Palladone SR capsules

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1. Name Of The Medicinal Product

PALLADONE®SR capsules 2 mg, 4 mg, 8 mg, 16 mg, 24 mg.

2. Qualitative And Quantitative Composition

The capsules contain Hydromorphone Hydrochloride USP 2 mg, 4 mg, 8 mg, 16 mg, 24 mg.

For excipients, see 6.1.

3. Pharmaceutical Form

Prolonged release capsule.

Hard gelatin capsule containing spherical prolonged release pellets.

PALLADONE SR capsules 2 mg are yellow/white capsules marked HCR 2.

PALLADONE SR capsules 4 mg are pale blue/clear capsules marked HCR 4.

PALLADONE SR capsules 8 mg are pink/clear capsules marked HCR 8.

PALLADONE SR capsules 16 mg are brown/clear capsules marked HCR 16.

PALLADONE SR capsules 24 mg are dark blue/clear capsules marked HCR 24.

4. Clinical Particulars 4.1 Therapeutic Indications

For the relief of severe pain in cancer.

4.2 Posology And Method Of Administration

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 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 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 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.

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

Pre-operative administration of PALLADONE SR capsules is not recommended and is not an approved indication.

4.4 Special Warnings And Precautions For Use

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 SR 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 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. 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.

The prolonged release capsules may be opened and their contents sprinkled on to soft cold food. However the capsule contents should not be chewed or crushed. The administration of chewed or crushed hydromorphone pellets may lead 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 Pregnancy And Lactation

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

4.7 Effects On Ability To Drive And Use Machines

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

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 anti-emetics

Common (incidence of

 

Common

Uncommon

Cardiac and vascular disorders

Hypotension

 

Eye disorders

 

Blurred vision

Miosis

Gastrointestinal and hepatobiliary disorders

Constipation

Dry mouth

Nausea

Vomiting

Biliary colic

Paralytic ileus

General disorders

Asthenic conditions

Drug withdrawal syndrome

Drug tolerance

Peripheral oedema

Immune system disorders

 

Hypersensitivity reactions (including oropharyngeal swelling)

Nervous system disorders

Dizziness

Somnolence

Convulsions

Dyskinesia

Headache

Sedation

Tremor

In particular in high doses hyperalgesia that will not respond to a further dose of hydromorphone (possibly dose reduction or change in opioid required).

Psychiatric disorders

Confusion

Drug addiction

Agitation

Dysphoria

Euphoria

Hallucination

Renal and urinary disorders

Urinary retention

 

Respiratory, thoracic and mediastinal disorders

 

Respiratory depression

Skin and subcutaneous tissue disorders

Pruritus

Rash

Sweating

Urticaria

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 0.01mg/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.

5.2 Pharmacokinetic Properties

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 and with smaller amounts of unchanged hydromorphone, dihydroisomorphine and dihydromorphine. PALLADONE SR capsules have been formulated to produce therapeutic plasma levels following 12-hourly dosing.

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. Pharmaceutical Particulars 6.1 List Of Excipients

Microcrystalline cellulose

Hypromellose

Ethylcellulose (N10)

Colloidal anhydrous silica

Dibutyl sebacate

Capsule shells

Gelatin

Sodium dodecylsulphate

Titanium dioxide (E171)

Black Printing ink

Shellac

Propylene glycol

Iron oxide (E172)

The following colours are included in the capsule shells:

2 mg Quinoline yellow (E104);

4 mg Erythrosine (E127), indigo carmine (E132);

8 mg Erythrosine (E127);

16 mg Iron oxide (E172);

24 mg Indigo carmine (E132).

6.2 Incompatibilities

None known.

6.3 Shelf Life

Eighteen months.

6.4 Special Precautions For Storage

Do not store above 25oC. Store in the original package.

6.5 Nature And Contents Of Container

PVdC/PVC blister packs with aluminium backing foil containing 56 capsules.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

8. Marketing Authorisation Number(S)

PL 16950/0051-0055

9. Date Of First Authorisation/Renewal Of The Authorisation

12 February 1997 / 17 January 2006

10. Date Of Revision Of The Text

May 2011

Palladone SR capsules

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