SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Candox 5 mg Prolonged-release Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 5 mg oxycodone hydrochloride equivalent to

4.5 mg oxycodone.

Excipient:

Each prolonged-release tablet contains a maximum of 15 mg sucrose.

For a full list of excipients, see section 6.1.

3.    PHARAMCEUTICAL FORM

Prolonged-release tablet.

White to off-white, round, biconvex, tablets with a diameter of 5.2 mm.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Severe pain, which can be adequately managed only with opioid analgesics. Candox is indicated in adults and adolescents aged > 12 years.

4.2    Posology and method of administration

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 medicinal products are available.

The following general dosage recommendations apply:

Adults and adolescents (> 12 years)

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 minimise the incidence of adverse reactions.

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 Candox after conversion from other opioids, with 50-75% of the calculated oxycodone dose.

Some patients who take Candox following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Candox is 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 Candox. Use of the rescue medication more than twice daily indicates that the dose of Candox 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 administration (the same dose mornings and evenings) 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 doses 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 the tolerance and risk of undesirable effects.

Duration of administration

Candox should not 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.

Elderly patients

Elderly patients without clinical 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, i.e. 10 mg, may not be suitable as a starting dose. Dose titration should be performed in accordance with the individual clinical situation.

Children under 12 years of age

Candox is not recommended for children under 12 years of age.

Method of administration For oral use.

Candox should be taken twice daily based on a fixed schedule at the dosage determined.

The prolonged-release tablets may be taken with or independent of meals with a sufficient amount of liquid. Candox must be swallowed whole, not chewed, divided or crushed.

Candox should not be used with alcoholic beverages.

4.3 Contraindications

-    hypersensitivity to the active substance 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

-    acute abdomen, delayed gastric emptying.

4.4 Special warnings and precautions for use

Caution is required in

•    elderly or debilitated patients,

•    patients with severe impairment of lung, liver or kidney function,

•    myxoedema, hypothyroidism,

•    Addison’s disease (adrenal insufficiency),

•    intoxication psychosis (e.g. alcohol),

•    prostatic hypertrophy,

•    alcoholism, known opioid dependence,

•    delirium tremens,

•    pancreatitis,

•    diseases of the biliary tract,

•    biliary or ureteric colic,

•    conditions with increased brain pressure,

•    disturbances of circulatory regulation,

•    epilepsy or seizure tendency

•    patients taking MAO inhibitors.

Surgical procedures

Special care should be taken when oxycodone is applied in patients undergoing bowel-surgery. Opioids should only be administered postoperatively when the bowel function has been restored.

The safety of Candox used pre-operatively has not been established and cannot be recommended.

Respiratory and cardiac depression

Respiratory depression is the most significant risk induced by opioids and is most likely to occur in elderly or debilitated patients. The respiratory depressant effect of oxycodone can lead to increased carbon dioxide concentrations in blood and hence in cerebrospinal fluid. In predisposed patients opioids can cause severe decrease in blood pressure.

Tolerance and dependence

Long-term use of oxycodone can cause the development of tolerance which leads to the use of higher doses in order to achieve the desired analgesic effect. There is a cross-tolerance to other opioids. Chronic use of oxycodone can cause physical dependence. Withdrawal symptoms may occur following abrupt discontinuation of therapy. If therapy with oxycodone is no longer required it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of a withdrawal syndrome.

Oxycodone has a primary dependence potential. However, when used as directed in patients with chronic pain the risk of developing physical or psychological dependence is markedly reduced or needs to be assessed in a differentiated manner. There are no data available on the actual incidence of psychological dependence in chronic pain patients. In patients with a history of alcohol and drug abuse the medicinal product must be prescribed with special care.

Abuse

In case of abusive parenteral venous injection the tablet excipients may lead to necrosis of the local tissue, granulomas of the lung or other serious, potentially fatal events. To avoid damage to the controlled release properties of the tablets the prolonged-release tablets must not be chewed or crushed. The administration of chewed or crushed tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone (see section 4.9).

Alcohol

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

Special patient groups

Patients with severe hepatic impairment should be closely monitored. Paediatric patients

Candox has not been studied in children younger than 12 years of age. The safety and efficacy of the tablets have not been demonstrated and the use in children younger than 12 years of age is therefore not recommended.

Anti-doping warning

Athletes must be aware that this medicine may cause a positive reaction to ‘anti-doping’ tests.

Use of Candox as a doping agent may become a health hazard.

Excipients

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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 other opioids, sedatives, hypnotics, anti-depressants, phenothiazines, neuroleptic drugs, anaesthetics, muscle relaxants, antihistamines, antiemetics. MAO-inhibitors are known to interact with narcotic analgesics. MAO-inhibitors causes 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 Candox, concomitant use should be avoided.

Anticholinergics (e.g. neuroleptics, antihistamines, antiemetics, antiparkinson medicinal products) can enhance the anticholinergic undesirable effects of oxycodone (such as constipation, dry mouth or micturition disorders).

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 John's 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.

The effect of other relevant isoenzyme inhibitors on the metabolism of oxycodone is not known. Potential interactions should be taken into account.

Clinically relevant changes in International Normalised Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with oxycodone. .

There are no studies investigating the effect of oxycodone on CYP catalysed metabolism of other active substances.

4.6 Fertility, pregnancy and lactation

Pregnancy

Limited data on the use of oxycodone during pregnancy in humans reveal no evidence of an increased risk of congenital abnormalities. Oxycodone crosses the placenta. Animal studies with oxycodone have not revealed any teratogenic or embryotoxic effects.

Prolonged use of oxycodone during pregnancy can cause withdrawal symptoms in newborns. Use of oxycodone during labour can cause foetal respiratory depression. Oxycodone should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate.

Lactation

Oxycodone is excreted into breast milk. The milk/plasma concentration ratio was 3.4:1 and oxycodone effects in the suckling infant are therefore conceivable. A risk to the suckling child cannot be excluded in particular following intake of multiple doses of oxycodone by the breast-feeding mother. Breast-feeding should be discontinued during treatment with oxycodone.

4.7 Effects on ability to drive and use machines

Oxycodone can impair alertness and reactivity to such an extent that the ability to drive and operate machinery is affected or ceases altogether. In these circumstances Candox has moderate to major influence on the ability to drive and use machines.

With stable therapy, a general ban on driving a vehicle is not necessary. In these circumstances Candox has minor influence on the ability to drive and use machines. The treating physician must assess the individual situation.

4.8 Undesirable effects

Oxycodone can cause respiratory depression, miosis, bronchial spasms and spasms of the smooth muscles and can suppress the cough reflex. Tolerance and dependence may occur (see section 4.4).

The adverse reactions considered at least possibly related to treatment are listed below by system organ class and absolute frequency. The following frequency categories form the basis for classification of the undesirable effects:

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
Frequency not known	Cannot be estimated from the available data

Infections and infestations

Blood and lymphatic system disorders Rare:    lymphadenopathy

Immune system disorders

Uncommon:    hypersensitivity

Frequency unknown:    anaphylactic responses

Endocrine disorders

Uncommon:    syndrome of inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

loss of appetite up tp anorexia

dehydration

increased appetite

somnolence, dizziness, headache tremor

both increased and decreased muscle tone; involuntary muscle contractions; convulsion, in particular in epileptic patients or patients with tendency to convulsions; hypoaesthesia; speech disorder; syncope; paraesthesia; coordination disturbances; dysgeusia; amnesia hyperalgesia

Eye disorders

Uncommon:    lacrimation disorder, miosis, visual impairment

Ear and labyrinth disorders

Uncommon:    hyperacousis, vertigo

Cardiac disorders

Uncommon:    supraventricular tachycardia, palpitations (in the context of

withdrawal syndrome)

Vascular disorders

Uncommon:    vasodilatation

Rare:    hypotension, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common:	dyspnoea, bronchospasm
Uncommon:	respiratory depression, increased coughing, pharyngitis, rhinitis, voice changes
Gastrointestinal disorders Very common	constipation, nausea, vomiting
Common:	dry mouth; gastrointestinal disorders such as abdominal pain, diarrhoea, dyspepsia
Uncommon:	oral ulcers, gingivitis, stomatitis, flatulence, eructation, dysphagia,
ileus
Rare:	gingival bleeding, tarry stool, tooth staining and damage
Frequency unknown:	dental caries
Hepato-biliary disorders: Uncommon:	increased hepatic enzymes
Frequency unknown:	cholestasis, biliary colic
Skin and subcutaneous tissue disorders
Very common	pruritus
Common:	skin eruptions including rash, in rare cases increased photosensitivity, in isolated cases exfoliative dermatitis, hyperhidrosis
Uncommon:	dry skin
Rare:	urticaria
Musculosceletal and connective tissue disorders
Rare:	muscle spasm
Renal and urinary disorders
Common:	increased urge to urinate
Uncommon:	urinary retention
Rare:	haematuria
Reproductive system and breast disorders
Uncommon:	erectile dysfunction
Frequency unknown:	amenorrhoea
General disorders and administration site conditions
Common:	asthenic conditions
Uncommon:	chills, pain (e.g. chest pain), oedema, peripheral oedema, migraine, drug withdrawal syndrome, drug tolerance, malaise, thirst
Rare:	weight changes (increase or decrease), cellulitis
Injury, poisoning and procedural complications
Uncommon:	accidental injuries

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

Symptoms of overdose

Miosis, respiratory depression, somnolence, reduced skeletal muscle tone and drop in blood pressure. In severe cases circulatory collapse, stupor, coma, bradycardia and non-cardiogenic lung oedema; abuse of high doses of strong opioids such as oxycodone can be fatal.

Therapy of overdose

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

In the event of overdosing intravenous administration of an opiate antagonist (e.g. 0.4-2 mg intravenous naloxone) may be indicated. Administration of single doses must be repeated depending on the clinical situation at intervals of 2 to 3 minutes. Intravenous infusion of 2 mg of naloxone in 500 ml isotonic saline or 5% dextrose solution (corresponding to 0.004 mg naloxone/ml) is possible. The rate of infusion should be adjusted to the previous bolus injections and the response of the patient.

Gastric lavage can be taken into consideration. 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. 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.

For speeding up the passage a suitable laxative (e.g. a PEG based solution) may be useful.

Supportive measures (artificial respiration, oxygen supply, administration of vasopressors and infusion therapy) should, if necessary, be applied in the treatment of accompanying circulatory shock. Upon cardiac arrest or cardiac arrhythmias cardiac massage or defibrillation may be indicated. If necessary, assisted ventilation as well as maintenance of water and electrolyte balance.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; opioids; natural opium alkaloids, ATC-Code: N02AA05

Oxycodone shows an affinity to kappa, mu and delta opioid receptors in the brain and spinal cord. It acts at these receptors as an opioid agonist without an antagonistic effect. The therapeutic effect is mainly analgesic and sedative. Compared to rapid-release oxycodone, given alone or in combination with other substances, the prolonged-release tablets provide pain relief for a markedly longer period without increased occurrence of undesirable effects.

Pharmacokinetic properties

Absorption

The relative bioavailability of Candox is comparable to that of rapid release oxycodone with maximum plasma concentrations being achieved after approximately 3 hours after intake of the prolonged-release tablets compared to 1 to 1.5 hours. Peak plasma concentrations and oscillations of the concentrations of oxycodone from the prolonged-release and rapid-release formulations are comparable when given at the same daily dose at intervals of 12 and 6 hours, respectively.

A fat-rich meal before the intake of the tablets does not affect the maximum concentration or the extent of absorption of oxycodone.

The tablets must not be crushed or chewed as this leads to rapid oxycodone release due to the damage of the prolonged-release properties.

Distribution

The absolute bioavailability of oxycodone is approximately two thirds relative to parenteral administration. In steady state, the volume of distribution of oxycodone amounts to 2.6 l/kg; plasma protein binding to 38-45%; the elimination half-life to 4 to 6 hours and plasma clearance to 0.8 l/min. The elimination half-life of oxycodone from prolonged-release tablets is 4-5 hours with steady state values being achieved after a mean of 1 day.

Metabolism

Oxycodone is metabolised in the intestine and liver via the P450 cytochrome system to noroxycodone and oxymorphone as well as to several glucuronide conjugates. In vitro studies suggest that therapeutic doses of cimetidine probably have no relevant effect on the formation of noroxycodone. In man, quinidine reduces the production of oxymorphone while the pharmacodynamic properties of oxycodone remain largely unaffected. The contribution of the metabolites to the overall pharmacodynamic effect is irrelevant.

Elimination

Oxycodone and its metabolites are excreted via urine and faeces. Oxycodone crosses the placenta and is found in breast milk.

Linearity/non-linearity

Across the 5-80 mg dose range of prolonged release oxycodone tablets linearity of plasma concentrations was demonstrated in terms of rate and extent of absorption.

5.3 Preclinical safety data

Oyxcodone had no 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 malformations 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.

Long-term carcinogenicity studies were not performed.

Oxycodone shows a clastogenic potential in in vitro assays. No similar effects were observed, however, under in vivo conditions, even at toxic doses. The results indicate that the mutagenic risk of oxycodone to humans at therapeutic concentrations may be ruled out with adequate certainty.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

Sugar spheres (sucrose, maize starch)

Hypromellose

Talc

Ethylcellulose Hyprolose Propylene glycol Carmellose sodium Cellulose, microcrystalline Magnesium stearate Silica, colloidal anhydrous

Tablet coating:

Polyvinyl alcohol Macrogol 3350 Talc

Titanium dioxide (E171)

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

31/03/2014

10    DATE OF REVISION OF THE TEXT

31/03/2014