Consumer medicine information

Zaldiar

Tramadol hydrochloride; Paracetamol

BRAND INFORMATION

Brand name

Zaldiar

Active ingredient

Tramadol hydrochloride; Paracetamol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zaldiar.

What is in this leaflet

Read this leaflet carefully before you start taking this medicine.

This leaflet answers some common questions about ZALDIAR Film Coated Tablets.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking ZALDIAR Film Coated Tablets against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

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

What ZALDIAR is used for

ZALDIAR Film Coated Tablets contain a combination of two analgesics, tramadol hydrochloride and paracetamol, which act together to relieve your pain.

ZALDIAR 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.

Ask your doctor if you have any questions about why ZALDIAR has been prescribed for you. Your doctor may have prescribed it for another reason.

ZALDIAR is available only with a doctor's prescription.

Before you take ZALDIAR

When you must not take it

Do not take ZALDIAR if you have an allergy (hypersensitivity) to:

  • any medicine containing tramadol hydrochloride or paracetamol
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • drop of blood pressure and fainting

Do not take ZALDIAR if you:

  • have consumed a lot of alcohol
  • have taken more than the recommended amount of:
    - sleeping tablets
    - other medication to relieve pain that your doctor has prescribed or that you have bought from a pharmacy, supermarket or health food shop
    - psychotropic medications (medicines that affect mood and emotions)
  • are also taking or have taken MAO inhibitors within the last 14 days
  • suffer from severe liver disorder
  • have uncontrolled epilepsy
  • weigh less than 37.5kg

Do not give ZALDIAR to children of 12 years and under. Safety and effectiveness in children younger than 12 years has not been established.

Do not take ZALDIAR if the expiry date (Exp.) printed on the pack has passed.

Do not take ZALDIAR if the packaging is torn or shows signs of tampering. If it has expired or the packaging is damaged, return it to your pharmacist for disposal.

Before you start to take Zaldiar

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you take other medicines containing paracetamol or tramadol hydrochloride.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • liver problems or liver disease or if you notice your eyes and skin turning yellow. This may suggest jaundice or problems with your bile ducts.
  • kidney problems
  • severe breathing difficulties, such as asthma or have severe lung problems
  • epilepsy or have already experienced fits or seizures
  • recent head injury, shock or severe headaches associated with vomiting
  • any drug dependence
  • taking other medicines to treat pain that contain buprenorphine or pentazocine
  • dehydration
  • eating disorders (anorexia, bulimia)
  • a wasting syndrome including unexplained weight loss, fatique, weakness and loss of appetite
  • malnutrition (low reserves of glutathione)
  • hypovolaemia (decreased blood volume)

If you plan to have any surgery or procedure that requires an anaesthetic tell your doctor or dentist that you are taking ZALDIAR.

Tell your doctor if you drink alcohol.

Tell your doctor if you cannot have lactose. Zaldiar film coated tablets contain a small amount of lactose.

Tell your doctor if you are pregnant or plan to become pregnant or are breast feeding. This medicine contains tramadol hydrochloride which should not be taken during pregnancy and breast feeding.

If you become pregnant during treatment, consult your doctor before taking any further tablet.

If you have not told your doctor about any of the above, tell him/her before you start taking ZALDIAR.

Taking other medicines

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

Tell your doctor if you are taking any other medicines which contain tramadol hydrochloride or paracetamol. This will ensure you do not exceed the maximum daily doses allowed for tramadol hydrochloride and / or paracetamol.

You must not take Zaldiar together with monoamine oxidase inhibitors (“MAOIs”)(see also section “Do not take Zaldiar”).

Some medicines may be affected by ZALDIAR Film Coated Tablets, or may affect how well it works.

Therefore, Zaldiar is not recommended to be taken with the following:

  • Carbamazepine, a drug used to treat epilepsy or some types of pain
  • Buprenorphine or pentazocine which are also used to treat pain

The risk of side effects increases

  • if you are taking triptans (for migraine) or selective serotonin re-uptake inhibitors, “SSRIs” (for depression). If you experience confusion, restlessness, fever, sweating, uncoordinated movement of limbs or eyes, uncontrollable jerking of muscles or diarrhoea you should call your doctor.
  • if you are taking certain antidepressants. Zaldiar may interact with these medicines and you may experience symptoms such as involuntary, rhythmic contractions of muscles, including the muscles that control movement of the eye, agitation, excessive sweating, tremor, exaggeration of reflexes, increased muscle tension, body temperature above 38 °C.
  • if you are taking tranquillizers, sleeping pills, other pain relievers such as morphine and codeine (also as cough medicine), baclofen (a muscle relaxant) medicines used to lower blood pressure, medicines to treat allergies. You may feel drowsy or feel faint. If this happens, tell your doctor.
  • if you are taking medicines which may cause convulsions (fits), such as certain antidepressants, antipsychotics, bupropion (used to stop smoking). The risk of having a fit may increase if you take Zaldiar at the same time.
  • if you are taking warfarin or phenprocoumon (for blood thinning). The effectiveness of such medicines may be altered and bleeding may occur. Any prolonged or unexpected bleeding should be reported to your doctor immediately.

The effect of Zaldiar may be altered if you also take:

  • Metoclopramide, domperidone or ondansetron, used to treat nausea and vomiting
  • Cholestyramine, used to reduce cholesterol in the blood
  • Ketoconazole or erythromycin, used to treat infections

Your doctor will tell you whether Zaldiar is suitable for you.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ZALDIAR.

How to take ZALDIAR

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

If you do not understand the instructions in this leaflet, ask your doctor or pharmacist for help.

How much to take

The usual starting dose for adults and adolescents over 12 years is 2 tablets.

Additional tablets can be taken as recommended by your doctor. The shortest time between doses must be at least 6 hours.

Do not take more than 8 tablets per day.

If you weigh between 37.5kg and 50kg you should not take more than 6 ZALDIAR tablets daily.

The dosage should be adjusted to the intensity of your pain and your individual pain sensitivity. In general the lowest pain-relieving dose should be taken.

Your doctor may reduce the maximum number of tablets you can take each day if you:

  • Are over 75 years of age
  • Have mild to moderate liver problems
  • Have kidney problems

Your doctor will check how well ZALDIAR is working at regular intervals.

How to take ZALDIAR Film Coated Tablet

Swallow the tablet(s) with a full glass of water or other liquid.

Do not break or chew the tablet.

If you forget to take ZALDIAR

The pain is likely to return.

Take it as soon as you remember, and then go back to taking it as before.

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

If you are not sure what to do, ask your doctor or pharmacist.

How long to take ZALDIAR for

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.

Zaldiar given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

If you take too much ZALDIAR (overdose)

If you or someone else receive too much (overdose), and experience one or more of the symptoms below, immediately 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 Zaldiar 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 used too much Zaldiar, 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 ZALDIAR

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking ZALDIAR.

If you become pregnant while taking ZALDIAR tell your doctor.

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

Tell your doctor if you feel the dose you are taking is too strong or too weak. If the dose is too strong you may feel very drowsy or have difficulty breathing.

If the dose is too weak you may continue to feel some pain between doses.

Things you must not do

Do not stop taking ZALDIAR, or change the dose, without checking with your doctor. On rare occasions, especially if you have been taking Zaldiar for a while stopping treatment abruptly can make you feel unwell.

Do not take ZALDIAR to treat any other conditions unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how ZALDIAR affects you. It may cause dizziness and drowsiness in some people. Make sure you know how you react to Zaldiar before you drive a car, or do anything else that could be dangerous if you are dizzy.

This effect may be made worse by drinking alcohol or some other medicines that act on the central nervous system.

Addiction
You can become addicted to Zaldiar even if you take it exactly as prescribed. Zaldiar 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 Zaldiar. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking Zaldiar suddenly, so it is important to take it exactly as directed by your doctor.

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

Side effects

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

This medicine helps most people with your condition, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

Tell your doctor if you notice any of the following and they worry you:

Very common:

  • Nausea
  • Dizziness
  • Drowsiness

Common:

  • Vomiting
  • Digestion problems (constipation, wind, diarrhoea)
  • Stomach pain
  • Dry mouth
  • Itching
  • Sweating (hyperhidrosis)
  • Headache
  • Shaking
  • Confusional state
  • Sleep disturbances
  • Mood change

Uncommon:

  • Increase in pulse or blood pressure, heart rate or rhythm disorders
  • Difficulty or pain on passing water
  • Skin reactions (e.g. rash, hives)
  • Tingling, numbness or feeling of pins and needles in the limbs, ringing in the ear, involuntary muscle twitching
  • Depression, nightmares, hallucinations, memory lapses
  • Difficulty swallowing
  • Blood in stools
  • Shivering, hot flushes, pain in chest
  • Difficulty breathing

Rare:

  • Fits, difficulties in carrying out coordinated movements
  • Addiction
  • Blurred vision
  • Fainting (syncope)
  • Speech disorder
  • Delirium
  • Constriction of the pupil (miosis)
  • Excessive dilation of the pupils (mydriasis)

The following are recognized side effects which have been reported by people using medicines that contain only tramadol hydrochloride or only paracetamol.

However, tell your doctor as soon as possible if you notice any of the following:

  • Feeling faint when getting up from a lying or sitting position
  • Slow heart rate
  • Fainting
  • Changes in appetite
  • Muscle weakness
  • Slower or weaker breathing
  • Mood changes
  • Changes in activity
  • Changes in perception
  • Worsening of existing asthma

If any of the following happen, stop treatment and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • skin rash
  • sudden swelling of the face and neck
  • difficulties breathing
  • drop of blood pressure and fainting
  • yellowing of the skin and /or eyes, also called jaundice

Some of the above could be a sign of an allergic reaction. You may need urgent medical attention or hospitalisation. Allergic reactions are rare.

In rare cases, taking a medicine of the type of tramadol hydrochloride may make you become dependent on it, making it hard to stop taking it.

On rare occasions, people who have been taking tramadol hydrochloride for some time may feel unwell if they stop treatment abruptly. Symptoms may include:

  • feeling agitated, anxious, nervous or shaky

Very few people may also get:

  • panic attacks,
  • hallucinations,
  • unusual perceptions, such as itching, tingling and numbness, noise in the ears (tinnitus)

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

After taking ZALDIAR

Storage

Keep ZALDIAR where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your medicine in a cool dry place where the temperature stays below 25°C. Do not refrigerate or freeze.

Keep your tablets in their packaging until it is time to take them. If you take them out of the carton box, and blister or foil pack, they may not keep well.

Do not store ZALDIAR or any other medicine in the bathroom or near a sink.

Do not leave ZALDIAR in the car or on window sills. Heat and dampness can destroy some 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

What it looks like

ZALDIAR Film Coated Tablets are pale yellow film-coated tablets, marked with the manufacturer‘s logo on one side and marked ‘T5’ on the other side.

The tablets are packed in a white opaque plastic blister pack

Each carton contains 2, 6, 10, 20 or 50 tablets, respectively.

Not all pack sizes may be marketed.

Ingredients

The active substances are tramadol hydrochloride and paracetamol.

Each tablet contains 37.5 mg of tramadol hydrochloride and 325 mg of paracetamol.

The other ingredients in the film coated tablet are:

Tablet core: powdered cellulose; pregelatinised maize starch; sodium starch glycollate (type A); maize starch; magnesium stearate.

Film-coating light yellow: hypromellose, lactose monohydrate, titanium dioxide, Macrogol 6000, iron oxide yellow, propylene glycol, purified talc.

Sponsor

Aspen Pharmacare, 34-36 Chandos St.,
St Leonards NSW 2065

Australian registration numbers:

Zaldiar Film Coated Tablets:
AUST R 179677

Date of preparation:
November 2020

Published by MIMS December 2020

BRAND INFORMATION

Brand name

Zaldiar

Active ingredient

Tramadol hydrochloride; Paracetamol

Schedule

S4

 

1 Name of Medicine

Tramadol hydrochloride and paracetamol.

2 Qualitative and Quantitative Composition

One film-coated or effervescent tablet contains 37.5 mg tramadol hydrochloride and 325 mg paracetamol.

List of excipients with known effect.

Excipient with known effect in film coated tablet: lactose.
Excipient with known effect in effervescent tablet: saccharin. 179.4 mg of elemental sodium per tablet.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.

Pale yellow film-coated tablet, marked with the manufacturer's logo on one side and 'T5' on the other side.

Effervescent tablet.

Off white to slightly rosy coloured with some coloured speckles, of round shape, flat with bevelled edges.

4 Clinical Particulars

4.1 Therapeutic Indications

Zaldiar 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

Adults and adolescents (12 years and older).

The dose should be individually adjusted according to intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected.
An initial dose of two tablets of Zaldiar (equivalent to 75 mg tramadol hydrochloride and 650 mg paracetamol) is recommended. Additional doses can be taken as needed, not exceeding 8 tablets (film-coated or effervescent) (equivalent to 300 mg tramadol and 2600 mg paracetamol) per day.
The dosing interval should not be less than 6 hours.
Patients weighing between 50 and 37.5 kg should receive a maximum of 6 Zaldiar tablets daily. Patients weighing less than 37.5 kg should not receive Zaldiar.
Zaldiar should under no circumstances be administered for longer than is strictly necessary (see Section 4.4 Special Warnings and Precautions for Use). If repeated use or long term treatment with Zaldiar is required as a result of the nature and severity of the illness, then careful, regular monitoring should take place (with breaks in the treatment, where possible), to assess whether continuation of the treatment is necessary.

Method of administration.

Oral use.
Zaldiar film-coated tablets must be swallowed whole, with a sufficient quantity of liquid. They must not be broken or chewed.
Zaldiar effervescent tablets should be taken dissolved in a glass of drinking water.

4.3 Contraindications

Hypersensitivity to tramadol, paracetamol or to any of the excipients, including the colouring agent sunset yellow E110, listed at the end of this document.
Acute intoxication with alcohol, hypnotic drugs, centrally-acting analgesics, opioids or psychotropic drugs.
Zaldiar should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In cases of severe hepatocellular insufficiency.
In patients with severe respiratory disease, acute respiratory disease and respiratory depression.
In patients with hepatic failure or decompensated active liver disease.
Epilepsy not controlled by treatment (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Zaldiar contains the opioid tramadol hydrochloride and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Zaldiar 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 Zaldiar.
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 Zaldiar with anyone else. Misuse or abuse poses a significant risk to the abuser that could result in overdose and death.

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 Zaldiar 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 hepatic and renal impairment (see Section 4.4, Use in hepatic impairment, Use in renal impairment) and 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, and in opioid naïve patients. 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.

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 Zaldiar 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 Zaldiar 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 Zaldiar. When large doses of tramadol are administered with anaesthetic medications or alcohol, respiratory depression may result.

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.
Withdrawal symptoms may occur if Zaldiar is discontinued. 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, tremors myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, rigors, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, piloerection, upper respiratory symptoms, rarely hallucinations, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing Zaldiar 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 and see Section 4.2 Dose and Method of Administration). Other symptoms that have been reported less frequently with Zaldiar discontinuation include: panic attacks, severe anxiety, and paresthesias.

Accidental ingestion/exposure.

Accidental ingestion or exposure of Zaldiar tablets, especially by children, can result in a fatal overdose of tramadol hydrochloride. Patients and their caregivers should be given information on safe storage and disposal of unused Zaldiar tablets (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.

Maximum daily dose.

In adults and adolescents 12 years and older, the total dose of 8 tablets of Zaldiar (equivalent to 300 mg tramadol hydrochloride and 2600 mg paracetamol) per day should not be exceeded. The dosing interval should not be less than six hours. In order to avoid inadvertent overdose, patients should be advised not to exceed the recommended dose and not to use any other paracetamol (including over the counter) or tramadol hydrochloride containing products concurrently without the advice of a physician.
Zaldiar contains tramadol HCl and paracetamol. Paracetamol has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of paracetamol at doses that exceed 4,000 milligrams per day, and often involve more than one paracetamol-containing product.

Sleep-related breathing disorders.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Opioid-dependent patients.

Tramadol is not recommended as a substitute in opioid-dependent patients. Although tramadol is an opioid-agonist, it cannot suppress opioid withdrawal symptoms. Animal experiments have shown that under certain circumstances the administration of tramadol may provoke a withdrawal syndrome in opioid dependent monkeys.
Concomitant use of opioid agonists-antagonists (buprenorphine, pentazocine) is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Patients with glutathione depletion.

Zaldiar should be used with caution in patients with glutathione depleted states (e.g. patients with severe renal or hepatic impairment, sepsis or malnutrition), as the use of paracetamol may increase the risk of metabolic acidosis (see Section 4.9 Overdose).
Caution is advised in patients treated with Zaldiar alone or when co-administering with isoxazolyl penicillins (e.g. flucloxacillin) due to the increased risk of pyroglutamic acidosis (PGA), a rare type of high anion gap metabolic acidosis (HAGMA). Patients at high risk for PGA/HAGMA are especially those with potential pre-existing glutathione depletion status, especially if maximum daily doses of paracetamol are used with prolonged treatment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).

Increased intracranial pressure, head trauma, shock or reduced levels of consciousness.

Zaldiar should be used with caution in patients with increased intracranial pressure, head injury, shock or a reduced level of consciousness of uncertain origin. Pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating mental status in these patients if they are receiving Zaldiar.

Risk of seizures.

Convulsions have been reported in tramadol-treated patients susceptible to seizures or taking other medications that lower the seizure threshold, especially selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with Zaldiar only if there are compelling circumstances. Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper dose limit.

Use during anaesthesia.

In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intraoperative recall. Until further information is available, use of tramadol during light planes of anaesthesia should be avoided.
Zaldiar effervescent tablets contain colorant Sunset yellow E110 which may cause allergic reactions. Zaldiar effervescent tablets also contain 7.8 mmol (or 179.4 mg) sodium per dose which should be taken into consideration by patients on a controlled sodium diet.
Zaldiar film-coated tablets contain a small amount of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in hepatic impairment.

The pharmacokinetics of Zaldiar have not been studied in patients with hepatic impairment. Tramadol and paracetamol are both extensively metabolized by the liver.
In patients with hepatic impairment, the elimination of tramadol is delayed. In these patients, prolongation of dosage interval should be carefully considered according to the patient's requirements.
Because of the presence of paracetamol, Zaldiar should not be used in patients with severe hepatic impairment.

Tramadol HCl.

The relationship between degree of hepatic impairment and half-life of tramadol has not been extensively studied to provide a dosing recommendation for tramadol; instead, an individual dosing regimen based on the patient's needs is proposed. A dose interval prolongation should be carefully considered.

Paracetamol.

In patients with chronic or active hepatic disease, especially those with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), and dehydration, the paracetamol dose should not exceed 3 g/day. It is of note that the maximum daily dose of Zaldiar (8 tablets) is equivalent to 2.6 g paracetamol.

Use in renal impairment.

In patients with renal insufficiency, the elimination of tramadol is delayed. In these patients, prolongation of dosage interval should be carefully considered according to the patient's requirements.
Zaldiar effervescent tablets also contain 7.8 mmol (or 179.4 mg) sodium per dose which should be taken into consideration by patients on a controlled sodium diet.

Use in the elderly.

A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years elimination may be prolonged. Therefore, if necessary, the dosage interval is to be extended according to the patient's requirements.

Paediatric use.

The effective and safe use of Zaldiar has not been established in children below the age of 12 years. Treatment is therefore not recommended in this population.
Zaldiar should not be given to children aged less than 12 years or to those who weigh less than 37.5 kg. Dose reduction is required for patients with body weight less than 50 kg (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concomitant use is contraindicated.

Non-selective MAO inhibitors.

Risk of serotoninergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.

Selective-A MAO inhibitors.

Extrapolation from non-selective MAO inhibitors.
Risk of serotoninergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.

Selective-B MAO inhibitors.

Central excitation symptoms evocative of a serotoninergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.
In case of recent treatment with MAO inhibitors, a delay of two weeks should occur before treatment with tramadol.

Concomitant use is not recommended.

Alcohol.

Alcohol increases the sedative effect of opioid analgesics. The effect on alertness can make driving of vehicles and the use of machines dangerous. Avoid intake of alcoholic drinks and of medicinal products containing alcohol.

Carbamazepine and other enzyme inducers.

Risk of reduced efficacy and shorter duration due to decreased plasma concentrations of tramadol.

Opioid agonists-antagonists (buprenorphine, pentazocine).

Decrease of the analgesic effect by competitive blocking effect at the receptors, with the risk of occurrence of withdrawal syndrome.

Concomitant use which needs to be taken into consideration.

Serotonergic drugs.

Concomitant use of tramadol and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), MAO inhibitors, tricyclic antidepressants and mirtazapine may cause serotonin toxicity. 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 or ocular clonus. Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.

Other opioid derivatives (including antitussive drugs and substitutive treatments), benzodiazepines and barbiturates.

Increased risk of respiratory depression which can be fatal in cases of overdose (see Section 4.4 Special Warnings and Precautions for Use).

Other CNS depressants.

Other opioid derivatives (including antitussive drugs and substitutive treatments), barbiturates, benzodiazepines, other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, sedatives, gabapentinoids, cannabis, centrally-acting anti-emetics, antipsychotics, neuroleptics, centrally-acting antihypertensive drugs, thalidomide and baclofen can cause increased central depression. The effect on alertness can make driving of vehicles and the use of machines dangerous (see Section 4.4 Special Warnings and Precautions for Use).

Warfarin.

Periodic evaluation of prothrombin time should be performed when Zaldiar and warfarin-like compounds are administered concurrently due to reports of increased INR.

CYP450 interactions.

Drugs that inhibit CYP2D6 isozyme may increase concentrations of tramadol and decrease concentrations of active metabolite M1. Drugs that inhibit CYP3A4 isozyme may inhibit the metabolism of tramadol and probably M1. The clinical importance of these potential interactions has not been studies. The CYP-mediated metabolism of tramadol may be inhibited in vivo by amitriptyline, fluoxetine and norfluoxetine.

Drugs reducing the seizure threshold.

Tramadol can induce convulsions and increase the potential for serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol). The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

Ondansetron.

In a limited number of studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

Busulfan.

Busulfan is eliminated from the body via conjugation with glutathione. Concomitant use with paracetamol may result in reduced busulfan clearance.

Diflunisal.

Concomitant diflunisal increases paracetamol plasma concentrations and this may increase hepatotoxicity.
Caution should be taken when Zaldiar is used concomitantly with isoxazolyl penicillins (e.g. flucloxacillin), as concurrent intake of paracetamol and isoxazolyl penicillins has been reported to be associated with pyroglutamic acidosis (PGA), especially in patients with risk factors and prolonged treatment (see Section 4.4 Special Warnings and Precautions for Use, Patients with glutathione depletion; Section 4.8 Adverse Effects (Undesirable Effects), Paracetamol).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies with the fixed combination (tramadol and paracetamol) have not been performed. No effect on fertility has been observed after oral administration of tramadol to male and female rats at respective doses up to 50 and 75 mg/kg/day. Mice continuously exposed to paracetamol 1430 mg/kg/day in the diet showed effects in offspring (fewer pups, retarded growth, increased abnormal sperm). The clinical significance of these findings is unknown.
(Category C)
Since Zaldiar is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy.
There is inadequate evidence available to assess the safety of tramadol in pregnant women. Tramadol administered before or during birth does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Long-term treatment during pregnancy may lead to withdrawal symptoms in the newborn after birth, as a consequence of habituation.
Oral administration of the tramadol/paracetamol combination to rats during the period of organogenesis elicited embryofetal toxicity at materno-toxic doses (at 50/434 mg/kg tramadol/ paracetamol or 1.5 times the maximal recommended clinical dose on a mg/m2 basis), but no teratogenicity was observed. Oral administration of tramadol alone during organogenesis to rats (up to 75 mg/kg/day) and rabbits (up to 175 mg/kg/day) was associated with embryofetal toxicity (reduced fetal and placental weight, delayed ossification) along with maternal toxicity. Mice continuously exposed to paracetamol alone (1430 mg/kg/day in the diet) showed offspring effects (fewer pups, retarded growth, increased abnormal sperm) but no teratogenicity was observed in these studies.
 Since Zaldiar is a fixed combination of active ingredients including tramadol, it should not be ingested during breastfeeding.
Tramadol and its metabolites are found in small amounts in human breast milk. An infant could ingest about 0.1% of the dose given to the mother. Tramadol should not be ingested during breast feeding.
Animal studies with fixed combination (tramadol and paracetamol) have not been performed. Oral administration of tramadol to rats from late gestation to weaning at 80 mg/kg/day (2.5 times the maximal recommended clinical dose on a mg/m2 basis) was associated with clinical toxicity in pups, including reduced survival and weight gain; the no-effect dose was 40 mg/kg/day.
Tramadol is excreted into milk. The use of Zaldiar during breastfeeding is not recommended.

4.7 Effects on Ability to Drive and Use Machines

Tramadol may cause drowsiness or dizziness, which may be enhanced by alcohol or other CNS depressants. If affected, the patient should not drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Table 1 shows the most frequent (> 1%) treatment emergent adverse events (independent from causal relationship) observed in pooled clinical trials with Zaldiar versus tramadol alone.
The safety profile of Zaldiar is characterized by the following adverse reactions. The most commonly adverse reactions were nausea, dizziness and somnolence, observed in more than 10% of the patients. All adverse reactions identified for Zaldiar are listed below under the corresponding body organ systems according to the following classification: very common ≥ 10%; common ≥ 1% to < 10%; uncommon ≥ 0.1% to < 1%; rare ≥ 0.01% to < 0.1%.

Cardiac disorders.

Uncommon: arrhythmia, tachycardia, palpitations, syncope.

Vascular disorders.

Uncommon: hypertension, hot flush.

Central and peripheral nervous system disorders.

Very common: dizziness, somnolence.
Common: headache, trembling.
Uncommon: muscle contractions involuntary, paraesthesia, tinnitus.
Rare: ataxia, convulsions, speech disorders.

Psychiatric disorders.

Common: confusional state, mood altered (anxiety, nervousness, euphoric mood), sleep disorders.
Uncommon: depression, hallucinations, nightmares, amnesia.
Rare: delirium, drug dependence.

Post-marketing surveillance.

Very rare: abuse.

Eye disorders.

Rare: vision blurred, miosis, mydriasis.

Respiratory, thoracic and mediastinal system disorders.

Uncommon: dyspnoea.

Gastrointestinal disorders.

Very common: nausea.
Common: vomiting, constipation, dry mouth, diarrhoea, abdominal pain, dyspepsia, flatulence.
Uncommon: dysphagia, melaena.

Skin and subcutaneous tissue disorders.

Common: hyperhidrosis, pruritus.
Uncommon: dermal reactions (e.g. rash, urticaria).

Urinary system disorders.

Uncommon: albuminuria, micturition disorders (dysuria and urinary retention).

General disorders and administration site conditions.

Uncommon: chills, chest pain.

Investigations.

Uncommon: transaminases increased.
Although not observed during clinical trials, the occurrence of the following adverse effects known to be related to the administration of tramadol or paracetamol cannot be excluded.

Tramadol.

Postural hypotension, bradycardia, collapse (tramadol).
Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.
Rare cases (≥ 1/10,000 to < 1/1000): allergic reactions with respiratory symptoms (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.
Rare cases (≥ 1/10,000 to < 1/1000): changes in appetite, motor weakness, and respiratory depression.
Psychic side effects may occur following administration of tramadol which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood (usually euphoric mood occasionally dysphoria), changes in activity (usually suppression occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour perception disorders).
Worsening of asthma has been reported though a causal relationship has not been established.
Symptoms of drug withdrawal syndrome, similar to those occurring during opiate withdrawal may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have very rarely been seen if tramadol hydrochloride is discontinued abruptly include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.

Endocrine disorders.

Cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in literature.

Metabolism and nutrition disorders.

Hypoglycaemia with frequency not known, cases of hyponatremia have been reported in literature.

Respiratory, thoracic and mediastinal disorders.

Not known: central sleep apnea syndrome.

Paracetamol.

Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.
There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.
Patients with chronic or active hepatic disease, especially those with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), and dehydration are more likely to experience hepatic toxicity from the paracetamol component of Zaldiar. The maximum dose of Zaldiar must not be exceeded in these patients.

Metabolism and nutrition disorders.

Cases of PGA were reported with frequency not known, when paracetamol is used alone or paracetamol is co-administered with isoxazolyl penicillins (e.g. flucloxacillin), especially in patients with risk factors and prolonged treatment (see Section 4.4 Special Warnings and Precautions for Use, Patients with glutathione depletion; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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

Zaldiar contains a fixed combination of active ingredients. In case of overdose, the symptoms may include the signs and symptoms of toxicity of tramadol or paracetamol or of both these active ingredients.

Symptoms of overdose from tramadol.

In principle, on intoxication with tramadol, symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular, miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.

Symptoms of overdose from paracetamol.

In paracetamol overdose, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects also may occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.
In the treatment of paracetamol overdose, gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if paracetamol ingestion is known or suspected to have occurred within a few hours of presentation. Serum paracetamol levels should be obtained immediately if the patient presents 4 or more hours after ingestion to assess potential risk of hepatotoxicity; paracetamol levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.
Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs early in the course of intoxication.

Emergency treatment.

Transfer immediately to a specialised unit.
Maintain respiratory and circulatory functions.
Prior to starting treatment, a blood sample should be taken as soon as possible after overdose in order to measure the plasma concentration of paracetamol and tramadol and in order to perform hepatic tests.
Perform hepatic tests at the start (of overdose) and repeat every 24 hours. An increase in hepatic enzymes (ASAT, ALAT) is usually observed, which normalizes after one or two weeks.
Empty the stomach by causing the patient to vomit (when the patient is conscious) by irritation.
Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted; naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam.
Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore, treatment of acute intoxication with Zaldiar with haemodialysis or haemofiltration alone is not suitable for detoxification.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

Pharmacotherapeutic group: tramadol, combinations.
ATC code: N02AX52.

5.1 Pharmacodynamic Properties

Mechanism of action.

Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is a pure nonselective agonist of the mu, δ, and κ opioid receptors with a higher affinity for the mu receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. Unlike morphine, a broad range of analgesic doses of tramadol has no respiratory depressant effect. The effect of tramadol on gastrointestinal motility is lower than with pure opioid analgesics. At therapeutic doses, tramadol has no clinically significant effect on left ventricular function or cardiac index. Orthostatic changes in blood pressure have been observed. The potency of tramadol is considered to be one-tenth to one-sixth that of morphine.
Antagonism studies demonstrated that both opioid and non-opioid properties of tramadol contribute to its analgesic activity.
Apart from analgesia, tramadol may produce other symptoms similar to that of opioids including: dizziness, somnolence, nausea, constipation, sweating and pruritus.
The precise mechanism of the analgesic properties of paracetamol is unknown and may involve central and peripheral effects.
Zaldiar is positioned as a step II analgesic in the WHO pain ladder and should be utilised accordingly by the physician.

Clinical trials.

Acute pain.

A total of 1200 subjects (400/study) aged over 16 years with moderate or severe pain following an oral surgical procedure (extraction of 2 ipsilateral, or > 2, third molars requiring bone removal) were enrolled. Subjects were stratified by baseline pain severity: moderate or severe, and received one of 5 single dose treatments (tramadol/ paracetamol 75 mg/650 mg, tramadol 75 mg, paracetamol 650 mg, ibuprofen 400 mg or placebo). Subjects could receive a supplemental analgesic during the studies. If a subject took rescue medication or discontinued prematurely, remaining observations points were filled using the last observation carried forward (LOCF) method.
Across the studies most subjects were female (55-63%) and Caucasian (75-93%). Mean age was 21.1-21.7 years (range 16-46 years). Baseline pain intensity was consistent across the studies (moderate for 66-70%, severe for 30-34%); mean rating (6.1-6.2); and the majority of subjects had 4 molars removed (64-83%). 64% to 74% of subjects given T/A 75/650 in the pivotal studies required additional analgesia at least once during the study. Table 2 presents the primary summary efficacy variables (TOTPAR, SPID, and SPRID) and statistical comparisons for the intervals, 0-4 hours, and 0-8 hours, for each of these studies.

Chronic pain.

Efficacy of Zaldiar in the relief of chronic pain has not been examined in comparison to tramadol and/or paracetamol given alone. Efficacy and safety of Zaldiar in patients with chronic pain was examined in 5 placebo-controlled, multiple-dose studies conducted over 3 months (CAPSS-104, CAPSS-112, CAPSS-113, CAPSS-114 and PRI/TRP/CAN1). Subjects were primarily 40-75 years of age and taking a stable daily dose of an NSAID for at least 3 months before study entry. In CAPSS-114, subjects who had been taking a COX-2 selective inhibitor for pain relief were permitted to continue taking it while in the trial. Mean pain severity ranged from 67.8 mm to 80.1 mm, on a standard pain visual analogue (PVA) scale, 0-10 mm. Study drug was titrated from one (tramadol HCl 37.5 mg with paracetamol 325 mg) to 4 tablets/day over the first 10 days, followed by a regimen of 1 or 2 tablets every 4 to 6 hours, as needed. The maximum dose allowed was 8 tablets/day (tramadol HCl 300 mg with paracetamol 2600 mg).
Zaldiar was statistically superior to placebo in lowering the PVA score in PRI/TRP/CAN1 and CAPSS-112 and CAPSS-114, and in increasing the time to discontinuation due to efficacy failure in CAPSS-113 and PRI/TRP/CAN1. Statistical significance in lowering the PVA score was not demonstrated in CAPSS-114.
The efficacy of Zaldiar in the treatment of patients with cancer has not been investigated in clinical trials.

5.2 Pharmacokinetic Properties

Tramadol is administered in racemic form and the [-] and [+] forms of tramadol and its metabolite M1, are detected in the blood. Although tramadol is rapidly absorbed after administration, its absorption is slower (and its half-life longer) than that of paracetamol.
After a single oral administration of a tramadol/ paracetamol (37.5 mg/325 mg) tablet, peak plasma concentrations of 64.3/55.5 nanogram/mL [(+)-tramadol/(-)-tramadol] and 4.2 microgram/mL (paracetamol) are reached after 1.8 h [(+)-tramadol/(-)-tramadol] and 0.9 h (paracetamol) respectively. The mean elimination half-lives t1/2 are 5.1/4.7 h [(+)-tramadol/(-)-tramadol] and 2.5 h (paracetamol).
During pharmacokinetic studies in healthy volunteers after single and repeated oral administration of Zaldiar, no clinical significant change was observed in the kinetic parameters of each active ingredient compared to the parameters of the active ingredients used alone.

Use in children.

The pharmacokinetics of Zaldiar has not been studied in children or adolescents aged under 16 years.

Use in the elderly.

Population PK and dedicated PK studies using tramadol alone did not reveal a relevant effect of age on the PK of tramadol up to the age of 75 years. Above the age of 75 years the elimination half-life of tramadol was slightly prolonged by about 15% and exposure (AUC) increased by about 50% in comparison to subjects aged between 65 - 75 years.

Absorption.

Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100 mg dose is approximately 75%. After repeated administration, the bioavailability is increased and reaches approximately 90%.
After administration of Zaldiar, the oral absorption of paracetamol is rapid and nearly complete and takes place mainly in the small intestine. Peak plasma concentrations of paracetamol are reached in one hour and are not modified by concomitant administration of tramadol.
The oral administration of Zaldiar with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol so that Zaldiar can be taken independently of meal times.

Distribution.

Tramadol has a high tissue affinity (Vd,β = 203 ± 40 L). It has a plasma protein binding of about 20%.
Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of paracetamol is bound to plasma proteins.

Metabolism.

Tramadol is extensively metabolized after oral administration. About 30% of the dose is excreted in urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.
Tramadol is metabolised through O-demethylation (catalysed by the enzyme CYP2D6) to the metabolite M1, and through N-demethylation (catalysed by CYP3A) to the metabolite M2. M1 is further metabolised through N-demethylation and by conjugation with glucuronic acid. The plasma elimination half-life of M1 is 7 hours. The metabolite M1 has analgesic properties and is more potent than the parent drug. The plasma concentrations of M1 are several fold lower than those of tramadol and the contribution to the clinical effect is unlikely to change on multiple dosing.
Paracetamol is principally metabolized in the liver through two major hepatic routes: glucuronidation and sulphation. The latter route can be rapidly saturated at doses above the therapeutic doses. A small fraction (less than 4%) is metabolized by cytochrome P450 to an active intermediate (the N-acetyl benzoquinoneimine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, during massive overdose, the quantity of this metabolite is increased.

Use in hepatic impairment.

The pharmacokinetics of Zaldiar has not been studied in patients with hepatic impairment. Tramadol and paracetamol are both extensively metabolized by the liver. In patients with severe hepatic impairment Zaldiar should not be used.

Excretion.

Tramadol and its metabolites are eliminated mainly by the kidneys. The half-life of paracetamol is approximately 2 to 3 hours in adults. It is shorter in children and slightly longer in the newborn and in cirrhotic patients. Paracetamol is mainly eliminated by dose-dependent formation of glucuro- and sulpho-conjugate derivatives. Less than 9% of paracetamol is excreted unchanged in urine. In renal insufficiency, the half-life of both compounds is prolonged.

Use in renal impairment.

The pharmacokinetics of Zaldiar has not been studied in patients with renal impairment. Based on studies using tramadol alone, excretion of tramadol and its metabolite M1 is reduced in patients with CKD stages 4 or 5.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies with the fixed combination (tramadol and paracetamol) have not been performed. There was no evidence of genotoxicity with tramadol in a standard battery of in vitro and in vivo tests. Paracetamol can cause chromosomal damage in vitro and in vivo, but only at high concentrations or at large doses associated with hepatotoxicity.

Carcinogenicity.

Carcinogenicity studies with the fixed combination (tramadol and paracetamol) have not been performed.
Results of carcinogenicity tests do not suggest a potential risk of tramadol for man.
Long-term studies in rats and mice yielded no evidence of relevant tumorigenic effects at non-hepatotoxic dosages of paracetamol.

6 Pharmaceutical Particulars

6.1 List of Excipients

Film-coated tablet.

Tablet core: powdered cellulose, pregelatinised maize starch, sodium starch glycollate type A, maize starch, magnesium stearate.
Film-coating light yellow: hypromellose, lactose monohydrate, titanium dioxide, macrogol 6000, iron oxide yellow, propylene glycol, purified talc.

Effervescent tablet.

Sodium dihydrogen citrate, citric acid, povidone, sodium bicarbonate, macrogol 6000, colloidal anhydrous silica, magnesium stearate, Orange Juice Flavour Permaseal PHS-140561, acesulfame potassium, saccharin sodium, sunset yellow FCF.

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 25°C.

6.5 Nature and Contents of Container

Zaldiar film-coated tablets (AUST R 179677) are packed in white opaque PVC/aluminium foil or white opaque polypropylene/aluminium foil.
Box of 2, 6, 10, 20, 50, and 100 tablets.
Not all pack sizes may be marketed.
Zaldiar effervescent tablets (AUST R 179678) are packed in child-resistant strips of thermo-sealed aluminium foil; outside coated with polyethylene terephthalate, inside coated with polyethylene.
Pack sizes of 2, 6, 10, 20, 50, and 100 effervescent tablets packed in coated aluminium strips.
Not all pack sizes may be marketed.

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

Tramadol hydrochloride.

(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride.

Chemical structure.


Molecular formula: C16H25NO2.HCl. Relative molecular mass: Mr = 299.8.

CAS number.

36282-47-0.
White or almost white, crystalline powder; freely soluble in water and methanol, very slightly soluble in acetone pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7.

Paracetamol.

N-(4-hydroxyphenyl) acetamide.

Chemical structure.


Molecular formula: C8H9NO2. Relative molecular mass: Mr = 151.2.

CAS number.

103-90-2.
White or almost white, crystalline powder; sparingly soluble in water, freely soluble in alcohol, very slightly soluble in methylene chloride (15-25°C) pKa of 9.5 at 25°C. Partition coefficient (logP) of 0.51.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes