OxyContin 40 MG Prolonged Release Tablets

For the treatment of moderate to severe pain in patients with cancer and post-operative pain. For the treatment of severe pain requiring the use of a strong opioid.

Adults over 18 years:

OxyContin tablets should be taken at 12-hourly intervals. The dosage is dependent on the severity of the pain, and the patient’s previous history of analgesic requirements.

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with oxycodone in order to minimize the risk of addiction and drug withdrawal syndrome (see section 4.4).

OxyContin is not intended for use as a prn analgesic.

Increasing severity of pain will require an increased dosage of OxyContin tablets, using the 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg tablet strengths, either alone or in combination, to achieve pain relief. The correct dosage for any individual patient is that which controls the pain and is well tolerated for a full 12 hours. Patients should be titrated to pain relief unless unmanageable adverse drug reactions prevent this. If higher doses are necessary, increases should be made in 25% – 50% increments. The need to escape medication more than twice a day indicates that the dosage of OxyContin tablets should be increased.

The usual starting dose for opioid naïve patients or patients presenting with severe pain uncontrolled by weaker opioids is 10 mg, 12-hourly. Some patients may benefit from a starting dose of 5 mg to minimize the incidence of side effects. The dose should then be carefully titrated, as frequently as once a day if necessary, to achieve pain relief. For the majority of patients, the maximum dose is 200 mg 12-hourly. However, a few patients may require higher doses. Doses in excess of 1000 mg daily have been recorded.

Conversion from oral morphine:

Patients receiving oral morphine before OxyContin therapy should have their daily dose based on the following ratio: 10 mg of oral oxycodone is equivalent to 20 mg of oral morphine. It must be emphasized that this is a guide to the dose of OxyContin tablets required. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.

Elderly patients:

A dose adjustment is not usually necessary in elderly patients.

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.

Pediatric population

OxyContin should not be used in patients under 18 years of age.

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.

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.

Method of administration

OxyContin tablets are for oral use.

OxyContin tablets must be swallowed whole and not broken, chewed, or crushed.

Duration of treatment

Oxycodone should not be used for longer than necessary.

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.

Hypersensitivity to oxycodone or to any of the excipients listed in section 6.1. Oxycodone must not be used in any situation where opioids are contraindicated: severe respiratory depression with hypoxia, paralytic ileus, acute abdomen, delayed gastric emptying, severe chronic obstructive lung disease, cor pulmonale, severe bronchial asthma, elevated carbon dioxide levels in the blood, moderate to severe hepatic impairment, chronic constipation.

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

The major risk of opioid excess is respiratory depression. Caution must be exercised when administering oxycodone to the debilitated elderly; patients with severely impaired pulmonary function, patients with impaired hepatic or renal function; patients with myxoedema, hypothyroidism, Addison’s disease, toxic psychosis, prostate hypertrophy, adrenocortical insufficiency, alcoholism, delirium tremens, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, hypotension, hypovolaemia, raised intracranial pressure, head injury (due to risk of increased intracranial pressure) or patients taking benzodiazepines, other CNS depressants (including alcohol) or MAO inhibitors.

Concomitant use of benzodiazepines and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs with opioids should be reserved for patients for whom alternative treatment options are not possible.

If a decision is made to prescribe benzodiazepines concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).

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 environment to be aware of these symptoms (see section 4.5).

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

OxyContin tablets are not recommended for pre-operative use or within the first 12-24 hours postoperatively.

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.

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

OxyContin 60 mg, 80 mg, and 120 mg 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.

For appropriate patients who suffer with chronic non-malignant pain, opioids should be used as part of a comprehensive treatment program 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 minimize 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 physicians and patients 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.

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 the 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.

Comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, 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 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 oxycodone.

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 minimize symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterized 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, diarrhea, 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 the 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 the opioid dose.

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

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

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

Empty matrix (tablets) may be seen in the stools.

Opioids such as oxycodone hydrochloride, 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 manifest from these hormonal changes.

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

Drugs that affect the CNS include, but are not limited to: alcohol, tranquilizers, anesthetics, hypnotics, anti-depressants, non-benzodiazepine sedatives, phenothiazines, neuroleptic drugs, other opioids, muscle relaxants and antihypertensives.

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, diarrhea). Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

Concomitant administration of oxycodone with anticholinergics or medicines with anticholinergic activity (e.g. tricyclic anti-depressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects. Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

MAO inhibitors are known to interact with narcotic analgesics. MAO inhibitors cause CNS excitation or depression associated with hypertensive or hypotensive crises (see section 4.4).

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

Oxycodone is metabolized 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.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin, and telithromycin), azole 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, carbamazepine, 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. 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 nor oxycodone level was observed, (Cmax by 50%; AUC by 85%, and t½ Elim. by 42%). The pharmacodynamic effects of oxycodone were not altered.

Pregnancy

OxyContin tablets are not recommended for use in pregnancy nor during labor. There are limited data from the use of oxycodone in pregnant women. Regular use in pregnancy may cause drug dependence in the fetus, leading to withdrawal symptoms in the neonate. If opioid use is required for a prolonged period in pregnant women, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labor may depress respiration in the neonate and an antidote for the child should be readily available.

Breastfeeding

Administration to nursing women is not recommended as oxycodone may be secreted in breast milk and may cause respiratory depression in the infant.

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.

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 offense to drive while you have this medicine in your body over a specified limit unless you have a defense (called the ‘statutory defense’).

• This defense applies when:

• Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).”

Details regarding a new driving offense concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law

Adverse drug reactions are typical of full opioid agonists. Tolerance and dependence may occur (see Section 4.4). Constipation may be prevented with an appropriate laxative. If nausea and vomiting are troublesome, oxycodone may be combined with an anti-emetic.

The following frequency categories form the basis for classification of the undesirable effects: