Consumer medicine information

Palexia IR

Tapentadol

BRAND INFORMATION

Brand name

Palexia IR

Active ingredient

Tapentadol

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Palexia IR.

What is in this leaflet

This leaflet answers some common questions about PALEXIA® IR.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you having PALEXIA® IR against the benefits they expect it will have for you.

If you have any concerns about this medicine, ask your doctor, nurse or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What PALEXIA® IR is used for

PALEXIA® (tapentadol) IR is used to relieve severe pain. This strong pain reliever belongs to a group of medicines known as opioid analgesics.

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

Your doctor may have prescribed PALEXIA® IR for another reason.

Ask your doctor if you have any questions about why PALEXIA® IR has been prescribed for you.

Before you take PALEXIA® IR

When you must not take it

You must not take PALEXIA® IR if you:

  • are allergic to tapentadol or any of the ingredients listed at the end of this leaflet. Signs of allergic reaction may include a skin rash, itching, shortness of breath or swelling of the face, lips or tongue
  • have asthma or if your breathing is dangerously slow or shallow (respiratory depression, hypercapnia)
  • have paralysis of the gut
  • have acute poisoning with alcohol, sleeping pills, pain relievers or other psychotropic medicines (medicines that affect mood and emotions)
  • are taking medicine for depression containing a monoamine oxidase inhibitor (MAOI) medicine (such as Nardil, Parnate) or have taken a MAOI within the last 14 days. Ask your doctor or pharmacist if any of your medicines is an MAOI.

Do not take PALEXIA® IR if the packaging is torn or shows signs of tampering or the tablets do not look quite right.

Do not take PALEXIA® IR if the expiry date on the pack has passed.

You should only start taking PALEXIA® IR under direct supervision of your doctor due to the following risks:

Addiction
You can become addicted to PALEXIA® IR even if you take it exactly as prescribed. PALEXIA® IR may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence
As with all other opioid containing products, your body may become used to you taking PALEXIA® IR. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking PALEXIA® IR suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance
Tolerance to PALEXIA® IR may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

Withdrawal
Continue taking your medicine for as long as your doctor tells you. If you stop having this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • loss of appetite, nausea, vomiting or diarrhoea
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you:

  • have slow or shallow breathing
  • have sleep-related breathing disorders
  • suffer from increased pressure in the brain or disturbed consciousness up to coma
  • have had a head injury or a brain tumour
  • have had an epileptic fit or seizure or if you have an increased risk of having epileptic fits or seizures
  • suffer from a liver or kidney disease
  • suffer from a pancreatic or biliary tract disease including pancreatitis
  • are breastfeeding
  • are pregnant, or planning to become pregnant
  • have an addiction or history of abuse of alcohol, opioids or other drugs
  • have been told that you have an intolerance to some sugars. Lactose is an ingredient in these tablets.

Tell your doctor if you are pregnant or planning to become pregnant. You should not take PALEXIA® IR during pregnancy unless your doctor has told you to do so. Taking PALEXIA® IR during pregnancy may lead to withdrawal symptoms in the newborn baby. You should not take PALEXIA® IR during labour as it can cause breathing problems and signs of withdrawal in the newborn. Your doctor will discuss the risks and benefits of using PALEXIA® IR.

Tell your doctor if you are breastfeeding. You should not take PALEXIA® IR if you are breastfeeding as it may pass into your breast milk.

Taking other medicines

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

Some medicines and PALEXIA® IR may interfere with each other. These medicines include:

  • medicines for depression, sleeplessness or mental conditions such as selective serotonin reuptake inhibitors (SSRI’s), serotonin-norephinephrine reuptake inhibitors (SNRI’s), tricyclic anti-depressants (TCAs), monoamine oxidase inhibitor (MAOIs) and triptans
  • other pain relievers such as morphine or codeine
  • some cough medicines
  • general anaesthetics such as propofol or midazolam (examples are Propofol™ or Midazolam™)
  • medicines that slow the brain activity (central nervous system (CNS) depressants or phenothiazines). These medicines can be used to treat anxiety, muscle tension, pain, insomnia, acute stress reactions, panic attacks or seizure disorders such as sleeping pills, tranquilizers, hypnotics or sedatives (examples are Stelazine™, Largactil™, Valium™, Temaze™, or Xanax™).

Taking these medicines with PALEXIA® IR may increase the risk of possible side effects (see Side Effects). Your breathing may become seriously slow or shallow (respiratory depression) and your blood pressure may decrease. Your consciousness may be decreased, you may feel drowsier or feel that you might faint. If this happens tell your doctor.

Do not take PALEXIA® IR with alcohol. Some side effects such as drowsiness may be increased.

Other medications can also interfere with PALEXIA® IR and make you feel drowsy (see Warning information at the start of this document). Ask your doctor or pharmacist for more information.

How to take PALEXIA® IR

You should only start taking PALEXIA® IR under the direct supervision of your doctor.

Your doctor will tell you how much you should take, when and how often. It is important that you take this medicine as directed by your doctor.

If you are unsure ask your doctor or pharmacist.

How much to take

The usual dose is 1 tablet every 4 to 6 hours.

Your doctor may prescribe a different, more appropriate dose or interval of dosing, if this is necessary for you.

If you feel that the effect of these tablets is too strong or too weak, talk to your doctor or pharmacist.

PALEXIA® IR is not suitable for children and adolescents below the age of 18 years.

In elderly patients (above 65 years) usually no dose adjustment is necessary. However, the excretion of tapentadol may be delayed in some patients of this age group. If this applies to you, your doctor may recommend a different dosage regimen.

Patients with severe liver problems should not take these tablets. If you have moderate problems, your doctor will recommend a different dosage regimen.

Patients with severe kidney problems should not take these tablets.

Carefully follow all directions given to you by your doctor and pharmacist. These directions may differ from the information in this leaflet.

When and how should you take the tablets

PALEXIA® IR tablets should be swallowed whole with water. They may be taken, before, with, or after food.

Do not chew, divide or break the tablets. Chewing, dividing or breaking the tablets will release the medicine quickly and side effects may then occur.

How long to take it

This differs between individuals depending on how severe your pain is, how you respond to PALEXIA® IR and the cause of your pain. Ask your doctor for advice on how long you need to take PALEXIA® IR.

Carefully follow all directions given to you by your doctor and pharmacist. These directions may differ from the information contained in this leaflet.

If you forget to take it

If you forget to take a dose, you can take it as soon as you remember. The next dose should be taken after four or six hours, or as prescribed by your doctor.

Do not take a double dose to make up for the dose that you missed.

If you take too much (overdose)

If you or someone else receive too much (overdose), and experience one or more of the symptoms below, call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you have accidentally used PALEXIA® IR that was prescribed for you. If someone takes an overdose, they may experience one or more of the following symptoms:

  • Slow, unusual or difficult breathing
  • Drowsiness, dizziness or unconsciousness
  • Slow or weak heartbeat
  • Nausea or vomiting
  • Convulsions or fits

If you think you or someone else may have taken too much PALEXIA® IR, 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.

When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken.

While you are taking PALEXIA® IR

Things you must do

Be sure to keep all of your doctor’s appointments so that your progress can be checked.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking PALEXIA® IR.

Tell your doctor if you believe that PALEXIA® IR is not helping your condition.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise your doctor may think it is not working effectively and change your treatment unnecessarily.

If you become pregnant while you are taking PALEXIA® IR, tell your doctor immediately.

If you plan to have surgery, even at the dentist’s, tell your doctor, anaesthetist or dentist that you are taking this medicine. It may affect other medicines used during surgery.

Things you must not do

If you wish to stop treatment, please tell your doctor first before stopping treatment. Do not stop taking this medicine unless your doctor tells you to. If your doctor wants you to stop taking your tablets, he/she will tell you how to do this. This may include a gradual reduction in the dose.

Some people may feel unwell if they suddenly stop taking PALEXIA® IR. If you suddenly stop taking PALEXIA® IR you may experience withdrawal symptoms (see Withdrawal section above).

Do not give PALEXIA® IR to anyone else, even if they have the same condition as you.

Do not take PALEXIA® IR for any other complaints unless your doctor tells you to.

Things to be careful of

Do not drive or operate heavy machinery until you know how PALEXIA® IR affects you. PALEXIA® IR can make you sleepy, dizzy, or lightheaded.

Do not drink alcohol while you are taking PALEXIA® IR tablets. Drinking alcohol while taking PALEXIA® IR may make you feel more sleepy and increase the risk of serious side effects, such as shallow breathing, with the risk of stopping breathing and loss of consciousness.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PALEXIA® IR.

Like all medicines, PALEXIA® IR can cause some unwanted side effects in some people. Sometimes they are serious, most of the time they are not. Side effects not listed in this leaflet may occur in some patients. You may need to get medical attention if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Very common:

  • nausea
  • vomiting
  • dizziness
  • drowsiness
  • headache.

Common:

  • decreased appetite
  • anxiety
  • confusion
  • hallucination
  • difficulty sleeping
  • abnormal dreams
  • trembling
  • flushing or reddening of the face and neck
  • constipation
  • diarrhoea
  • indigestion
  • dry mouth
  • itching
  • increased sweating
  • rash
  • muscle cramps
  • feeling of weakness
  • fatigue
  • feeling of body temperature change.

Uncommon:

  • depressed mood
  • disorientation
  • excitability (agitation)
  • nervousness
  • restlessness
  • euphoric mood
  • disturbance in attention
  • memory impairment
  • near fainting
  • sedation
  • difficulty in controlling movements
  • difficulty in speaking
  • numbness
  • abnormal sensations of the skin (e.g. tingling, prickling)
  • muscle twitches
  • abnormal vision
  • faster or irregular heart beat
  • decreased blood pressure
  • dangerously slow or shallow breathing
  • shortness of breath
  • abdominal discomfort
  • hives
  • sensation of heaviness
  • delay in passing urine
  • frequent urination
  • drug withdrawal syndrome (see “Things you must not do”)
  • accumulation or retention of water in the tissues (oedema)
  • feeling abnormal
  • feeling drunk
  • irritability
  • feeling of relaxation.

Rare:

  • allergic reaction
  • thinking abnormal thoughts
  • epileptic fit
  • depressed level of consciousness
  • abnormal coordination
  • slower heart beat
  • impaired gastric emptying.

If any of the following happen, tell your doctor or go to accident and emergency at your nearest hospital immediately:

  • skin rash (red spots or patches), itching, hives
  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • chest tightness, wheezing or pain in the chest
  • heart palpitations
  • faintness or collapse
  • hallucinations
  • seizures, fits or convulsions.

These are very serious side effects. If you have them, you may have had a serious allergic reaction to PALEXIA® IR. You may need urgent medical attention or hospitalisation.

If you notice any unwanted effects not mentioned in this leaflet, please inform your doctor, or pharmacist.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using PALEXIA® IR

Storage

Keep PALEXIA® IR tablets in the blister pack until it is time to take them.

Keep your tablets in a cool, dry place where the temperature stays below 30°C.

Do not store PALEXIA® IR in the bathroom or near a sink.

Do not leave them in a car or on a window sill Heat and dampness can destroy some medicines.

Keep PALEXIA® IR tablets where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

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.

Product Description

There are 3 distinct strengths of PALEXIA® IR tablets:

PALEXIA® IR 50 mg tablets
White round shaped film-coated tablets of 7 mm diameter, marked with Grünenthal logo on one side and “H6” on the other side.

PALEXIA® IR 75 mg tablets
Pale yellow round shaped film-coated tablets of 8 mm diameter, marked with Grünenthal logo on one side and “H7” on the other side.

PALEXIA® IR 100 mg tablets
Pale pink round shaped film-coated tablets of 9 mm diameter, marked with Grünenthal logo on one side and “H8” on the other side.

The registered pack sizes for PALEXIA® IR tablets are:5, 10, 14, 20, 28, 30, 40, 50, 56, 60, 90 and 100 tablets.

All strengths and pack sizes may not be available.

PALEXIA® IR tablets are sealed in a blister foil pack.

Ingredients

Active ingredients

PALEXIA® IR 50 mg tablets - each tablet contains 50 mg tapentadol (as hydrochloride).

PALEXIA® IR 75 mg tablets - each tablet contains 75 mg tapentadol (as hydrochloride).

PALEXIA® IR 100 mg tablets - each tablet contains 100 mg tapentadol (as hydrochloride).

Inactive ingredients

PALEXIA® IR tablets also contain the following inactive ingredients:

  • microcrystalline cellulose
  • lactose monohydrate
  • croscarmellose sodium
  • povidone (K30)
  • magnesium stearate
  • polyvinyl alcohol
  • titanium dioxide (E171)
  • macrogol 3350
  • purified talc
  • iron oxide yellow (E172) (75 and 100 mg tablets only)
  • iron oxide red (E172) (75 and 100 mg tablets only)
  • iron oxide black (E172) (100 mg tablets only).

PALEXIA® IR contains lactose.

PALEXIA® IR does not contain:

  • gluten
  • preservative.

Further information

You can obtain more information from your doctor or pharmacist.

Australian sponsor:

Seqirus Pty Ltd
ABN 26 160 735 035
63 Poplar Road
Parkville, VIC 3052
Australia

PALEXIA® IR is distributed in Australia by:

Seqirus(Australia) Pty Ltd
ABN 66 120 398 067
63 Poplar Road
Parkville, VIC 3052
Australia

PALEXIA® IR is manufactured by:

Grünenthal GmBH, Germany

Australian Registration Numbers:

PALEXIA® IR 50 mg tablets
AUST R 165310

PALEXIA® IR 75 mg tablets
AUST R 165317

PALEXIA® IR 100 mg tablets
AUST R 165318

This leaflet was prepared in September 2020.

PALEXIA® is a registered trademark of Grünenthal GmBH, used under licence.

Published by MIMS December 2020

BRAND INFORMATION

Brand name

Palexia IR

Active ingredient

Tapentadol

Schedule

S8

 

1 Name of Medicine

Tapentadol (as hydrochloride).

2 Qualitative and Quantitative Composition

Palexia IR tablets contain 50, 75 or 100 mg tapentadol (as hydrochloride).
Palexia IR tablets contain lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Palexia IR 50 mg tapentadol (as hydrochloride) immediate release tablets.

White round shape biconvex film-coated tablets with Grünenthal logo embossed on one side and "H6" engraving on the other side.

Palexia IR 75 mg tapentadol (as hydrochloride) immediate release tablets.

Pale yellow round shape biconvex film-coated tablets with Grünenthal logo embossed on one side and "H7" engraving on the other side.

Palexia IR 100 mg tapentadol (as hydrochloride) immediate release tablets.

Pale pink round shape biconvex film-coated tablets with Grünenthal logo embossed on one side and "H8" engraving on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Palexia IR is indicated for the short-term management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.

4.2 Dose and Method of Administration

As with many centrally acting analgesic medications, the dosing regimen should be individualised according to the severity of pain being treated, the previous treatment experience and the ability to monitor the patient.
The recommended oral starting dose is 50, 75, or 100 mg Palexia IR every 4 to 6 hours depending upon the initial pain intensity. On the first day of dosing, a second dose may be taken as soon as one hour after the initial dose, if pain control is not achieved. Thereafter, the usual recommended dose is 50 to 100 mg Palexia IR every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability.
Palexia IR should be taken whole with sufficient liquid.
Palexia IR may be administered with or without food.
Total starting daily doses greater than 700 mg Palexia IR and maintenance daily doses greater than 600 mg Palexia IR have not been studied and are therefore, not recommended.

Discontinuation of treatment.

Withdrawal symptoms could occur after abrupt discontinuation of treatment with Palexia IR. When a patient no longer requires therapy with Palexia IR it may be advisable to taper the dose gradually to prevent symptoms of withdrawal (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

No dosage adjustment is recommended in patients with mild or moderate renal impairment (see Section 5.2 Pharmacokinetic Properties).
Palexia IR has not been studied in controlled efficacy studies in patients with severe renal impairment and its use is not recommended. A pharmacokinetic study showed an increased level of an inactive metabolite in subjects with renal impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No dosage adjustment is recommended in patients with mild hepatic impairment (see Section 5.2 Pharmacokinetic Properties).
Palexia IR should be used with caution in patients with moderate hepatic impairment. Treatment in these patients should be initiated at 50 mg Palexia IR and not be administered more frequently than once every 8 hours (maximum of three doses in 24 hours). Further treatment should reflect maintenance of analgesia with acceptable tolerability, to be achieved by either shortening or lengthening the dosing interval (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
Palexia IR has not been studied in patients with severe hepatic impairment and, therefore, use in this population is not recommended (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Elderly patients (persons aged 65 years and over).

In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, care should be taken in dose selection as recommended (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Paediatric patients.

Palexia IR is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy in this population (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Palexia IR is contraindicated:
in patients with a known hypersensitivity to the active substance, tapentadol, or any component of the product;
in patients with severe respiratory disease, acute respiratory disease and respiratory depression;
in any patient who has or is suspected of having paralytic ileus;
in patients with acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
in patients who are receiving MAO inhibitors or who have taken them within the last 14 days (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Palexia IR contains the opioid tapentadol (as hydrochloride) and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Palexia IR at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Palexia IR.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Palexia IR with anyone else.

Respiratory depression.

Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Palexia IR but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients and in patients with moderate hepatic impairment or existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma). Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, in opioid naïve patients and when used concomitantly with other CNS depressants. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
Palexia IR should be employed only under careful medical supervision at the lowest effective dose. If respiratory depression occurs, it should be treated as any mu-opioid receptor agonist-induced respiratory depression (see Section 4.9 Overdose).

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Palexia IR with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Palexia IR concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Palexia IR.

Use of opioids in chronic (long-term) non-cancer pain (CNCP).

Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised non-pharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naïve patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids).

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
In a study conducted over 3 months, 17.3% of patients given Palexia IR had objective signs of opioid withdrawal compared with 26.1% given oxycodone IR when assessed between 2-5 days after the last dose of study drug. Only 0.3% of patients given Palexia IR and 3% given oxycodone IR were considered by investigators to have moderate withdrawal. No subjects had moderately severe or severe withdrawal.
When discontinuing Palexia IR in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Palexia IR, especially by children, can result in a fatal overdose of tapentadol. Patients and their caregivers should be given information on safe storage and disposal of unused Palexia IR (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Sleep-related breathing disorders.

Drugs with mu-opioid receptor agonist activity, such as Palexia IR, can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Use of these drugs increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Head injury and increased intracranial pressure.

Like other drugs with mu-opioid receptor agonist activity, Palexia IR should not be used in patients who may be particularly susceptible to the intracranial effects of carbon dioxide retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Analgesics with mu-opioid receptor agonist activity may obscure the clinical course of patients with head injury. Palexia IR should be used with caution in patients with head injury and brain tumours.

Seizures.

Palexia IR has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. However, like other analgesics with mu-opioid receptor agonist activity Palexia IR should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures. In addition, tapentadol may increase the seizure risk in patients taking other medicinal products that lower the seizure threshold (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in renal impairment.

For patients with mild or moderate renal impairment, no dosage adjustment is recommended (see Section 4.2 Dose and Method of Administration).
Palexia IR has not been studied in controlled efficacy studies in patients with severe renal impairment, therefore use in this population is not recommended (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in hepatic impairment.

For patients with mild hepatic impairment, no dosage adjustment is recommended (see Section 4.2 Dose and Method of Administration).
A study of Palexia IR in subjects with hepatic impairment showed higher serum concentrations than in those with normal hepatic function. Palexia IR should be used with caution in patients with moderate hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Palexia IR has not been studied in patients with severe hepatic impairment and, therefore, use in this population is not recommended (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in pancreatic/biliary tract disease.

Drugs with mu-opioid receptor agonist activity may cause spasm of the sphincter of Oddi. Palexia IR should be used with caution in patients with biliary tract disease, including acute pancreatitis.

Use in the elderly (persons aged 65 years and over).

In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, care should be taken in dose selection as recommended (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Palexia IR is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy in this population.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Tapentadol is mainly metabolised by glucuronidation, a system with a very high capacity which is not easily saturated even in disease. As therapeutic concentrations of drugs that are subject to glucuronidation are generally well below the concentrations needed for potential inhibition of glucuronidation, the risk of clinically relevant interaction between these drugs is generally low. The following substances have been included in a set of interaction studies without any clinically significant finding: paracetamol, acetylsalicylic acid, naproxen, probenecid, omeprazole and metoclopramide (see Section 5.2 Pharmacokinetic Properties).
Only a small amount of tapentadol is metabolised by oxidative pathways (see Section 5.2 Pharmacokinetic Properties). Tapentadol was shown to be a weak inhibitor of human CYP2D6 activity in vitro but at concentrations 180 to 1400-fold higher than maximum concentrations in humans. In vitro induction experiments in human hepatocytes showed that CYP1A2, CYP2C9, and CYP3A4 activities were not markedly induced. Thus in vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Tapentadol is an inducer of CYP1A, CYP2B and CYP2E in rats in vivo. The potential clinical relevance of this finding is unknown.

Mixed-opioid agonists/antagonists.

Care should be taken when combining Palexia IR with mixed mu-opioid agonist/antagonists (e.g. pentazocine, nalbuphine) or partial mu-opioid agonists (e.g. buprenorphine).
Palexia IR can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other medicinal products that lower the seizure threshold to cause convulsions.

CNS depressants.

Patients receiving other mu-opioid receptor agonist analgesics, general anaesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, benzodiazepines, gabapentinoids, cannabis, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics or other CNS depressants (including alcohol and illicit drugs) concomitantly with Palexia IR may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with Palexia IR. When such combined therapy is contemplated, the reduction of dose of one or both agents should be considered (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Monoamine oxidase (MAO) inhibitors.

Palexia IR is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on noradrenaline levels which may result in adverse cardiovascular events (see Section 4.3 Contraindications).

Serotonin syndrome.

Palexia IR is a centrally acting synthetic analgesic combining mu-agonist and noradrenaline reuptake inhibition activity.
A causal relationship between tapentadol and serotonin syndrome has not been established. However, in isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), MAOIs and triptans. Signs of serotonin syndrome may include confusion, agitation, fever, sweating, ataxia, hyper-reflexia, myoclonus and diarrhoea. Serotonin syndrome is likely when one of the following is observed: spontaneous clonus; inducible or ocular clonus with agitation or diaphoresis; tremor and hyperreflexia; hypertonia and body temperature > 38°C and inducible clonus or ocular clonus.
Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no apparent effects on the fertility of male rats at intravenous doses up to 12 mg/kg/day, although histopathology analyses were not conducted. In female rats, the numbers of corpora lutea and implantations were reduced, and pre- and post-implantation losses were increased, at intravenous tapentadol doses associated with maternal toxicity. The clinical relevance of these findings is unknown.
(Category C)
There are no adequate and well controlled studies of tapentadol in pregnant women. Palexia IR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Long-term maternal use of opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NOWS).
The effect of tapentadol on labour and delivery in humans is unknown. Palexia IR is not recommended for use in women during and immediately prior to labour and delivery. Due to the mu-opioid receptor agonist activity of tapentadol, neonates whose mothers have been taking tapentadol should be monitored for respiratory depression.
Tapentadol crosses the placenta in pregnant rats. Tapentadol was evaluated for teratogenic effects in rats and rabbits following intravenous and subcutaneous administration during organogenesis. Embryofetal toxicity such as delays in skeletal maturation and cerebral ventricular dilation was observed in rats concomitant with maternal toxicity at subcutaneous doses of 10 mg/kg/day or greater (plasma AUC exposure less than maximum anticipated clinical exposure). Subcutaneous administration of tapentadol to rabbits revealed embryofetal toxicity at doses of 10-24 mg/kg/day (AUC exposure 1 to 2-fold the maximum anticipated human exposure), along with reduced fetal viability, skeletal delays and other variations, and multiple malformations including gastroschisis/ thoracogastroschisis, amelia/ phocomelia and cleft palate at 10-24 mg/kg/day, and ablepharia, encephalopathy and spina bifida at 24 mg/kg/day. There were no teratogenic effects observed in similar studies conducted in rats and rabbits via the intravenous route (up to 15 mg/kg/day). Embryofetal toxicity, including malformations, may be secondary to maternal toxicity in these species.
 There is limited information on the excretion of tapentadol in breast milk. Tapentadol is excreted into milk in lactating rats following oral dosing. Oral tapentadol administration to rats during lactation resulted in increased postnatal pup mortality, at doses lower than those associated with maternal toxicity (exposure (AUC) less than maximum anticipated clinical exposure). The potential relevance to humans is unknown. Physicochemical and available pharmacodynamic/ toxicological data on tapentadol point to excretion in breast milk and risk to the suckling child cannot be excluded. Palexia IR should not be used during breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

Like drugs with mu-opioid receptor agonist activity, Palexia IR may have a major influence on the ability to drive and use machines, due to the fact that it may cause sedation and adversely affect central nervous system functions (see Section 4.8 Adverse Effects (Undesirable Effects)). This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilizers (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients should be cautioned as to whether driving or use of machines is permitted.

4.8 Adverse Effects (Undesirable Effects)

Treatment emergent adverse events in the double-blind phase 2/3 studies.

In the phase 2/3 multiple-dose double-blind studies, the percentage of subjects administered Palexia IR with at least 1 TEAE was 71.9%. This was higher when compared with the placebo group (47.8%), lower than in the oxycodone HCl IR group (84.0%) (Table 1).
Compared with oxycodone HCl IR there was better gastrointestinal tolerability with Palexia IR. In the phase 2/3 multiple-dose double-blind studies, the incidence of nausea (27.8%), vomiting (16.4%), and constipation (7.8%) was lower with Palexia IR than with oxycodone HCl IR (44.1%, 30.8%, and 19.7%, respectively) (Table 1).
Fewer Palexia IR subjects discontinued treatment due to gastrointestinal events compared to oxycodone HCl IR (3.8% vs 12.1%, respectively).
The following adverse drug reactions (ADRs) were reported from clinical trials performed with Palexia IR:
Very common (≥ 1/10).

Nervous system disorders.

Dizziness, somnolence, headache.

Gastrointestinal disorders.

Nausea, vomiting.
Common (≥ 1/100 to < 1/10).

Metabolism and nutrition disorders.

Decreased appetite.

Psychiatric disorders.

Anxiety, confusional state, hallucination, sleep disorder, abnormal dreams.

Nervous system disorders.

Tremor.

Vascular disorders.

Flushing.

Gastrointestinal disorders.

Constipation, diarrhoea, dyspepsia, dry mouth.

Skin and subcutaneous tissue disorders.

Pruritus, hyperhidrosis, rash.

Musculoskeletal and connective tissue disorder.

Muscle spasms.

General disorders and administration site conditions.

Asthenia, fatigue, feeling of body temperature change.
Uncommon (≥ 1/1,000 to < 1/100).

Psychiatric disorders.

Depressed mood, disorientation, agitation, nervousness, restlessness, euphoric mood.

Nervous system disorders.

Disturbance in attention, memory impairment, presyncope, sedation, ataxia, dysarthria, hypoaesthesia, paraesthesia, muscle contractions involuntary.

Eye disorders.

Visual disturbance.

Cardiac disorders.

Heart rate increased, palpitations.

Vascular disorders.

Blood pressure decreased.

Respiratory, thoracic and mediastinal disorders.

Respiratory depression, oxygen saturation decreased, dyspnoea.

Gastrointestinal disorders.

Abdominal discomfort.

Skin and subcutaneous tissue disorders.

Urticaria.

Musculoskeletal and connective tissue disorder.

Sensation of heaviness.

Renal and urinary disorders.

Urinary hesitation, pollakiuria.

General disorders and administration site conditions.

Drug withdrawal syndrome, oedema, feeling abnormal, feeling drunk, irritability, feeling of relaxation.
Rare (≥ 1/10,000 to < 1/1,000).

Immune system disorders.

Drug hypersensitivity.

Psychiatric disorders.

Thinking abnormal.

Nervous system disorders.

Convulsion, depressed level of consciousness, coordination abnormal.

Cardiac disorders.

Heart rate decreased.

Gastrointestinal disorders.

Impaired gastric emptying.

Treatment emergent adverse events with prolonged treatment.

A total of 679 subjects with moderate to severe pain from low back pain or osteoarthritis of the knee or hip were treated with a flexible dosing regimen of Palexia IR (50 mg or 100 mg every 4 hours to 6 hours, as needed) in a 90 day safety study (KF5503/34). The dosing regimen is considered to mimic the clinical use of mu-opioid receptor agonists in an outpatient setting. There were 318 subjects who received treatment for at least 90 days, and the maximum duration of treatment with Palexia IR was 105 days.
The overall TEAE profile for prolonged treatment did not differ from the profile observed in short-term treatment. The percentage of subjects with at least 1 TEAE was 76.3% in the Palexia IR (50 mg or 100 mg) and 82.9% in the oxycodone HCl IR (10 mg or 15 mg) groups (Table 2). Subjects administered Palexia IR had a lower incidence of gastrointestinal events compared to oxycodone HCl IR (44.2% vs 63.5% respectively) (Table 2).
Discontinuations due to TEAEs occurred less frequently in the Palexia IR treated group compared with oxycodone IR (20.8% and 30.6%).
Discontinuations due to gastrointestinal TEAEs also occurred less frequently in the Palexia IR treated group compared with oxycodone IR (8.8% and 21.2%).

Post marketing experience.

In addition to adverse events reported in clinical trials, the following adverse events have been observed during post approval use of Palexia. As these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Suicidal ideation has been reported during post approval use of Palexia. Post-marketing rare events of angioedema, anaphylaxis and anaphylactic shock have been reported. Post marketing cases of delirium have also been observed in patients with additional risk factors such as cancer and advanced age.

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

Experience with Palexia IR overdose is very limited. Preclinical data suggest that symptoms similar to those of other centrally acting analgesics with mu-opioid receptor agonist activity are to be expected upon intoxication with tapentadol. In the clinical setting, these symptoms may include miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.
Management of overdose should be focused on treating symptoms of mu-opioid receptor agonism. Primary attention should be given to re-establishment of a patent airway and institution of assisted or controlled ventilation when overdose of Palexia IR is suspected. Pure opioid antagonists such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. Administration of an opioid antagonist is not a substitute for continuous monitoring of airway, breathing, and circulation following an opioid overdose. If the response to opioid antagonists is suboptimal or only brief in nature, an additional antagonist should be administered as directed by the manufacturer of the product.
Gastrointestinal decontamination may be considered in order to eliminate unabsorbed drug. Gastrointestinal decontamination with activated charcoal may be considered within 2 hours after intake. Before attempting gastrointestinal decontamination, care should be taken to secure the airway.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tapentadol is a centrally acting synthetic analgesic combining opioid and non-opioid activity in a single molecule. It has 18 times less binding affinity than morphine to the human mu-opioid receptor but was only 2-3 times less potent in producing analgesia in animal models (on a dose per bodyweight basis). This low in vivo potency difference is consistent with its two mechanisms of action. Tapentadol has been shown to inhibit noradrenaline reuptake in the brains of rats resulting in increased noradrenaline concentrations. In preclinical models, the analgesic activity due to the mu-opioid receptor agonist activity of tapentadol can be antagonised by selective mu-opioid receptor antagonists (e.g. naloxone), whereas the noradrenaline reuptake inhibition is sensitive to noradrenaline modulators. Tapentadol exerts its analgesic effects directly without a pharmacologically active metabolite.

Effects on the cardiovascular system.

In repeat dose toxicity studies in conscious dogs, nonpersistent QT/QTc interval prolongation was observed at exposures similar to or lower than the clinical plasma Cmax. These effects were not observed in safety pharmacology studies with repeated ECG measurements. Heart rate was increased in conscious rats and dogs at peak plasma concentrations at least twice the clinical plasma Cmax, but there was no clear effect on other ECG parameters (PR interval, QRS duration, T wave or U wave morphology). In a thorough QT trial in healthy subjects, no effect of multiple therapeutic and supratherapeutic doses of tapentadol on the QT interval was shown. Similarly, tapentadol had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).

Clinical trials.

The efficacy and safety of Palexia IR tablets in the treatment of moderate to severe pain has been investigated in four pivotal phase III randomised, double-blind, active- and placebo-controlled, parallel group, multicentre studies; two in in-patients following bunionectomy (clinical trials KF5503/32 and KF5503/37), one in in-patients following abdominal hysterectomy (clinical trial KF5503/35), and one in out-patients with end stage degenerative joint disease of the hip or knee (clinical trial KF5503/33).

Orthopaedic surgery - bunionectomy.

The first bunionectomy clinical trial (KF5503/32) (n = 603) investigated the efficacy of Palexia IR tablets (50, 75 and 100 mg) against placebo and active comparator (oxycodone HCl IR 15 mg). The primary objective was to determine the efficacy of Palexia IR tablets using the sum of pain intensity difference (SPID) over 48 hours compared to placebo, and to assess the safety and tolerability of repeat doses of Palexia IR tablets over the double-blind treatment period.
Palexia IR (50, 75 or 100 mg), (n = 119, 120 and 118 respectively), placebo (n = 121) or oxycodone HCl IR (15 mg) (n = 125) were administered as a single dose, once every 4 to 6 hours over the 72 hours following randomisation.
The results for SPID48 for the ITT population are provided in Table 3. All Palexia IR treatment groups showed a statistically significant (p < 0.001) improvement in pain compared to placebo (mean SPID48: 119.1, 139.1, 167.2 in the 50, 75 and 100 mg groups respectively). There was a numerical trend of increasing efficacy with increasing dose of Palexia IR. Oxycodone HCl (mean SPID48: 172.3) also showed a statistically significant (p < 0.001) difference to placebo (mean SPID48: 24.5).
The second bunionectomy clinical trial (KF5503/37) (n = 291) investigated the efficacy of Palexia IR 75 mg against placebo and active comparator (morphine IR 30 mg). The primary objective was to determine the efficacy of Palexia IR 75 mg using the sum of pain intensity difference (SPID) over 48 hours compared to placebo, and to assess the efficacy and safety of Palexia IR 75 mg compared to morphine IR 30 mg.
Palexia IR 75 mg (n = 96), placebo (n = 99) or morphine IR 30 mg (n = 96) were administered as a single dose, once every 4 to 6 hours over the 72 hours following randomisation.
In the ITT population, for SPID48, Palexia IR 75 mg showed a statistically significant improvement in pain relief compared to placebo (LS mean difference to placebo of 70.8, p < 0.0001). Morphine IR 30 mg also demonstrated a statistically significant improvement in pain relief compared to placebo (LS mean difference to placebo of 109.4; p-value < 0.0001) (Table 4).

Abdominal surgery - hysterectomy.

The abdominal hysterectomy clinical trial (KF5503/35) (n = 854) investigated the efficacy and tolerability of Palexia IR (50, 75 and 100 mg) against placebo and active comparator (morphine IR 20 mg). The primary objective was to determine the efficacy of Palexia IR using the sum of pain intensity difference (SPID) over 24 hours compared to placebo, and to assess the safety and tolerability of repeat doses of Palexia IR over the double-blind treatment period.
Palexia IR (50, 75 or 100 mg) (n = 168, 171 and 176 respectively), placebo (n = 169) or morphine IR (20 mg) (n = 170) were administered as a single dose, once every 4 to 6 hours over the 72 hours following randomisation.
In the ITT population, all Palexia IR treatment groups showed statistically significant improvement in pain relief compared to the placebo group for the primary variable, SPID24 (p < 0.0001) (Table 5). There was a numerical trend of increasing efficacy with increasing dose of Palexia IR (LS means difference to placebo for SPID24: 18.1, 20.8 and 23.3 in the 50, 75 and 100 mg groups respectively). Morphine IR 20 mg (LS means difference to placebo for SPID24: 20.6) also showed a statistically significant (p < 0.0001) difference to placebo.

End-stage degenerative joint disease.

The clinical trial in subjects with end-stage degenerative joint disease of the hip or knee (clinical trial KF5503/33) (n = 674) investigated the efficacy and tolerability of Palexia IR (50 and 75 mg) against placebo and active comparator (oxycodone HCl IR 10 mg). The primary objective was to determine the efficacy of Palexia IR using the sum of pain intensity difference (SPID) over 5 days compared to placebo, and to assess the safety and tolerability of repeat doses of Palexia IR over the double-blind treatment period.
Palexia IR (50 or 75 mg) (n = 161 and 169 respectively), placebo (n = 172) or oxycodone HCl IR (10 mg) (n = 172) were administered as a single dose, once every 4 to 6 hours over 10 days following randomisation.
In the ITT population, both Palexia IR 50 mg and 75 mg treatment groups showed a significant improvement in pain compared to placebo for the primary efficacy variable of SPID at 5 days (all p-values < 0.001) (Table 6). There was no numerical trend of increasing efficacy with increasing dose of Palexia IR (LS means difference to placebo for SPID5 days: 101.2 and 97.5 respectively). Oxycodone HCl IR (10 mg) also showed a statistically significant (p < 0.001) difference to placebo (Table 6).
This study also included the pre-specified assessment of the non-inferiority of Palexia IR (50 and 75 mg) compared to oxycodone HCl IR (10 mg) with respect to efficacy (based on 5-day SPID) and tolerability (based on incidence of the reported evaluation of nausea and vomiting as adverse events of nausea and/or vomiting and constipation). For 5-day SPID, both Palexia IR 50 mg and Palexia IR 75 mg were noninferior to oxycodone HCl IR 10 mg.

5.2 Pharmacokinetic Properties

Absorption.

Tapentadol is rapidly and completely absorbed after oral administration of Palexia IR. Mean absolute bioavailability after single dose administration (fasting) is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after administration of Palexia IR tablets. Dose proportional increases in the Cmax and AUC values of tapentadol have been observed after administration of Palexia IR tablets over the oral therapeutic dose range. Steady-state serum concentrations of tapentadol are reached on the second day of the treatment regimen. A multiple (every 6 hour) dose study with doses ranging from 75 to 175 mg tapentadol administered as immediate release tablets showed an accumulation ratio between 1.4 and 1.7 for the parent drug and between 1.7 and 2.0 for the major metabolite tapentadol-O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite.

Food effect.

The AUC and Cmax increased by 25% and 16%, respectively, when Palexia IR tablets were administered after a high-fat, high-calorie breakfast. Palexia IR tablets may be given with or without food.

Distribution.

Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 ± 98 L. The serum protein binding is low and amounts to approximately 20%.

Metabolism.

In humans, the metabolism of tapentadol is extensive. About 97% of the parent compound is metabolised. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. Uridine diphosphate glucuronyl transferase (UGT) is the primary enzyme involved in the glucuronidation (mainly UGT1A6, UGT1A9 and UGT2B7 isoforms). A total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolised to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolised by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation. None of the metabolites contribute to the analgesic activity.

Excretion.

Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average 4 hours after oral administration. The total clearance is 1530 ± 177 mL/min.

Elderly patients.

The mean exposure (AUC) to tapentadol was similar in elderly subjects compared to young adults, with a 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects.

Renal impairment.

AUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild, moderate, and severe renal impairment, the AUC of tapentadol-O-glucuronide was 1.5, 2.5, and 5.5-fold higher compared with normal renal function, respectively.

Hepatic impairment.

Administration of tapentadol resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratios of tapentadol pharmacokinetic parameters for the mild and moderate hepatic impairment groups in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.

Pharmacokinetic interactions.

Tapentadol is mainly metabolised by phase 2 glucuronidation, and only a small amount is metabolised by phase 1 oxidative pathways.
As glucuronidation is a high capacity/low affinity system, any clinically relevant interactions caused by phase 2 metabolism are unlikely to occur. This has been evidenced by clinical pharmacokinetic drug-drug interaction studies with probe drugs naproxen and probenecid with increases in AUC of tapentadol by 17% and 57%, respectively. No changes in the pharmacokinetic parameters of tapentadol were observed when paracetamol and acetylsalicylic acid were given concomitantly. Tapentadol was shown to be a weak inhibitor of human CYP2D6 activity in vitro but at concentrations 180 to 1400-fold higher than maximum concentrations in humans. In vitro induction experiments in human hepatocytes showed that CYP1A2, CYP2C9, and CYP3A4 activities were not markedly induced. Thus in vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Tapentadol is an inducer of CYP1A, CYP2B and CYP2E in rats in vivo. The potential clinical relevance of this finding is unknown.
The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively.
Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low.

5.3 Preclinical Safety Data

Genotoxicity.

Tapentadol did not induce gene mutations in bacteria, but was clastogenic at cytotoxic concentrations in an in vitro chromosomal aberration test with metabolic activation in Chinese hamster V79 cells in 1 of 2 assays. The one positive result for tapentadol was not confirmed in vivo in rats, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, at extrapolated exposures (AUC) similar to the maximum anticipated human exposure. The weight of evidence indicates that tapentadol presents no significant genotoxic potential at clinical doses.

Carcinogenicity.

Tapentadol was administered to rats (diet) and mice (oral gavage) for two years. A significant trend towards increased hepatocellular tumours (adenoma and carcinoma) was observed in mice at oral doses of 100 mg/kg/day or greater. A dose related increased incidence of hepatocellular hypertrophy (but not tumours) was observed in rats at dietary doses of 125 mg/kg/day or greater. Exposures (plasma AUC) in both species were less than that at the maximum recommended clinical dose. These findings may derive from adaptive changes following hepatic enzyme induction. The potential clinical relevance is unknown.

6 Pharmaceutical Particulars

6.1 List of Excipients

Excipients in the tablet core are: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, povidone (K30) and magnesium stearate.
Excipients in the film coating are: polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, purified talc, iron oxide yellow (E172) (75 and 100 mg tablets only), iron oxide red (E172) (75 and 100 mg tablets only), and iron oxide black (E172) (100 mg tablets only).

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Blister packs of 5, 10, 14, 20, 28, 30, 40, 50, 56, 60, 90, 100 tablets.
Not all tablet strengths or 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

Palexia IR immediate release tablets contain tapentadol hydrochloride (HCl) which is a centrally acting synthetic analgesic combining mu-agonist and noradrenaline re-uptake inhibition activity in a single molecule. Tapentadol is a white to off-white powder; freely soluble in water and methanol, and soluble in ethanol. The pKa1 is 9.36 and pKa2 is 10.37 determined in 0.15 M KCl solution. The partition coefficient is defined as the ratio of the equilibrium concentrations of a single neutral molecular species in a 1-octanol/aqueous buffered solution 2-phase system. The value of log P for tapentadol hydrochloride in 1-octanol/water is 2.89 ± 0.01. The chemical name for tapentadol HCl is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol monohydrochloride. The molecular weight of tapentadol HCl is 257.80, and the empirical formula is C14H23NO.HCl.

Chemical structure.

The structural formula of tapentadol HCl (CAS number: 175591-09-0) is:

CAS number.

(CAS number: 175591-09-0).

7 Medicine Schedule (Poisons Standard)

Controlled Drug, S8.

Summary Table of Changes