SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Palladone SR 16mg prolonged-release Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains hydromorphone hydrochloride 16 mg.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged release capsule.

Hard gelatin capsule containing spherical controlled release pellets. PALLADONE-SR capsules 16 mg are brown/clear capsules marked HCR16.

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

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

Contra-indicated.

Children under 12 years

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 other ingredients in the formulation.

It is also contra-indicated in respiratory depression with hypoxia or elevated carbon dioxide levels in the blood, coma, acute abdomen, hepatic impairment, paralytic ileus, concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use.

4.4    Special warnings and precautions for use

The major risk of opioid excess is respiratory depression. Hydromorphone should be used with caution in patients with head injury (due to the risk of increased intracranial pressure), convulsive disorders, alcoholism, debilitated elderly patients and in patients with severely impaired pulmonary function, toxic psychosis, delirium tremens, pancreatitis, hypothyroidism, hypotension with hypovolaemia, chronic obstructive airways disease, renal or adrenocortical insufficiency (e.g. Addison’s disease), prostatic hypertrophy, shock or reduced respiratory reserve.

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.

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with hydromorphone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Hydromorphone has an abuse profile similar to other strong opioid agonists. Hydromorphone may be sought and abused by people with latent or manifest addiction disorders. There is a potential for development of psychological dependence (addiction) to opioid analgesics including hydromorphone. Hydromorphone should be used with particular care in patients with a history of alcohol and drug abuse.

Hyperalgesia that will not respond to a further dose increase of hydromorphone may very rarely occur in particular in high doses. A hydromorphone dose reduction or change in opioid may be required.

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, 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.

4.5 Interaction with other medicinal products and other forms of interaction

Centrally acting drugs such as major and minor tranquillisers, anaesthetics, barbiturates, antiemetics, antidepressants, neuroleptics, hypnotics, other opioids, monoamine oxidase inhibitors (see section 4.3) and sedatives may interact with hydromorphone, and potentiate the effects of either drug, e.g. sedation, respiratory depression, etc.

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 and the risk of neonatal respiratory depression. Chronic use during pregnancy may lead to withdrawal symptoms in the new-born infant (see section 5.3)

Breast-feeding

Hydromorphone is excreted into breast milk in low amounts. PALLADONE-SR capsules should not be used during breast-feeding.

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/drug-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:

Term	Frequency
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

	Very common	Common	Uncommon	Rare	Very rare	Not known
Immune system disorders						Hypersensitivit y reactions (including oropharyngeal swelling); Anaphylactic reactions
Metabolism and nutrition disorders		Decreased appetite
Psychiatric disorders		Anxiety Confusional state Insomnia	Agitation Depression Euphoric mood Hallucinatio n Nightmares			Drug dependence Dysphoria
Nervous system disorders	Dizziness Somnolence	Headache	Myoclonus Paraesthesia Tremor	Sedation Lethargy		Convulsions Dyskinesia Hyperalgesia (see section 4.4)
Eye disorders			Visual impairment			Miosis
Cardiac disorders				Tachycardia
Vascular disorders			Hypotensio n			Flushing
Respiratory, thoracic and mediastinal disorders			Dyspnoea	Respiratory depression
Gastrointestina l disorders	Constipatio n Nausea	Abdominal pain Dry mouth Vomiting	Diarrhoea Dysgeusia			Paralytic ileus
Hepatobiliary disorders			Hepatic enzymes

			increased
Skin and subcutaneous tissue disorders		Pruritus Hyperhidrosi s	Rash			Urticaria
Renal and urinary disorders			Urinary retention
Reproductive system and breast disorders			Erectile dysfunction
General disorders and administration site conditions		Asthenia	Drug withdrawal syndrome Fatigue Malaise Peripheral oedema			Drug tolerance

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.

4.9 Overdose

Signs of hydromorphone toxicity and overdosage are pin-point pupils, respiratory depression and hypotension. Circulatory failure and somnolence progressing to stupor or deepening coma, skeletal muscle flaccidity, bradycardia and death may occur in more severe cases. Rhabdomylosis progressing to renal failure has been reported in opioid overdosage.

Treatment of overdosage:

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

In the case of massive overdosage, administer naloxone intravenously (0.4 to 2 mg for an adult and 0.01 mg/kg body weight for children), if the patient is in a coma or respiratory depression is present. Repeat the dose at 2 minute intervals if there is no response. If repeated doses are required then an infusion of 60% of the initial dose per hour is a useful starting point. A solution of 10 mg made up in 50 ml dextrose will produce 200 micrograms/ml for infusion using an IV pump (dose adjusted to the clinical response). Infusions are not a substitute for frequent review of the patient’s clinical state.

Intramuscular naloxone is an alternative in the event IV access is not possible. As the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Naloxone is a competitive antagonist and large doses (4 mg) may be required in seriously poisoned patients. For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdosage. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on hydromorphone. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Other supportive measures as indicated by the patient’s progress and clinical condition should be considered

Additional/other considerations:

Consider activated charcoal (50 g for adults, 1g/kg for children), if a substantial amount has been ingested within 1 hour, provided the airway can be protected. It may be reasonable to assume that late administration of activated charcoal may be beneficial for prolonged release preparations; however there is no evidence to support this.

Palladone SR capsules will continue to release and add to the hydromorphone load for up to 12 hours after administration and management of hydromorphone overdosage should be monitored accordingly. Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug, particularly when a prolonged release formulation has been taken.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Natural opium alkaloid ATC code: NO2A 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

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 be manifest from these hormonal changes.

Other pharmacological effects

In vitro and pre clinical 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 Ethyl cellulose (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.

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.

6.6    Special precautions for disposal

None stated.

7    MARKETING AUTHORISATION HOLDER

Napp Pharmaceuticals Limited Cambridge Science Park Milton Road Cambridge CB4 0GW

8    MARKETING AUTHORISATION NUMBER(S)

PL 16950/0054

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/01/2006

10    DATE OF REVISION OF THE TEXT

09/10/2015