PALLADONE SR 16 MG PROLONGED-RELEASE CAPSULES - Summary of medicine characteristics

Palladone SR 16mg prolonged-release Capsules

2 QUALITATIVE AND QUANTITATIVECOMPOSITION

Each capsule contains hydromorphone hydrochloride 16 mg.

For the full list of excipients, see section 6.1.

Prolonged release capsule.

Hard gelatin capsule containing spherical controlled release pellets.

PALLADONE-SR capsules 16 mg are brown/clear capsules marked HCR16.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the relief of severe pain in cancer.

PALLADONE-SR capsules are indicated in adults and children aged 12 years and above.

4.2 Posology and method of administration

Posology

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with hydromorphone in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Adults and children aged 12 years and above

Palladone SR capsules should be used at 12 hourly intervals. The dosage is dependent upon the severity of the pain and the patient’s previous history of analgesic requirements. 4 mg of hydromorphone has an efficacy approximately equivalent to 30 mg of morphine sulphate given orally. A patient presenting with severe pain should normally be started on a dosage of 4 mg Palladone SR capsules 12 hourly. Increasing severity of pain may require increased dosage of hydromorphone to achieve the desired relief.

Elderly and patients with renal impairment

The elderly and patients with renal impairment should be dose titrated with Palladone SR capsules in order to achieve adequate analgesia. It should be noted, however, that these patients may require a lower dosage to achieve adequate analgesia.

Patients with hepatic impairment

Contraindicated.

Paediatric population.

Not recommended.

Method of administration

For oral use.

The capsules can be swallowed whole or opened and their contents sprinkled on to cold soft food.

4.3 Contraindications

Hydromorphone is contra-indicated in patients with:

Known hypersensitivity to hydromorphone or any of the excipients

Severe respiratory depression with hypoxia and/or hypercapnia

Severe chronic obstructive lung disease

Severe bronchial asthma

Paralytic ileus

Acute abdomen

Coma

Hepatic impairment

Concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation

4.4 Special warnings and precautions for use

Hydromorphone should be administered 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

Alcoholism

Delirium tremens

Convulsive disorders

Constipation

Shock or reduced respiratory reserve.

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 preexisting 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 SR capsules 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 SR capsules 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).

Palladone SR capsules are not recommended for pre-operative use or in the first 24 hours post-operatively. After this time they should be used with caution, particularly following abdominal surgery.

Palladone SR capsules should not be used where there is the possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Palladone SR capsules should be discontinued.

Patients about to undergo cordotomy or other pain relieving surgical procedures should not receive Palladone SR capsules for 24 hours prior to surgery. If further treatment with Palladone SR capsules is indicated then the dosage should be adjusted to the new post-operative requirement.

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 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.

The prolonged release capsules may be opened and their contents sprinkled onto soft cold food.

The content (pellets) of the prolonged release capsules must be swallowed whole, and not broken, chewed or crushed. The administration of broken, chewed or crushed hydromorphone pellets leads to a rapid release and absorption of a potentially fatal dose of hydromorphone (see section 4.9).

Concomitant use of alcohol and Palladone SR capsules may increase the undesirable effects of Palladone SR capsules; concomitant use should be avoided.

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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 effects. 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.

Co-administration with monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use is contraindicated (see section 4.3).

Alcohol may enhance the pharmacodynamic effects of Palladone SR capsules; concomitant use should be avoided.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no well-controlled studies of hydromorphone in pregnant women. Hydromorphone should not be used in pregnancy unless clearly necessary. Palladone SR capsules are 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.

4.7 Effects on ability to drive and use machines

Hydromorphone may cause drowsiness and patients should not drive or operate machinery if affected.

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/…-driving-law

4.8 Undesirable effects

Hydromorphone may cause constipation, nausea and vomiting. Constipation may be treated with appropriate laxatives. When nausea and vomiting are troublesome Palladone SR capsules can be readily combined with antiemetics.

The following frequency categories form the basis for classification of the undesirable effects:

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.

4.9 Overdose

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: natural opium alkaloid

ATC code: N02A A03

Like morphine, hydromorphone is an agonist of mu receptors. The pharmacological actions of hydromorphone and morphine do not differ significantly. The oral analgesic potency ratio of hydromorphone to morphine is approximately 5–10:1. Hydromorphone and related opioids produce their major effects on the central nervous system and bowel. The effects are diverse and include analgesia, drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting and alteration of the endocrine and autonomic nervous system.

Endocrine system See section 4.4.

Other pharmacological effects

In vitro and preclinical 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.

5.2 Pharmacokinetic properties

Absorption:

Hydromorphone is absorbed from the gastrointestinal tract and undergoes presystemic elimination resulting in an oral bioavailability of about 32%.

Distribution

Plasma protein binding of hydromorphone is low (< 10 %). This percentage remains constant up to very high plasma levels of approximately 80 ng/ml, which are only very rarely achieved with very high hydromorphone do­ses.

Metabolism

Hydromorphone is metabolised by direct conjugation or reduction of the keto group with subsequent conjugation. Hydromorphone is primarily metabolised to hydromorphone-3-glucuronide, hydromorphone-3-glucoside and dihydroisomorphine-6-glucuronide. Smaller portions of the metabolites dihydroisomorphine-6-glucoside, dihydromorphine and dihydroisomorphine have also been found. Hydromorphone is metabolised via the liver; a smaller portion is excreted unchanged via the kidneys.

Elimination

Hydromorphone metabolites were found in plasma, urine and human hepatocyte test systems. There are no indications to hydromorphone being metabolised in vivo via the cytochrome P 450 enzyme system. In vitro, hydromorphone has but a minor inhibition effect (IC50 > 50 pM) on recombinant CYP isoforms, including CYP1A2, 2A6, 2C8, 2D6 und 3A4. Hydromorphone is therefore not expected to inhibit the metabolism of other active substances which metabolise via these CYP isoforms.

5.3 Preclinical safety data

Carcinogenicity

Hydromorphone was non-genotoxic in a bacterial mutation test, in the in vitro human lymphocyte chromosome aberration assay and the in vivo mouse micronucleus assay but positive in the mouse lymphoma assay with metabolic activation. Similar findings have been reported with other opioid analgesics. Long term carcinogenicity studies have not been performed.

Reproductive toxicity

No effects have been observed on male or female fertility or sperm parameters in rats.

Hydromorphone was not teratogenic in pregnant rats nor rabbits given oral doses during the major period of organ development. Evidence of a teratogenic effect in mice and hamsters has been reported in the literature.

In a rat pre- and post-natal study, 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.

6.1 List of excipients

Microcrystalline cellulose Hypromellose

Ethylcellulose (N10) Colloidal anhydrous silica Dibutyl sebacate

Capsule shells

Gelatin

Sodium laurilsulfate

Titanium dioxide (E171)

Iron oxide (E172)

Black printing ink Shellac

Propylene glycol Iron oxide (E172)

6.2. Incompatibilities

None known.

6.3. Shelf Life

Eighteen months.

6.4. Special Precautions for Storage

Do not store above 25°C. Store in the original package.

6.5. Nature and Contents of Container

a) PVdC/PVC blister packs with aluminium backing foil.

b) Polypropylene containers with polyethylene lids.

Pack sizes: 30, 56, 60 capsules.