SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Palladone 1.3mg Capsules

2 QUALITATIVE    AND    QUANTITATIVE

COMPOSITION

Each capsule contains hydromorphone hydrochloride 1.3 mg.

Excipient with known effect:

Each capsule contains 39.35 mg of lactose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, hard.

Hard gelatin capsule with opaque orange, body and clear uncoloured cap, marked HNR 1.3.

4.1 Therapeutic indications

For the relief of severe pain in cancer.

Palladone 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 capsules should be used at 4 hourly intervals. The dosage is dependent upon the severity of the pain and the patient’s previous history of analgesic requirements. 1.3 mg of hydromorphone has an efficacy approximately equivalent to 10 mg of morphine given orally. A patient presenting with severe pain should normally be started on a dosage of one PALLADONE capsule 4 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 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 capsules should be used with caution pre-operatively and within the first 24 hours post-operatively, particularly following abdominal surgery.

PALLADONE capsules should not be used where there is the possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, PALLADONE capsules should be discontinued immediately. Patients about to undergo cordotomy or other pain relieving surgical procedures should not receive PALLADONE capsules for 4 hours prior to surgery. If further treatment with PALLADONE 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.

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

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

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, alcohol, 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.

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 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 newborn infant (see section 5.3)

Breast-feeding

Hydromorphone is excreted into breast milk in low amounts. Palladone 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 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						Hypersensitivity reactions (including oropharyngeal swelling);

						Anaphylactic reactions
Metabolism and nutrition disorders		Decreased appetite
Psychiatric disorders		Anxiety Confusional state Insomnia	Agitation Depression Euphoric mood Hallucination 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			Hypotension			Flushing
Respiratory, thoracic and mediastinal disorders			Dyspnoea	Respiratory depression
Gastrointestinal disorders	Constipation Nausea	Abdominal pain Dry mouth Vomiting	Diarrhoea Dysgeusia			Paralytic ileus
Hepatobiliary disorders			Hepatic enzymes increased
Skin and subcutaneous tissue disorders		Pruritus Hyperhidrosis	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.

Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: natural opium alkaloid ATC code: N02A A03

Hydromorphone is an opioid agonist with no antagonist activity. Its therapeutic action is mainly analgesic, anxiolytic, antitussive and sedative. The mechanism of action involves CNS opioid receptors for endogenous compounds with opioid-like activity. Hydromorphone and related opioids produce their major effects on the central nervous system and bowel.

The oral analgesic potency ratio of hydromorphone to morphine is approximately 5-10:1.

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 Pharmacologic Effects

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.

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

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.1 List of excipients

Microcrystalline cellulose Lactose (anhydrous)

Capsule shells Gelatin

Erythrosine (E127)

Iron oxide (E172) Titanium dioxide (E171) Sodium laurilsulfate

Black printing ink Shellac

Propylene glycol Iron oxide (E172)

6.2. Incompatibilities

None known.

6.3. Shelf Life

Two years.

6.4. Special Precautions for Storage

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

Nature and Contents of Container

PVdC coated PVC blisters with aluminium backing foil containing 30, 56 or 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 16950/0049

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/12/2005

10 DATE OF REVISION OF THE TEXT

05/11/2015