Summary of medicine characteristics - ALIVIO 10 MG PROLONGED-RELEASE TABLETS
Alivio 10 mg prolonged-release tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 10 mg oxycodone hydrochloride equivalent to 9 mg oxycodone.
Excipient with known effect:
Each prolonged-release tablet contains a maximum of 30 mg sucrose.
For the full list of excipients, see section 6.1.
Prolonged-release tablet.
Pink, oblong, biconvex, film coated tablets with break scores on both sides. The height of the tablet is between 4 and 5 mm, the width is 4.8 mm and the length is 10.3 mm.
The tablet can be divided into equal doses.
4.1 Therapeutic indications
Severe pain, which can be adequately managed only with opioid analgesics.
Alivio is indicated in adults and adolescents aged 12 years and older.
4.2 Posology and method of administration
Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with Alivio in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).
Posology
The dosage depends on the intensity of pain and the patient’s individual susceptibility to the treatment.
The following general dosage recommendations apply:
Adults and adolescents (>12 years)
Dose titration
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 doses taking into account their experience with former opioid therapies.
For doses not realisable/practicable with this medicinal product, other strengths and medicinal products are available.
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 Alivio prolonged-release tablets after conversion from other opioids, with 50–75% of the calculated oxycodone dose.
Dose adjustment
Some patients who take Alivio following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Alivio 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 Alivio. Use of the rescue medication more than twice daily indicates that the dose of Alivio 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.
Elderly patients
A dose adjustment is not usually necessary in elderly patients.
Duration of administration
Alivio 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.
Patients with renal or hepatic impairment
The plasma concentration in this population may be increased. 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.
Paediatric population
Children under 12 years of age
Alivio should not be used in children under 12 years of age because of safety and efficacy concerns.
Restless legs syndrome (RLS)
Oxycodone is indicated for patients suffering from RLS for at least 6 months. RLS symptoms should be present daily and during daytime (> 4 days/week). Oxycodone should be used after failure of previous dopaminergic treatment. Dopaminergic treatment failure is defined as inadequate initial response, a response that has become inadequate with time, occurrence of augmentation or unacceptable tolerability despite adequate doses. Previous treatment with at least one dopaminergic medicinal product should have lasted in general 4 weeks. A shorter period might be acceptable in case of unacceptable
tolerability with dopaminergic therapy.
The dosage should be adjusted to the sensitivity of the individual patient.
Treatment of patients with restless legs syndrome with Oxycodone should be under the supervision of a clinician with experience in the management of restless legs syndrome.
Unless otherwise prescribed, Oxycodone should be administered as follows:
Adults
The usual starting dose is 5 mg/2.5 mg of oxycodone hydrochloride/naloxone hydrochloride at 12 hourly intervals.
Titration on a weekly basis is recommended in case higher doses are required. The mean daily dose in the pivotal study was 20mg/10mg oxycodone hydrochloride/naloxone hydrochloride. Some patients may benefit from higher daily doses up to a maximum of 60 mg/30 mg oxycodone hydrochloride/naloxone hydrochloride.
Oxycodone is taken at the determined dosage twice daily according to a fixed time schedule. While symmetric administration (the same dose mornings and evenings) subject to a fixed time schedule (every 12 hours) is appropriate for the majority of patients, some patients, depending on the individual situation, may benefit from asymmetric dosing tailored to the individual patient. In general, the lowest effective dose should be selected.
For doses not realisable/practicable with this strength other strengths of this medicinal product are available.
Restless legs syndrome
At least every three months during therapy with Oxycodone patients should be clinically evaluated. During the initiation of treatment and dose adjustments, more frequent evaluation may be undertaken.
Treatment should only be continued if Oxycodone is considered effective and the benefit is considered to outweigh adverse effects and potential harms in individual patients. Prior to continuation of RLS treatment beyond 1 year a discharge regimen by gradually tapering down of Oxycodone over a period of approximately one week should be considered to establish if continued treatment with Oxycodone is indicated.
When a patient no longer requires opioid therapy cessation of treatment by tapering down over a period of approximately one week is recommended in order to reduce the risk of a withdrawal reaction (see section 4.4).
Method of administration
For oral use.
Alivio 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 (^ glass of water).
Alivio must not be taken divided, broken, chewed or crushed.
Alivio 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 chronic obstructive lung disease
Cor pulmonale
Severe bronchial asthma
Severe respiratory depression with hypoxia
Elevated carbon dioxide levels in the blood
Paralytic ileus
4.4 Special warnings and precautions for use
Caution must be exercised when administering oxycodone to the debilitated elderly, patients with severely impaired pulmonary function, impaired hepatic or renal function, patients with myxoedema, hypothyroidism, Addison’s disease , toxic psychosis (e.g. alcohol), prostate hypertrophy, alcoholism, known opioid dependence, delirium tremens, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, hypotension, hypovolaemia, head injury (due to risk of increased intracranial pressure), epilepsy or seizure tendency and in patients taking MAO inhibitors.
In suspicion or in case of paralytic ileus administration of Alivio has to be stopped immediately.
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.
Alivio is not recommended for pre-operative use or within the first 12–24 hours postoperatively.. 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 Alivio depends on a careful risk-benefit assessment for each individual patient.
Respiratory- and cardiac depression
The major risk of opioid excess is respiratory depression.
Drug dependence, tolerance and potential for abuse
For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).
Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.
A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained online, and past and present medical and psychiatric conditions. Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.
Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.
Patients should be closely monitored for signs of misuse, abuse, or addiction. The clinical need for analgesic treatment should be reviewed regularly.
Drug withdrawal syndrome
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with {Invented name}. Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months. The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.
Hyperalgesia
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.
Alivio 5 mg prolonged-release tablets
To avoid damage to the controlled release properties of the prolonged release, tablets must be swallowed whole, and not divided, broken, chewed or crushed. The administration of divided, 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).
Alivio 10 mg prolonged-release tablets
Alivio 20 mg prolonged-release tablets
Alivio 30 mg prolonged-release tablets
Alivio 40 mg prolonged-release tablets
Alivio 60 mg prolonged-release tablets
Alivio 80 mg prolonged-release tablets
To avoid damage to the controlled release properties of the prolonged release, tablets must not be swallowed 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).
Alcohol
Concomitant use of alcohol and Alivio may increase the undesirable effects of Alivio; concomitant use should be avoided.
‚Anti-doping‘ warning
Athletes must be aware that this medicine may cause a positive reaction to ‚anti-doping‘ tests. Use of Alivio 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 sucrose 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 medicinal products which affect the CNS, such as sedatives, hypnotics, phenothiazines, neuroleptics, anaesthetics, antidepressants, muscle relaxants) and other opioids or alcohol, in particular respiratory depression.
– 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).
– Monoaminooxidase (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 MAOinhibitors or who have received MAO-inhibitors during the last two weeks (see section 4.4).
Alcohol may enhance the pharmacodynamic effects of Alivio; concomitant use should be avoided.
Oxycodone is metabolised mainly by CYP3A4, with a contribution from CYP2D6. The activities of these metabolic pathways may be inhibited or induced by various co-administered medicinal products or dietary elements.
– CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azolantifungals (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).
– Clinically relevant changes in International Normalised Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with oxycodone.
– 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.
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.
4.6 Fertility, pregnancy and lactation
Pregnancy
Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.
Breast-feeding
Administration to nursing women is not recommended a {invented name} may be secreted in breast milk and may cause respiratory depression in the infant.
Fertility
Human data are not available. In animal studies, oxycodone had no adverse effects on fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
Oxycodone may impair the ability to drive and use machines. Oxycodone may modify patients' reactions to a varying extent depending on the dosage and individual susceptibility. Therefore patients should not drive or operate machinery if affected.
4.8 Undesirable effects
Due to its pharmacological properties oxycodone may cause respiratory depression, miosis, bronchial spasm and spasm of unstriated muscles and may suppress the cough reflex.
The most frequently reported undesirable effects are nausea (especially at the beginning of treatment) and constipation.
Respiratory depression is the chief hazard of an opioid overdose and occurs most commonly in elderly or debilitated patients. Opioids may cause severe hypotension in susceptible individuals.
The following frequency categories form the basis for classification of the undesirable effects:
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)
Infections and infestations
Rare: Herpes simplex
Immune system disorders:
Uncommon: hypersensitivity
Not Known: anaphylactic response, anaphylactoid response
Metabolism and nutrition disorders
Common: decreased appetite up to loss of appetite
Uncommon: dehydration
Rare: increased appetite
Psychiatric disorders
Common: anxiety, confusion, depression, insomnia, nervousness, mental
disorders, decreased activity, restlessness, psychomotor hyperactivity
Uncommon: agitation, affectability, euphoric mood, perceptual disturbances (e.g.-hallucinations, derealization) decreased libido, drug dependence (see section 4.4).
Not known: aggression, drug dependence (see section 4.4).
Nervous system disorders
Very common: somnolence, sedation, dizziness, headache
Common: tremor, lethargy
Uncommon: amnesia, convulsions (especially in people with epilepsy or predisposition to seizures) decreased concentration, migraine, hypertension,, hypertonia, hypoaesthesia, involuntary muscle contractions, coordination disorders, speech disorder, syncope, paraesthesia, dysgeusia
Not known: hyperalgesia.
Eye disorders
Uncommon: visual impairment, miosis
Ear and labyrinth disorders:
Uncommon: vertigo, hearing disorders
Cardiac disorders
Uncommon: tachycardia, palpitations (as a symptom of withdrawal syndrome)
Vascular disorders
Uncommon: vasodilatation
Rare: hypotension, orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders
Common: dyspnea.
Uncommon: respiratory depression, dysphonia, cough
Gastrointestinal disorders
Very common: constipation, nausea, vomiting
Common: abdominal pain, diarrhoea, dry mouth, dyspepsia, hiccups
Uncommon: oral ulcers, stomatitis, dysphagia, flatulence, belching, ileus
Rare: melaena, gum bleeding, tooth staining and damage
Not known: dental caries
Hepatobiliary disorders:
| Uncommon: | increased hepatic enzymes |
| Not known: | cholestasis, biliary colic |
Skin and subcutaneous tissue disorders
Very common: pruritus
| Common: Uncommon: | rash, hyperhidrosis dry skin |
| Rare: | urticaria |
Renal and urinary disorders
Common: dysuria, increased urge to urinate
Uncommon: urinary retention.
Reproductive system and breast disorders
Uncommon: erectile dysfunction, hypogonadism
Not known: amenorrhoea
General disorders and administration site conditions
| Common: Uncommon: | asthenic, fatigue chills, drug withdrawal syndrome, pain (E.g.-chest pain), malaise, oedema, peripheral oedema, drug tolerance, thirst |
| Rare: | weight gain, weight loss |
| Not known: | drug withdrawal syndrome in newborns |
Injury, poisoning and procedural complications
Uncommon: Injuries from accidents
Description of selected adverse reactions
Tolerance and dependence may develop with chronic use and a withdrawal syndrome may occur upon abrupt cessation of therapy. The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, 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 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 Overdose
4.9 OverdosePateints should be informed of the sign and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.
Symptoms of intoxication
Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, hypotonia, miosis, bradycardia, hypotension, pulmonary oedema and death.
Therapy of intoxication
A patent airway must be maintained. The pure opioid antagonists such as naloxone are specific antidotes against symptoms from opioid overdose. Other supportive measures should be employed as needed.
Naloxone: For example 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.
Other supportive measures: These include artificial ventilation, oxygen, vasopressors, and fluid infusions in the management of circulatory shock accompanying an overdose. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Fluid and electrolyte metabolism should be maintained.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics; Opioids; Natural opium alkaloids ATC-Code: N02AA05
Mechanism of action
Oxycodone is a full opioid agonist with no antagonist properties. It has an affinity to kappa, mu and delta opioid receptors in the brain and spinal cord.
Oxycodone is similar to morphine in its action. The therapeutic effect is mainly analgesic, anxiolytic, antitussive and sedative.
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.
5.2 Pharmacokinetic properties
Absorption
The relative bioavailability of Alivio is comparable to that of rapid release oxycodone with maximum plasma concentrations being achieved after approximately 3–5 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.
Biotransformation
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
5.3 Preclinical safety dataReproductive and developmental toxicity Oxycodone had no effect on fertility or early embryonic development in male and female rats at doses as high as 8 mg/kg/d. Also, oxycodone did not induce any deformities in rats at doses as high as 8 mg/kg/d or in rabbits at doses as high as 125 mg/kg/d. Dose-related increases in developmental variations (increased incidences of extra (27) presacral vertebrae and extra pairs of ribs) were observed in rabbits when the data for individual fetuses were analyzed. However, when the same data were analyzed using litters as opposed to individual fetuses, there was no dose-related increase in developmental variations although the incidence of extra presacral vertebrae remained significantly higher in the 125 mg/kg/d group compared to the control group. Since this dose level was associated with severe pharmacotoxic effects in the pregnant animals, the fetal findings may have been a secondary consequence of severe maternal toxicity.
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.
Data from genotoxicity studies with oxycodone reveal no special hazard for humans. Long-term studies on carcinogenicity have not been performed. Oxycodone showed a clastogenic potential in some in vitro investigations. However, under in vivo conditions such findings were not observed, 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.
6.1 List of excipients
Tablet core:
Sugar spheres (sucrose, maize starch)
Hypromellose
Talc
Ethyl cellulose
Hydroxypropylcellulose
Propylene glycol
Carmellose sodium
Cellulose, microcrystalline Magnesium stearate (Ph. Eur.)
Silica, colloidal anhydrous
Tablet coating:
Polyvinyl alcohol
Titanium dioxide (E171)
Macrogol 3350
Iron oxide red (E172)
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
6.5 Nature and contents of containerChild resistant white opaque PVC/PE/PVDC-aluminium perforated unit dose blisters. HDPE bottles with PP child-resistant closure.
Pack sizes:
10×1, 14×1, 20×1, 28×1, 30×1, 50×1, 56×1, 98×1, 100×1 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
Bristol Laboratories Ltd,
Unit 3, Canalside,
Northbridge Road, Berkhamsted,
Hertfordshire, HP4 1EG,
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0559
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
03/02/2020