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Mundipharma Pharmaceuticals Limited - Formerly Napp Laboratories

Millbank House, Arkle Road, Sandyford, Dublin 18, Ireland
Telephone: +353 1 206 3800
Medical Information e-mail: info@mundipharma.ie


Summary of Product Characteristics last updated on medicines.ie: 14/08/2015
SPC OxyNorm Capsules


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1. NAME OF THE MEDICINAL PRODUCT

OxyNorm® 5, 10, 20 mg capsules


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 4.5, 9 or 18 mg of oxycodone as 5, 10 or 20 mg of oxycodone hydrochloride.

Excipients: Each 5 mg capsule contains 0.019 mg sunset yellow (E110).

For the full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Capsule, hard

OxyNorm capsules 5 mg are orange/beige, printed ONR 5.

OxyNorm capsules 10 mg are white/beige, printed ONR 10.

OxyNorm capsules 20 mg are pink/beige, printed ONR 20.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

For the treatment of severe pain.


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4.2 Posology and method of administration

Posology

Adults:

OxyNorm capsules should be taken at 4-6 hourly intervals. The dosage is dependent on the severity of the pain and the patient's previous history of analgesic requirements, the patient's body weight, and sex (higher plasma concentrations are produced in females).

The usual starting dose for debilitated elderly patients, opioid naïve patients or patients presenting with severe pain uncontrolled with weaker opioids is 5 mg 4-6 hourly. The dose should then be carefully titrated, every day if necessary, to achieve pain relief. Increases should be made where possible in 25-50% increments. The correct dosage for any individual patient is that which controls the pain and is well tolerated throughout the dosage interval. The need for escape medication more than twice a day indicates that the dosage of OxyNorm capsules should be increased.

Conversion from oral morphine:

Patients receiving oral morphine before oxycodone therapy should have their daily dose based on the following ratio: 10 mg of oral oxycodone is equivalent to 20 mg of oral morphine. It must be emphasised that this is a guide to the dose of OxyNorm capsules required. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.

Elderly patients:

A dose adjustment is not usually necessary in elderly patients.

Controlled pharmacokinetic studies in elderly patients (aged over 65 years) have shown that compared with younger adults the clearance of oxycodone is only slightly reduced. No untoward adverse drug reactions were seen based on age, therefore adult doses and dosage intervals are appropriate.

Non-malignant pain:

Treatment with oxycodone should be short and intermittent to minimise the risk of dependence. The need for continued treatment should be assessed at regular intervals. Patients should not usually require more than 160 mg per day. For the long-term treatment of severe pain prolonged release formulations of oxycodone are available.

Cancer-related pain:

Patients should be titrated up to a dose which achieves pain relief unless unmanageable adverse drug reactions prevent this.

Patients with renal or hepatic impairment:

Unlike morphine preparations, the administration of oxycodone does not result in significant levels of active metabolites. However, the plasma concentration of oxycodone in this patient population may be increased compared with patients having normal renal or hepatic function. The dose initiation should follow a conservative approach in these patients. The recommended adult starting dose should be reduced by 50% (for example a total daily dose of 10 mg orally in opioid naïve patients), and each patient should be titrated to adequate pain control according to their clinical situation.

Adults under 20 years and paediatric population:

Not recommended.

Method of administration:

Oral use.

The capsules should be swallowed whole with water.

Duration of treatment:

Oxycodone should not be used longer than necessary.

Discontinuation of treatment:

When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.


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4.3 Contraindications

Hypersensitivity to oxycodone or to any of the excipients listed in section 6.1.

Oxycodone must not be used in any situation where opioids are contraindicated: severe respiratory depression with hypoxia, elevated carbon dioxide levels in the blood (hypercarbia), head injury, paralytic ileus, acute abdomen, delayed gastric emptying, severe chronic obstructive lung disease, severe bronchial asthma, cor pulmonale, known sensitivity to morphine or other opioids.


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4.4 Special warnings and precautions for use

The major risk of opioid excess is respiratory depression.

Caution must be exercised when administering oxycodone to the debilitated elderly; patients with severely impaired pulmonary function, impaired hepatic or renal function; patients with myxoedema, hypothyroidism, Addison's disease, toxic psychosis, adrenocortical insufficiency, prostate hypertrophy, head injury (due to the risk of raised intracranial pressure), convulsive disorders, delirium tremens, disorders of consciousness, hypotension, hypovolaemia. Use with caution in opioid dependent patients, diseases of the biliary tract, biliary or ureteric colic, pancreatitis, obstructive and inflammatory bowel disorders, chronic obstructive airways disease, reduced respiratory reserve, alcoholism or patients taking MAO inhibitors. In patients in whom caution is required, a reduction in dosage may be advisable.

OxyNorm capsules should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, OxyNorm capsules should be discontinued immediately (see section 4.3).

OxyNorm should be used with caution pre-operatively and within the first 12-24 hours post-operatively.

As with all opioid preparations, patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive OxyNorm capsules for six hours prior to the intervention. If further treatment with OxyNorm capsules is indicated then the dosage should be adjusted to the new post-operative requirement.

As with all opioid preparations, oxycodone products should be used with caution following abdominal surgery as opioids are known to impair intestinal motility and should not be used until the physician is assured of normal bowel function.

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of this product may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. Withdrawal symptoms may include yawning, mydriasis, lacrimation, rhinorrhoea, tremor, hyperhidrosis, anxiety, agitation, convulsions and insomnia.

Hyperalgesia that will not respond to a further dose increase of oxycodone may occur, particularly in high doses. An oxycodone dose reduction or change to an alternative opioid may be required.

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

The capsules should be swallowed whole, and not chewed or crushed. Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

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

It should be emphasised that patients, once titrated to an effective dose of a certain opioid, should not be changed to other analgesic preparations without clinical assessment and careful retitration as necessary. Otherwise, a continuous analgesic action is not ensured.

OxyNorm 5 mg capsules contain sunset yellow which may cause allergic reactions.


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4.5 Interaction with other medicinal products and other forms of interaction

There can be an enhanced CNS depressant effect during concomitant therapy with drugs which affect the CNS such as phenothiazines, antidepressants, anaesthetics, hypnotics, sedatives, muscle relaxants, other opioids, neuroleptic drugs, antihypertensives and SSRIs. Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

Concomitant administration of oxycodone with anticholinergics or medicines with anticholinergic activity (e.g. tricyclic anti-depressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects. Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

Monoamine oxidase inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression associated with hypertensive or hypotensive crisis (see section 4.4). Oxycodone should be used with caution in patients administered MAO-inhibitors or who have received MAO-inhibitors during the last two weeks (see section 4.4).

Alcohol may enhance the pharmacodynamic effects of OxyNorm, concomitant use should be avoided.

Oxycodone is metabolised mainly by CYP3A4, with a contribution from CYP2D6. The activities of these metabolic pathways may be inhibited or induced by various co-administered drugs or dietary elements.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azol-antifungals (e.g. ketoconazole, voriconazole, itraconazole, and posaconazole), protease inhibitors (e.g. boceprevir, ritonavir, indinavir, nelfinavir and saquinavir), cimetidine and grapefruit juice may cause a reduced clearance of oxycodone that could cause an increase of the plasma concentrations of oxycodone. Therefore the oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

• Itraconazole, a potent CYP3A4 inhibitor, administered 200 mg orally for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 2.4 times higher (range 1.5 - 3.4).

• Voriconazole, a CYP3A4 inhibitor, administered 200 mg twice-daily for four days (400 mg given as first two doses), increased the AUC of oral oxycodone. On average, the AUC was approximately 3.6 times higher (range 2.7 - 5.6).

• Telithromycin, a CYP3A4 inhibitor, administered 800 mg orally for four days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.8 times higher (range 1.3 – 2.3).

• Grapefruit Juice, a CYP3A4 inhibitor, administered as 200 ml three times a day for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.7 times higher (range 1.1 – 2.1).

CYP3A4 inducers, such as rifampicin, carbamazepin, phenytoin and St John´s Wort may induce the metabolism of oxycodone and cause an increased clearance of oxycodone that could cause a reduction of the plasma concentrations of oxycodone. The oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

• St Johns Wort, a CYP3A4 inducer, administered as 300 mg three times a day for fifteen days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 50% lower (range 37-57%).

• Rifampicin, a CYP3A4 inducer, administered as 600 mg once-daily for seven days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 86% lower.

Drugs that inhibit CYP2D6 activity, such as paroxetine and quinidine, may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations.


4.6 Fertility, pregnancy and lactation

Use of this medicinal product should be avoided to the extent possible in patients who are pregnant or lactating.

Pregnancy

There are limited data from the use of oxycodone in pregnant women. Infants born to mothers who have received opioids during the last 3 to 4 weeks before giving birth should be monitored for respiratory depression. Withdrawal symptoms may be observed in the newborn of mothers undergoing treatment with oxycodone.

Studies in rats and rabbits with oral doses of oxycodone equivalent to 3 and 47 times an adult human dose of 160 mg/day respectively, did not reveal evidence of harm to the foetus due to oxycodone.

Oxycodone penetrates the placenta. Oxycodone should not be used during pregnancy and labour due to impaired uterine contractility and the risk of neonatal respiratory depression.

Breast-feeding

Oxycodone may be secreted in breast milk and may cause respiratory depression in the newborn. Oxycodone should, therefore, not be used in breast-feeding mothers.


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4.7 Effects on ability to drive and use machines

Oxycodone may impair the ability to drive and use machines. Oxycodone may modify patients' reactions to a varying extent depending on the dosage and individual susceptibility. If affected, patients should not drive or operate machinery.


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4.8 Undesirable effects

The most commonly reported adverse reactions are nausea and constipation, both occurring in approximately 25 to 30 % of patients. If nausea or vomiting are troublesome, oxycodone may be combined with an antiemetic. Constipation should be anticipated as with any strong opioid, and treated appropriately with laxatives. Should opioid related adverse events persist, they should be investigated for an alternative cause.

Adverse drug reactions are typical of full opioid agonists, and tend to reduce with time, with the exception of constipation. Anticipation of adverse drug reactions and appropriate patient management can improve acceptability.

The most serious adverse reaction, as with other opioids, is respiratory depression (see Overdose section). This is most likely to occur in elderly, debilitated or opioid-intolerant patients.

Adverse drug reactions seen during clinical trials and from spontaneous reports are listed below:

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

Not known

Immune system disorders

hypersensitivity

anaphylactic responses

Endocrine disorders

syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders

decreased appetite

dehydration, weight fluctuation

Psychiatric disorders

abnormal dreams, abnormal thinking, anxiety, confusional state, depression, insomnia, nervousness

agitation, depersonalisation, affect lability, euphoric mood, hallucinations, decreased libido, drug dependence (see section 4.4)

aggression

Nervous system disorders

somnolence, dizziness, headache

tremor, lethargy

amnesia, convulsion, hyperkinesia, hypertonia, hypoaesthesia, hypotonia, involuntary muscle contractions, speech disorder, stupor, paraesthesia, dysgeusia, syncope

hyperalgesia

Eye disorders

lacrimation disorder, miosis, visual impairment

Ear and labyrinth disorders

tinnitus, vertigo

Cardiac disorders

palpitations (in the context of withdrawal syndrome)

Vascular disorders

vasodilatation

hypotension, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

dyspnoea, bronchospasm

rhinitis, epistaxis, hiccup, voice alteration, respiratory depression

Gastrointestinal disorders

constipation, nausea, vomiting

abdominal pain, diarrhoea, dry mouth, dyspepsia

dysphagia, flatulence, gastritis, mouth ulceration, eructation, gastrointestinal disorders, ileus, stomatitis

dental caries

Hepatobiliary disorders

hepatic enzyme increased

biliary colic, cholestasis

Skin and subcutaneous tissue disorders

pruritus

rash, hyperhidrosis

dry skin

urticaria

Renal and urinary disorders

urinary disorders

urinary retention

Reproductive system and breast disorders

erectile dysfunction, hypogonadism

amenorrhoea

General disorders and administration site conditions

asthenia, fever, fatigue

chills, chest pain, drug withdrawal syndrome, gait disturbance, malaise, oedema, peripheral oedema, drug tolerance, thirst

drug withdrawal syndrome neonatal

Tolerance may occur in patients treated with oxycodone, although this has not been a significant problem in the clinical trial programme. Patients requiring marked dose escalation should have their pain control regimen carefully reviewed.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie


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4.9 Overdose

Acute overdose with oxycodone can be manifested by respiratory depression, somnolence, progressing to stupor or coma, hypotonia, misosis, bradycardia, hypotension, pulmonary oedema and death.

Treatment of oxycodone overdose: A patent airway must be maintained. The pure opioid antagonists such as naloxone are specific antidotes against symptoms from opioid overdose. Other supportive measures should be employed as needed.

In the case of massive overdose, administer naloxone 0.8 mg intravenously. Repeat at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/ml).

The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient's response. However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established.

For less severe overdose, 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 oxycodone overdose. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on oxycodone. In such cases, an abrupt or complete reversal of opioid effects may precipitate pain and an acute withdrawal syndrome.

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


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Natural opium alkaloids

ATC code: N02A A05

Oxycodone is a full opioid agonist with no antagonist properties and has an affinity for kappa, mu and delta opiate receptors in the brain and spinal cord. The therapeutic effect is mainly analgesic, anxiolytic, antitussive and sedative. The mechanism of action involves CNS opioid receptors for endogenous compounds with opioid-like activity.

Gastrointestinal System

Opioids may induce spasm of the sphincter of Oddi.

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 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 oxycodone, a semi-synthetic opioid has immunological effects similar to morphine is unknown.


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5.2 Pharmacokinetic properties

After administration of OxyNorm capsules, peak oxycodone plasma concentrations are observed after approximately 1 hour (range 0.5 – 5.0 hours). Plasma concentrations increase in a dose linear manner for the 5-20 mg dosage range.

Oxycodone has a high absolute bioavailability of up to 87% following oral administration. It has an elimination half-life of approximately 3 hours and is metabolised principally to noroxycodone via CYP 3A4 and oxymorphone via CYP 2D6. Oxymorphone has some analgesic activity but is present in plasma in low concentrations and is not considered to contribute to oxycodone's pharmacological effect.


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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.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Cellulose, microcrystalline

Magnesium stearate

Titanium dioxide (E171)

Iron oxide (E172)

Indigo carmine (E132)

Sodium laurilsulfate

Gelatin

The 5 mg capsule also contains:

Sunset Yellow (E110)

The capsules are printed with ink containing shellac, iron oxide (E172) and propylene glycol.


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

Three years.


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6.4 Special precautions for storage

Do not store above 25°C.


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6.5 Nature and contents of container

PVdC coated PVC blister packs with aluminium backing foil.

Pack size: 56 capsules


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6.6 Special precautions for disposal and other handling

No special requirements.


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7. MARKETING AUTHORISATION HOLDER

Mundipharma Pharmaceuticals Limited

Millbank House

Arkle Road

Sandyford

Dublin 18


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8. MARKETING AUTHORISATION NUMBER(S)

PA 1688/6/4-6


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28 April 2000 / 27 April 2010


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10. DATE OF REVISION OF THE TEXT

July 2015

® OxyNorm, NAPP and the NAPP logo are Registered Trade Marks.

© 2011-2014 Napp Pharmaceuticals Limited.



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Active Ingredients

 
   Oxycodone Hydrochloride