episodes associated with Bipolar 1 Disorder in adults as monotherapy or in combination with lithium or sodium valproate;
prevention of relapse of manic or mixed episodes in Bipolar 1 Disorder in adults as monotherapy or in combination with lithium or sodium valproate.

4.2 Dose and Method of Administration

Schizophrenia.

The recommended dose range of Saphris is 5 mg to 10 mg twice daily. Saphris should be administered at an initial daily dose of 5 mg twice daily. An increase in dose to 10 mg twice daily is recommended only after clinical assessment. In controlled trials, there was no suggestion of added benefit with a higher dose of 10 mg twice daily but there was a clear increase in certain adverse reactions. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Acute and maintenance treatment of manic or mixed episodes in bipolar 1 disorder.

The recommended starting dose of Saphris as monotherapy is 10 mg twice daily. The dose can be reduced to 5 mg twice daily, according to clinical assessment.
For combination therapy a starting dose of 5 mg twice daily is recommended. Depending on the clinical response and tolerability in the individual patient, the dose can be increased to 10 mg twice daily. Saphris has not been adequately assessed for the long term treatment of patients with bipolar 1 disorder. It has shown efficacy in the prevention of relapse of manic or mixed episodes when used as monotherapy or in combination with lithium or sodium valproate for up to 12 weeks. When used as monotherapy or in combination with lithium or sodium valproate, it is generally recommended that responding patients be continued beyond the acute response. If Saphris is used for extended periods in bipolar 1 disorder, the long-term risks and benefits of the drug for the individual patient should be periodically re-evaluated.

Method of administration.

The wafer should not be removed from the blister until ready to take it. Use dry hands when handling the wafer. Do not push the wafer through the wafer pack. Do not cut or tear the wafer pack. Peel back the coloured tab and gently remove the wafer. Do not crush the wafer.
To ensure optimal absorption, place the Saphris wafer under the tongue and allow it to dissolve completely. The wafer will dissolve in saliva within seconds. Do not chew or swallow the Saphris wafers. Do not eat or drink for 10 minutes.
When used in combination with other medication, Saphris should be taken last.
Treatment with Saphris is not advised in patients who are unable to comply with this method of administration as the bioavailability of asenapine when swallowed is low (< 2% with an oral tablet formulation).

Elderly.

Saphris should be used with care in the elderly. Limited data on safety and efficacy are available in patients 65 years of age or older (see Section 5.2 Pharmacokinetic Properties, Special populations).

Renal impairment.

No dosage adjustment is required for patients with renal impairment.

Hepatic impairment.

No dosage adjustment is required for patients with mild to moderate hepatic impairment. In subjects with severe hepatic impairment (Child-Pugh C), a 7-fold increase in asenapine exposure was observed. Thus, Saphris is not recommended in patients with severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special populations).

Children.

Use of Saphris in children below the age of 18 is not recommended.

4.3 Contraindications

Saphris is contraindicated in:
Patients who are hypersensitive to any component of the wafer or to asenapine. Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed in patients treated with asenapine.

4.4 Special Warnings and Precautions for Use

Elderly patients with dementia-related psychosis.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo. A meta-analysis of 17 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 Zyprexa (olanzapine), Abilify (aripiprazole), Risperdal (risperidone) and Seroquel (quetiapine). Over the course of these trials averaging about ten weeks in duration, 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. Saphris is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic malignant syndrome.

Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur with antipsychotics, including Saphris. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure.
If a patient develops signs and symptoms indicative of NMS, Saphris must be discontinued.

Seizures.

In clinical trials, cases of seizure were occasionally reported during treatment with Saphris. Therefore, Saphris should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.

Suicide.

The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder; close supervision of high-risk patients should accompany treatment. Prescriptions for Saphris should be written for the smallest quantity of wafers, consistent with good patient management, in order to reduce the risk of overdose.

Weight increase.

In the combined short-term and long-term schizophrenia and bipolar mania trials, the mean weight change for patients treated with asenapine was 0.8 kg. The mean body weight change from baseline to endpoint in the placebo-controlled short-term schizophrenia trials was 1.1 kg for Saphris, 0.1 kg for placebo, and 2.4 kg for olanzapine. The proportion of subjects with clinically significant weight gain (> 7% weight gain from baseline to endpoint) in the short-term schizophrenia trials was 5.3% for asenapine-treated subjects compared to 2.3% for placebo. In the placebo-controlled short-term bipolar mania trials, mean weight changes were 1.3 kg for Saphris, 0.2 kg for placebo, and 2.3 kg for olanzapine. The proportion of subjects with clinically significant weight gain in the short-term bipolar mania trials was 6.5% for asenapine-treated patients compared with 0.6% for placebo.
In the open-label phase of Study A7501012 the mean change in body weight from baseline to open-label endpoint was 0.5 kg. Clinically relevant weight gain (> 7% from baseline) occurred in 7.0% of the subjects, while clinically relevant weight loss occurred in 4.3%. In the double-blind phase, mean change in body weight from double-blind baseline to double-blind endpoint was -1.2 kg in the placebo treatment group and 0.0 kg in the asenapine treatment group. Clinically relevant weight gain in the double-blind phase occurred in 3.7% of the asenapine-treated subjects and in 0.5% of the placebo-treated subjects, while clinically relevant weight loss occurred in 3.2% of the asenapine subjects and in 9.6% of placebo subjects. There were no subjects in either the asenapine or placebo group who discontinued from the study due to weight increased or weight decreased.
In the long-term trials, the mean body weight changes from baseline to endpoint for Saphris were 0.6 kg and 2.0 kg (schizophrenia and bipolar mania trials, respectively). The mean body weight changes in these trials for olanzapine were 3.7 kg and 4.5 kg (schizophrenia and bipolar mania trials, respectively).

Orthostatic hypotension.

Saphris may induce orthostatic hypotension and syncope, especially early in treatment, probably reflecting its α1-adrenergic antagonist properties. Elderly patients are particularly at risk for experiencing orthostatic hypotension. In clinical trials, cases of syncope were occasionally reported during treatment with Saphris. As with other atypical antipsychotics, Saphris should be used with caution in elderly patients and patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolaemia, and treatment with antihypertensive medications).

Tardive dyskinesia.

Medicines with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. In clinical trials, cases of tardive dyskinesia were occasionally reported during treatment with Saphris. The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on Saphris, discontinuation of treatment should be considered.
Saphris should be prescribed in a manner that is most likely to minimise the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer 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.

Hyperprolactinaemia.

Like other drugs that antagonise dopamine D2 receptors, Saphris can elevate prolactin levels, and the elevation can persist during chronic administration. Hyperprolactinaemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhoea, amenorrhoea and gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinaemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. In Saphris clinical trials, the incidence of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo.
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. Neither clinical studies nor epidemiological 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.

Leukopenia, neutropenia, and agranulocytosis.

In clinical trials and postmarketing experience, events of leukopenia/neutropenia have been reported temporarily related to antipsychotic agents, including Saphris. 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 (BC) monitored frequently during the first few months of therapy and Saphris should be discontinued at the first signs 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 Saphris and have their WBC followed until recovery.

QT interval.

Clinically relevant QT prolongation does not appear to be associated with asenapine. Caution should be exercised when Saphris is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicines thought to prolong the QT interval.
The effects of asenapine on the QT/QTc interval were evaluated in a dedicated QT study. This trial involved asenapine doses of 5 mg, 10 mg, 15 mg and 20 mg twice daily and placebo, and was conducted in 151 clinically stable patients with schizophrenia with electrocardiographic assessments throughout the dosing interval at baseline and steady state. At these doses, asenapine was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with Saphris experienced QTc increases ≥ 60 msec from baseline measurement, nor did any patient experience a QTc of ≥ 500 msec.
Electrocardiogram (ECG) measurements were taken at various time points during the Saphris clinical trial program (5 mg or 10 mg twice daily doses). Post-baseline QT prolongations exceeding 500 msec were reported at comparable rates for asenapine and placebo in these short-term trials.

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia has been reported in patients treated with atypical antipsychotics including Saphris. In clinical trials with Saphris, there were no significant differences in the incidence rates of hyperglycaemia-related adverse events compared to placebo. However, in short term clinical studies there was a mean increase in fasting insulin of 11.8 picomol/L for subjects given asenapine. The increase in fasting insulin was less than occurred in subjects given olanzapine (23.8 picomol/L). 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 hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia-related adverse events in patients treated with atypical antipsychotics. Precise risk estimates for hyperglycaemic-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with 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 hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Metabolic changes.

Saphris is associated with metabolic changes in adults and children. These metabolic changes are weight increased (including severe weight gain of > 7% of total body weight), hyperglycaemia and Diabetes Mellitus and dyslipidaemia. The frequency and severity of these risks appear higher in children compared to adults. Cases of Metabolic Syndrome, as defined by the International Diabetes Federation, have been observed in paediatric subjects exposed to Saphris in short-term clinical studies.
In adult trials, incidence of weight gain > 7% varied, with rates ranging from 6-7%. Hyperglycaemia and Diabetes Mellitus have been observed in patients treated with asenapine. According to the Australian Psychotropic Therapeutic Guidelines (2013), dyslipidaemia is listed as occurring moderately frequently in adults.

Paediatric subjects.

Saphris is not approved for use in subjects < 18 years of age.
In a 3-week paediatric trial of 403 subjects with bipolar 1 disorder (Study P06107), weight gain of > 7% was seen in 8.9%-14.1% of patients. There was evidence of abnormalities of blood insulin and blood sugar and clear evidence of dyslipidaemia. Eleven subjects (2.8%) developed new-onset Metabolic Syndrome, compared to no subjects in placebo. In the long-term, open-label extension trial (50 weeks), 34.8% of subjects experienced weight increase of ≥ 7% of total body weight.
In an 8-week study of 306 patients with schizophrenia (Study P05896), severe weight gain was significantly higher in 5 mg BID group compared to placebo, occurring at a frequency of 13%. A pattern for increase in both insulin and fasting insulin was observed in the asenapine treatment groups in a dose-dependent fashion. Lipids parameters were generally higher in the treatment groups compared to placebo. Three subjects (1%) developed new-onset Metabolic Syndrome in the Saphris treatment groups, compared to no subjects in placebo.

Dysphagia.

Oesophageal dysmotility and aspiration have been associated with antipsychotic treatment. Cases of dysphagia were occasionally reported in patients treated with Saphris.

Body temperature regulation.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicines. From the clinical trials, it is concluded that clinically relevant body temperature dysregulation does not appear to be associated with asenapine. Appropriate care is advised when prescribing Saphris 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 medicinal products with anticholinergic activity or being subject to dehydration.

Extrapyramidal symptoms (EPS).

From the short-term (6 week) schizophrenia trials there appears to be a dose-response relationship for akathisia in patients treated with asenapine, and for parkinsonism there was an increasing trend with higher doses.
The presentation of akathisia may be variable and comprise subjective complaints of restlessness and an overwhelming urge to move presenting as either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot or both. Particular attention should be paid to the monitoring for such symptoms and signs as left untreated akathisia is associated with poor compliance and increased risk of relapse.
In the long term trials the overall incidence of EPS for subjects treated with Saphris 5-10 mg twice daily was approximately 16% for both the schizophrenia population (olanzapine 7.7%); and the bipolar mania population (olanzapine 16.2%).

Parkinson's disease.

Physicians should weigh the risks versus the benefits when prescribing asenapine to patients with Parkinson's disease or dementia with Lewy bodies (DLB) since both groups may be at increased risk of neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics. Manifestations of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Falls.

Asenapine may cause adverse effects such as somnolence, orthostatic hypotension, dizziness and extrapyramidal symptoms, which may lead to falls and, consequently, fractures or other injuries. Patients at risk for fall should be evaluated prior to prescribing asenapine.

Use in hepatic impairment.

Asenapine exposure is increased 7-fold in patients with severe hepatic impairment (Child-Pugh C). Therefore, Saphris is not recommended in such patients.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Renal impairment.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Elderly.

Paediatric use.

Saphris is not recommended for use in children and adolescents below 18 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Given the primary CNS effects of asenapine (see Section 4.8 Adverse Effects (Undesirable Effects)), caution should be used when it is taken in combination with other centrally acting drugs. Patients should be advised to avoid alcohol while taking Saphris.

Potential for other medicines to affect Saphris.

Asenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). The potential effects of inhibitors and an inducer of several of these enzyme pathways on asenapine pharmacokinetics were studied (Table 1). With the exception of fluvoxamine (strong CYP1A2 inhibitor), none of the interacting drugs resulted in clinically relevant alterations in asenapine pharmacokinetics.

Potential for Saphris to affect other medicines.

Because of its α1-adrenergic antagonism with potential for inducing orthostatic hypotension (see Section 4.4 Special Warnings and Precautions for Use), Saphris may enhance the effects of certain antihypertensive agents.
In vitro studies indicate that asenapine weakly inhibits CYP2D6. Following coadministration of dextromethorphan and asenapine in healthy subjects, the ratio of dextrorphan/dextromethorphan (DX/DM) as a marker of CYP2D6 activity was measured. Indicative of CYP2D6 inhibition, treatment with asenapine 5 mg twice daily resulted in a fractional decrease in DX/DM ratio to 0.43. In the same study, treatment with paroxetine 20 mg daily decreased the DX/DM ratio to 0.032. In a separate study, coadministration of a single 75 mg dose of imipramine with a single 5 mg dose of asenapine did not affect the plasma concentrations of the metabolite desipramine (a CYP2D6 substrate). Coadministration of a single 20 mg dose of paroxetine (a CYP2D6 substrate and inhibitor) during treatment with 5 mg asenapine twice daily in 15 healthy male subjects resulted in an almost 2-fold increase in paroxetine exposure. In vivo asenapine appears to be at most a weak inhibitor of CYP2D6. However, asenapine may enhance the inhibitory effects of paroxetine on its own metabolism.
Therefore, Saphris should be coadministered cautiously with drugs that are both substrates and inhibitors for CYP2D6.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility in rats was unaffected by oral asenapine administration that resulted in an estimated drug exposure (based on plasma AUC) 11 fold that expected in humans with the maximum recommended dose.
(Category C)
There are no adequate data from the use of Saphris in pregnant women. Asenapine was not teratogenic in rats or rabbits at oral or intravenous doses that resulted in estimated drug exposures up to 11 (rat, based on plasma AUC) or 24 (rabbit, based on body surface area) times the expected human values with the maximum recommended dose. Reproductive toxicity studies were conducted using oral and intravenous routes, rather than the sublingual route used clinically. Increases in pre- and post-implantation losses were observed in some studies in rats, with pre-implantation loss increased after oral doses that resulted in estimated exposures (based on AUC) 3 times that expected in humans at the maximum recommended dose.
In rats treated intravenously from early gestation to weaning, increased early mortality and reduced weight gain were seen in pups at maternal doses resulting in exposures (based on AUC) approximately 3 fold that expected in humans at the maximum recommended dose. A cross-fostering study suggests that the increased pup mortality was mainly due to prenatal drug effects.

Non-teratogenic class effect.

Neonates exposed to antipsychotic drugs (including Saphris) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been post-marketing 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 additional medical treatment or monitoring. Saphris should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.
 Asenapine and/or its metabolites were excreted in the milk of rats during lactation. It is not known whether asenapine and/or its metabolites are excreted in human milk. It is recommended that women receiving Saphris should not breast feed.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Asenapine may cause somnolence and sedation. Therefore, patients should be cautioned about operating machinery, including motor vehicles, until they are reasonably certain that Saphris therapy does not affect them adversely.

4.8 Adverse Effects (Undesirable Effects)

Saphris has been administered in clinical trials to approximately 4500 subjects, including more than 3150 patients in phase 2/3 trials with schizophrenia or manic episodes associated with bipolar I disorder. In the table below, all treatment-related adverse events that have an incidence of ≥ 2% have been listed from the phase 2/3 schizophrenia and bipolar mania trials (Table 2).
Metabolic changes, including hyperglycaemia and diabetes mellitus, dyslipidaemia and weight gain of > 7% of total body weight, have been observed in adults exposed to Saphris. See Section 4.4 Special Warnings and Precautions for Use, Metabolic changes.
Asenapine has anaesthetic properties. Oral hypoaesthesia and oral paraesthesia may occur directly after administration and usually resolve within 1 hour.
The local anaesthetic properties of asenapine should be considered as a possible alternative etiology for the oropharyngeal symptoms.

Paediatric population.

Asenapine is not approved for use in this population as the efficacy and safety has not been established.
Saphris is not approved for use in subjects < 18 years of age. The incidence of dystonia in paediatric clinical trials using a gradual up-titration was similar to that seen in adult trials. Based on a small pharmacokinetic study, paediatric patients aged 10-17 years appeared to be more sensitive to dystonia when a gradual up-titration schedule was not followed. Metabolic changes, somnolence and sedation were more common in children compared to what has been observed in adults. For metabolic changes, see Section 4.4 Special Warnings and Precautions for Use, Metabolic changes.

Bipolar disorder.

The safety of Saphris was evaluated in 403 paediatric patients (ages 10-17 years) with manic or mixed episodes associated with bipolar I disorder who participated in a single, three-week, placebo-controlled, double-blind trial, of whom 302 patients received Saphris at fixed doses ranging from 2.5 mg to 10 mg twice daily.
Saphris is not approved for use in subjects < 18 years with bipolar 1 disorder.
The most common adverse reactions (≥ 5% and at least twice the rate of placebo) were somnolence (31.3%-34.3%), sedation (15.4%-19.2%), dizziness (5.1% to 10.1%), dysgeusia (3.8%-9.1%), hypoaesthesia oral (17.3%-20.2%), paraesthesia oral (8.7%-11%), nausea (4.8%-6.1%), increased appetite (6.1%-9.6%), fatigue (3.8%-13.1%), and weight increased (2.0%-5.8%).
Eleven subjects (2.8%) developed new-onset metabolic syndrome, as defined by the International Diabetes Federation, compared to no subjects in placebo, see Section 4.4 Special Warnings and Precautions for Use, Metabolic changes.

Schizophrenia.

The safety of Saphris was also evaluated in an eight-week, placebo-controlled, double-blind, randomised, fixed-dose trial in 306 adolescent patients aged 12-17 years with schizophrenia at doses of 2.5 mg and 5 mg twice daily.
Saphris is not approved for use for subjects < 18 years with schizophrenia.
The most common adverse reactions (proportion of patients ≥ 5% and at least twice placebo) were somnolence (17.0%-20.4%), sedation (4.1%-11.3%), akathisia (4.1%-6.6%), dizziness (1.9%-7.1%), dysguesia (3.8%-9.1%) and hypoaesthesia oral (4.7%-5.1%). The number of patients with ≥ 7% weight gain was significantly higher for asenapine 5 mg twice daily (13.1%) compared to placebo (3.1%). Three subjects (1%) developed new-onset metabolic syndrome compared to no cases in placebo, see Section 4.4 Special Warnings and Precautions for Use, Metabolic changes.

Post-market experience.

The following additional adverse reactions have been identified during post-marketing use of Saphris. Because these reactions are reported voluntarily from a population of an uncertain size, it is generally not possible to reliably estimate their frequency.

Immune system disorders.

Serious hypersensitivity reactions, including anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash. In several cases, these reactions occurred after the first dose.

Gastrointestinal disorders.

Oral mucosal lesions (ulcerations, blistering and inflammation); salivary hypersecretion.

Psychiatric disorders.

Anxiety.

Cardiac disorders.

QT interval prolongation.

Falls.

Falls may occur as a result of one or more adverse events such as the following: somnolence, orthostatic hypotension, dizziness, extrapyramidal symptoms.

Reporting suspected adverse 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.

4.9 Overdose

Few cases of overdose were reported in the asenapine program. Reported estimated doses were between 15 and 400 mg. In most cases it was not clear if asenapine had been taken sublingually. Treatment-related adverse events included agitation and confusion, akathisia, orofacial dystonia, sedation, and asymptomatic ECG findings (bradycardia, supraventricular complexes, intraventricular conduction delay).
No specific information is available on the treatment of overdose with Saphris. There is no specific antidote to Saphris. The possibility of multiple drug involvement should be considered. Cardiovascular monitoring is necessary to detect possible arrhythmias and management of overdose should concentrate on supportive therapy, maintaining an adequate airway oxygenation and ventilation, and management of symptoms. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (adrenaline (epinephrine) and dopamine should not be used, since beta stimulations may worsen hypotension in the setting of Saphris-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism of action of asenapine, as with other drugs having efficacy in schizophrenia and bipolar disorder, is not fully understood. However, based on its receptor pharmacology, it is proposed that the efficacy of asenapine is mediated through a combination of antagonist activity at D2 and 5-HT2A receptors. Actions at other receptors e.g. 5-HT1A, 5-HT1B, 5-HT2C, 5-HT6, 5-HT7, D3, and α2-adrenergic receptors, may also contribute to the clinical effects of asenapine.

Clinical trials.

Schizophrenia.

Acute schizophrenia.

The efficacy of Saphris in the treatment of schizophrenia was investigated in three fixed-dose, short-term (6 weeks), randomised, double-blind, placebo- and active-controlled trials of patients who met DSM IV criteria for schizophrenia and were having an acute exacerbation of their schizophrenic illness. The primary efficacy rating scale was the Positive and Negative Syndrome Scale (PANSS), which assesses the symptoms of schizophrenia. Secondary efficacy endpoints included each of the PANSS subscales (PANSS positive, negative and general psychopathology subscales), the PANSS subscales based on the Marder factor analysis and the Clinical Global Impression (CGI). Study 041004 was a trial (n=174) comparing Saphris (5 mg twice daily) to placebo with risperidone (3 mg twice daily) as the active control. Study 041023 was a trial (n=448) comparing two fixed doses of Saphris (5 and 10 mg twice daily), to placebo with haloperidol (4 mg twice daily) as the active control. Study 041021 was a trial (n=386) comparing two fixed doses of Saphris (5 and 10 mg twice daily) to placebo with olanzapine (15 mg once daily) as the active control. The results for the efficacy variables (change from baseline in PANSS total score and 30% responder rates) are presented in Tables 3, 4 and 5.

Maintenance in schizophrenia.

Study A7501012. This study was a randomized, placebo-controlled, double-blind, multicentre, multinational clinical trial evaluating the efficacy and safety of sublingually administered Saphris (5 or 10 mg twice daily) compared to placebo in the prevention of relapse in subjects with schizophrenia. A total of 700 patients entered the open-label treatment with Saphris for up to 26 weeks. Of these, a total of 386 patients met criteria for stabilization on Saphris and were randomised to treatment in the 26-week double-blind placebo-controlled phase of the trial.
Saphris was significantly more effective than placebo in preventing relapse, as measured by the endpoint of the trial estimated through Kaplan-Meier curves. At the 26 week endpoint, 47% of the placebo-treated patients relapsed, compared with only 12% of the asenapine-treated patients (p < 0.0001) (Figure 1).
Bipolar 1 disorder.

Acute treatment of manic or mixed episodes.

Two similarly designed 3-week, randomised, double-blind, placebo and active-controlled (olanzapine) monotherapy trials involving 488 (Study A751004) and 489 (Study A751005) patients, respectively, with acute manic or mixed episode of bipolar I disorder with or without psychotic features, investigated the efficacy of Saphris compared to placebo in the reduction of manic symptoms over 3 weeks. The primary efficacy end point was the reduction from baseline in YMRS mean change from BL score and for Saphris a statistically significant effect was noted as early as Day 2, and was maintained until the last trial visit (Day 21) when compared to placebo. The main efficacy results are presented in Tables 6 and 7.

Maintenance of effect.

A 9-week extension trial (Study A751006; n=181 for asenapine and n=229 for olanzapine) was conducted to demonstrate non-inferiority of the maintenance of effectiveness of Saphris compared with olanzapine for up to 12 weeks. The primary efficacy endpoint was the change from baseline YMRS score to week 12. Saphris was shown not to be statistically (PP: 1.1 with 95% CI -0.47 to 2.78; ITT: 1.2 with 95% CI -0.42 to 2.81) inferior to olanzapine in the treatment of subjects with a manic or mixed bipolar episode.

Combination therapy with lithium or sodium valproate.

A 12-week randomised, double-blind, placebo-controlled, flexible dose trial (Study A751008) examined the efficacy of Saphris (5 mg as the starting dose with the option to uptitrate to 10 mg) when administered concurrently with lithium or sodium valproate compared with lithium or sodium valproate monotherapy. The primary efficacy endpoint was the change from baseline to Day 21 (3 weeks) in the YMRS score (LOCF-ITT). Multiple secondary parameters were investigated including YMRS responder and remitter rates. The results are presented below up to 84 days (12 weeks) of treatment (Table 8).
The efficacy of combination therapy beyond 12 weeks has not been demonstrated.

5.2 Pharmacokinetic Properties

Absorption.

Following sublingual administration, asenapine is rapidly absorbed with peak plasma concentrations occurring within 0.5 to 1.5 hours. The average peak plasma concentrations at steady state of 5 and 10 mg twice daily were 3.6 nanogram/mL and 7.0 nanogram/mL respectively. The absolute bioavailability of sublingual asenapine at 5 mg is 35%. Increasing the dose from 5 to 10 mg twice daily (a two-fold increase) results in less than linear (1.7 times) increases in both the extent of exposure and maximum concentration. The absolute bioavailability of asenapine when swallowed is low (< 2% with an oral tablet formulation). The intake of water several (2 or 5) minutes after asenapine administration resulted in decreased (19% and 10%, respectively) asenapine exposure. Therefore, eating and drinking should be avoided for 10 minutes after administration (see Section 4.2 Dose and Method of Administration).

Distribution.

Asenapine is rapidly distributed and has a large volume of distribution (approximately 1700 L), indicating extensive extravascular distribution. Asenapine is highly bound (95-97% at 1-500 nanogram/mL) to plasma proteins in vitro, including albumin and α1-acid glycoprotein.

Metabolism.

Asenapine is extensively metabolised. Oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2) and direct glucuronidation by UGT1A4 are the primary metabolic pathways for asenapine. In an in vivo study in humans with radio-labelled asenapine, the predominant drug-related entity in plasma was asenapine N+-glucuronide; others included N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine in smaller amounts. Saphris activity is primarily due to the parent drug.
Asenapine is a weak inhibitor of microsomal CYP2D6 activity. Asenapine does not cause induction of CYP1A2 activity and slightly increased CYP3A4 activity at high concentrations in cultured human hepatocytes. Coadministration of asenapine with known inhibitors, inducers or substrates of these metabolic pathways has been studied in a number of drug-drug interaction studies (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

Asenapine is a high clearance drug, with a clearance after intravenous administration of 52 L/h. In a mass balance study, the majority of the radioactive dose was recovered in urine (about 50%) and faeces (about 40%), with only a small amount excreted in faeces (5-16%) as unchanged drug. Following an initial more rapid distribution phase, the terminal half-life of asenapine is approximately 24 hours. Steady-state concentrations of asenapine are reached within 3 days of twice daily dosing. Overall, steady-state asenapine pharmacokinetics are similar to single-dose pharmacokinetics.

Special populations.

Renal impairment.

The pharmacokinetics of asenapine following a single dose of 5 mg asenapine were similar among subjects with varying degrees of renal impairment and subjects with normal renal function.

Hepatic insufficiency.

The pharmacokinetics of asenapine were similar among subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment and subjects with normal hepatic function. In subjects with severe hepatic impairment (Child-Pugh C), a 7-fold increase in asenapine exposure was observed (see Section 4.2 Dose and Method of Administration, Hepatic impairment).

Elderly.

Interim results from 33 subjects aged 65-85 years indicate approximately 30% higher exposure to asenapine in elderly patients compared to adult patients.

Paediatric patients (10-17 years of age).

Asenapine is rapidly absorbed with Cmax occurring approximately at 1.5 hours (0.5-3 hours) and an initial rapid decline in plasma concentrations is followed by a slower elimination phase. Asenapine exposure increases in a dose-proportional manner over the range of 1 to 10 mg twice daily. Steady-state is achieved within 6-8 days of twice daily dosing and the mean terminal half-life is approximately 20 hours (range: 16-25 hours). Population pharmacokinetic analysis of asenapine in paediatric patients suggests that age, gender, BMI and race have no clinically meaningful effect on the pharmacokinetics of asenapine.

Smoking.

A population pharmacokinetic analysis indicated that smoking, which induces CYP1A2, has no effect on the clearance of asenapine. In a dedicated study, concomitant smoking during administration of a single 5 mg sublingual dose had no effect on the pharmacokinetics of asenapine.

Gender.

A population pharmacokinetic analysis indicated that there is no evidence of gender related differences in the pharmacokinetics of asenapine.

Race.

A single dose pharmacokinetic study did not demonstrate any significant differences in pharmacokinetic parameters between Japanese and Caucasian healthy subjects. Additionally, in a population pharmacokinetic analysis, no clinically relevant effects of race on the pharmacokinetics of asenapine were found.

5.3 Preclinical Safety Data

Genotoxicity.

Asenapine was not genotoxic in in vitro (bacterial reverse mutation, mammalian cell forward mutation, chromosomal aberration, sister chromatid exchange) and in vivo (rat micronucleus) tests.

Carcinogenicity.

Long term carcinogenicity studies with subcutaneous administration were conducted in mice and rats. Doses used resulted in estimated drug exposures (based on plasma AUC) that were up to 3-4 fold the expected human value with the maximum recommended dose. No oncogenic responses to asenapine treatment were observed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each wafer of Saphris contains gelatin and mannitol.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

The expiry date can be found on the packaging. In Australia, information on the shelf life can be found on the public summary of the ARTG.

6.4 Special Precautions for Storage

Store below 30°C.
Protect from light and moisture.
Store in original container.

6.5 Nature and Contents of Container

Saphris is available in Al/Al blister packs of 20, 60 and 100 wafers.
Not all pack sizes may be available.

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

Saphris is a novel antipsychotic, belonging to the dibenzo-oxepino pyrroles. It has antagonist activity on the dopamine 2 (D2) and serotonin (5-HT)-2A receptors.
Asenapine maleate is chemically identified as (3aR,12bR)-rel-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz(2,3:6,7)oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1).
Molecular formula: C17H16ClNO.C4H4O4 (and enantiomer).
Molecular weight: 401.84.
The solubility of asenapine (active entity) in water is 3.7 mg/mL, in 0.1 M HCl is 13 mg/mL and in aqueous buffers of pH 4.0 and 7.0 the solubility is 3.8 mg/mL and 3.0 mg/mL, respectively. The pKa of asenapine is 8.6 (determined in water/methanol). Asenapine has a log P (n-octanol/water) of 4.9 for the neutral species and 1.4 for the cationic species.

Chemical structure.

Asenapine maleate has the following structural formula:

CAS number.

85650-56-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes