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A size 0, yellow and green capsule containing a white free-flowing powder. Each CAPADEX capsule contains 32.5mg of dextropropoxyphene hydrochloride and 325mg of paracetamol.
Dextropropoxyphene hydrochloride is a centrally acting, synthetic opioid analgesic structurally related to methadone. It binds to opioid receptors at many sites within the central nervous system affecting the processes for both the physiological perception of pain and the emotional response to pain. There are multiple subtypes of central and peripheral opioid receptors each mediating therapeutic and/or adverse effects of opioid agents. The potency of dextropropoxyphene hydrochloride is from two thirds to equal that of codeine.
Paracetamol is a non-opioid analgesic and an anti-pyretic. The analgesic effect of paracetamol is thought to be due to the inhibition of prostaglandin synthesis in the central nervous system and the periphery, and, to a lesser extent, by blocking the pain impulse generation in the periphery. The anti-pyretic effect is due to a central action on the hypothalamic heat regulating centre to produce peripheral vasodilatation and subsequent heat loss.
The combination of dextropropoxyphene with paracetamol produces greater analgesia than that produced by either agent administered alone.
Dextropropoxyphene is readily absorbed from the gastrointestinal tract but is subject to considerable first pass metabolism. Equimolar doses of dextropropoxyphene hydrochloride or dextropropoxyphene napsylate provide similar plasma concentrations. Following administration of 65, 130 or 195mg of dextropropoxyphene hydrochloride, the bioavailability of dextropropoxyphene is equivalent to that of 100, 200 or 300mg respectively of dextropropoxyphene napsylate. Peak plasma concentrations of dextropropoxyphene are reached in 2 to 2½ hours. After a 65mg oral dose of dextropropoxyphene hydrochloride, peak plasma levels of 0.05 to 0.1mcg/ml are achieved.
Repeated doses of dextropropoxyphene at six-hour intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 hours.
Dextropropoxyphene is metabolised in the liver to yield norpropoxyphene. Dextropropoxyphene has a half-life of 6 to 12 hours, whereas that of norpropoxyphene is 30 to 36 hours.
Paracetamol is absorbed readily and completely from the small intestine after oral administration. Peak plasma paracetamol concentrations occur 30 to 120 minutes after oral administration. It is uniformly distributed throughout most body fluids with an apparent volume of distribution of 1 to 1.2L/kg. Plasma protein binding is negligible at the usual therapeutic concentrations but increases with increasing concentrations.
Approximately 90 to 95% of a dose of paracetamol is metabolised by the hepatic microsomal system. In adults at therapeutic doses, paracetamol is mainly conjugated with glucuronide (45-55%) or sulphate (20-30%). A minor proportion (less than 20%) is metabolised to catechol derivatives. Paracetamol is metabolised differently by infants and children compared with adults, the sulphate conjugate being predominant.
Paracetamol is excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol with 85-90% of the dose being eliminated in the urine within 24 hours of ingestion. The elimination half-life of paracetamol varies from about 1 to 4 hours. Food delays paracetamol absorption.
Relief of chronic pain of moderate severity.
CAPADEX should only be prescribed to patients in whom treatment with therapeutic doses of alternative therapeutic agents, including combination products, have been used and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient.
The usual adult dosage is 2 capsules three or four times daily. The maximum daily dose of CAPADEX is 8 capsules. Consideration should be given to reducing the total daily dose of CAPADEX in patients with hepatic or renal impairment. For example, one capsule three or four times daily may be preferred for certain patients.
The administration of CAPADEX is not recommended to children under 14 years.
Dextropropoxyphene products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a major cause of medicine-related deaths. Fatalities within the first hour of overdosage are not uncommon. In a survey of deaths due to overdosage conducted in 1975, in approximately 20% of the fatal cases, death occurred within the first hour (5% occurred within 15 minutes).
Dextropropoxyphene should not be taken in doses higher than those recommended by the physician. The judicious prescribing of dextropropoxyphene is essential to the safe use of this medicine. In patients who are depressed or suicidal, consideration should be given to the use of non-opioid analgesics. Patients should be cautioned about the concurrent use of dextropropoxyphene products and alcohol because of the potentially serious CNS-additive effects of these agents. Because of its added depressant effects, dextropropoxyphene should be prescribed with caution for those patients whose medical condition requires the concurrent administration of sedatives, anxiolytics, muscle relaxants, antidepressants, or other CNS-depressant medicines. Patients should be advised of the additive depressant effects of these combinations.
Many of the dextropropoxyphene-related deaths have occurred in patients with previous histories of emotional disturbance or suicidal ideation or attempts as well as histories of misuse of tranquillisers, alcohol, and other CNS-active medicines. Caution should be exercised in prescribing dextropropoxyphene hydrochloride for such patients (see Overdosage). Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of dextropropoxyphene alone or in combination with other medicines. Patients taking dextropropoxyphene should be warned not to exceed the dosage recommended by the physician.
Dextropropoxyphene, when taken in higher than recommended doses over long periods of time, can produce medicine dependence characterised by psychic dependence and, less frequently, physical dependence and tolerance. Dextropropoxyphene will only partially suppress the withdrawal syndrome in individuals physically dependent on morphine or other narcotics. The abuse liability of dextropropoxyphene should be prescribed with the same degree of caution appropriate to the use of codeine.
Dextropropoxyphene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly.
Dextropropoxyphene should be administered with caution to patients with renal or hepatic impairment since higher serum concentration or delayed elimination may occur.
Dextropropoxyphene should be used with caution in patients with respiratory impairment as it may depress respiration.
CAPADEX should not be used in pregnant women unless, in the judgement of the physician, the potential benefits outweigh the possible hazards.
Dextropropoxyphene may cause respiratory depression in the newborn infant. Safe use in pregnancy has not been established relative to possible adverse effects on foetal development. Instances of withdrawal symptoms in the neonate have been reported following usage during pregnancy.
Paracetamol can cross the placenta. However, in rats and mice no teratogenic effects have been observed after doses of up to 250mg/kg.
Low levels of dextropropoxyphene have been detected in human milk. In postpartum studies involving nursing mothers who were given dextropropoxyphene, no adverse effects were noted in infants receiving mother's milk.
Paracetamol is excreted in breast milk. The amount available for ingestion by the infant has been reported variously as less than 0.1% of a single 500mg dose and as 0.04 to 0.23% of a single 650mg dose. Maternal ingestion of paracetamol in usual analgesic doses does not appear to present a risk to the nursing infant.
CAPADEX is not recommended for use in children. The safety and effectiveness of dextropropoxyphene in children has not been established.
The elderly are more likely to have age related renal impairment and increased susceptibility to the respiratory depressant effects of opioid analgesics. The rate of dextropropoxyphene metabolism may be reduced in some patients. An increased dosing interval or dose reduction should be considered.
Clinical toxicity studies in animals have shown that high doses of paracetamol cause testicular atrophy and inhibition of spermatogenesis; the relevance of this finding to use in humans is not known.
The most commonly reported adverse reactions are dizziness, sedation, nausea, and vomiting. Some of these adverse reactions may be alleviated if the patient lies down.
Other less frequent to rarely reported adverse reactions are light headedness, headache, weakness, euphoria, dysphoria, hallucinations, constipation, abdominal pain, hepatic impairment, minor visual disturbances, skin rashes, allergic reactions, thrombocytopenia, leucopenia, pancytopenia, neutropenia, agranulocytosis.
Hepatic dysfunction has been reported in association with both dextropropoxyphene and paracetamol. Dextropropoxyphene therapy has been associated with abnormal liver function tests and, more rarely, with instances of reversible jaundice (including cholestatic jaundice).
Hepatic necrosis may result from acute paracetamol overdose (see overdosage). In chronic alcohol abusers this has been reported rarely with short-term use of paracetamol doses of 2.5 to 10g/day. Fatalities have occurred.
The chronic ingestion of dextropropoxyphene in doses exceeding 720mg per day has caused toxic psychoses and convulsion. A single dose of 1200mg of dextropropoxyphene has caused convulsions.
Renal papillary necrosis may result from chronic paracetamol use, particularly when the dose is greater than recommended and when combined with aspirin.
Subacute painful myopathy has occurred following chronic dextropropoxyphene overdose.
General
Dextropropoxyphene may inhibit the hepatic metabolism of concurrently administered medicines. Should this occur, higher serum concentrations of the concurrently administered medicine may result in increased pharmacological and/or adverse effects of that medicine. Such occurrences have been reported when dextropropoxyphene has been administered to patients receiving antidepressants, anticonvulsants, or warfarin-like medicines.
CNS Depressants including Alcohol
Dextropropoxyphene in combination with alcohol, tranquillisers, sedative-hypnotics, and other central nervous system depressants has additive depressant effects, and the patient should be so advised. Patients taking CAPADEX should be warned not to exceed the dosage recommended by their physician (see Warnings and Precautions).
CNS Stimulants
The convulsant action of dextropropoxyphene may be enhanced by CNS stimulants.
Warfarin
Concurrent warfarin and dextropropoxyphene administration may increase serum concentrations of warfarin. Paracetamol may affect prothrombin time in patients receiving anticoagulant therapy. Warfarin dosage adjustments may be required.
Carbamazepine
Concurrent carbamazepine and dextropropoxyphene administration significantly increases carbamazepine concentration and may result in moderate to severe neurotoxicity (ataxia, nystagmus, diplopia, headache, vomiting, apnoea, seizures, coma).
Ritonavir
Concurrent ritonavir and dextropropoxyphene administration may increase serum concentrations of dextropropoxyphene resulting in an increased risk of CNS depression or other serious adverse effects.
Beta-Blockers
Oral bioavailability of metoprolol and propanolol may increase when they are given concurrently with dextropropoxyphene.
Orphenadrine
Confusion, anxiety and tremors have been reported in a few patients receiving dextropropoxyphene concurrently with orphenadrine.
Doxepin
Concurrent administration of dextropropoxyphene and doxepin may double steady state doxepin and desmethyldoxepin plasma concentration. This may increase doxepin toxicity (sedation, lethargy, dry mouth, urinary retention).
Chloramphenicol
Concurrent administration of paracetamol and chloramphenicol may increase chloramphenicol serum concentrations.
Cholestyramine
Concurrent administration of paracetamol and cholestyramine can lower plasma paracetamol concentrations.
Diflunisal
Concurrent administration of paracetamol and diflunisal can increase paracetamol plasma concentrations by up to 50%.
Phenytoin
Concurrent administration of paracetamol and phenytoin can increase the metabolism of paracetamol by more than 40% and decrease its half-life by about 25%. There is an increased risk of paracetamol hepatotoxicity with concurrent administration of these two agents.
Lamotrigine
Concurrent administration of paracetamol and lamotrigine may slightly increase the elimination of lamotrigine.
Probenecid
Concurrent administration of paracetamol and probenecid may prolong the half-life and decrease the clearance of paracetamol. The clinical significance of this is unclear.
Sulfinpyrazone
Concurrent administration of paracetamol and sulfinpyrazone can increase the metabolism of paracetamol.
Zidovudine
Concurrent administration of paracetamol and zidovudine has been associated with an increased incidence of neutropenia, especially during chronic therapy.
There are a disturbing number of fatalities from either accidental or intentional overdosage with dextropropoxyphene, many emphasizing the rapidity with which death ensues. The first priority is, therefore, management of the CNS effects of dextropropoxyphene overdosage.
The manifestations of acute overdosage with dextropropoxyphene are similar to those of narcotic overdosage. The patient is usually somnolent, but may be stuperose or comatose and convulsing. Respiratory depression is characteristic. The ventilatory rate and/or tidal volume is decreased, which results in cyanosis and hypoxia. Pupils, initially pinpoint, may become dilated as hypoxia increases. Cheyne-Stokes respiration and apnoea may occur. Blood pressure and heart rate are usually normal initially, but blood pressure falls and cardiac performance deteriorates, which ultimately results in pulmonary oedema and circulatory collapse, unless the respiratory depression is corrected and adequate ventilation is restored promptly. Cardiac arrhythmias and conduction delay may be present. A combined respiratory-metabolic acidosis occurs owing to retained CO2 (hypercapnoea) and to lactic acid formed during anaerobic glycolysis. Death may occur.
Attention should be directed first to establishing a patent airway and to restoring ventilation. Mechanically assisted ventilation, with or without oxygen, may be required, and positive pressure respiration may be desirable if pulmonary oedema is present. The narcotic antagonist naloxone will markedly reduce the degree of respiratory depression, and 0.4 to 2mg should be administered promptly, preferably intravenously. If the desired degree of counteraction with improvement in respiratory functions is not obtained, naloxone should be repeated at 2 to 3 minute intervals. The duration of action of the antagonist may be brief. If no response is observed after 10mg of naloxone have been administered, the diagnosis of dextropropoxyphene toxicity should be questioned. Naloxone may also be administered by continuous intravenous infusion.
The usual initial dose of naloxone in children is 0.01mg/kg body weight given intravenously. If this dose does not result in the desired degree of clinical improvement, a subsequent increased dose of 0.1mg/kg body weight may be administered. If an IV route of administration is not available, naloxone may be administered IM or subcutaneously in divided doses. If necessary, naloxone can be diluted with Sterile Water for Injection.
Blood gases, pH, and electrolytes should be monitored in order that acidosis and any electrolyte disturbance present may be corrected promptly. Acidosis, hypoxia, and generalised CNS depression predispose to the development of cardiac arrhythmias. Ventricular fibrillation or cardiac arrest may occur and necessitate the full complement of cardiopulmonary resuscitation (CPR) measures. Respiratory acidosis rapidly subsides as ventilation is restored and hypercapnoea eliminated, but lactic acidosis may require intravenous bicarbonate for prompt correction.
Electrocardiographic monitoring is essential. Prompt correction of hypoxia, acidosis and electrolyte disturbance (when present) will help prevent these cardiac complications and will increase the effectiveness of agents administered to restore normal cardiac function.
In addition to the use of a narcotic antagonist, the patient may require careful titration with an anticonvulsant to control convulsions. General supportive measures, in addition to oxygen, include, when necessary, intravenous fluids, vasopressor-inotropic compounds, and, when infection is likely, anti-infective agents. Gastric lavage may be useful, and activated charcoal can absorb a significant amount of ingested dextropropoxyphene. Dialysis is of little value in poisoning due to dextropropoxyphene. Efforts should be made to determine whether other agents, such as alcohol, barbiturates, tranquillisers, other CNS depressants, were also ingested, since these increase CNS depression as well as cause specific toxic effects.
Shortly after oral ingestion of an overdose of paracetamol and for the next 24 hours, anorexia, nausea, vomiting, diaphoresis, general malaise and abdominal pain have been noted. The patient may then present no symptoms but evidence of liver dysfunction may become apparent up to 72 hours after ingestion, with elevated serum transaminase and lactic dehydrogenase levels, an increase in serum bilirubin concentrations, and a prolonged prothrombin time. Death from hepatic failure may result 3 to 7 days after overdosage.
Acute renal failure may accompany the hepatic dysfunction and has been noted in patients who do not exhibit signs of fulminant hepatic failure. Typically, renal impairment is more apparent 6 to 9 days after ingestion of the overdoses.
Paracetamol in massive overdosage may cause hepatic toxicity in some patients. In all cases of suspected overdose, immediately call your regional poison centre for assistance in diagnosis and for directions in the use of N-acetylcysteine as an antidote.
In adults, hepatic toxicity has rarely been reported with acute overdoses of less than 10 g and fatalities with less than 15 g. Importantly, young children seem to be more resistant than adults to the hepatotoxic effect of a paracetamol overdose. Despite this, the measure out-lined below should be initiated in any adult or child suspected of having ingested a paracetamol overdose.
Because clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion, liver function studies should be obtained initially and repeated at 24 hours intervals.
Consider emptying the stomach promptly by lavage or by induction of emesis with syrup of ipecac. Patients' estimates of the quantity of a medicine ingested are notoriously unreliable. Therefore, if a paracetamol overdose is suspected, a serum paracetamol assay should be obtained as early as possible, but no sooner than 4 hours following ingestion. The antidote, N-acetylcysteine, should be administered as early as possible, and within 16 hours of the overdose ingestion for optimal results. Following recovery, there are no residual, structural, or functional hepatic abnormalities.
Store below 30°C. Protect from light and moisture.
Controlled Drug C5.
Capsules (green/yellow): blister packs of 20 capsules, cartons of 100 and 500 capsules.
Paracetamol is a white crystalline powder. It is sparingly soluble in water; soluble 1 in 20 of boiling water, and 1 in 10 of alcohol; very slightly soluble in ether and in methylene chloride. Store in airtight containers. Protect from light.
Dextropropoxyphene hydrochloride is a white or almost white odourless crystalline powder. It is very soluble in water, freely soluble in alcohol, soluble in acetone and chloroform, practically insoluble in ether. Store in an airtight container. Protect from sunlight.
Each CAPADEX capsule contains the following excipients: gelatin, croscarmellose sodium, magnesium stearate, brilliant blue FCF CI42090, yellow iron oxide, titanium dioxide.
Paracetamol is N-(4-Hydroxyphenyl)acetamide. It has the molecular formula C8H9NO2. The molecular weight is 151.2.
Dextropropoxyphene hydrochloride is (+)-(1S,2R)-1-Benzyl-3-dimethylamino-2-methyl-1-phenylpropyl propionate hydrochloride. It has the molecular formula C22H29NO2HCl. The molecular weight is 375.9.
New Zealand distributor:
Pharmacy Retailing (NZ) Limited
Trading as Healthcare Logistics
58 Richard Pearce Drive
Airport Oaks
Auckland
Phone: (09) 918 5100
Fax: (09) 918 5101
22 March 2006