CANDOX 5 MG PROLONGED-RELEASE TABLETS - Summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

2.   QUALITATIVE AND QUANTITATIVE COMPOSITION

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

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 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 naïve 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 treatment

Candox should not be used for 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.

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.

Elderly patients

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

Patients with renal or hepatic impairment

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.

Risk patients

Risk patients, for example patients with low body weight or slow metabolism of medicinal products, should initially receive half the recommended adult dose if they are opioid naïve. 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),

prostatic hypertrophy,

alcoholism, known opioid dependence,

intoxication psychosis (e.g. alcohol),

delirium tremens,

pancreatitis,

conditions with increased brain pressure such as head injury,

disturbances of circulatory regulation,

diseases of the biliary tract, inflammatory bowel disorders, biliary or ureteric colic,

hypotension,

hypovolaemia,

epilepsy or seizure tendency,

patients taking MAO inhibitors.

Surgical procedures

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.

Candox is not recommended for pre-operative use or within the first 12–24 hours post-operatively.

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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Candox and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Candox concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Tolerance and dependence

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 very rarely occur, particularly in high doses. An oxycodone dose reduction or change to an alternative opioid may be required.

Oxycodone has a primary dependence potential. 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. 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.

The prolonged release tablets must be swallowed whole, and not broken, chewed or crushed. The administration of broken, chewed or crushed controlled release oxycodone tablets leads to a rapid release and absorption of a potentially fatal dose of oxycodone (see section 4.9).

Endocrine effects

Opioids, such as oxycodone hydrochloride, may influence the hypothalamic-pituitaryadrenal 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 manifest from these hormonal changes.

Alcohol

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

Hepatic impairmentPatients with severe hepatic impairment should be closely monitored.

Paediatric population

Oxycodone hydrochloride 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 ‘antidoping’ 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.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

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, antidepressants, phenothiazines, neuroleptic drugs, anaesthetics, muscle relaxants, antihistamines, and antiemetics.

Sedative medicines such as benzodiazepines or related drugs:

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

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).

Concomitant administration of oxycodone with serotonin agents, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) may cause serotonin toxicity. The symptoms of serotonin toxicity may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

Alcohol may enhance the pharmacodynamic effects of oxycodone, 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 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 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:

Infections and infestations

Rare:           herpes simplex

Blood and lymphatic system disorders

Rare:          lympha­denopathy

Immune system disorders

Uncommon:     hypersensi­tivity

Not known:      anaphylactic responses

Endocrine disorders

Uncommon:     syndrome of inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

Psychiatric disorders

Nervous system disorders

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

Gastrointestinal disorders

Hepato-biliary disorders:

Uncommon:     increased hepatic enzymes

Not known:       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

Not known:     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

Not known: drug withdrawal syndrome neonatal.

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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9

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.

5.2 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)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Child resistant PVC/PE/PVDC-aluminium blisters consisting of a white opaque PVC/PE/PVDC laminated foil and an aluminium foil.

HDPE bottles with child-resistant PP screw caps.

Pack sizes:

20, 25, 28, 30, 50, 56, 98, 100 prolonged-release tablets in blister.

100, 250 prolonged-release tablets in HDPE bottles.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Teva UK Limited

Brampton Road

Hampden Park

Eastbourne

East Sussex

BN22 9AG

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/1709