SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Shortec 10 mg capsules, hard

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each capsule contains 9 mg of oxycodone as 10 mg of oxycodone hydrochloride. For full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Capsule, hard (capsule)

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

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of moderate to severe pain in patients with cancer and postoperative pain. For the treatment of severe pain requiring the use of a strong opioid.

4.2    Posology and method of administration

Route of administration:

Oral

In common with other strong opioids, the need for continued treatment should be assessed at regular intervals.

Adults over 18 years:

Shortec 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.

Increasing severity of pain will require an increased dosage of Shortec capsules. The correct dosage for any individual patient is that which controls the pain and is well tolerated throughout the dosing period. Patients should be titrated to pain relief unless unmanageable adverse drug reactions prevent this.

The usual starting dose for opioid naive patients or patients presenting with severe pain uncontrolled by weaker opioids is 5 mg, 4-6 hourly. The dose should then be carefully titrated, as frequently as once a day if necessary, to achieve pain relief. The majority of patients will not require a daily dose greater than 400 mg. However, a few patients may require higher doses.

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 Shortec 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.

Patients with renal or hepatic impairment:

The plasma concentration in this patient population may be increased. 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 naive patients), and each patient should be titrated to adequate pain control according to their clinical situation.

Children under 18 years:

Shortec capsules should not be used in patients under 18 years.

Use in non-malignant pain:

Opioids are not first-line therapy for chronic non-malignant pain, nor are they recommended as the only treatment. Types of chronic pain which have been shown to be alleviated by strong opioids include chronic osteoarthritic pain and intervertebral disc disease. The need for continued treatment in non-malignant pain should be assessed at regular intervals.

Duration of treatment

Oxycodone should not be used for 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.

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, head injury, paralytic ileus, acute abdomen, delayed gastric emptying, severe chronic obstructive lung disease, cor pulmonale, severe bronchial asthma, elevated carbon dioxide levels in the blood, moderate to severe hepatic impairment, chronic constipation.

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; opioid-dependent patients; patients with severely impaired pulmonary function, patients with impaired hepatic or renal function; patients with myxedema, hypothyroidism, Addison’s disease, toxic psychosis, prostate hypertrophy, adrenocortical insufficiency, alcoholism, delirium tremens, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, hypotension, hypovolaemia, and patients with raised increased intracranial pressure, head injury (due to risk of increased intracranial pressure) or patients taking MAO inhibitors.

Shortec capsules should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Shortec capsules should be discontinued immediately.

Shortec capsules should be used with caution pre-operatively and within the first 1224 hours post-operatively.

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.

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive Shortec capsules for 6 hours prior to the intervention. If further treatment with oxycodone is indicated then the dosage should be adjusted to the new post-operative requirement.

For appropriate patients who suffer with chronic non-malignant pain, opioids should be used as part of a comprehensive treatment programme involving other medications and treatment modalities. A crucial part of the assessment of a patient with chronic non-malignant pain is the patient’s addiction and substance abuse history.

If opioid treatment is considered appropriate for the patient, then the main aim of treatment is not to minimise the dose of opioid, but rather to achieve a dose which provides adequate pain relief with a minimum of side effects. There must be frequent contact between physician and patient so that dosage adjustments can be made. It is strongly recommended that the physician defines treatment outcomes in accordance with pain management guidelines. The physician and patient can then agree to discontinue treatment if these objectives are not met.

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.

The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate or heart rate.

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 agonist opioids. Oxycodone 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. Shortec should be used with particular care in patients with a history of alcohol and drug abuse.

As with other opioids, infants who are born to dependent mothers may exhibit withdrawal symptoms and may have respiratory depression at birth.

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 Shortec capsules may increase the undesirable effects of Shortec capsules; concomitant use should be avoided.

Sunset yellow, a constituent of the 5mg capsule, can cause allergic-type reactions such as asthma. This is more common in people who are allergic to aspirin.

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 tranquillisers, anaesthetics, hypnotics, antidepressants, sedatives, phenothiazines, neuroleptic drugs, other opioids, muscle relaxants and antihypertensives.

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.

MAO inhibitors are known to interact with narcotic analgesics. MAO-inhibitors cause CNS excitation or depression associated with hypertensive or hypotensive crisis (see section 4.4).

Alcohol may enhance the pharmacodynamic effects of Shortec, 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 coadministered drugs or dietary elements.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azole-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, carbamazepine, phenytoin and St Johns 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.

Concurrent administration of quinidine resulted in an increase in oxycodone Cmax by 11%, AUC by 13%, and t'A elim. by 14%. Also an increase in noroxycodone level was observed, (Cmax by 50%; AUC by 85%, and t'A elim. by 42%). The pharmacodynamic effects of oxycodone were not altered.

4.6 Fertility, pregnancy and lactation

Pregnancy

Shortec capsules are not recommended for use in pregnancy nor during labour. 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.

Breastfeeding

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

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. Therefore, 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

Adverse drug reactions are typical of full opioid agonists. Tolerance and dependence may occur (see Section 4.4). Constipation may be prevented with an appropriate laxative. If nausea and vomiting are troublesome, oxycodone may be combined with an anti-emetic.

The following frequency categories form the basis for classification of the undesirable effects:

Term	Frequency
Very common Common Uncommon Rare Very rare Frequency not known	> 1/10 >    1/100 to <1/10 >    1/1,000 to <1/100 >1/10,000 to <1/1,000 <1/10,000 Cannot be estimated from the available data

Immune system disorders:

Uncommon', hypersensitivity, anaphylactic responses.

Frequency not known: anaphylactic reaction, anaphlactoir reaction Metabolism and nutrition disorders:

Common: decreased appetite.

Uncommon: dehydration.

Psychiatric disorders:

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

Uncommon: agitation, affect lability, euphoric mood, hallucinations, decreased libido, drug dependence (see section 4.4), disorientation, mood altered, restlessness, dysphoria Frequency not known: aggression.

Nervous system disorders:

Very common: somnolence, dizziness, headache.

Common: tremor, lethargy, sedation.

Uncommon: amnesia, convulsion, hypertonia, hypoaesthesia, involuntary muscle contractions, speech disorder, syncope, paraesthesia, dysgeusia, hypotonia.

Frequency not known: hyperalgesia.

Eye disorders:

Uncommon: visual impairment, miosis.

Ear and labyrinth disorders:

Uncommon: vertigo.

Cardiac disorders:

Uncommon: palpitations (in the context of withdrawal syndrome), supraventricular tachycardia.

Vascular disorders:

Uncommon: vasodilatation, facial flushing,

Rare: hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea, bronchospasm, cough decreased.

Uncommon: respiratory depression, hiccups.

Gastrointestinal disorders:

Very common: constipation, nausea, vomiting.

Common: abdominal pain, diarrhoea, dry mouth, dyspepsia.

Uncommon:, dysphagia, flatulence, eructation, ileus, gastritis.

Frequency not known: dental caries.

Hepato-biliary disorders:

Uncommon: increased hepatic enzymes, biliary colic.

\Frequency not known: cholestasis.

Skin and subcutaneous tissue disorders:

Very common: pruritus.

Common: rash, hyperhidrosis.

Uncommon: dry skin, exfoliative dermatitis.

Rare: urticaria.

Renal and urinary disorders:

Uncommon: urinary retention, ureteral spasm.

Reproductive system and breast disorders:

Uncommon: erectile dysfunction, hypoganadism.

Frequency not known: amenorrhoea.

General disorders and administration site conditions:

Common: asthenia, fatigue .

Uncommon: drug withdrawal syndrome, malaise, oedema, peripheral oedema, drug tolerance, thirst, pyrexia, chills.

Frequency not known: drug withdrawal syndrome neonatal..

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

Acute overdose with oxycodone can be manifested by miosis, respiratory depression and hypotension. Circulatory failure and somnolence progressing to stupor or deepening coma, hypotonia, bradycardia, pulmonary oedema and death may occur in more severe cases.

Treatment of oxycodone overdosage: primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation. 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 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 2minute 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 that 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 oxycodone overdosage. 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.

Additional/other considerations:

•    Consider activated charcoal (50 g for adults, 10-15 g 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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Natural opium alkaloids ATC code: N02A A05

Oxycodone is a full opioid agonist with no antagonist properties. It has an affinity for kappa, mu and delta opiate receptors in the brain and spinal cord. The therapeutic effect is mainly analgesic, anxiolytic and sedative.

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 semisynthetic opioid, has immunological effects similar to morphine is unknown.

5.2 Pharmacokinetic properties

Compared with morphine, which has an absolute bioavailability of approximately 30%, oxycodone has a high absolute bioavailability of up to 87% following oral administration. Oxycodone has an elimination half-life of approximately 3 hours and is metabolised principally to noroxycodone via CYP450-3A and oxymorphone via

CYP450-2D6. Oxymorphone has some analgesic activity but is present in the plasma in low concentrations and is not considered to contribute to oxycodone’s pharmacological effect.

5.3 Preclinical safety data

Oxycodone was not mutagenic in the following assays: Ames Salmonella and E. coli test with and without metabolic activation at doses of up to 5000 pg, chromosomal aberration test in human lymphocytes (in the absence of metabolic activation and with activation after 48 hours of exposure) at doses of up to 1500 pg g/ml, and in the in vivo bone marrow micronucleus assay in mice (at plasma levels of up to 48 pg g/ml). Mutagenic results occurred in the presence of metabolic activation in the human chromosomal aberration test (at greater than or equal to 1250 pg g/ml) at 24 but not 48 hours of exposure and in the mouse lymphoma assay at doses of 50 pg g/ml or greater with metabolic activation and at 400 pg/ml or greater without metabolic activation. The data from these tests indicate that the genotoxic risk to humans may be considered low.

Studies of oxycodone in animals to evaluate its carcinogenic potential have not been conducted owing to the length of clinical experience with the drug substance.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose, microcrystalline Magnesium stearate Titanium dioxide (E171) Iron oxide (E172)

Indigo carmine (E132) Sodium laurilsulfate Gelatin

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

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

Four years.

6.4    Special precautions for storage

Do not store above 30°C.

6.5    Nature and contents of container

PVdC coated PVC blister packs with aluminium backing foil. Polypropylene containers with polyethylene lids.

Pack sizes: 28, 56, 112 capsules.

6.6    Special precautions for disposal

None stated.

7 MARKETING AUTHORISATION HOLDER

Qdem Pharmaceuticals Ltd Cambridge Science Park Milton Road Cambridge CB4 0AB