PALLADONE Solution for injection or infusion Ref.[8902] Active ingredients: Hydromorphone

Hydromorphone should be used with caution in the debilitated elderly and in patients with:

• Severely impaired respiratory function
• Sleep apnoea
• CNS depressants co-administration (see below and section 4.5)
• Head injury, intracranial lesions or increased intracranial pressure, reduced level of consciousness of uncertain origin
• Hypotension with hypovolaemia
• Pancreatitis
• Hypothyroidism
• Toxic psychosis
• Prostatic hypertrophy
• Adrenocortical insufficiency (e.g., Addison’s disease)
• Severely impaired renal function
• Severely impaired hepatic function
• Convulsive disorders
• Alcoholism
• Delirium tremens
• Biliary tract diseases, biliary or ureteric colic
• Obstructive or inflammatory bowel disorders
• Reduced respiratory reserve
• Constipation

In all these patients, reduced dosage may be advisable.

Respiratory Depression

The major risk of opioid excess is respiratory depression.

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). In patients who present with CSA, consider decreasing the total opioid dosage.

Risk from concomitant use of sedative medicines such as benzodiazepines (and other CNS depressants):

Concomitant use of Palladone injection and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Palladone injection concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g. major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with hydromorphone.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Palladone injection should not be used where the occurrence of paralytic ileus is possible. Should paralytic ileus be suspected or occur during use, hydromorphone treatment must be discontinued immediately.

Palladone injection should be used with caution pre- or intraoperatively and within the first 24 hours postoperatively.

Patients about to undergo additional pain-relieving procedures (e.g. surgery, plexus blockade) should not receive hydromorphone for 4 hours prior to the intervention. If further treatment with Palladone injection is indicated, the dosage should be adjusted to the post-operative requirement.

Opioids, such as hydromorphone, 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 be manifest from these hormonal changes.

It should be emphasised that patients, once adjusted (titrated) to an effective dose of a specific opioid, should not be changed to other opioid analgesics without clinical assessment and careful retitration as necessary. Otherwise a continuous analgesic action is not ensured.

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially “sodium-free”.

Sedative medicines such as benzodiazepines or other drugs that depress the CNS:

The concomitant use of opioids with sedative medicines such as benzodiazepines or other drugs that depress the CNS increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4). Drugs which depress the CNS include, but are not limited to: other opioids, anxiolytics, hypnotics and sedatives (including benzodiazepines), anaesthetics (e.g. barbiturates), antiemetics, antidepressants, antipsychotics (e.g. phenothiazines), antihistamines and alcohol.

Medicinal products with an anticholinergic effect (e.g. psychotropics, antiemetics, antihistamines or antiparkinsonian medicinal products) may enhance the anticholinergic undesirable effects of opioids (e.g. constipation, dry mouth or urinary retention).

Concurrent administration of hydromorphone and mono-amine oxidase inhibitors or within two weeks of discontinuation of their use is contraindicated (see section 4.3).

No interaction studies have been performed.

Pregnancy

There are no well-controlled studies of hydromorphone in pregnant women.

Hydromorphone should not be used in pregnancy unless clearly necessary.

Palladone injection is not recommended during pregnancy and labour due to impaired uterine contractility. Regular use in pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in pregnant women, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breast-feeding

Administration to nursing women is not recommended as hydromorphone is excreted into breast milk in low amounts and may cause respiratory depression in the infant.

Fertility

Non clinical toxicology studies in rats have not shown any effects on male or female fertility or sperm parameters.

Hydromorphone may impair the ability to drive and use machines. This is particularly likely at the initiation of treatment with hydromorphone, after dose increase or product rotation and if hydromorphone is combined with alcohol or other CNS depressant substances. Patients stabilised on a specific dosage will not necessarily be restricted. Patients should therefore consult with their physician whether driving or the use of machinery is permitted.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive.
• Do not drive until you know how the medicine affects you.
• It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the ‘statutory defence’). This defence applies when:
  • The medicine has been prescribed to treat a medical or dental problem; and
  • You have taken it according to the instructions given by the prescriber and in the information provided with the medicine.
• Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law.

The following frequency categories form the basis for classification of the undesirable effects: 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: Frequency cannot be estimated from the available data.

Immune system disorders

Not known: hypersensitivity reactions (including oropharyngeal swelling) anaphylactic reactions

Metabolism and nutrition disorders

Common: decreased appetite

Psychiatric disorders

Common: anxiety, confusional state, insomnia

Uncommon: agitation, depression, euphoric mood, hallucinations, nightmares

Not known: drug dependence (see section 4.4), dysphoria

Nervous system disorders

Very common: dizziness, somnolence

Common: headache

Uncommon: tremor, myoclonus, paraesthesia

Rare: sedation, lethargy

Not known: convulsions, dyskinesia, hyperalgesia (see section 4.4), sleep apnoea syndrome

Eye disorders

Uncommon: visual impairment

Not known: miosis

Cardiac disorders

Rare: bradycardia, palpitations, tachycardia

Vascular disorders

Uncommon: hypotension

Not known: flushing

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea

Rare: respiratory depression, bronchospasm

Gastrointestinal disorders

Very common: constipation, nausea

Common: abdominal pain, dry mouth, vomiting

Uncommon: dyspepsia, diarrhoea, dysgeusia

Not known: paralytic ileus

Hepato-biliary disorders

Uncommon: hepatic enzymes increased

Rare: elevation of pancreatic enzymes

Skin and subcutaneous tissue disorders

Common: pruritus, hyperhidrosis

Uncommon: rash

Not known: urticaria

Renal and urinary disorders

Common: urinary urgency

Uncommon: urinary retention

Reproduction system and breast disorders

Uncommon: decreased libido, erectile dysfunction

General disorders and administration site conditions

Common: asthenia, injection site reactions

Uncommon: drug withdrawal syndrome, fatigue, malaise, peripheral oedema

Very rare: injection site induration (particularly after repeated s.c. administration)

Not known: drug tolerance, drug withdrawal syndrome neonatal

Paediatric population

For infants born to mothers receiving hydromorphone see section 4.6.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Cyclizine lactate was found to precipitate in the presence of Palladone injection unless the solution is sufficiently diluted with water for injection. It is recommended that water for injection be used as a diluent as cyclizine was found to precipitate in the presence of 0.9% saline.