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 moderate to 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.

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 childbirth because it could lead to dangerously slow or shallow breathing (respiratory depression) in the newborn. Your doctor will discuss the risks and benefits of using PALEXIA® IR.

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

There is a risk of abuse or addiction with pain medicines such as PALEXIA® IR. If you have abused drugs in the past, you may have a higher chance of developing abuse or addiction again while using PALEXIA® IR.

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. 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

Depending on the medical condition for which you require PALEXIA® IR, your doctor may tell you to take it for only a day or two or longer, up to a few months or more.

Take the tablets every day for as long as your doctor tells you to. If you stop taking PALEXIA® IR too soon, your pain is likely to return.

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)

Immediately telephone your doctor or the Poisons Information Centre (131 126) or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much PALEXIA® IR. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too many PALEXIA® IR tablets, this may result in vomiting, pin-point pupils, fast heartbeat, difficulty breathing or stopping breathing, drop in blood pressure, epileptic fits, convulsion, disturbed consciousness, collapse or loss of consciousness (coma). If you experience any of these, seek urgent medical attention.

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. Your doctor may need to change the dose.

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 such as:

  • restlessness
  • watery eyes or runny nose
  • yawning
  • sweating or chills
  • muscle pain
  • dilated pupils
  • irritability or anxiety
  • backache or joint pain
  • weakness
  • abdominal cramps
  • difficulty in sleeping
  • nausea, loss of appetite
  • vomiting or diarrhea
  • increases in blood pressure, breathing or heart rate.

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.

Note the expiry date on the pack. Do not use after this expiry date.

Disposal

If your doctor tells you to stop taking PALEXIA® IR or the expiry date has passed, ask your pharmacist what to do with any tablets that are left over.

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.

PALEXIA® IR tablets are supplied in boxes of 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
  • croscarmellose sodium
  • povidone (K30)
  • magnesium stearate
  • polyvinyl alcohol
  • titanium dioxide (E171)
  • macrogol 3350
  • 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 May 2020.

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

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Palexia IR

Active ingredient

Tapentadol

Schedule

S8

 

1 Name of Medicine

Tapentadol (as hydrochloride).

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).

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 Grunenthal 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 Grunenthal 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 Grunenthal logo embossed on one side and "H8" engraving on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tapentadol is a centrally acting synthetic analgesic combining opioid and nonopioid 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 inpatients following bunionectomy (clinical trials KF5503/32 and KF5503/37), one in inpatients following abdominal hysterectomy (clinical trial KF5503/35), and one in outpatients 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) (see 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.

Endstage degenerative joint disease.

The clinical trial in subjects with endstage 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) (see 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 (see Table 6).
This study also included the prespecified assessment of the noninferiority 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Palexia IR is indicated for the relief of moderate to severe pain.

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 situations where drugs with mu-opioid receptor agonist activity are contraindicated, i.e. patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment), and patients with acute or severe bronchial asthma or hypercapnia;
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

Potential for abuse.

As with other drugs that have mu-opioid receptor agonist activity, Palexia IR has a potential for abuse. This should be considered when prescribing or dispensing Palexia IR in situations where there is concern about an increased risk of misuse, abuse, or diversion.
Drugs that have mu-opioid receptor agonist activity may be abused by crushing, chewing, snorting or injecting the product. Such practices pose a significant risk to the abuser and may result in overdose or death.
All patients treated with drugs that have mu-opioid receptor agonist activity should be carefully monitored for signs of abuse and addiction.

Drug dependence.

Tolerance.

Repeated administration of opioids may lead to tolerance. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia, in the absence of disease progression or other external factors.

Withdrawal symptoms.

Withdrawal symptoms could occur after abrupt discontinuation of treatment with tapentadol (see Section 4.2 Dose and Method of Administration). 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.

Respiratory depression.

At high doses or in mu-opioid receptor agonist sensitive patients, Palexia IR may produce dose related respiratory depression. Therefore, Palexia IR should be administered with caution to patients with impaired respiratory functions. Alternative non-mu-opioid receptor agonist analgesics should be considered and Palexia IR should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid receptor agonist induced respiratory depression (see Section 4.9 Overdose).

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.

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.

Mu-opioid agonists/ antagonists.

There is no clinical data on the concomitant use of Palexia IR with mixed opioid agonist/ antagonists or partial mu-opioid agonists. As with pure mu-opioid agonists, the analgesic effect provided by the mu-opioid component of Palexia IR may be theoretically reduced in such circumstances. Therefore, care should be taken when combining Palexia IR with these medicinal products.

CNS depressants.

Patients receiving other mu-opioid receptor agonist analgesics, general anaesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics 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.

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.

4.8 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%) (see 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) (see 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 (see Table 2). Subjects administered Palexia IR had a lower incidence of gastrointestinal events compared to oxycodone HCl IR (44.2% vs 63.5% respectively) (see 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.

4.2 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).

4.7 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 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.

4.9 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 or by gastric lavage 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).

7 Medicine Schedule (Poisons Standard)

Controlled Drug, S8.

6 Pharmaceutical Particulars

6.1 List of Excipients

Excipients in the tablet core are: microcrystalline cellulose, lactose, croscarmellose sodium, povidone (K30) and magnesium stearate.
Excipients in the film coating are: polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, 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.

Summary Table of Changes