Consumer medicine information

Medsurge Hydromorphone Injection/ Hydromorphone HP Injection/ Hydromorphone XHP Concentrated Injection

Hydromorphone hydrochloride

BRAND INFORMATION

Brand name

Medsurge Hydromorphone, HP

Active ingredient

Hydromorphone hydrochloride

Schedule

What is in this leaflet

This leaflet answers some common questions about Medsurge Hydromorphone, Medsurge Hydromorphone HP (HP = High Potency) and Medsurge Hydromorphone XHP (XHP = Extra High Potency) injections.

It does not contain all 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 benefits of you using this medicine against the risks it may have for you.

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

Keep this leaflet in a safe place. You may need to read it again.

What Hydromorphone injections are used for

Medsurge Hydromorphone, Hydromorphone HP and Hydromorphone XHP injections contain HYDROmorphone hydrochloride. Hydromorphone belongs to a group of medicines called opioid analgesics.

Medsurge Hydromorphone/Hydromorphone HP/Hydromorphone XHP injections is used to provide the short-term management of severe pain for which other treatment options have failed or are otherwise inappropriate to provide sufficient management of pain. They can be given as a single injection, or as an infusion into a vein, or as an injection into the tissue under the skin, or as an injection into the muscle.

Opioid analgesics have been used to treat pain for many years. Your doctor, however, may prescribe it for another purpose.

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

As with all strong painkillers, your body may become used to you having hydromorphone. Being given it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop having hydromorphone suddenly, so it is important that you are given Hydromorphone hydrochloride injections exactly as directed by your doctor.

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

Before you use Hydromorphone injections

When you must not have it

You should not have Hydromorphone hydrochloride injections if you:

suffer from shallow or difficult breathing or have any acute breathing problems such as bronchitis or asthma
have severe abdominal pain with bloating, cramps or vomiting
have a condition where your small bowel does not work properly
take medicine for depression called a 'monoamine oxidase inhibitor' or have taken any in the last two weeks
have been prescribed Medsurge Hydromorphone HP injection or Medsurge Hydromorphone XHP concentrated injection and you have not used any opioid medicine before.

You should not have Hydromorphone hydrochloride injections if you are allergic to HYDROmorphone hydrochloride, opioid analgesics, or any of the ingredients listed at the end of this leaflet.

Do not use this medicine after the expiry date (EXP) printed on the pack. If you have it after the expiry date has passed, it may not work very well or may no longer be sterile.

Do not use this medicine if the packaging is damaged or shows signs of tampering or if the solution in the ampoule shows any visible signs of deterioration.

Do not have this medicine during labour for the delivery of premature infants.

Hydromorphone given to the mother can cause breathing problems in the newborn, especially premature babies.

Do not have this medicine if you are pregnant or intend to become pregnant whilst having this medicine. Like most medicines of this kind, Hydromorphone hydrochloride injections should not be given during pregnancy. Your doctor will discuss the risks of having it if you are pregnant.

Do not give this medicine to a child, and especially not to a premature newborn. Safety and efficacy in children have not been established.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

are severely drowsy, have a reduced level of consciousness or are feeling faint or dizzy upon standing
heart problems or heart disease
low blood pressure
chronic lung disease
suffer from sleep apnoea (temporarily stopping breathing while you sleep)
have just drunk a large amount of alcohol, regularly drink large amounts of alcohol or have confusion and shaking due to stopping drinking alcohol
convulsions, fits or seizures
head injury, brain tumour or increased pressure in your head
are about to have surgery or have had surgery in the last 24 hours
recent gastrointestinal surgery
chronic liver or kidney disease
increased prostate size or difficulty passing urine
problems with or recent surgery of your bile duct
problems with your gall bladder
inflammation of the pancreas
adrenal glands not working properly
underactive thyroid gland
severe mental condition involving losing contact with reality or an inability to think clearly
an addiction or history of abuse of alcohol, opioids or other drugs.

Check with your doctor if you are pregnant or intend to become pregnant.

Tell your doctor if you are breastfeeding or intend to breastfeed. Low levels of opioid analgesics have been detected in human milk.

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

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

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

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

Hydromorphone/Hydromorphone HP/Hydromorphone XHP injections given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

If you have not told your doctor about any of the above, tell them before you have Hydromorphone/Hydromorphone HP/Hydromorphone XHP injections.

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.

Some medicines and Hydromorphone hydrochloride injections may interfere with each other. Using hydromorphone hydrochloride injections with medicines that can make you feel drowsy may result in severe drowsiness, decreased awareness, breathing problems, coma and death. These include:

sleeping tablets and other sedatives (including benzodiazepines and barbiturates)
gabapentinoids
cannabis
antihistamines
anxiolytics
general anaesthetics
antiemetics
antidepressants (including tricyclic antidepressants),
antipsychotics (including phenothozines)
other opioids
alcohol.

Hydromorphone hydrochloride injections may enhance the action of neuromuscular blocking agents and affect your breathing.

Hydromorphone hydrochloride injections should not be used if you are taking non-selective monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such treatment.

These medicines and alcohol may be affected by Hydromorphone hydrochloride injections, may affect how well Hydromorphone hydrochloride injections work or may increase side effects. You may need to use different amounts of your medicines or take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while having this medicine.

Taking Hydromorphone injections

How much is given

Your doctor will decide the appropriate dose for you.

How it is given

A doctor or nurse will usually prepare and administer the injection or infusion.

Hydromorphone hydrochloride injections can be given as a single injection or infusion into the vein. It can also be administered through a fine needle into the tissue under the skin or into the muscle.

Your doctor will decide the most appropriate way for you to have hydromorphone. Using this medicine in a manner other than that prescribed by your doctor can be harmful to your health.

When it is given

You should be given Hydromorphone hydrochloride injections as directed by your doctor.

If you begin to experience pain, tell your doctor as your dosage may have to be reviewed.

How long it is given for

You should be given this medicine for as long as directed by your doctor.

If you stop having this medicine suddenly, your pain may worsen and you may experience withdrawal symptoms such as:

body aches
loss of appetite, nausea (feeling sick), stomach cramps or diarrhoea
fast heart rate
sneezing or runny nose
chills, tremors, shivering or fever
trouble sleeping, nervousness or restlessness
increased sweating and yawning
weakness.

If you forget to have it

If you forget to have a dose, contact your doctor or pharmacist for advice.

Do not have a double dose to make up for the dose you have missed. Having extra medicine will increase the chance of an unwanted side effects.

If you have received too much (overdose)

If you or someone else receive too much (overdose), and experience one or more of the symptoms below, call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you have accidentally used hydromorphone hydrochloride that was prescribed for you. If someone has 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 hydromorphone hydrochloride, 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 being given Hydromorphone injections

Things you must do

You should be given Hydromorphone hydrochloride injections exactly as your doctor has prescribed.

Before you start on a new medicine, remind your doctor and pharmacist you are having Hydromorphone hydrochloride injections.

Tell any other doctors, dentists and pharmacists who treat you that you are having this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are having this medicine. It may affect other medicines used during surgery.

If you become pregnant while having this medicine, tell your doctor immediately.

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

Tell your doctor if your pain is getting worse. Also discuss any problems or difficulties you have while you are having this medicine with your doctor.

Tolerance to hydromorphone may develop which means that the effect of the medicine may decrease. If this happens, your doctor may review the dose so that you get adequate pain relief.

Things you must not do

Do not use Hydromorphone hydrochloride injections to treat any other complaint unless your doctor tells you to.

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

Do not stop using this medicine, exceed the dose recommended or change the dose without checking with your doctor. Over time your body may become used to hydromorphone so if you stop having it suddenly, your pain may worsen and you may have unwanted side effects such as withdrawal symptoms. This is called physical dependence.

If you need to stop having this medicine, your doctor will gradually reduce the amount you have each day, if possible, before stopping the medicine completely.

Do not drink alcohol while you are having this medicine. Drinking alcohol while using this medicine may make you feel more sleepy and could increase the risk of serious side effects, such as shallow breathing with the risk of stopping breathing and loss of consciousness.

Things to be careful of

Tell your doctor if you find that you cannot concentrate or that you feel more sleepy than normal when you start having this medicine or when the dose is increased.

This feeling should wear off after a few days.

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

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

Do not drive or operate machinery until you know how Hydromorphone hydrochloride injections affect you. As with other opioid analgesics, Hydromorphone hydrochloride injections may cause drowsiness, dizziness, hallucinations, disorientation, blurred vision or other vision problems or may affect alertness. Discuss these aspects and any impact on your driving or operating machinery with your doctor.

Be careful if you are elderly, unwell or taking other medicines. Some people may experience side effects such as unsteadiness, dizziness, drowsiness or confusion which may increase the risk of a fall.

Tell your doctor if you suffer from nausea or vomiting when having Hydromorphone hydrochloride injections.

Your doctor may be able to give you some medicine to help.

Tell your doctor if having Hydromorphone hydrochloride injections causes constipation.

Your doctor can advise you about your diet, the proper use of laxatives and other ways to help manage constipation.

There is potential for abuse of hydromorphone and the development of addiction to hydromorphone. It is important that you discuss this issue with your doctor.

Side effects

All medicines may have some unwanted side effects. Sometimes they are serious but most of the time they are not. Your doctor has weighed the risks of this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects. Not everybody experiences them.

Tell your doctor as soon as possible if you do not feel well while you are having Hydromorphone hydrochloride injection.

This medicine helps most people with moderate to severe pain, but it may have unwanted side effects in some people. Other side effects not listed here may also occur.

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

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

mild abdominal problems such as, feeling nauseous (feeling sick), loss of appetite, constipation or diarrhoea
dry mouth or changes in taste
feeling agitated, nervous or anxious
have trouble sleeping
trouble with your balance
problems with your eyesight
skin rash, itching or sweating
uncoordinated muscle movements and stiffness, tremor, tingling and numbness
feeling faint
swelling, including but not only, of the legs or ankles
redness and soreness at site of injection
chills
erectile dysfunction.

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

stomach discomfort or cramps, vomiting, indigestion or abdominal pain
changes in mood
light-headedness, fainting or dizziness especially when standing up
drowsiness or feeling extremely sedated
feeling disorientated and having nightmares
slow or noticeable heartbeats
headache, confusion or hallucinations
unusual weakness or loss of strength
difficulty passing urine, pain or feeling the need to urinate urgently.

The above list includes serious side effects that may require medical treatment.

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

your breathing slows or weakens
you have an allergic reaction: shortness of breath, wheezing, shallow or difficult breathing; swelling of the tongue, throat, face, lips or other parts of the body; rash, itching or hives on the skin
seizures, fits or convulsions
fast or irregular heartbeats.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

When seeking medical attention, take this leaflet and any remaining medicine with you to show the doctor.

After being given Hydromorphone injections

Storage

Hydromorphone hydrochloride injections should be given immediately after opening the ampoule. Once opened, any unused portion should be discarded.

If you are having Hydromorphone hydrochloride injections in hospital, the ampoules will be stored in the pharmacy or on the ward.

If you have some of this medicine at home, keep the ampoules in a cool, dry place where the temperature stays below 30°C and protected from light.

Do not store it or any other medicine in the bathroom, near a sink or on a window sill.

Do not leave it in the car. Heat can destroy some medicines.

Keep it 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.

Disposal

If your doctor tells you to stop having this medicine, or the expiry date has passed, ask your pharmacist how to dispose of medicines no longer required.

Product description

What it looks like

Medsurge Hydromorphone injection, Medsurge Hydromorphone HP injection and Medsurge Hydromorphone XHP concentrated injection comes in amber glass ampoules containing a clear, colourless to yellowish solution.

There are different strengths and presentations available:

Not all presentations and/or pack sizes are marketed.

Ingredients

As well as HYDROmorphone hydrochloride, the active ingredient, the ampoules also contain sodium citrate dihydrate, citric acid, sodium chloride, hydrochloric acid or sodium hydroxide (to adjust pH) and water for injections.

This medicine does not contain lactose, sucrose, gluten, tartrazine or other azo dyes.

Sponsor

Australian Sponsor

Medicianz Healthcare Pty Ltd
Unit 2, 6-7 Gilda Court
MULGRAVE
VICTORIA 3170

Marketed and distributed by

Medsurge Healthcare Pty Ltd
Tel: 1300 788 261
www.medsurge.com.au

Registration Numbers

MEDSURGE HYDROMORPHONE 2 mg/1 mL AUST R 309688

MEDSURGE HYDROMORPHONE HP 10 mg/1 mL AUST R 309689

MEDSURGE HYDROMORPHONE HP 20 mg/1 mL AUST R 309683

MEDSURGE HYDROMORPHONE HP 100 mg/10 mL AUST R 309682

MEDSURGE HYDROMORPHONE XHP 50 mg/1 mL AUST R 309686

This leaflet was prepared in December 2020.

Published by MIMS February 2021

BRAND INFORMATION

Brand name

Medsurge Hydromorphone, HP

Active ingredient

Hydromorphone hydrochloride

Schedule

Notes

Distributed by Medsurge Healthcare Pty Ltd

1 Name of Medicine

Hydromorphone hydrochloride.

2 Qualitative and Quantitative Composition

Hydromorphone hydrochloride 2 mg/1 mL.
Hydromorphone hydrochloride 10 mg/1 mL.
Hydromorphone hydrochloride 100 mg/10 mL.
Hydromorphone hydrochloride 20 mg/1 mL.
Hydromorphone hydrochloride 50 mg/1 mL.
Hydromorphone hydrochloride, a hydrogenated ketone of morphine, is an opioid analgesic.
Hydromorphone hydrochloride is a fine, white or practically white, odourless, crystalline powder. It is freely soluble in water, sparingly soluble in ethanol and practically insoluble in ether.
For the full list of excipients, (see Section 6.1 List of Excipients).

3 Pharmaceutical Form

Solution for injection or concentrated solution for injection.
Medsurge Hydromorphone injection, Medsurge Hydromorphone HP injection and Medsurge Hydromorphone XHP concentrated injection are presented as a clear colourless to yellowish solution.
The solution does not contain any antioxidant or preservative.

4 Clinical Particulars

4.1 Therapeutic Indications

Medsurge Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection 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

Warning.

Medsurge Hydromorphone HP injection (high potency) and Medsurge Hydromorphone XHP concentrated injection (extra high potency) are highly concentrated solutions of hydromorphone intended for use in opioid-tolerant patients. Do not confuse Medsurge Hydromorphone HP injection and Medsurge Hydromorphone XHP concentrated injection with standard parenteral formulations of Medsurge Hydromorphone or other opioids. Overdose and death could result.

General.

Hydromorphone hydrochloride, like other opioids, may cause clinically significant physical dependence usually after several weeks of continued opioid therapy, but in some patients, it may be clinically relevant after a shorter treatment period (see Section 4.4 Special Warnings and Precautions for Use, Drug abuse and dependence). Tolerance, i.e. when increasingly larger doses are required to produce a given clinical effect, is initially manifested as a shortened duration of action followed by a decrease in the intensity of analgesic effect. Tolerance is a normal and expected sequela of continued opioid therapy and may become a significant consideration. Hydromorphone hydrochloride dosage, in these patients, should be titrated to the desired analgesic effect.

Adult.

Individualisation of dosage. As with other opioid analgesics, safe and effective administration of hydromorphone hydrochloride preparations to patients with pain depends upon a comprehensive assessment of the patient. The nature of the pain (severity, frequency, aetiology and pathophysiology) as well as the concurrent medical status of the patient will affect selection of the starting dosage.
Owing to the varied response observed to opioids between individuals, it is recommended that all patients be started at a conservative dose of hydromorphone and titrated to an adequate level of analgesia, balanced with an acceptable level of adverse effect(s).
Non opioid-tolerant patients. The recommended initial dose is as follows:

Intramuscular or subcutaneous.

1 to 2 mg every four to six hours.

Intravenous.

0.5 to 1.0 mg (given slowly over 2 to 3 minutes). Intravenous or subcutaneous administration is usually not painful.

Patient-controlled analgesia (PCA).

There are limited data available on the use of intravenous hydromorphone administered as PCA. One regimen described in the literature is as follows: Adequate analgesia should be established prior to commencement of the PCA. A background continuous intravenous infusion of 0.1 mg per hour should be used together with patient-administered bolus doses of 0.2 mg at no more than 5 minutely intervals and up to a maximum of 1.2 mg per hour.

Continuous intravenous infusion.

Limited data are available. An infusion of up to 0.3 mg per hour has been used in a small number of patients.
In general, and irrespective of route of administration, elderly patients may require lower doses of hydromorphone hydrochloride preparations (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).
Patients currently receiving opioids. When converting patients currently receiving opioids to a hydromorphone hydrochloride preparation, both the dose of hydromorphone and the duration of its analgesic effect will vary substantially depending on the patient's opioid tolerance. A hydromorphone dose should be selected and adjusted so that at least 3-4 hours of pain relief is achieved. In patients taking opioid analgesics, the starting dose of hydromorphone should be based on the prior daily opioid dose. This should be done by converting the total daily dose of the previous opioid to an equivalent total daily dose of hydromorphone using the equianalgesic table. For opioids not in the table, first estimate the equivalent total daily dose of morphine, then use the table to determine the equivalent total daily dose of hydromorphone. See Table 1.

Once the total daily dosage of hydromorphone has been estimated, it should be divided into the desired number of doses. Since there is individual variation in response to different opioid drugs, only 1/2 to 2/3 of the estimated dose of hydromorphone calculated from the equianalgesic table should be given for the first few doses, then increased as needed according to the patient's response to its analgesic effect.
The Medsurge Hydromorphone range of products (see Section 2 Qualitative and Quantitative Composition) provides total flexibility in respect of dose and route of administration. Hence, the appropriate hydromorphone hydrochloride dosage form should be carefully considered, consistent with the route of administration, to achieve the pain relief sought for the patient.
Periodic reassessment after initial dosing is always required. If pain management is not satisfactory and, in the absence of significant opioid-induced adverse events, the hydromorphone dose may be increased gradually. If excessive opioid side effects are observed early during the dosing interval, the hydromorphone dose should be reduced. If this results in breakthrough pain at the end of the dosing interval, the dosing interval may need to be shortened. Dose titration should be guided by the need for analgesia rather than the absolute dose of opioid employed.
Medsurge Hydromorphone HP injection (HP = High Potency) and Medsurge Hydromorphone XHP concentrated injection (XHP = Extra High Potency) are only recommended for patients who are already receiving high doses of parenteral opioids where the volume required for parenteral administration (to achieve the high dose) becomes unacceptably large for the chosen route of administration (e.g. subcutaneous).
Hydromorphone XHP 50 mg/1 mL concentrated injection must be diluted with an appropriate sterile diluent (e.g. 0.9% sodium chloride solution (saline), 5% glucose solution, water for injections solution) to a suitable concentration that can be tolerated by the patient.
Continuous subcutaneous infusion has also been used as a method of delivering large daily doses of hydromorphone in opioid-tolerant patients with severe pain.

Transferring patients between oral and parenteral hydromorphone.

Switching patients from parenteral hydromorphone to oral hydromorphone should be guided by the sensitivity of the individual patient. The oral starting dose should not be overestimated (for oral bioavailability see Section 5.2 Pharmacokinetic Properties, Metabolism).

Pediatric use.

Safety and efficacy have not been established in children.
Product is for single use in one patient only. Discard any residue.

4.3 Contraindications

Hydromorphone hydrochloride preparations are contraindicated in patients with: known hypersensitivity to hydromorphone or to any of the ingredients; severe respiratory disease, acute respiratory disease and respiratory depression; status asthmaticus, paralytic ileus, concurrent monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapy, pregnancy; premature infants and children, or during labour for delivery of premature infants.

4.4 Special Warnings and Precautions for Use

Tolerance and opioid use disorder (abuse and dependence).

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids.

Hazardous and harmful use.

Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection contains the opioid hydromorphone hydrochloride and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection at recommended doses.
Abuse or intentional misuse of Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or family history (parents or siblings) of substance abuse disorders (including alcohol and prescription and illicit drugs) in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders). 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 Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection.
All patients receiving opioids should be routinely monitored for signs of drug-seeking behaviour (e.g. too early requests for refills), misuse and abuse.
Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include the review of concomitant opioids and psycho-active drugs (like benzodiazepines), 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 or intentional misuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, such as overdose and/or death. For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.
Patients should be advised not to share Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection with anyone else.

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
Opioid withdrawal has been well described in the literature and its severity in a particular patient can vary from mild discomfort to potential cardiovascular collapse. Without treatment most observable symptoms resolve in 5-14 days. A period of "subacute withdrawal" lasting up to 6 months has also been described in which previously dependent patients experience difficulty concentrating, insomnia, irritability, myalgias and autonomic instability.
Various regimens have been described for treatment of withdrawal, including but not limited to methadone substitution, clonidine, benzodiazepines, and phenothiazines. Supportive care is essential and associated symptoms, such as dehydration and gastrointestinal disturbances, should be treated accordingly.
When discontinuing Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection 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).

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 Medsurge Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection 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, in patients with hepatic and renal impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, Use in renal impairment) and in patients with 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).
Respiratory depression occurs most frequently in overdose situations, in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.
Hydromorphone should be used with extreme caution in patients with cor pulmonale, patients having a substantially decreased respiratory reserve (e.g. kyphoscoliosis), hypoxia, or hypercapnia. In such patients even usual therapeutic doses of opioid analgesics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnoea.
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, (see Section 4.2 Dose and Method of Administration), together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.

Sleep-related breathing disorders.

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent manner. Opioids may also cause worsening of pre-existing sleep apnoea (see Section 4.8 Adverse Effects (Undesirable Effects)). In patients who present with CSA, consider decreasing the total opioid dosage.

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 Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection and the concomitant use 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 Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection 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 Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection.

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).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection, especially by children, can result in a fatal overdose of hydromorphone hydrochloride. Patients and their caregivers should be given information on safe storage and disposal of unused Hydromorphone/Hydromorphone HP/Hydromorphone XHP injection (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.

Endocrine effects.

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes.

Special risk patients.

In general, opioids should be given with caution and the initial dose should be reduced in the debilitated and those with severe impairment of pulmonary function; sleep apnoea; myxoedema or hypothyroidism; adrenocortical insufficiency (e.g. Addison's disease); CNS depression or coma; toxic psychosis; prostatic hypertrophy or urethral stricture; gall bladder disease; acute alcoholism; delirium tremens; pancreatitis; constipation or following gastrointestinal surgery as opioids are known to impair intestinal motility and should not be used until the physician is assured of normal bowel function. Should paralytic ileus be suspected or occur during use, hydromorphone hydrochloride preparations should be discontinued immediately. The administration of opioid analgesics including hydromorphone may obscure the diagnoses or clinical course in patients with acute abdominal conditions and may aggravate pre-existing convulsions in patients with convulsive disorders. Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients, administered high doses of parenteral hydromorphone, for cancer and severe pain.

Head injury and increased intracranial pressure.

The respiratory depressant effects of hydromorphone with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or pre-existing increase in intracranial pressure. Opioid analgesics, including hydromorphone, may produce effects which can obscure the clinical course and neurologic signs of further increase in intracranial pressure in patients with head injuries.

Hypotensive effect.

Opioid analgesics, including hydromorphone, may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by depleted blood volume or a concurrent administration of drugs such as phenothiazines or general anaesthetics (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Therefore, hydromorphone should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Hydromorphone may produce orthostatic hypotension in ambulatory patients.

Use in surgery.

Hydromorphone hydrochloride injections should be used with caution pre- or intra-operatively and within the first 24 hours post-operatively.
Opioid analgesics including hydromorphone should also be used with caution in patients requiring biliary tract procedures since it may cause spasm of the sphincter of Oddi.

Use in hepatic impairment.

Opioids should be given with caution and the initial dose should be reduced in those with hepatic impairment.

Use in renal impairment.

Opioids should be given with caution and the initial dose should be reduced in those with renal impairment.

Use in the elderly.

Elderly subjects have been shown to have at least twice the sensitivity (as measured by EEG changes) of young adults to some opioids. When administering hydromorphone hydrochloride preparations to the elderly, the initial dose should be reduced (see Section 4.2 Dose and Method of Administration).

Paediatric use.

See Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Central nervous system (CNS).

The concomitant use of other central nervous system depressants which include, but are not limited to sedatives (including benzodiazepines), gabapentinoids, cannabis, antihistamines, anxiolytics, hypnotics, general anaesthetics (e.g. barbiturates), phenothiazines, tranquillisers, antiemetics, antidepressants (including tricyclic antidepressants), antipsychotics, neuroleptics, other opioids or alcohol may produce additive depressant effects. Respiratory depression, hypotension and profound sedation, coma or death may occur (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol). The dose and duration of concomitant use should be limited (see Section 4.4 Special Warnings and Precautions for Use).
The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression and death.
Hydromorphone should not be given to patients taking non-selective MAOIs or within 14 days of stopping such treatment.
Opioid analgesics including hydromorphone may enhance the action of neuromuscular blocking agents and produce an extensive degree of respiratory depression.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effects have been observed on male or female fertility or sperm parameters in rats.
(Category C¹)
Literature reports of hydromorphone hydrochloride administered to pregnant Golden hamsters showed that hydromorphone is teratogenic at subcutaneous (SC) doses greater than 14 mg/kg. Evidence of a teratogenic effect has also been reported in the literature in mice and hamsters but was not observed in rat and rabbit studies conducted by the sponsor. The relevance of these findings to humans is unknown since there are no well-controlled studies of hydromorphone in pregnant women.
A pre- and post-natal study in rats showed that there was an increase in pup mortality and reduced body weight gain in the early postnatal period, associated with maternal toxicity. No effects on continued pup development or reproductive performance were observed.
Like other opioid analgesics, hydromorphone may cause respiratory depression in the newborn infant. Hydromorphone should only be used during labour after considering the needs of the mother against the risk to the foetus. In long-term treatment during pregnancy, the risk of neonatal withdrawal should be considered.
¹Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible.
Low levels of opioid analgesics have been detected in human milk. As a general rule, breast feeding should not be undertaken while a patient is receiving hydromorphone since it, and other drugs in this class, may be excreted in the milk.

4.7 Effects on Ability to Drive and Use Machines

Hydromorphone may cause drowsiness and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g. driving, operating machinery). Patients should be cautioned accordingly.

4.8 Adverse Effects (Undesirable Effects)

The adverse effects of hydromorphone are similar to those of other opioid agonist analgesics, and represent established pharmacological effects of the drug class. The major hazards include respiratory depression and apnoea. To a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest have occurred.
Adverse effects reported commonly (frequency > 1%) seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Syncopal reactions and related symptoms in ambulatory patients may be alleviated if the patient lies down.

Cardiovascular disorders.

Common: hypotension.
Uncommon: bradycardia, hypertension, palpitation, tachycardia.
Unknown: flushing.

Eye disorders.

Uncommon: blurred vision, diplopia, miosis, visual impairment.

Gastrointestinal disorders.

Very common: constipation, nausea.
Common: abdominal pain, dry mouth, vomiting.
Uncommon: cramps, diarrhoea, dysgeusia (taste alteration), paralytic ileus.

General disorders and administration site conditions.

Common: asthenia, injection site reactions (following parenteral administration only).
Uncommon: chills, drug tolerance, drug withdrawal syndrome, drug withdrawal syndrome neonatal, peripheral oedema, fatigue, malaise.

Hepatobiliary disorders.

Uncommon: biliary colic, increased hepatic enzymes.

Immune system disorders.

Uncommon: anaphylactic reactions, hypersensitivity reactions (including oropharyngeal swelling).

Metabolism and nutrition disorders.

Common: anorexia.

Nervous system disorders.

Very common: dizziness, somnolence.
Common: headache, light-headedness, sedation.
Uncommon: convulsions, dyskinesia, faintness, hyperalgesia, increased intracranial pressure, myoclonus, uncoordinated muscle movement, muscle rigidity, paraesthesia, syncope, tremor, weakness.
Rare: lethargy.
Not known: central sleep apnoea syndrome.

Psychiatric disorders.

Common: anxiety, confusional state, dysphoria, euphoria, insomnia, nervousness.
Uncommon: agitation, drug dependence, alterations of mood (apprehension, depression, floating feelings), transient hallucinations, disorientation, nightmares.

Renal and urinary disorders.

Common: urinary retention.
Uncommon: antidiuretic effects, urinary hesitancy.

Reproductive system and breast disorders.

Uncommon: erectile dysfunction.

Respiratory, thoracic and mediastinal disorders.

Uncommon: bronchospasm, dyspnoea, laryngospasm, respiratory depression.

Skin and subcutaneous tissue disorders.

Common: hyperhidrosis (sweating), pruritus, rash.
Uncommon: urticaria and other skin rashes.

Key.

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Other.

In clinical trials, neither local tissue irritation nor induration was observed at the site of subcutaneous injection of hydromorphone hydrochloride HP injection/XHP concentrated injection; pain at the injection site was rarely observed.

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

Symptoms.

Serious overdosage with hydromorphone is characterised by respiratory depression (reduced respiratory rate and/or tidal volume, cyanosis), extreme somnolence, progressing to stupor, coma or pneumonia aspiration, skeletal muscle flaccidity, cold and/or clammy skin, pupillary constriction, and possibly bradycardia, hypotension and death. Severe overdose may result in apnoea, pulmonary oedema, circulatory collapse and death.
Toxic leukoencephalopathy has been observed with hydromorphone overdose.

Treatment.

The primary concern in the treatment of opioid overdose is immediate supportive therapy with the establishment of adequate respiratory exchanges through the provision of, and maintenance of, adequate ventilation - patients may need ventilatory support up to and including endotracheal intubation and controlled ventilation. Adequate body temperature and fluid balance should be maintained. Oxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated.
Tolerance to the respiratory and CNS-depressant effects of opioids develops concomitantly with tolerance to the analgesic effects, therefore making respiratory depression unlikely in an opioid-tolerant patient taking the usual therapeutic doses of hydromorphone. Activated charcoal may reduce absorption of the drug if given within one to two hours after ingestion. A potentially serious recent oral ingestion of hydromorphone, if suspected, may be treated with activated charcoal in a patient who is fully conscious with an intact gag reflex or a secured airway. Initial dose of charcoal is 30 to 100 g in adults and 1 - 2 g/kg in children and is given as a slurry via nasogastric tube. In patients who are not fully conscious or have an impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
If there are signs of clinically significant respiratory or cardiovascular depression, the use of an opioid antagonist such as naloxone should be considered (please refer to naloxone product information for further information).
Caution should always be observed when using an opioid antagonist for the treatment of suspected hydromorphone overdose as the duration of action of hydromorphone may exceed that of the antagonist. Continuing surveillance is mandatory to prevent recurrence of respiratory depression and supportive care - including ventilatory and circulatory resuscitation/support when indicated - should always be provided. Additional doses of antagonist may be given as indicated by the clinical situation.
Opioid antagonists such as naloxone may precipitate withdrawal in opioid-dependent patients and should be carefully titrated to the desired degree of reversal. The severity of the withdrawal precipitated by administration of an opioid antagonist is contingent upon the degree of dependence and the dose of antagonist given. Too rapid or complete reversal may induce nausea, vomiting, sweating and circulatory stress and may reverse the desirable therapeutic effects (analgesia) as well.

Toxicity.

Toxicity may result from overdosage but because of the great interindividual variation in sensitivity to opioids it is difficult to determine an exact dose of any opioid that is toxic or lethal. The toxic effects and signs of overdosage may be less pronounced than expected, when pain and/or tolerance are manifest.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Hydromorphone is an opioid agonist with no antagonist activity. Many of the effects described below for hydromorphone are common to the class of mu-opioid agonist analgesics (e.g. morphine). In some instances, data may not exist to distinguish the effects of hydromorphone from those observed with other opioid analgesics. However, in the absence of data to the contrary, it is assumed that hydromorphone would mirror the pharmacological effects of mu-agonist opioids.
Although estimates vary, hydromorphone is thought to be approximately eight times as potent (by weight) as morphine. It is estimated that 1.3 mg of intramuscular (IM) hydromorphone is equianalgesic to 10 mg of IM morphine. The relative potency, (based on a single dose bioassay) of oral hydromorphone was found to be approximately one-fifth that of IM hydromorphone - this ratio being similar to that for morphine. However, clinical experience with morphine indicates that this 1:5 ratio changes to 1:2 with chronic oral dosing. Such a change in oral-parenteral relative potency may also occur with hydromorphone.
Opioid analgesics exert their primary effects on the central nervous system (CNS) and organs containing smooth muscle. The principal actions of therapeutic value are analgesia and sedation. A significant feature of the analgesia is that it can occur without loss of consciousness. Opioid analgesics also suppress the cough reflex and may cause respiratory depression, mood changes, mental clouding, euphoria, dysphoria, nausea, vomiting and electroencephalographic changes. The precise mode of analgesic action of opioid analgesics is unknown. However, specific CNS opiate receptors have been identified. Opioids are believed to express their pharmacological effects through interaction with these receptors.
Opioids depress the respiratory reflex by a direct effect on brain stem respiratory centres and reducing the responsiveness of these centres to increases in carbon dioxide.
Opioids can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi. Gastric, biliary and pancreatic secretions are decreased by opioids. Opioids cause a reduction in gastrointestinal motility. Digestion of food in the small intestine is delayed and propulsive contractions are decreased resulting in constipation.
Certain opioids produce peripheral vasodilation which may result in orthostatic hypotension. Release of histamine may occur with opioids and may contribute to drug-induced hypotension. Other manifestations of histamine release may include pruritus, flushing and red eyes.
Effects on the myocardium after intravenous (IV) administration of opioids are not significant in normal persons, vary with different opioid analgesic agents and vary with the haemodynamic state of the patient, state of hydration and sympathetic drive.
In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown. Whether hydromorphone, a semisynthetic opioid, has immunological effects similar to morphine is unknown.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Hydromorphone (8 mg) is rapidly absorbed after oral administration and the plasma half-life ranges from 2.3-2.6 hours.

Distribution.

Following intravenous administration of hydromorphone to normal volunteers, the mean volume of distribution was 301 L, suggesting extensive tissue uptake. Hydromorphone is rapidly removed from the blood stream and distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Hydromorphone also crosses the placental membranes.

Metabolism.

Hydromorphone undergoes extensive first-pass metabolism resulting in oral bioavailability of about 25%. Dose proportionality between the 8 mg hydromorphone tablets and other strengths of hydromorphone tablets has not been established.
Hydromorphone metabolism is typical of that seen for the 5-ring morphinan derivatives - the primary pathway being glucuronidation in the liver. The 3-glucuronide metabolite of hydromorphone (H3G) can be isolated in a ratio of roughly 25:1 to parent drug after oral administration of hydromorphone to patients with normal renal function.

Excretion.

Following intravenous administration of hydromorphone to normal volunteers, the mean half-life of elimination was 2.64 ± 0.88 hours. Total plasma clearance following IV administration is approximately 1.85 L/min.
The major metabolite, hydromorphone-3-glucuronide (H3G), small amounts of parent drug and the minor 6-hydroxy reduction metabolites are excreted primarily in the urine.
In patients with renal impairment, suspected of having adverse reactions due to the accumulation of metabolite, H3G levels were identified at levels more than four times higher than predicted. Such accumulation of H3G may be responsible for the psychomimetic reactions occasionally reported in patients taking high doses of hydromorphone. Accumulation of neuroexcitatory metabolites is also postulated as the aetiology of similar and occasionally severe dystonic reactions reported with high doses of morphine and semi-synthetic opioids.

5.3 Preclinical Safety Data

Genotoxicity.

Hydromorphone was non-genotoxic in the Ames test and the in vivo mouse micronucleus assay but positive in mouse lymphoma assay with metabolic activation. Similar findings have been reported with other opioid analgesics such as codeine and oxycodone.

Carcinogenicity.

Long term carcinogenicity studies have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, water for injections, citric acid, sodium citrate dihydrate, hydrochloric acid or sodium hydroxide.

6.2 Incompatibilities

Pharmaceutical incompatibility.

Hydromorphone hydrochloride is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions which do not have a pH > 7.
Hydromorphone hydrochloride injection is incompatible with soluble barbiturates.

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. Protect from light.

6.5 Nature and Contents of Container

Medsurge Hydromorphone injection, Medsurge Hydromorphone HP injection and Medsurge Hydromorphone XHP concentrated injection are presented as a clear colourless to yellowish solution, available in type 1 amber glass ampoules in the following presentations and pack sizes (see Table 2).
Not all presentations and pack sizes are marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The structural formula of hydromorphone hydrochloride is:

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