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1. Elenoxy 40mg Prolonged-Release Tablets
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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Elenoxy 40 mg prolonged-release tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 40 mg of oxycodone hydrochloride equivalent to 35.9 mg of oxycodone

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release tablet.

White to off-white, elliptic, 11 x 5.5 mm, biconvex, coated tablets embossed with “40” on one side and “LT” on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

Elenoxy is indicated in adults and adolescents (from 12 years    of age).

4.2    Posology and method of administration

Posology

The dosage should be adjusted to the intensity of the pain and the sensitivity of the individual patient.

The following general dosage recommendations apply:

Adults and adolescents (from 12 years of age)

Starting dose

The usual starting dose for an opioid naive patient is 10 mg oxycodone hydrochloride per os at 12 hour intervals. Some patients may benefit from a starting dose of 5 mg to minimize the incidence of adverse reactions.

Patients already receiving opioids may be initiated on higher Elenoxy doses depending on their previous opioid experience.

Based on well-controlled clinical studies 10 to 13 mg oxycodone hydrochloride correspond to approximately 20 mg of morphine sulphate, each with retarded release.

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

Dose adjustment

Elenoxy is a prolonged-release formulation and therefore is not intended for therapy of breakthrough pain. Some patients given around-the-clock controlled release opioid therapy will require immediate release analgesic as "rescue" from breakthrough pain. The single rescue medication should amount to a sixth of the equianalgesic daily dose. The need for more than two "rescues" per day is usually an indication that the controlled release Elenoxy basal dose requires upward titration. Titration should be done at a frequency of no less than 1 or 2 days until a stable 12 hour1y dose is reached. Beyond the increase from 10 mg to 20 mg every 12 hours, increase the dose by approximately one-third until the desired effect is obtained. The goal is to establish a patient-specific 12 hour1y dose that will maintain adequate analgesia with acceptable undesirable effects and minimal use of "rescue” medication for as long as pain control is necessary.

While symmetric (same dose in the morning and in the evening), around-the-clock,

12 hour1y dosing is appropriate for the majority of patients, some patients may benefit from asymmetric dosing tailored to their pain pattern. Generally, the lowest analgesically effective dose should be selected. In non-cancer pain 40 mg is usually a sufficient daily dose, higher doses may be needed. Patients with pain due to cancer may need extended doses of 80 to 120 mg, up to 400 mg in individual cases. If even higher doses are required, the dose should be decided individually balancing efficacy with tolerance and the risk of undesirable effects.

Slightly elevated peak plasma concentrations should be taken into account when a regimen consisting of four 10 mg tablets is used (see section 5.2).

Duration of treatment

Oxycodone should not be administered for longer than absolutely necessary. If longterm pain treatment is necessary in view of the nature and severity of the illness, careful and regular monitoring should be carried out to establish whether and to what extent further treatment is necessary. When the patient no longer requires opioid therapy, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Older people

A dose adjustment is usually not necessary in elderly patients without clinically manifest impairment of hepatic or renal function.

Patients at risk

Patients at risk, e.g. with renal or hepatic insufficiency, low body weight or slow metabolisers, who are opioid naive, should initially be treated with half the dose usually recommended for adults. Therefore the lowest recommended dosage 10 mg oxycodone hydrochloride, may not be suitable as a starting dose and in such cases 5 mg oxycodone hydrochloride can be used.

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

Paediatric population

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

Method of administration

Oral use.

Elenoxy prolonged-release tablets are taken in the determined dosage twice daily in a fixed time schedule.

Elenoxy may be taken with or without food with sufficient liquid. It must be swallowed whole and must not be cut, broken, chewed, crushed, or dissolved.

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.

4.4 Special warnings and precautions for use

Paediatric population

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

Other special populations

The major risk of opioid excess is respiratory depression. Caution must be exercised when administering oxycodone to the 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, oxycodone should be immediately discontinued.

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, 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 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.

Elenoxy, like all opioids, should be used with particular care in patients with a history of alcohol and drug abuse.

Abuse may occur by taking intact tablets without legitimate purpose, by crushing, chewing or snorting the crushed formulation, or by injecting a solution made from the crushed formulation. Abuse of the tablets by parenteral administration can be expected to result in serious adverse events, such as local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, which may be fatal.

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

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

The use of Elenoxy may produce positive results in doping controls. Use of Elenoxy as a doping agent may become a health hazard.

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

4.5 Interaction with other medicinal products and other forms of interaction

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, antiemetic and other opioids or alcohol. 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).

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

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

A clinically relevant decrease or increase of INR (International Normalized Ratio) has been observed in individual cases in simultaneous use of oxycodone and coumarin anticoagulants.

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.

4.6 Fertility, Pregnancy and lactation

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

Pregnancy

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

Breast-feeding

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

4.7 Effects on ability to drive and use machines

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

Patients stabilised on a specific dose will not necessarily be restricted. Therefore, the 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 may suppress the cough reflex.

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

Constipation may be prevented with an appropriate treatment.

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:

Term    Frequency

Very common:    > 1/10

Common:    > 1/100 to < 1/10

Uncommon:    > 1/1,000 to < 1/100

Rare:    > 1/10,000 to < 1/1,000

Very rare:    < 1/10,000

Not known (cannot be estimated from the available data)

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

Organ System	Frequency	Adverse drug reaction
Infections and	Rare	Herpes simplex
infestations
Immune system	Uncommon	Hypersensitivity
disorders	Not known	Anaphylactic reaction
Metabolism	Common	Decreased appetite up to loss of
and nutrition		appetite
disorders	Uncommon	Dehydration
	Rare	Increased appetite
Psychiatric	Common	Altered mood and personality
disorders		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, reduced libido, drug dependence (see section 4.4)
	Not known	Aggression

Organ System	Frequency	Adverse drug reaction
Nervous system disorders	Very common	Sedation (somnolence up to a depressed level of consciousness), dizziness, headache
	Common	Syncope, paraesthesia, tremor
	Uncommon	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	Hypotension Vasodilatation
	Rare	Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders	Common Uncommon Not known	Dyspnoea, bronchospasm Dysphonia, cough, respiratory depression Suppression of cough reflex
Gastrointestinal disorders	Very common	Constipation, vomiting, nausea
	Common	Abdominal pain, diarrhoea, dry mouth, hiccups, dyspepsia
	Uncommon	Mouth ulceration, stomatitis, flatulence, dysphagia, eructation, ileus
	Rare	Melaena, tooth disorder, gingival bleeding
	Not known	Dental caries
Hepatobiliary disorders	Uncommon Not known	Hepatic enzymes increased Biliary colic, cholestasis
Skin and subcutaneous tissue disorders	Very common Common	Pruritus Skin reactions/rash, hyperhidrosis

Organ System	Frequency	Adverse drug reaction
	Uncommon	Dry skin
	Rare	Urticaria
Renal and urinary disorders	Common	Urinary retention, dysuria, micturition urgency
Reproductive system and breast disorders	Uncommon Not known	Erectile dysfunction Amenorrhoea
General disorders and administration site conditions	Common Uncommon	Chills, asthenia 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 Yellow Card Scheme at: 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 as well as hypotension. Coma, non-cardiogenic pulmonary edema and circulatory failure may occur in more severe cases 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.

Patients and their carers must be instructed that Elenoxy contains oxycodone in an amount that can be fatal to a child or non-patient.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; opioids; natural opium alkaloids.

ATC code: N02A A05.

Mechanism of action

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 (immediate release) oxycodone product, Elenoxy prolonged-release tablets provide pain relief for a markedly longer period without increased occurrence of undesirable effects.

Pharmacodynamic 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 controlled-release properties of the tablets Elenoxy tablets must not be cut, broken, crushed, chewed or dissolved, as this may lead to rapid oxycodone release.

The relative bioavailability of Elenoxy is comparable to the conventional immediate release oral oxycodone, but the former achieves maximal plasma concentrations in 6 to 10 hours rather than 1 to 1.5 hours. Fluctuation between peak and trough concentrations of Elenoxy prolonged-release tablets are low. Mean estimates of the absolute bioavailability of oxycodone range from 42 to 87% relative to parenteral active substance. Oxycodone has a volume of distribution at steady state of 2.6 l/kg; a plasma protein binding of approximately 45% and an elimination half-life of 4 to 6 hours after administration of conventional immediate release forms. The apparent elimination half-life of oxycodone from the Elenoxy is about 6 to 8 hours with steady-state achieved in about 2 days on the average. Ingestion of a standard high-fat meal does not alter the extent of oxycodone absorption.

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 cimetidine 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 faeces. Oxycodone also crosses the placenta and may be detected in breast milk.

Tablets of various dose strengths may be combined when tailoring individual doses according to the patient’s analgesic requirements and tolerability. In rare case of interchange of four 10 mg tablets by one 40 mg tablet, however, it should be borne in mind that Cmax is slightly lower (by 13.55 %) with one 40 mg tablet than with four 10 mg tablets. Nevertheless, this slight difference in Cmax does not translate into clinically relevant effects with regard to efficacy and safety.

5.3 Preclinical safety data

In rat studies, oxycodone had no effect on fertility and embryonic development. However, in rabbits, at dose levels which produced maternal toxicity, a dose related increase in developmental variations was observed (increased presacral vertebrae, extra pairs of ribs). In a rat study on pre- and post-natal development, there were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices.

Data from genotoxicity studies with oxycodone reveal no special hazard for humans.

Long-term carcinogenicity studies were not performed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hypromellose Polyvinyl acetate Povidone K30 Sodium lauryl sulphate Silica

Microcrystalline cellulose

Silicon dioxide

Magnesium stearate

Dibutyl sebacate

Ethylcellulose

Cetyl alcohol

Talc

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

Peelable, child resistant blister:

Opaque Polyamide-Aluminium-PVC / Aluminium-PET foil blister, contained in a cardboard outer carton.

Pack sizes: 10, 20, 28, 30, 40, 50, 56, 60, 100,112 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6    Special precautions    for disposal

No special requirements.