1 Name of Medicine
Hydromorphone hydrochloride.
2 Qualitative and Quantitative Composition
Hydromorphone-hameln 2 mg injection contains 2 mg hydromorphone hydrochloride in 1 mL solution.
Hydromorphone-hameln-HP 10 mg injection contains 10 mg hydromorphone hydrochloride in 1 mL solution.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Clear, colourless solution for injection in a clear glass ampoule.
4.1 Therapeutic Indications
Hydromorphone-hameln/Hydromorphone-hameln-HP injections are 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.
Hydromorphone-hameln-HP injection (high potency) is a highly concentrated solution of hydromorphone intended for use in opioid-tolerant patients. Do not confuse Hydromorphone-hameln-HP injection with standard parenteral formulations of Hydromorphone-hameln or other opioids. Overdose and death could result.
General.
Hydromorphone, 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, Tolerance, dependence and withdrawal). 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-hameln/Hydromorphone-hameln-HP dosage, in these patients, should be titrated to the desired analgesic effect.
Product is for single use in one patient only. Discard any residue.
Adult.
Individualisation of dosage. As with other opioid analgesics, safe and effective administration of Hydromorphone-hameln/Hydromorphone-hameln-HP 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-hameln/Hydromorphone-hameln-HP 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-hameln/Hydromorphone-hameln-HP 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 (Table 1). 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.
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 (Table 1) should be given for the first few doses, then increased as needed according to the patient's response to its analgesic effect.
The Hydromorphone-hameln/Hydromorphone-hameln-HP 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-hameln/Hydromorphone-hameln-HP 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.
Hydromorphone-hameln-HP Injection (HP = High Potency) is 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).
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).
Children.
Safety and efficacy have not been established in children.4.3 Contraindications
Hydromorphone-hameln/Hydromorphone-hameln-HP 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-hameln/Hydromorphone-hameln-HP injections contain the opioid hydromorphone and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Hydromorphone-hameln/Hydromorphone-hameln-HP injections at recommended doses.
Abuse or intentional misuse of Hydromorphone-hameln/ Hydromorphone-hameln-HP 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-hameln/Hydromorphone-hameln-HP injections.
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-hameln/Hydromorphone-hameln-HP injections 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-hameln/Hydromorphone-hameln-HP injections 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 hydromorphone, 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, patients with renal and hepatic 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.
Opioids may cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use may increase the risk of CSA in a dose-dependent manner in some patients. 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.
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-hameln/Hydromorphone-hameln-HP injections and the concomitant use with other CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active antiemetics 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-hameln/Hydromorphone-hameln-HP 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 using Hydromorphone-hameln/Hydromorphone-hameln-HP 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). 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, especially by children, can result in a fatal overdose of hydromorphone. Patients and their caregivers should be given information on safe storage and disposal of unused hydromorphone 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, above). 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. 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 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 injection 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 preparations to the elderly, the initial dose should be reduced (see Section 4.2 Dose and Method of Administration).
Paediatric use.
Safety and efficacy have not been established in children.
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), 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 C)
Australian Categorisation of Medicines in Pregnancy: Category 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. Accompanying texts should be consulted for further details.
Literature reports of hydromorphone hydrochloride administered to pregnant Golden hamsters showed that hydromorphone is teratogenic at subcutaneous 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.
Low levels of opioid analgesics have been detected in human milk. As a general rule, breastfeeding 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 high potency hydromorphone 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
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
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.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
The inactive ingredients in Hydromorphone-hameln 2 mg injection ampoule and Hydromorphone-hameln-HP 10 mg injection ampoule are sodium citrate dihydrate, citric acid monohydrate, sodium chloride, hydrochloric acid or sodium hydroxide, and water for injections.
6.2 Incompatibilities
Hydromorphone-hameln/Hydromorphone-hameln-HP injections are 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
Packs of 5 x 1 mL and 10 x 1 mL ampoules.
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 name: 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride.
Molecular weight: 321.81.
Chemical structure.
CAS number.
71-68-1.7 Medicine Schedule (Poisons Standard)
Schedule 8 (Controlled Drug).
Summary Table of Changes
