This information is intended for use by health professionals

1. Name of the medicinal product

Oxypro 80 mg prolonged-release tablets

2. Qualitative and quantitative composition

Each prolonged-release tablet contains 80 mg oxycodone hydrochloride corresponding to 71.7 mg oxycodone.

Excipients with known effect:

Each prolonged-release tablet contains 60 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Green, round, biconvex, prolonged-release tablets with a diameter of 8.6 - 9.0 mm and a height of 5.0 - 5.6 mm.

4. Clinical particulars
4.1 Therapeutic indications

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

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

4.2 Posology and method of administration

Posology

The dosage should be adjusted to the intensity of pain and the patient's individual susceptibility.

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

Unless otherwise prescribed the following general dosage recommendations apply for Oxypro:

Adults and adolescents (12 years of age and older)

Dose titration

The usual starting dose for an opioid naïve patient is 10 mg oxycodone hydrochloride per dose given at intervals of 12 hours.

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, each with prolonged-release formulation.

Dose adjustment

Some patients who receive Oxypro following a fixed schedule additionally need rapid release analgesics as rescue medication in order to control breakthrough pain. Oxypro prolonged-release tablets are not indicated for the treatment of these breakthrough pain. The single dose of the rescue medication should amount to 1/6 of the equianalgesic daily dose of Oxypro. Use of the rescue medication more than twice daily indicates that the dose of Oxypro prolonged-release tablets needs to be increased. The dose should not be adjusted more often than once every 1-2 days until a stable 12 hours dose is reached.

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 until the desired effect is obtained. The aim is a patient-specific 12 hourly dose maintaining adequate analgesia with tolerable undesirable effects as well as a minimal rescue medication as low as possible and as long as pain control is needed.

Although the constant administration (the same dose mornings and evenings) following a fixed schedule (every 12 hours) is appropriate for the majority of the patients for some patients it may be advantageous - depending on the individual pain situation - 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 require in generally dosages of 80 to 120 mg, which in individual cases can be increased to up to 400 mg.

Duration of treatment

Oxypro 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 treatment

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

Elderly patients

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

Patients with hepatic or renal impairment

The treatment 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. Therefore the lowest recommended dosage mentioned in this SmPC i.e. 10 mg, may not be suitable as a starting dose. In this case Oxypro 5 mg prolonged release tablets should be used.

Other risk patients

In patients with low body weight or in slow metabolisers who are also opioid-naive, the recommended starting dose should be reduced to half of the recommended starting dose for adults. Therefore the lowest recommended dosage mentioned in this SmPC, i.e. 10 mg, may not be suitable as a starting dose. In this case Oxypro 5 mg prolonged release tablets should be used.

Children (under 12 years of age)

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

Method of administration

For oral use.

Oxypro 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. Oxypro must not be divided, chewed or crushed.

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.

4.4 Special warnings and precautions for use

Respiratory depression is the most significant risk induced by opioids.

Caution must be exercised when administering oxycodone to elderly debilitated patients, in patients with severe impairment of pulmonary function, impaired hepatic or renal function, patients with myxoedema, hypothyroidism, Addison's disease, prostatic hypertrophy, toxic psychosis, alcoholism, delirium tremens, known opioid dependence, disease of the biliary tract pancreatitis, obstructive and inflammatory bowel disorders, head injuries (due to risk of increased intracranial pressure), hypotension, hypovolemia, epileptic disorder or predisposition to convulsions and in patients taking MAO inhibitors.

With the occurrence or suspicion of paralytic ileus, oxycodone should be discontinued immediately.

Only for Oxypro 80 mg:

Oxypro 80 mg prolonged-release tablets should not be used in opioid naïve patients because this strength may lead to a life-threatening respiratory depression.

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

Long-term use of Oxypro may cause the development of tolerance which leads to the use of higher doses in order to achieve the desired analgesic effect. Prolonged use of Oxypro may lead to 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 withdrawal syndromes.

Withdrawal symptoms may include yawning, mydriasis, lacrimation, rhinorrhoea, tremor, hyperhidrosis, anxiety, agitation, convulsions, insomnia or myalgia.

Oxycodone has an abuse profile similar to other strong opioid receptor agonist. Oxycodone may be abused by people with latent or manifest dependence disorders. There is potential for development of psychological dependence (addiction) after administration of opioid containing analgesics as Oxypro. Oxycodone should be used with particular care in patients with a history of alcohol and drug abuse.

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

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.

Oxypro should not be used in children younger than 12 years of age because of safety and efficacy concerns.

Oxypro is not recommended for pre-operative use or within the first 12 – 24 hours post operatively. Depending on the type and extent of the surgical procedure, the selected anaesthetic procedure, the other concomitant medication and the patient's individual condition, the timing of the postoperative use of Oxypro must be determined after careful consideration of the benefit and risk in each individual case.

Like all opioid containing preparations Oxypro should be used with caution to patients undergoing bowel-surgery due to the known impairments of intestinal motility. Opioids should only be used after the doctor has verified the normalisation of the bowel function.

Oxypro consist of a polymer matrix and is intended for oral use only. In case of abusive parenteral venous injection the tablet excipients (especially talc) may lead to serious, potentially fatal events.

The empty tablet matrix may be excreted visibly with the faeces.

Anti-doping warning

The use of Oxypro may lead to positive results for doping controls.

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

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.

4.5 Interaction with other medicinal products and other forms of interaction

The concomitant therapy with drugs affecting the central nervous system (CNS) such as sedatives, hypnotics, phenothiazines, neuroleptics, antidepressants, antihistamines and antiemetics as well as other opioids, may increase the CNS depressant effect and can enhance the adverse reactions of oxycodone, in particular respiratory depression.

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

Agents with anticholinergic activity (e.g. psychotropic drugs, antihistamines, antiemetics, muscle relaxants, medicinal products against Morbus Parkinson) may result in increased anticholinergic adverse effects e.g constipation, dry mouth or dysfunction of urinary excretion.

Oxypro should be used with caution in patients administered MAO-inhibitors or who have received MAO-inhibitors during the last two weeks.

A clinically relevant reduction or increase of the Prothrombin time (INR, Quick´s value) has been observed in individual cases in simultaneous use of oxycodone and coumarin anticoagulants.

Oxycodone is metabolised mainly by cytochrome P450 3A4, with a contribution from CYP2D6. The activities of these metabolic pathways may be inhibited or induced by various co-administered drugs or dietary elements. The following sections explain these interactions in more detail.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azolantifungals (e.g. ketoconazole, voriconazole, itraconazole, or posaconazole), protease inhibitors (e.g. boceprevir, ritonavir, indinavir, nelfinavir or 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 of CYP3A4 enzyme inhibition 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 or 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 of CYP3A4 enzyme inhibition are provided below:

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

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

Drugs that inhibit CYP2D6 activity, such as paroxetine and quinidine, may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations.

4.6 Fertility, pregnancy and lactation

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

Pregnancy

There are only limited data from the use of oxycodone in pregnant women. Animal studies have only shown reproductive toxicity in maternal toxic dosages (see section 5.3) New-borns 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 new-borns of mothers undergoing treatment with oxycodone.

Breast-feeding

Oxycodone may be secreted in breast milk and may cause sedation and respiratory depression to the breast-feeding baby. Oxycodone should, therefore, not be used in breastfeeding mothers.

Fertility

For Oxycodone no human data are available. Animal studies have not shown any effects upon 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. This is particular likely at the beginning of the treatment with Oxypro, after dose increase or change of product and if Oxycodone is combined with other CNS depressant agents.

With stable therapy, a general ban on driving a vehicle is not necessary.

The treating physician should decide on a case-by-case basis whether the patient is allowed to drive or operate machines.

4.8 Undesirable effects

Due to its pharmacological properties oxycodone can cause respiratory depression, miosis, bronchial spasms and spasms of the smooth muscles and can suppress the cough reflex.

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

The most serious adverse reaction, as with other opioids, is respiratory depression. This is most likely to occur in elderly, debilitated or opioid-intolerant patients.

In susceptible patients' opioids may cause a severe drop in blood pressure.

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)

Very common

Common

Uncommon

Rare

Not known

Infections and infestations

Herpes simplex

Immune system disorders:

Hypersensitivity reactions.

Anaphylactic reactions, anaphylactoid reaction

Metabolism and nutrition disorders:

decreased appetite up to to loss of appetite, Anorexia;

Dehydration.

Increased appetite.

Psychiatric disorders:

Anxiety, confusional state, depressions, decreased activity, restlessness, psychomotor hyperactivity, nervousness, insomnia, abnormal thinking

Agitation, affect lability; euphoric mood; perception disorder (e.g. hallucinations, derealisation); decreased libido, drug dependence (see section 4.4),

Aggression.

Nervous system disorders:

Somnolence; sedation, dizziness; headache.

Tremor; lethargy,

Amnesia; convulsion (especially in patients with epilepsy or predisposition to convulsions), concentration impaired, migraine, ; hypertonia; involuntary muscle contractions, hypoaesthesia; abnormal coordination, speech disorders, syncope, paraesthesia; dysgeusia;

.

Hyperalgesia.

Eye disorders:

visual impairment; miosis.

Ear and labyrinth disorders:

Hearing disorders, Vertigo,

Cardiac disorders:

tachycardia, palpitations (in context of withdrawal syndrome).

Vascular disorders:

Vasodilatation

Hypotension; orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

Dyspnoea,

Respiratory depression, Dysphonia, coughing;

Gastrointestinal disorders:

Constipation, vomiting. nausea,

abdominal pain, diarrhoea , dry mouth, hick up, ,, dyspepsia.

Oral ulcers, stomatitis, dysphagia, flatulence, eructation, ileus

Malaena, dental disease, tooth disorders, gingival bleeding

Dental caries.

Hepatobiliary disorders:

Increased hepatic enzymes;

Cholestasis; biliary colic.

Skin and subcutaneous tissue disorders:

Pruritus

Skin reaction/ rash

hyperhidrosis,

Dry skin.

urticaria.

Renal and urinary disorders:

Dysuria, Micturition urgency

Urinary retention

Reproductive system and breast disorders:

Erectil dysfunction, hypogonadism

Amenorrhoea.

General disorders and administration site conditions:

Asthenic conditions., fatigue,

chills; withdrawal syndrome, pain (e.g. chest pain), malaise, oedema, peripheral oedema, migraine, drug tolerance, thirst

Weight increase or decrease;

Drug withdrawal syndrome neonatal.

Injury, poisoning and procedural complications

Injuries from accidents

Reporting of suspected adverse reactions

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

4.9 Overdose

Symptoms of intoxication:

Acute overdose with oxycodone may result in respiratory depression, somnolence progressing up to stupor or coma, decreased skeletal muscle tone, miosis, bradycardia, drop in blood pressure, pulmonary edema, circulatory failure and death.

Therapy of intoxications:

The airways must be kept clear. Pure opioid antagonists such as naloxone are specific antidotes against symptoms from opioid overdose. Other supportive measures should be employed as needed.

Naloxone: e.g. 0.4-2 mg intravenous. Administration of single doses must be repeated depending on the clinical situation at intervals of 2 to 3 minutes. 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.

Other Supportive measures: Including artificial respiration, oxygen supply, administration of vasopressors and infusion therapy and should be applied in the treatment of accompanying circulatory shock. Upon cardiac arrest or cardiac arrhythmias cardiac massage or defibrillation may be indicated. Water and electrolyte balance should be maintained.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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, spinal cord and peripheral organs. Oxycodone 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.

Gastrointestinal System

Opioids may induce spasm of the sphincter of Oddi.

5.2 Pharmacokinetic properties

Absorption:

To avoid damage to the controlled release properties of the tablets the prolonged release tablets must not be used divided, chewed or crushed as this leads to rapid oxycodone release.

The relative bioavailability of Oxypro 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.

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 gut and the liver to noroxycodone and oxymorphone and to various glucuronide conjugates. Noroxycodone and oxymorphone are produced via the cytochrome P450 system. In vitro studies suggest that therapeutic doses of cimetidine 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.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity.

Oxycodone 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. There were no effects on the F2 generation.

Long-term carcinogenicity studies were not performed.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core:

Lactose monohydrate

Ammonio Methacrylate Copolymer, Type B

Povidone (K29/32)

Talc

Triacetin

Stearyl alcohol

Magnesium stearate

Tablet coating:

Oxypro 80 mg prolonged-release tablets

Hypromellose

Macrogol 400

Titanium dioxide (E171)

Indigo carmine aluminium lake (E132)

Iron oxide yellow (E172)

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/PVdC-Aluminium perforated unit dose blisters with 10x1, 14x1, 20x1, 25x1, 28x1, 30x1, 40x1, 50x1, 56x1, 60x1, 98x1 and 100x1 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Ridge Pharma Limited

1210 Parkview, Arlington Business Park

Reading RG7 4TY

UK

8. Marketing authorisation number(s)

PL 48804/0008

9. Date of first authorisation/renewal of the authorisation

December 2017

10. Date of revision of the text

November 2018