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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Daloxy 40 mg prolonged-release capsules, hard

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each prolonged-release capsule contains 40 mg of oxycodone hydrochloride equivalent to 35.86 mg of oxycodone.

Excipient with known effect:

40 mg prolonged-release capsule contains 105.51 mg sucrose.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release capsule, hard.

Daloxy 40 mg are opaque white capsules with a black inscription “OCR” on the body and “40” on the cap, containing white spherical microgranules.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Severe pain, which can be adequately managed only with opioid analgesics.

4.2    Posology and method of administration

Posology

The dosage depends on the intensity of pain and the patient’s individual susceptibility to the treatment.

For doses not realisable/practicable with this medicinal product, other strengths and medical products are available. However, this medicinal product is not available in 5 mg strength.

The following general dosage recommendations apply:

• Adults and adolescents 12 years of age and older

Dose titration and adjustment

In general, the initial dose for opioid naive patients is 10 mg oxycodone hydrochloride given at intervals of 12 hours. Some patients may benefit from a starting dose of 5 mg to minimize the incidence of adverse reactions. In this case, other oral available prolonged release oxycodone products have to be used for this specific 5 mg strength.

Patients already receiving opioids may start treatment with higher dosages taking into account their experience with former opioid therapies.

According to well-controlled clinical studies 10-13 mg oxycodone hydrochloride correspond to approximately 20 mg morphine sulphate, both in the prolonged-release formulation.

Because of individual differences in sensitivity for different opioids, it is recommended that patients should start conservatively with oxycodone hydrochloride prolonged-release capsules after conversion from other opioids, with 50-75% of the calculated oxycodone dose.

Some patients who take oxycodone hydrochloride prolonged-release capsules following a fixed schedule need rapid-release analgesic as rescue medication in order to control breakthrough pain.

Oxycodone hydrochloride prolonged-release capsules are not indicated for the treatment of acute pain and/or breakthrough pain. The single dose of the rescue medication should amount to 1/6 of the equianalgesic daily dose of oxycodone hydrochloride prolonged-release capsules. Use of the rescue medication more than twice daily indicates that the dose of oxycodone hydrochloride prolonged-release capsules needs to be increased. The dose should not be adjusted more often than once every 1-2 days until a stable twice daily administration has been achieved.

Following a dose increase from 10 mg to 20 mg, taken every 12 hours, dose adjustments should be made in steps of approximately one-third of the daily dose. The aim is a patient-specific dosage which, with twice daily administration, allows for adequate analgesia with tolerable undesirable effects and as little rescue medication as possible as long as pain therapy is needed.

Even distribution (the same dose in the morning and in the evening) following a fixed schedule (every 12 hours) is appropriate for the majority of the patients. For some patients it may be advantageous to distribute the dose unevenly. In general, the lowest effective analgesic dose should be chosen.

For the treatment of non malignant pain a daily dose of 40 mg is generally sufficient; but higher dosages may be necessary. Patients with cancer-related pain may require dosages of 80 to 120 mg, which in individual cases can be increased to up to 400 mg. If even higher doses are required, the dose should be decided individually balancing efficacy with tolerance and the risk of undesirable effects

•    Children under 12 years

There were no studies in patients below 12 years of age, therefore oxycodone hydrochloride should not be used in patients under 12 years.

•    Elderly people

Elderly patients without clinically manifestation of impaired liver and/or kidney function usually do not require dose adjustments.

• Risk patients

Risk patients, for example patients with impaired renal or hepatic function, low body weight or slow metabolism of medicinal products, should initially receive half the recommended adult dose if they are opioid naive. Therefore the lowest recommended dosage in the SmPC, i.e. 10 mg, may not be suitable as a starting dose. In this case, other oral available prolonged release oxycodone products have to be used for this specific 5 mg strength.

Dose titration should be performed in accordance with the individual clinical situation. Method of administration

For oral use.

Daloxy prolonged-release capsules should be taken twice daily based on a fixed schedule at the dosage determined.

The prolonged-release capsules may be taken with or independent of meals with a sufficient amount of liquid. Daloxy prolonged-release capsules must be swallowed whole, and they must not be broken, crushed or chewed to avoid damage to the prolonged-release characteristics of the microgranules.

Duration of treatment

Oxycodone should not to be taken longer than necessary. If long-term treatment is necessary due to the type and severity of the illness, careful and regular monitoring is required to determine whether and to what extent treatment should be continued. If opioid therapy is no longer indicated it may be advisable to reduce the daily dose gradually in order to prevent symptoms of a withdrawal syndrome.

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 and/or hypercapnia,

•    Severe chronic obstructive pulmonary disease,

•    Cor pulmonale,

•    Severe bronchial asthma,

•    Paralytic ileus,

•    Pregnancy (see section 4.6),

•    Lactation (see section 4.6),

•    Acute abdomen, delayed gastric emptying.

4.4 Special warnings and precautions for use

Daloxy is not recommended for use in children below the age of 12 years due to insufficient data on safety and efficacy.

The major risk of opioid excess is respiratory depression. Caution must be exercised when administering oxycodone to elderly or debilitated patients; patients with severe impairment of pulmonary, hepatic or renal function; patients with myxedema, hypothyroidism, adrenocortical insufficiency (Addison's disease), prostatic hypertrophy, toxic psychosis (e.g. alcohol), alcoholism, delirium tremens, known opioid dependence, pancreatitis, diseases of the biliary tract (cholelithiasis), obstructive and inflammatory intestinal diseases, hypotension, hypovolaemia, patients with head injury (due to risk of increased intracranial pressure) and those whose ability to maintain blood pressure has been compromised, epileptic disorder or predisposition to convulsions or patients taking MAO inhibitors. With the occurrence or suspicion of paralytic ileus, Daloxy should be immediately discontinued.

Patients with severe hepatic impairment should be closely monitored.

Respiratory depression is the chief hazard of an opioid overdose and occurs most commonly in elderly or debilitated patients. The respiratory depressant effects of oxycodone may cause carbon dioxide retention in the blood and secondarily in the cerebrospinal fluid. Opioids may cause severe hypotension in susceptible individuals.

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. Cross tolerance to other opioids usually occurs. 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, palpitations, convulsions and insomnia.

Hyperagelsia that will not respond to a further dose increase of oxycodone may very rarely 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. But when used as instructed in patients suffering from chronic pain, the risk of physical and psychological dependence is clearly reduced. There is potential for development of psychological dependence [addiction] to opioid analgesics, including oxycodone, however, data are not available to establish the true incidence of addiction in chronic pain patients.

Daloxy should be used with particular care in patients with a history of alcohol and drug abuse.

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

To avoid damage to the controlled release properties of the microgranules contained in the capsules the prolonged-release capsules and contents must be swallowed whole, and neither be broken, chewed nor crushed. The administration of broken, chewed or crushed controlled release oxycodone capsules leads to rapid release and absorption of a potentially fatal dose of oxycodone (see section 4.9).

Daloxy is intended for oral use only.

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

Daloxy is not recommended for pre-operative use or within the first 12-24 hours postoperatively. The exact timing for initiating Daloxy postoperative treatment depends on a careful risk-benefit assessment for each individual patient with regard to the type and extent of surgery, the anaesthetic procedure selected, other co-medication and the individual condition of the patient.

This medicinal product contains sucrose.

Patients with fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency, which are rare hereditary problems, should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol may enhance the pharmacodynamic effects of Daloxy; concomitant use should be avoided.

In-vitro studies have demonstrated that alcohol accelerates the release of oxycodone from Daloxy. For this reason the intake of alcohol is potentially dangerous during treatment with Daloxy and must be strictly avoided.

There can be an enhanced CNS depressant effect, especially the respiratory depression, during concomitant therapy with drugs which affect the CNS such as sedatives, hypnotics, phenothiazines, neuroleptics, antidepressants, antihistamines, antiemetics and other opioids or alcohol may enhance the adverse drug reactions.

Agents with anticholinergic effects (e.g. psychotropic drugs, antihistamines, antiemetics, medicinal products against Morbus Parkinson) may intensify the anticholinergic adverse drug reactions of oxycodone like constipation, dry mouth or dysfunction of urinary excretion.

Clinically relevant changes in International Normalized Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are coapplied with oxycodone.

MAO inhibitors are known to interact with narcotic analgesics. MAO inhibitors causes CNS excitation or depression associated with hyper- 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).

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), 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 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.

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

Daloxy must not be taken during pregnancy (see section 4.3).

There are limited data from the use of oxycodone in pregnant women. Oxycodone crosses the placenta.

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 sedation and respiratory depression in the breast-fed child. Daloxy is contraindicated during breastfeeding.

4.7 Effects on ability to drive and use machines

Oxycodone may impair the ability to drive and use machinery. This is more likely at the initiation of treatment with Daloxy, after dose increase or product rotation and if Daloxy is combined with alcohol or other CNS depressant agents.

Patients stabilised on a specific dose will not necessarily be restricted. Therefore, a physician should decide whether the patient is allowed to drive or use machinery.

4.8 Undesirable effects

Due to its pharmacological properties oxycodone may cause respiratory depression, miosis, bronchial spasm and spasm of unstriated muscles and may suppress the cough reflex.

The most frequently reported undesirable effects are nausea (especially at the beginning of treatment) and constipation.

Respiratory depression is the chief hazard of an opioid overdose and occurs most commonly in elderly or debilitated patients. Opioids may cause severe hypotension in susceptible individuals.

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

Frequency > 1/10

>    1/100 to < 1/10

>    1/1,000 to < 1/100

>    1/10,000 to < 1/1,000 < 1/10,000

Not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations Rare:	Herpes simplex
Immune system disorders Uncommon: Not known:	Hypersensitivity Anaphylactic reaction (shock)

Metabolism and nutrition disorders

Common:    Decreased appetite up to loss of appetite

Uncommon: Rare:	Dehydration Increased appetite
Psychiatric disorders Common:	Altered mood and personality change (e.g. anxiety, depression, euphoric mood), decreased activity, restlessness, psychomotor hyperactivity, agitation, nervousness, insomnia, abnormal thinking, confusion
Uncommon:	Perception disturbances (e.g. hallucination, derealisation), affect lability, decreased libido, drug dependence (see section 4.4)
Not known:	Aggression
Nervous system disorders Very common:	Sedation (somnolence up to a depressed level of consciousness), dizziness, headache
Common: Uncommon:	Syncope, paraesthesia, tremor Concentration impaired, migraine, dysgeusia, hypertonia, involuntary muscle contractions, hypoaesthesia, abnormal coordination, convulsions (especially in persons with epileptic disorder or predisposition to convulsions), amnesia, speech disorder
Not known:	Hyperalgesia
Eye disorders Uncommon:	Visual impairment, miosis

Ear and labyrinth disorders

Uncommon:    Hearing impaired, vertigo

Cardiac disorders Uncommon:	Tachycardia, palpitations (in the context of withdrawal syndrome)
Vascular disorders Common: Uncommon: Rare:	Hypotension Vasodilatation Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common:    Dyspnoea

Uncommon:    Dysphonia, cough, respiratory depression

Constipation, vomiting, nausea

Abdominal pain, diarrhoea, dry mouth, hiccups,

dyspepsia

Mouth ulceration, stomatitis, flatulence, dysphagia, eructation, ileus

Melaena, tooth disorder, gingival bleeding Dental caries

Skin and subcutaneous tissue disorders

Very common:    Pruritus

Common:    Skin reactions/rash, hyperhidrosis

Uncommon:    Dry skin

Rare:    Urticaria

Renal and urinary disorders

Common:    Urinary retention, dysuria, micturition urgency

Reproductive system and breast disorders

Uncommon:    Erectile dysfunction

Not known:    Amenorrhoea

General disorders and administration site conditions

Common:    Chills, asthenia

Uncommon:    Physical dependence with drug withdrawal syndrome,

pain (e.g. chest pain), malaise, edema, peripheral edema, drug tolerance, thirst

Rare:    Weight increase, weight decrease

Injury, poisoning and procedural complications

Uncommon:    Injuries from accidents

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 national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov .uk/yellowcard

4.9 Overdose

Symptoms of intoxication

Acute overdose with oxycodone can be manifested by miosis, respiratory depression, somnolence progressing up to stupor or coma, hypotonia, bradycardia and

hypotension. In more severe cases coma, non-cardiogenic pulmonary edema and circulatory failure may occur and may lead to a fatal outcome.

Therapy of intoxication

Overdose may be treated by the administration of opioid antagonists (e.g. naloxone 0.4-2 mg intravenously). Administration should be repeated at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of 0.9% sodium chloride or 5% dextrose (0.004 mg/ml naloxone). The infusion should be run at a rate related to the previously administered bolus doses and should be in accordance with the patient's response.

Emptying the stomach should be considered.

Supportive measures (including artificial ventilation, oxygen, vasopressors, and fluid infusions) should be employed in the management of shock accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Artificial ventilation should be applied if necessary. Fluid and electrolyte metabolism should be maintained.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: natural opium alkaloids, ATC code: N02AA05.

Oxycodone has affinity for kappa, mu and delta opiate receptors in the brain, spinal cord and peripheral organs. Oxycodone is an opioid agonist at these receptors with no antagonistic effect. The therapeutic effect is mainly analgesic and sedative.

Compared with conventional oxycodone, alone or in combination, Daloxy prolonged-release capsules provide a much longer period of pain relief without increased undesirable effects.

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 with these hormonal changes

5.2 Pharmacokinetic properties

Absorption and distribution

To avoid damage to the prolonged-release properties of the microgranules contained in the capsules the capsules and contents must neither be crushed nor chewed, as this leads to rapid oxycodone release.

The relative bioavailability of prolonged-release oxycodone is comparable to the conventional oral oxycodone, but the former achieves maximal plasma concentrations at about 3 hours rather than 1 to 1.5 hours. Peak and trough concentrations of the prolonged-release and the immediate-release oxycodone are similar when dosed 12 hourly and 6 hourly, respectively, with the same total daily dose. The absolute bioavailability of oxycodone amounts to about two-thirds relative to parenteral drug. Oxycodone has a volume of distribution at steady state of 2.6 l/kg; plasma protein binding in the range of 38 to 45%; an elimination half-life of 4 to 6 hours; a total plasma clearance of 0.8 l/min. Prolonged-release formulation steady-state is achieved in about one day on the average.

Biotransformation and elimination

Oxycodone is metabolized in the gut and the liver to noroxycodone and oxymorphone and to various glucuronide conjugates. Noroxycodone and oxymorphone are produced via the cytochrome P450 system. In vitro studies suggest that therapeutic doses of cimitidine are not likely to significantly influence the production of noroxycodone. Quinidine reduces the production of oxymorphone in man without substantially influencing the pharmacodynamics of oxycodone. The contribution of the metabolites to overall pharmacodynamic effect is insignificant. Oxycodone and its metabolites are excreted in both urine and feces. Oxycodone also crosses the placenta and may be detected in breast milk.

5.3 Preclinical safety data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Oxycodone wasn’t shown to have any effect on fertility and early embryonic development in male and female rats in doses of up to 8 mg/kg body weight and induced no malformation in rats in doses of up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when individual foetuses were used in statistical evaluation, a dose related increase in developmental variations was observed (increased incidences of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidence of 27 presacral vertebrae was increased and only in the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals. In a study on pre- and postnatal development in rats F1 body weights were lower at 6 mg/kg/d when compared to body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices. There were no effects on F2 generation.

Long term carcinogenicity studies have not been performed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content:

Sugar spheres (containing sucrose and maize starch) Hypromellose

Polyacrylate dispersion 30%

Talc

Capsule shell: Black Printing Ink:

Shellac

Black iron oxide (E172)

Daloxy 40 mg (White): Gelatin, Titanium dioxide (E 171)

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Do not store above 30° C.

6.5    Nature and contents of container

Polyvinylchloride / aluminium blisters.

20 prolonged-release capsules, hard 25 prolonged-release capsules, hard 28 prolonged-release capsules, hard 50 prolonged-release capsules, hard 56 prolonged-release capsules, hard 98 prolonged-release capsules, hard 100 prolonged-release capsules, hard

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements for disposal.

7    MARKETING AUTHORISATION HOLDER

ETHYPHARM

194 Bureaux de la Colline - Batiment D

92213 Saint Cloud Cedex

France

8    MARKETING AUTHORISATION NUMBER(S)

PL 06934/0165

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/02/2013

10    DATE OF REVISION OF THE TEXT

21/06/2013