Renocontin

Renocontin 5 mg prolonged-release tablets

Oxycodone Glenmark 5 mg prolonged-release tablets

Each prolonged-release tablet contains 5 mg oxycodone hydrochloride corresponding to 4.5 mg oxycodone.

Excipients with known effect:

Each prolonged-release tablet contains 64 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Prolonged-release tablet

Light blue, round, biconvex, prolonged-release tablets with a diameter of 6.9 – 7.3 mm and a height of 3.2 – 3.9 mm.

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

Oxycodone is indicated in adults and adolescents aged 12 years and older.

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 of age and older

Dose titration and adjustment

In general, the initial dose for opioid naïve patients is 10 mg oxycodone hydrochloride given at intervals of 12 hours. Some patients may benefit from a starting dose of 5 mg oxycodone hydrochloride to minimize the incidence of adverse reactions.

Patients already receiving opioids may start treatment with higher dosages taking into account their experience with former opioid therapies.

For doses not realisable/practicable with this strength other strengths of this medicinal product are available.

Because of individual differences in sensitivity for different opioids, it is recommended that patients should start conservatively with Oxycodone after conversion from other opioids, with 50-75% of the calculated oxycodone dose.

Some patients who take Oxycodone following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Oxycodone is not indicated for the treatment of acute pain and/or breakthrough pain. The single dose of the rescue medication should amount to 1/6 of the equianalgesic daily dose of Oxycodone. Use of the rescue medication more than twice daily indicates that the dose of Oxycodone 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. Doses in excess of 1000mg have been recorded.

Conversion from oral morphine

According to well-controlled clinical studies 10-13 mg oxycodone ¬hydrochloride correspond to approximately 20 mg morphine sulphate, both in the prolonged-release formulation.

Elderly patients

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

Controlled pharmacokinetic studies in elderly patients (aged over 65 years) have shown that, compared with younger adults, the clearance of oxycodone is only slightly reduced. No untoward adverse drug reactions were seen based on age, therefore adult doses and dosage intervals are appropriate.

Patients with low body weight or slow metabolism

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

Therefore the lowest recommended dosage, i.e. 10 mg, may not be suitable as a starting dose.

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

Patients with renal or hepatic impairment

The dose initiation should follow a conservative approach as the plasma concentration may be increased 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.

Use in non-malignant pain:

Opioids are not first line therapy for chronic non-malignant pain, nor are they recommended as the only treatment. Types of chronic pain which have been shown to be alleviated by strong opioids include chronic osteoarthritic pain and intervertebral disc disease. The need for continued treatment in non-malignant pain should be assessed at regular intervals.

Children under 12 years of age

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

Method of administration

For oral use.

Oxycodone 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. Oxycodone must be swallowed whole, not chewed, divided or crushed. Taking chewed, divided or crushed Oxycodone tablets may lead to a rapid release and absorption of a potentially fatal dose of oxycodone.

Oxycodone should not be taken with alcoholic beverages.

Duration of treatment

Oxycodone 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.

Discontinuation of treatmentWhen a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Severe respiratory depression with hypoxia and/or elevated carbon dioxide levels in the blood (hypercapnia).

• Severe chronic obstructive pulmonary disease.

• Cor pulmonale.

• Severe bronchial asthma.

• Paralytic ileus.

• Acute abdomen, delayed gastric emptying.

• Head injury.

• Moderate to severe hepatic impairment.

• Severe renal impairment (creatinine clearance <10 ml/min).

• Chronic constipation.

• Concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use.

Respiratory and cardiac depression

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

Oxycodone 60mg, 80mg and 120mg tablets should not be used in patients not previously exposed to opioids. These tablet strengths may cause fatal respiratory depression when administered to opioid naïve patients.

Tolerance and dependence

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 non-malignant pain is the patient's addiction and substance abuse history.

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.

Long-term use of Oxycodone can cause the development of tolerance which leads to the use of higher doses in order to achieve the desired analgesic effect. There is a cross-tolerance to other opioids. Chronic use of Oxycodone can cause physical dependence. Withdrawal symptoms may occur following abrupt discontinuation of therapy.

If therapy with oxycodone is no longer required it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of a withdrawal syndrome.

Withdrawal symptoms may include restlessness, perspiration, chills, myalgia, palpitations, yawning, mydriasis, lacrimation, rhinorrhoea, tremor, hyperhidrosis, anxiety, agitation, convulsions and insomnia. Other symptoms also may develop, including: irritability, backache, joint pain, weakness, abdominal cramps, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate or heart rate.

Hyperalgesia that will not respond to a further dose increase of oxycodone may occur, particularly in high doses. An oxycodone dose reduction or change to an alternative opioid may be required.

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

Abuse

Oxycodone has an abuse profile similar to other strong opioids. Oxycodone may be sought and abused by people with latent or manifest addiction disorders. There is potential for development of psychological dependence [addiction] to opioid analgesics, including oxycodone. Oxycodone should be used with particular care in patients with a history of alcohol and drug abuse.

Abuse of oral dosage forms by parenteral administration can be expected to result in other serious adverse events, such as local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, which may be fatal.

Alcohol

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

Special patient groups

Caution is required in elderly or debilitated patients, in patients with severe impairment of lung, hepatic or renal function, myxoedema, hypothyroidism, Addison's disease (adrenal insufficiency), intoxic psychosis (e.g. alcohol), prostatic hypertrophy, adrenocortical insufficiency, alcoholism, known opioid dependence, delirium tremens, pancreatitis, disease of the biliary tract, biliary or renalcolic, inflammatory bowel disorders, raised intracranial pressure, hypotension, hypovolemia, epilepsy or seizure tendency and in patients taking MAO inhibitors within the last two weeks. Patients with severe hepatic impairment should be closely monitored.

Oxycodone should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, oxycodone should be discontinued immediately.

Surgical procedures

Special care should be taken when oxycodone is applied to patients undergoing bowel-surgery as opioids are known to impair intestinal motility. Opioids should only be administered post-operatively when the bowel function has been restored.

The safety of Oxycodone used pre-operatively has not been established.

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

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive oxycodone tablets for 12 hours prior to the intervention. If further treatment with oxycodone tablets is indicated then the dosage should be adjusted to the new post-operative requirement.

Paediatric population

The safety and efficacy of Oxycodone in children younger than 12 years of age have not been established. Oxycodone should not be used in children younger than 12 years of age because of safety and efficacy concerns.

As with other opioids, infants who are born to dependent mothers may exhibit withdrawal symptoms and may have respiratory depression at birth.

Anti-doping warning

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

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

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

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

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

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

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.

Excipient

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

There can be an enhanced CNS depressant effect during concomitant therapy with drugs which affect the CNS such as tranquillisers, (e.g. sedatives, hypnotics, phenothiazines, neuroleptics, anaesthetics, antidepressants, muscle relaxants and antihypertensives, other opioids or alcohol increasing the adverse reactions of oxycodone, in particular respiratory depression.

Medications with anticholinergic effect (e.g. tricyclic antidepressants, antihistamines, antiemetics, antipsychotics, muscle relaxants, medicinal products against Morbus Parkinson) may intensify the anticholinergic adverse drug reactions of oxycodone such as constipation, dry mouth or dysfunction of urinary excretion.

MAO inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression 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).

Concomitant use of alcohol and Oxycodone may increase the undesirable effects of Oxycodone; 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 drugs or dietary elements. 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. Concurrent administration of quinidine resulted in an increase in oxycodone Cmax by 11%, AUC by 13%, and t½ elim. by 14%. Also an increase in noroxycodone level was observed, (Cmax by 50%; AUC by 85%, and t½ elim. by 42%). The pharmacodynamic effects of oxycodone were not altered.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azol antifungals (e.g. ketoconazole, voriconazole, itraconazole, and posaconazole), protease inhibitors (e.g. boceprevir, ritonavir, indinavir, nelfinavir and saquinavir), cimetidine and grapefruit juice may cause a reduced clearance of oxycodone that could cause an increase of the plasma concentrations of oxycodone. Therefore the oxycodone dose may need to be adjusted accordingly. Some specific examples are provided below:

• Itraconazole, a potent CYP3A4 inhibitor, administered 200 mg orally for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 2.4 times higher (range 1.5 - 3.4).

• Voriconazole, a CYP3A4 inhibitor, administered 200 mg twice-daily for four days (400 mg given as first two doses), increased the AUC of oral oxycodone. On average, the AUC was approximately 3.6 times higher (range 2.7 - 5.6).

• Telithromycin, a CYP3A4 inhibitor, administered 800 mg orally for four days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.8 times higher (range 1.3 - 2.3).

• Grapefruit Juice, a CYP3A4 inhibitor, administered as 200 ml three times a day for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.7 times higher (range 1.1 - 2.1).

CYP3A4 inducers, such as rifampicin, carbamazepin, phenytoin and St John´s Wort may induce the metabolism of oxycodone and cause an increased clearance of oxycodone that could cause a reduction of the plasma concentrations of oxycodone. The oxycodone dose may need to be adjusted accordingly. Some specific examples are provided below:

• St John's Wort, a CYP3A4 inducer, administered as 300 mg three times a day for fifteen days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 50% lower (range 37-57%).

• Rifampicin, a CYP3A4 inducer, administered as 600 mg once-daily for seven days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 86% lower

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

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

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

Sedative medicines such as benzodiazepines or related drugs:

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

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 serotoin 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.

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

Pregnancy

Oxycodone is not recommended for use in pregnancy nor during labour. 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.

Oxycodone may impair the ability to drive and use machines. This is particularly likely at the initiation of treatment with Oxycodone, after dose increase or product rotation and if Oxycodone is combined with 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.

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

Summary of the safety profile

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.

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)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

Symptoms of intoxication

Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing up 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.

Opioid antagonists: Naloxone (e.g. 0.4-2 mg naloxone intravenously). Administration should be repeated at 2-3 minute intervals as necessary, or by an infusion of 2 mg naloxone in 500 ml 0.9% w/v sodium chloride solution or 5% w/v glucose solution (corresponding to 0.004 mg naloxone/ml). 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 balance should be maintained.

Pharmacotherapeutic group: Analgesics; Opioids; Natural opium alkaloids

ATC-Code: N02A A05

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, anxiolytic, antitussiveand 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.

Gastrointestinal System

Opioids may induce spasm of the sphincter of Oddi.

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 semi-synthetic opioid, has immunological effects similar to morphinie is unkown.

Clinical studies

The efficacy of oxycodone 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 oxycodone 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.

Absorption:

The relative bioavailability of Oxycodone 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.

The tablets must not be crushed, divided, or chewed as this leads to rapid oxycodone release and absorption of a potentially fatal dose of oxycodone due to the damage of the prolonged release properties.

Distribution:

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

Metabolism:

Oxycodone is metabolized 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.

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 t½ 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 t½ elimination for oxycodone increased by 2.3 hours.

Reproductive 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 foetuses were analyzed.

However, when the same data were analyzed using litters as opposed to individual foetuses, 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 foetal 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.

Carcinogenicity

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 μg/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.

Tablet core:

Lactose monohydrate

Ammonio Methacrylate Copolymer, Type B dispersion 30%

Povidone (K29/32)

Talc

Triacetin

Stearyl alcohol

Magnesium stearate

Tablet coating:

Hypromellose

Talc

Macrogol 400

Titanium dioxide (E171)

Brilliant Blue FCF (E133)

Not applicable.

2 years

Do not store above 25°C

Child resistant PVC/PVdC-Aluminium blisters with 10, 14, 20, 25, 28, 30, 40, 50, 56, 60, 98 and 100 prolonged-release tablets.

Not all pack sizes may be marketed.

No special requirements.

Glenmark Pharmaceuticals Europe Limited

Laxmi House, 2B Draycott Avenue, Kenton, Middlesex

HA3 0BU

United Kingdom

PL 25258/0217

26/09/2018

05/06/2019