Zomestine 40 Mg Prolonged-Release Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zomestine 40 mg prolonged-release tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 40 mg oxycodone hydrochloride equivalent to 36 mg oxycodone.
Excipient with known effect: The prolonged-release tablets contain a maximum of 24 mg sucrose.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Prolonged-release tablet.
Pink, oblong, 12.4 - 12.5 mm in length and 5.8 - 5.9 mm in width, biconvex, prolonged-release tablets with break scores on both sides.
The tablet can be divided into equal halves.
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
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 Oxycodon-HCl Accord prolonged-release tablets after conversion from other opioids, with 50-75% of the calculated oxycodone dose.
Some patients who take Zomestine prolonged-release tablets following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Zomestine prolonged-release tablets 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 Zomestine prolonged-release tablets. Use of the rescue medication more than twice daily indicates that the dose of Zomestine prolonged-release tablets 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 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.
Method of administration For oral use.
Zomestine prolonged-release tablets 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. Zomestine prolonged-release tablets must be swallowed whole, not chewed.
Duration of administration
Zomestine prolonged-release tablets 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.
Children under 12 years of age
Zomestine prolonged-release tablets are not recommended for children under 12 years of age.
Patients older than 65 years
In older patients without clinical manifestation of impaired liver and/or kidney function usually do not require dose adjustments. However, in general, the initial dose in frail opioid-naive geriatric patients is 5 mg oxycodone hydrochloride given at intervals of 12 hours.
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.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• 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.
• Any situation where opioids are contra-indicated
• moderate to severe hepatic impairment
• severe renal impairment (creatinine clearance <10 ml/min)
• chronic constipation
• Not recommended for pre-operative use or for the first 24 hours post-operatively.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.4 Special warnings and precautions for use
Zomestine prolonged-release tablets have 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.
As with all narcotics, a reduction in dosage may be advisable in hypothyroidism .Caution is required in elderly or debilitated patients and infirm patients, in 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, hypotension, hypovolaemia, toxic psychosis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, alcoholism,disturbances of circulatory regulation, epilepsy or seizure tendency and in patients taking MAO inhibitors. Patients with head injury require careful dosing and cautious monitoring.
Zomestine prolonged-release tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Zomestine prolonged-release tablets should be discontinued immediately. As with all opioid preparations, patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive Zomestine prolonged-release tablets for 12 hours prior to the intervention. If further treatment with Zomestine prolonged-release tablets is indicated then the dosage should be adjusted to the new post-operative requirement.
Zomestine prolonged-release tablets 80 mg should not be used in patients not previously exposed to opioids. These tablet strength may cause fatal respiratory depression when administered to opioid naive patients.
Special care should be taken when oxycodone is applied in patients undergoing bowel-surgery. Opioids should only be administered post-operatively when the bowel function has been restored.
Patients with severe hepatic impairment should be closely monitored.
For appropriate patients who suffer with chronic non-malignant pain, opioids should be used as part of a comprehensive treatment programme involving other medications and treatment modalities. A crucial part of the assessment of a patient with chronic nonmalignant pain is the patient's addiction and substance abuse history. There is potential for development of psychological dependence (addiction) to opioid analgesics, including oxycodone. Zomestine prolonged-release tablets , like all opioids, should be avoided in patients with a history of, or present alcohol and drug abuse.
If opioid treatment is considered appropriate for the patient, then the main aim of treatment is not to minimise the dose of opioid but rather to achieve a dose which provides adequate pain relief with a minimum of side effects. There must be frequent contact between physician and patient so that dosage adjustments can be made. It is strongly recommended that the physician defines treatment outcomes in accordance with pain management guidelines. The physician and patient can then agree to discontinue treatment if these objectives are not met.
Zomestine prolonged-release tablets has an abuse profile similar to other strong opioids. Oxycodone may be sought and abused by people with latent or manifest addiction disorders.
As with other opioids, infants who are born to dependent mothers may exhibit withdrawal symptoms and may have respiratory depression at birth.
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.
Long-term use of Zomestine prolonged-release tablets 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 Zomestine prolonged-release tablets 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.
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.
Zomestine prolonged-release tablets have 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.
Zomestine prolonged-release tablets are not recommended for pre-operative use or within the first 12-24 hours post-operatively.
In case of abusive parenteral venous injection of Zomestine prolonged-release tablets, the tablet excipients may lead to necrosis of the local tissue, infection, increased risk of endocarditis, and valvular heart injury which may be fatal, 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).
Zomestine
Concomitant use of alcohol and Zomestine prolonged release tablet may increase the undesirable effects of Zomestine prolonged release tablet; concomitant use should be avoided.
Athletes must be aware that this medicine may cause a positive reaction to ‘antidoping’ tests.
Use of Zomestine as a doping agent may become a health hazard.
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
Central nervous system depressants & other Opioids
Concomitant administration of central nervous system depressants (e.g. sedatives, hypnotics, phenothiazines, neuroleptics, anaesthetics, antidepressants, muscle relaxants, antihistamines, antiemetics and antihypertensives ) and other opioids can enhance the CNS depressant effects or adverse reactions of oxycodone, in particular respiratory depression.
Alcohol
Alcohol may enhance the pharmacodynamic effects of Zomestine prolonged release tablet; concomitant use should be avoided.
Anticholinergics
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).
MAO-inhibitors
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 particular caution in patients administered MAO-inhibitors or who have received MAO-inhibitors during the last two weeks (see section 4.4).
Oxycodone is mainly metabolised by CYP3A4, with contribution from CYP2D6. The activities of these metabolic pathways may be inhibited or induced by various coadministered drugs or dietary elements.
CYP3A4 inhibitors
CYP3A4 inhibitors, such as macrolideantibiotics (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), cimetidin and grapefruit juice may cause a reduced clearance of oxycodone that could cause an increase of the plasma concentrations of oxycodone. Therefore a reduction of the oxycodone dose may be appropriate and retitration necessary.
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
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. Therefore caution is advised and further titration may be necessary to obtain pain control.
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
CYP2D6 inhibitors
Medicinal products that inhibit CYP2D6, such as paroxetine, fluoxetine and qunidine, may cause a reduced clearance of oxycodone that could cause increased plasma concentrations of oxycodone.
Quinidine
Concurrent administration of quinidine, an inhibitor of cytochrome P450-2D6, resulted in an increase in oxycodone Cmax by 11%, AUC by 13%, and t'Yelim. by 14%. Also an increase in noroxycodone level was observed, (Cmax by 50%; AUC by 85%, and t'Yelim. by 42%). The pharmacodynamic effects of oxycodone were not altered. This interaction may be observed for other potent inhibitors of cytochrome P450-2D6 enzyme.
Coumarin anticoagulants
Clinically relevant changes in International Normalised Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with Zomestine prolonged-release tablets.
There are no studies investigating the effect of oxycodone on CYP catalysed metabolism of other active substances.
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 breast-feeding mothers.
4.7 Effects on ability to drive and use machines
Zomestine prolonged-release tablets has major influence on ability to drive and use machines. This is particularly likely at the initiation of treatment with Zomestine prolonged-release tablets, after dose increase or product rotation and if Zomestine prolonged release tablets is combined with alcohol or other CNS depressant agents. With stable therapy, a general ban on driving a vehicle is not necessary. The treating physician must assess the individual situation.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called ‘statutory defence’) if:
o The medicine has been prescribed to treat a medical or dental problem and o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely
4.8 Undesirable effects
Adverse drug reactions are typical of full opioid agonists. Tolerance and dependence may occur (see Tolerance and Dependence, below). Constipation may be prevented with an appropriate laxative. If nausea and vomiting are troublesome, oxycodone may be combined with an anti-emetic.
Oxycodone can cause respiratory depression, miosis, bronchial spasms and spasms of the smooth muscles and can suppress the cough reflex.
The adverse reactions considered at least possibly related to treatment are listed below by system organ class and absolute frequency. Frequencies are defined as:
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.
Blood and lymphatic system disorders Rare: lymphadenopathy
Immune system disorders Uncommon: Hypersensitivity
Not known: Anaphylactic reaction, Anaphylactoid reaction,
Endocrine disorders
Uncommon: syndrome of inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders Common: decreased appetite Rare: dehydration
Psychiatric disorders
Common: various psychological adverse reactions including changes in mood (e.g. anxiety), changes in activity (mostly supression sometimes associated with lethargy, nervousness and insomnia) abnormal dreams, depression and changes in cognitive performance (abnormal thinking, confusion, amnesia)
Uncommon: change in perception such as depersonalisation, hallucinations, agitation , altered mood, restlessness, disorientation, dysphoria, euphoria , libido decrease, affect lability, change in taste, visual disturbances, hyperacousis drug dependence (see section
4.4 & sub heading Tolerance and dependence in section 4.8)
Nervous system disorders
Very common: somnolence, dizziness, headache Common: tremor,asthenia, sedation
Uncommon: both increased and decreased muscle tone, involuntary muscle contractions, hypoesthesia, paraesthesia, coordination disturbances, malaise, vertigo, amnesia, taste perversion (dysgeusia),, syncope, Speech disorders, convulsions, syncope, hypertonia
Rare: seizures, in particular in epileptic patients or patients with tendency to convulsions, muscle spasm
Not known: hyperalgesia
Eye disorders
Uncommon: lacrimation disorder, miosis, visual impairment
Ear and labyrinth disorders Uncommon: Vertigo
Cardiac disorders
Uncommon: supraventricular tachycardia, palpitations (in the context of withdrawal syndrome)
Vascular disorders
Common: lowering of blood pressure, rarely accompanied by secondary symptoms such as palpitations,
Uncommon: vasodilatation, facial flushing Rare: hypotension, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders Common: cough decreased, bronchospasm,dyspnoea
Uncommon: increased coughing, respiratory depression , pharyngitis, rhinitis, voice changes, hiccups
Gastrointestinal disorders
Very common: constipation, nausea, vomiting
Common: dry mouth, rarely accompanied by thirst and difficulty swallowing; abdominal pain, diarrhoea, eructation, dyspepsia, loss of appetite Uncommon: oral ulcers, gingivitis, tooth staining , dysphagia, eructation, gastritis, gastrointestinal disorders, ileus , stomatitis, flatulence Rare: gum bleeding, increased appetite, tarry stool,
Not known: dental caries
Hepato-biliary disorders Uncommon:increased hepatic enzymes Not known: biliary colics, cholestasis
Skin and subcutaneous tissue disorders
Very common: itching, pruritus
Common: skin eruptions including rash, hyperhidrosis
Uncommon: dry skin, exfoliative dermatitis
Rare: urticaria, manifestation of herpes simplex, increased photosensitivity
Musculoskeletal and connective tissue disorders Uncommon: Muscular rigidity
Renal and urinary disorders
Uncommon: micturition disturbances (urinary retention, but also increased urge to urinate), ureteral spasm Rare: haematuria
Reproductive system and breast disorders
Uncommon: reduced libido, erectile dysfunction (impotence )
Not known: amenorrhoea
General disorders and administration site conditions Common: sweating, asthenic conditions
Uncommon: accidental injuries, drug tolerance, pain (e.g. chest pain), oedema,
migraine, physical dependence with withdrawal symptoms, allergic reactions , oedema
peripheral, malaise, thirst, pyrexia, chills
Rare: weight changes (increase or decrease), cellulitis
Tolerance and dependence may develop.
Tolerance and Dependence:
Prolonged use of Zomestine prolonged-release tablets may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate or heart rate.
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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms of overdose
Miosis, respiratory depression, somnolence, reduced skeletal muscle tone (hypotonia) and drop in blood pressure. In severe cases circulatory collapse, stupor, coma, hypotension, and hallucinations, bradycardia and non-cardiogenic lung oedema may occur; abuse of high doses of strong opioids such as oxycodone can be fatal.
The effects of overdosage will be potentiated by the simultaneous ingestion of alcohol or other psychotropic drugs.
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 for an adult and 0.01mg/kg body weight for children) may be indicated if the patient is in a coma or respiratory depression is present. Administration of single doses must be repeated depending on the clinical situation at intervals of 2 to 3 minutes. If repeated doses are required then an infusion of 60% of the initial dose per hour is a useful starting point. A solution of 10 mg made up in 50 ml dextrose will produce 200 micrograms/ml for infusion using an IV pump (dose adjusted to the clinical response). Infusions are not a substitute for frequent review of the patient's clinical state. Intramuscular naloxone is an alternative in the event IV access is not possible. As the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Naloxone is a competitive antagonist and large doses (4 mg) may be required in seriously poisoned patients. 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.
For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.
The patient should be observed for at least 6 hours after the last dose of naloxone.
Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. Naloxone should be administered cautiously to patients who are known, or suspected, to be physically dependent on oxycodone. In such cases, an abrupt or complete reversal of opioid effects may precipitate pain and an acute withdrawal syndrome.
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.
Zomestine prolonged-release tablets will continue to release and add to the oxycodone load for up to 12 hours after administration and management of oxycodone overdosage should be modified accordingly. Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug, particularly when a prolonged release formulation has been taken.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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.
Endocrine system
Opioids may influence the hypothalamic-pituitary-adrenal or - gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.
Other pharmacological effects
In- vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown. Whether oxycodone, a semisynthetic opioid, has immunological effects similar to morphine is unknown.
Clinical studies
The efficacy of Zomestine prolonged-release tablets has been demonstrated in cancer pain, post-operative pain and severe non-malignant pain such as diabetic neuropathy, postherpetic neuralgia, low back pain and osteoarthritis. In the latter indication, treatment was continued for up to 18 months and proved effective in many patients for whom NSAIDs alone provided inadequate relief. The efficacy of Zomestine prolonged-release tablets in neuropathic pain was confirmed by three placebo-controlled studies.
In patients with chronic non-malignant pain, maintenance of analgesia with stable dosing was demonstrated for up to three years.
5.2 Pharmacokinetic properties
Compared with morphine, which has an absolute bioavailability of approximately 30%, oxycodone has a high absolute bioavailability of up to 87% following oral administration. Oxycodone has an elimination half-life of approximately 3 hours and is metabolised principally to noroxycodone and oxymorphone. Oxymorphone has some analgesic activity but is present in the plasma in low concentrations and is not considered to contribute to oxycodone's pharmacological effect.
Absorption
The relative bioavailability of Zomestine prolonged-release tablets 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
The main metabolic pathways of oxycodone are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone.. Oxycodone is extensively metabolized by multiple metabolic pathways to produce noroxycodone, oxymorphone and noroxymorphone, which are subsequently glucuronidated. Noroxycodone and noroxymorphone are the major circulating metabolites. CYP3A mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a lower contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs (see section 4.4).
Noroxycodone exhibits very weak anti-nociceptive potency compared to oxycodone, however, it undergoes further oxidation to produce noroxymorphone, which is active at opioid receptors. Although noroxymorphone is an active metabolite and present at relatively high concentrations in circulation, it does not appear to cross the blood-brain barrier to a significant extent. Oxymorphone is present in the plasma only at low concentrations and undergoes further metabolism to form its glucuronide and noroxymorphone. Oxymorphone has been shown to be active and possessing analgesic activity but its contribution to analgesia following oxycodone administration is thought to be clinically insignificant. Other metabolites (a- and B-oxycodol, noroxycodol and oxymorphol) may be present at very low concentrations and demonstrate limited penetration into the brain as compared to oxycodone. The enzymes responsible for ketoreduction and glucuronidation pathways in oxycodone metabolism have not been established.
CYP2D6 genetic polymorphism could affect oxycodone pharmacodynamics. Several case reports describe reduced analgesic effect of oxycodone in CYP2D6 poor metabolizers (see Samer CF et al). Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. (Br J Pharmacol. 2010. 160:919-930, and references therein).
Elimination
Oxycodone and its metabolites are excreted via urine and faeces. Oxycodone crosses the placenta and is found in breast milk.
Linearitv/non-linearitv
The 5, 10, 20, 40 and 80 mg prolonged-release tablets are bioequivalent in a dose proportional manner with regard to the amount of active substance absorbed as well as comparable with regard to the rate of absorption.
Elderly
The AUC in elderly subjects is 15% greater when compared with young subjects. Gender
Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.
Patients with renal impairment
Preliminary data from a study of patients with mild to moderate renal dysfunction show peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively and AUC values for oxycodone, noroxycodone and oxymorphone approximately 60%, 60% and 40% higher than normal subjects, respectively. There was an increase in t'A of elimination for oxycodone of only 1 hour.
Patients with mild to moderate hepatic impairment
Patients with mild to moderate hepatic dysfunction showed peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively, than normal subjects. AUC values were approximately 95% and 75% higher,
respectively. Oxymorphone peak plasma concentrations and AUC values were lower by 15% to 50%. The t./2 elimination for oxycodone increased by 2.3 hours.
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.
In a study of peri- and postnatal development in rats, maternal body weight and food intake parameters were reduced for doses ^2 mg/kg/d compared to the control group. Body weights were lower in the F1 generation from maternal rats in the 6 mg/kg/d dosing group. There were no effects on physical, reflexological, or sensory developmental parameters or on behavioural and reproductive indices in the F1 pups (the NOEL for F1 pups was 2 mg/kg/d based on body weight effects seen at 6 mg/kg/d). There were no effects on the F2 generation at any dose in the study.
Carcinogenicity
Long-term carcinogenicity studies were not performed.
Studies of oxycodone in animals to evaluate its carcinogenic potential have not been conducted owing to the length of clinical experience with the drug substance.
Mutagenicity
The results of in-vitro and in-vivo studies indicate that the genotoxic risk of oxycodone to humans is minimal or absent at the systemic oxycodone concentrations that are achieved therapeutically.
Oxycodone was not genotoxic in a bacterial mutagenicity assay or in an in-vivo micronucleus assay in the mouse. Oxycodone produced a positive response in the in-vitro mouse lymphoma assay in the presence of rat liver S9 metabolic activation at dose levels greater than 25 pg/mL. Two in-vitro chromosomal aberrations assays with human lymphocytes were conducted. In the first assay, oxycodone was negative without metabolic activation but was positive with S9 metabolic activation at the 24 hour time point but not at other time points or at 48 hour after exposure. In the second assay, oxycodone did not show any clastogenicity either with or without metabolic activation at any concentration or time point.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Sugar spheres (contains sucrose, maize starch, starch hydrolysates and colour additives)
Hypromellose
Talc
Ethylcellulose Hydroxypropylcellulose Propylene glycol Carmellose sodium Microcrystalline cellulose Magnesium stearate Silica, colloidal anhydrous
Tablet coating:
Titanium dioxide (E171)
Macrogol 3350 Talc
Red iron oxide (E 172)
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 twist-off caps.
Pack sizes:
10, 14, 20, 28, 30, 50, 56, 60, 98, 100, 120 prolonged-release tablets in blister.
10, 20, 30, 50, 100 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
Accord Healthcare Limited,
Sage house, 319 Pinner road,
North Harrow, Middlesex, HA1 4HF United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL20075/0329
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
31/12/2013
10 DATE OF REVISION OF THE TEXT
07/10/2015