PALLADONE^® capsules 1.3 mg and 2.6 mg.

PALLADONE capsules contain Hydromorphone Hydrochloride USP 1.3 mg or 2.6 mg.

For excipients, see 6.1

PALLADONE capsules 1.3 mg are orange/clear capsules marked HNR 1.3.

PALLADONE capsules 2.6 mg are red/clear capsules marked HNR 2.6.

For the relief of severe pain in cancer.

Route of administration

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

Dosage and administration

Adults and children over 12 years

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 will 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.

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, pregnancy, coma, acute abdomen, hepatic impairment, paralytic ileus, concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use. Hydromorphone should be avoided in patients with raised intracranial pressure or head injury, and also in patients with convulsive disorders or acute alcoholism.

The major risk of opioid excess is respiratory depression. As with all narcotics, a reduction in dosage may be advised in the elderly or infirm patients with severely impaired pulmonary function, toxic pyschosis, delirium tremens, pancreatitis, hypothyroidism, hypotension with hypovolaemia, chronic obstructive airways disease, renal or adrenocortical insufficiency, prostatic hypertrophy, shock or reduced respiratory reserve. PALLADONE capsules are not recommended in the first 24 hours post-operatively. After this time they should be used with caution, 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, 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. The patient may develop physical dependence; an abstinence syndrome may be seen following abrupt cessation. 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 a morphine-like abuse profile and may be sought and abused by people with latent or manifest addiction disorders. 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.

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.

PALLADONE capsules are not recommended in pregnancy or in the breast-feeding mother as there are insufficient animal or human data to justify such use.

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

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 anti-emetics.

Common (incidence of 1%) and uncommon ( 1%) adverse drug reactions are listed in the table below.

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 bodyweight 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 adult, 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.

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.

Hydromorphone is absorbed from the gastrointestinal tract and undergoes pre-systemic elimination resulting in an oral bioavailability of about 50%. It is metabolised and excreted in the urine mainly as conjugated hydromorphone, dihydroisomorphine and dihydromorphine.

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

Microcrystalline cellulose

Lactose (anhydrous)

Capsule shells

Gelatin

Erythrosine (E127)

Iron oxide (E172)

Titanium dioxide (E171)

Sodium dodecylsulphate

Black Printing Ink

Shellac

Propylene glycol

Iron oxide (E172)

None known.

Two years.

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

PVdC coated PVC blisters with aluminium backing foil containing 56 capsules.

None stated

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

PL 16950/0049, 0050

12 February 1997

September 2008