OxyNorm/OxyNorm Liquid

OxyNorm/OxyNorm Liquid

oxycodone

Manufacturer:

Mundipharma

Distributor:

Zuellig
Full Prescribing Info
Contents
Oxycodone hydrochloride.
Description
OxyNorm: Capsule: Oxycodone HCl (OxyNorm) 5 mg - Each capsule contains 4.5 mg of oxycodone as 5 mg of oxycodone HCl.
Oxycodone HCl (OxyNorm) 10 mg - Each capsule contains 9 mg of oxycodone as 10 mg of oxycodone HCl.
Injection: Each mL contains 9 mg of oxycodone as 10 mg oxycodone HCl.
Oxycodone HCl (OxyNorm) injection is a clear, colourless, sterile solution intended for parenteral administration via the intravenous or subcutaneous routes.
List of excipients: Capsule: Cellulose microcrystalline, magnesium stearate, sunset yellow, titanium dioxide, red iron oxide, indigo carmine, yellow iron oxide, sodium laurylsulfate, and gelatin.
The capsules are printed with ink containing shellac, iron oxide and propylene glycol.
Injection: sodium citrate, citric acid monohydrate, sodium chloride, hydrochloric acid, sodium hydroxide, water for injection.
OxyNorm Liquid: Each 5 mL contains: Oxycodone HCl 5 mg (equivalent to oxycodone base 4.5 mg), Sodium benzoate 5 mg.
List of excipients: Saccharin sodium, Sodium citrate, Citric acid monohydrate, Hydrochloric acid, Sodium hydroxide, Purified water, Hypromellose.
Action
Pharmacology: Pharmacodynamics: Oxycodone HCl is an opioid agonist with no antagonistic action. Its effects are similar to those of morphine.
The therapeutic effect is mainly analgesic, anxiolytic, antitussive and sedative. The mechanism of action involves CNS opioid receptors for endogenous compounds with opioid-like activity.
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.
Other Pharmacologic Effects: In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown. Whether oxycodone, a semisynthetic opioid, has immunological effects similar to morphine is unknown.
Pharmacokinetics: OxyNorm: Oxycodone controlled-release tablets release oxycodone more slowly than immediate-release oxycodone tablets or capsules. Release in vitro is pH-independent.
Absorption: The controlled-release tablets exhibit a two-phase absorption pattern with apparent absorption half-times of 0.6 and 6.9 hours. Peak plasma concentration is attained after three hours. The plasma elimination half-life is approximately 4.5 hours. Food intake has little or no effect on the absorption of oxycodone from controlled-release tablets.
Following absorption, oxycodone is distributed throughout the entire body. Approximately 45% is bound to plasma protein. Oxycodone is metabolized in the liver via CYP3A4 and CYP2D6 to noroxycodone, oxymorphone and noroxymorphone, which are subsequently glucuronidated/glucorinated. Noroxycodone and noroxymorphone are the major circulating metabolites. Noroxycodone is a weak mu opioid agonist. Noroxymorphone is a potent mu opioid agonist; however, it does not cross the blood-brain barrier to a significant extent. Oxymorphone is a potent mu opioid agonist but is present at very low concentrations following oxycodone administration. None of these metabolites are thought to contribute significantly to the analgesic effect of oxycodone.
The active drug and its metabolites are excreted in both urine and feces. The plasma concentrations of oxycodone are only nominally/minimally affected by age, being 15% greater in elderly as compared to young subjects.
Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis.
When compared to normal subjects, patients with mild to severe hepatic dysfunction may have higher plasma concentrations of oxycodone and noroxycodone, and lower plasma concentrations of oxymorphone. There may be an increase in the elimination half-life of oxycodone, and this may be accompanied by an increase in drug effects.
When compared to normal subjects, patients with mild to severe renal dysfunction (creatinine clearance <60 mL/min) may have higher plasma concentrations of oxycodone and its metabolites. There may be an increase in the elimination half-life of oxycodone, and this may be accompanied by an increase in drug effects.
OxyNorm Liquid: Compared with morphine, which has an absolute bioavailability of approximately 30%, oxycodone has a high absolute bioavailability of up to 87% following oral administration. Oxycodone has an elimination half-life of approximately 3-4 hours and is metabolized principally to noroxycodone and oxymorphone. Oxymorphone has some analgesic activity but is present in the plasma at low concentrations and is not considered to contribute to oxycodone's pharmacological effect.
A pharmacokinetic study in healthy volunteers has demonstrated that, following administration of a single 10 mg dose, Oxycodone HCl (OxyNorm liquid) provided an equivalent rate and extent of absorption of oxycodone. Mean peak plasma concentrations of approximately 20 ng/mL were achieved within 1.5 hours of administration, median tmax values from both strengths of oral solutions being less than one hour.
Studies involving controlled release oxycodone have demonstrated that the oral bioavailability of oxycodone is only slightly increased (16%) in the elderly. In patients with renal and hepatic impairment, the bioavailability of oxycodone was increased by 60% and 90% respectively, and a reduced initial dose is recommended in these groups.
Toxicology: Preclinical safety data: Teratogenicity: Oxycodone had no effect on fertility or early embryonic development in male and female rats at doses as high as 8 mg/kg/day. Also, oxycodone did not induce any malformations in rats at doses as high as 8 mg/kg/day or in rabbits at doses as high as 125 mg/kg/day. 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/day 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/day compared to the control group. Body weights were lower in the F1 generation from maternal rats in the 6 mg/kg/day dosing group. There were no effects on physical, reflexological, or sensory developmental parameters or on behavioral and reproductive indices in the F1 pups (the NOEL for F1 pups was 2 mg/kg/day based on body weight effects seen at 6 mg/kg/day). There were no effects on the F2 generation at any dose in the study.
Carcinogenicity: No animal studies to evaluate the carcinogenic potential of oxycodone have been conducted.
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 48 hours after exposure. In the second assay, oxycodone did not show any clastogenicity either with or without metabolic activation at any concentration or time point.
Indications/Uses
OxyNorm: 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 strong opioids.
OxyNorm Liquid: For the treatment of moderate to severe pain requiring the use of a strong opioid.
Dosage/Direction for Use
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.
Cessation of therapy: When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
OxyNorm (capsule)/OxyNorm Liquid: Route of administration: Oral.
Elderly and adults over 18 years: Oxycodone HCl (OxyNorm) capsules/(OxyNorm liquid) should be taken at 4-6 hourly intervals. The dosage is dependent on the severity of the pain, and the patient's previous history of analgesic requirements.
Increasing severity of pain will require an increased dosage of Oxycodone HCl (OxyNorm) capsules/(OxyNorm liquid). The correct dosage for any individual patient is that which controls the pain and is well tolerated throughout the dosing period. Patients should be titrated to pain relief unless unmanageable adverse drug reactions prevent this.
The usual starting dose for opioid naive patients or patients presenting with severe pain uncontrolled by weaker opioids is 5 mg, 4-6 hourly. The dose should then be carefully titrated, as frequently as once a day if necessary, to achieve pain relief. The majority of patients will not require a daily dose greater than 400 mg. However, a few patients may require higher doses.
Patients receiving oral morphine before oxycodone 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 Oxycodone HCl (OxyNorm) capsules/(OxyNorm liquid) required. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.
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.
Adults with mild to moderate renal impairment and mild hepatic impairment: The plasma concentration in this patient population may be increased. Therefore, dose initiation should follow a conservative approach. The starting dose for opioid naive patients is 2.5 mg oxycodone 6-hourly, given as Oxycodone HCl (OxyNorm) liquid.
Children under 18 years: Oxycodone HCl (OxyNorm) capsules/(OxyNorm liquid) should not be used in patients under 18 years.
OxyNorm: Capsule: In common with other strong opioids, the need for continued treatment should be assessed at regular intervals.
Injection: For intravenous or subcutaneous injection or infusion only.
Posology: The dose should be adjusted according to the severity of pain, the total condition of the patient and previous or concurrent medication.
Adults over 18 years: The following starting doses are recommended. A gradual increase in dose may be required if analgesia is inadequate or if pain severity increases.
i.v. (Bolus): Dilute to 1 mg/mL in 0.9% saline, 5% dextrose or water for injections. Administer a bolus dose of 1 to 10 mg slowly over 1-2 minutes. Doses should not be administered more frequently than every 4 hours.
i.v. (Infusion): Dilute to 1 mg/mL in 0.9% saline, 5% dextrose or water for injections. A starting dose of 2 mg/hour is recommended.
i.v. (PCA): Dilute to 1 mg/mL in 0.9% saline, 5% dextrose or water for injections. Bolus doses of 0.03 mg/kg should be administered with a minimum lock-out time of 5 minutes.
s.c. (Bolus): Use as 10 mg/mL concentration. A starting dose of 5 mg is recommended, repeated at 4-hourly intervals as required.
s.c. (Infusion): Dilute in 0.9% saline, 5% dextrose or water for injections if required. A starting dose of 7.5 mg/day is recommended in opioid naive patients, titrating gradually according to symptom control. Cancer patients transferring from oral oxycodone may require much higher doses.
Transferring patients between oral and parenteral oxycodone: 1 mg injectable oxycodone is equivalent to 2 mg oral oxycodone. However, inter-patient variability requires that dosage be individualized and the dose titrated to the patient's requirement.
Elderly patients: Use with caution and titrate to the lowest possible dose that will control pain.
Patients with renal or hepatic impairment: Use with caution and titrate to the lowest possible dose that will control pain.
Children under 18 years: There are no data to support the use of oxycodone injection among children within this age group.
Overdosage
Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, hypotonia, miosis, bradycardia, hypotension, pulmonary edema, and death.
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.
OxyNorm Liquid: In the case of massive overdosage, administer naloxone intravenously (0.4 to 2 mg for an adult and 0.01 mg/kg body weight for children) if the patient is in a coma or respiratory depression is present. Repeat the dose at 2 minute intervals if there is no response. If repeated doses are required then an infusion of 60% of the initial dose per hour is a useful starting point. A solution of 10 mg made up in 50 ml dextrose will produce 200 micrograms/mL for infusion using an IV pump (dose adjusted to the clinical response). Infusions are not a substitute for frequent review of the patient's clinical state. Intramuscular naloxone is an alternative in the event that IV access is not possible. As the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Naloxone is a competitive antagonist and large doses (4 mg) might be required in seriously poisoned patients.
For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes, if required.
Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdosage. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on oxycodone. In such cases, an abrupt or complete reversal of opioid effects may precipitate pain and an acute withdrawal syndrome.
Additional/other considerations: Consider activated charcoal (50 g for adults, 10-15 g for children), if a substantial amount has been ingested within 1 hour, provided the airway can be protected.
Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug.
Contraindications
OxyNorm: Oxycodone is contraindicated in patients with known hypersensitivity to oxycodone, or 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, or paralytic ileus.
OxyNorm Liquid: Oxycodone HCl (OxyNorm liquid) is contraindicated in patients with known hypersensitivity to oxycodone, or to any of the excipients listed in Description. 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 and/or hypercapnia, paralytic ileus, head injury, acute abdomen, delayed gastric emptying, hypercarbia, 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, pregnancy and lactation.
Special Precautions
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 myxedema, hypothyroidism, Addison's disease, toxic psychosis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypotension, head injury (due to risk of increased intracranial pressure) or patients taking benzodiazepines, other CNS depressants (including alcohol) or MAO inhibitors.
The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of this product may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
Hyperalgesia that will not respond to a further dose increase of oxycodone may very rarely occur in particular in high doses. An oxycodone dose reduction or change in opioid may be required.
Oxycodone has an abuse profile similar to other strong agonist 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 HCl (OxyNorm/OxyNorm Liquid) should be used with particular care in patients with a history of alcohol and drug abuse.
Oxycodone HCl (OxyNorm/OxyNorm Liquid) should be used with caution pre- or intra-operatively and within the first 12-24 hours post-operatively.
Effects on ability to drive and use machines: Oxycodone may impair the ability to drive and use machines.
OxyNorm (capsule)/OxyNorm Liquid: Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.
OxyNorm Liquid: Oxycodone HCl (OxyNorm liquid) should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Oxycodone HCl (OxyNorm liquid) should be discontinued immediately. As with all opioid preparations, patients should undergo additional pain relieving procedures (e. g. surgery, plexus blockade) should not receive Oxycodone HCl (OxyNorm liquid) for 6 hours prior to the intervention.
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. There is potential for development of psychological dependence (addiction) to opioid analgesics, including oxycodone.
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 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.
Opioids, such as Oxycodone HCl (OxyNorm liquid), 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.
Use In Pregnancy & Lactation
Use of this medicinal product should be avoided to the extent possible in patients who are pregnant or lactating.
Prolonged use of oxycodone during pregnancy can result in neonatal opioid withdrawal syndrome.
The drug penetrates the placenta and can be found in breast milk.
OxyNorm Liquid: Oxycodone HCl (OxyNorm liquid) is not recommended for use in pregnancy nor during labor.
Oxycodone HCl (OxyNorm liquid) should, therefore, not be used in breast-feeding mothers.
Adverse Reactions
The undesirable effects listed as follows are classified by body system according to their incidence (common or uncommon). Common adverse drug reactions have an incidence of ≥1% and uncommon adverse drug experiences have an incidence of <1%. (See table.)

Click on icon to see table/diagram/image
Drug Interactions
There can be an enhanced CNS depressant effect, which can result in profound sedation, respiratory depression, coma, and death, during concomitant therapy with benzodiazepines or other drugs which affect the CNS such as alcohol, other opioids, non-benzodiazepine, sedatives, hypnotics, anti-depressants, phenothiazines and neuroleptic drugs, etc.
Concomitant administration of oxycodone with anticholinergics or medications with anticholinergic activity (e.g. tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects.
Oxycodone is metabolized in part via the CYP2D6 and CYP3A4 pathways. The activities of these metabolic pathways may be inhibited or induced by various co-administered drugs or dietary elements. Oxycodone doses may need to be adjusted accordingly.
CYP3A4 inhibitors, such as macrolide antibiotics (e.g., clarithromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), and grapefruit juice may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations.
CYP3A4 inducers, such as rifampin, carbamazepine, phenytoin and St. John's wort, may induce the metabolism of oxycodone and cause increased clearance of the drug, resulting in a decrease in oxycodone plasma concentrations.
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.
Caution For Usage
OxyNorm: Incompatibilities: Capsule: Not Applicable.
Injection: Oxycodone HCl (OxyNorm) injection is compatible with parenteral formulations of hyoscine butylbromide, hyoscine hydrobromide, dexamethasone sodium phosphate, haloperidol, midazolam HCl, metoclopramide HCl and levomepromazine HCl.
However, Oxycodone HCl (OxyNorm) injection is formulated at acidic pH and is likely to be incompatible with alkaline pH formulations such as Fluorouracil (5-FU) which may lead to precipitation. In addition the Oxycodone HCl (OxyNorm) injection has been shown to be chemically incompatible with prochlorperazine. Precipitation has been shown to occur with the combination of Oxycodone HCl (OxyNorm) injection with cyclizine at concentrations greater than 3 mg/mL or when diluted with 0.9% saline.
It is recommended that Oxycodone HCl (OxyNorm) injection should not be administered in combination with other parenteral formulations unless there is compatibility data to support the combination.
Instructions for disposal and other handling: Injection: Administer the injection soon after opening the ampoule. Unused portions of an opened ampoule should be discarded. Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature.
From a microbiological point of view the product should be used immediately. If not used immediately, the in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C unless reconstitution/dilution took place in controlled and validated aseptic conditions. However, inappropriate handling may compromise the sterility of the product.
Oxycodone HCl (OxyNorm) injection undiluted or diluted to 1 mg/mL with 0.9% w/v saline, 5% w/v dextrose or water for injection, is physically and chemically stable when in contact with representative brands of polypropylene or polycarbonate syringes, polyethylene or PVC tubing and PVC or EVA infusion bags over a 24-hour period at room temperature.
OxyNorm Liquid: Incompatibilities: Not applicable.
Special precautions for disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Storage
Store at temperatures not exceeding 30°C.
Shelf life: OxyNorm: Capsule: 36 months.
Injection: 5 years unopened.
After opening use immediately. For further information see Instructions for disposal and other handling under Cautions for Usage.
OxyNorm Liquid: 3 years.
ATC Classification
N02AA05 - oxycodone ; Belongs to the class of natural opium alkaloids. Used to relieve pain.
Presentation/Packing
OxyNorm: IR cap 5 mg (size 4 hard gelatin orange/beige opaque capsules printed with ONR and 5 in black ink) x 28's. 10 mg (size 4 hard gelatin white/beige opaque capsules printed with ONR and 10 in black ink) x 28's. Inj (amp) 10 mg/mL (clear, colourless, sterile solution) x 1 mL x 5's, 2 mL x 5's.
OxyNorm Liquid: Oral soln 5 mg/5 mL (clear, colourless/straw-coloured solution) x 250 mL.
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