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PARADEX tablets: Flat round white bevelled edge tablet, 11mm diameter with 'PDX' embossed on one surface. Each paradex tablet contains 50mg of dextropropoxyphene napsylate and 325mg of paracetamol.
Actions Dextropropoxyphene is a mild narcotic analgesic structurally related to methadone. The potency of dextropropoxyphene napsylate is from two-thirds to equal that of codeine.
PARADEX provides the analgesic activity of dextropropoxyphene napsylate and the antipyretic-analgesic activity of paracetamol.
The combination of dextropropoxyphene and paracetamol produces greater analgesia than that produced by either dextropropoxyphene or paracetamol administered alone.
Pharmacokinetics Dextropropoxyphene is a centrally acting narcotic analgesic agent. Equimolar doses of dextropropoxyphene hydrochloride or napsylate provide similar plasma concentrations. Following administration of 65, 130 or 195mg of dextropropoxyphene hydrochloride, the bioavailabiltiy 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 2.5 hours.
After a 100mg oral dose of dextropropoxyphene napsylate, peak plasma levels of 0.05 to 0.1 mcg/mL are achieved. The napsylate salt tends to be absorbed more slowly than the hydrochloride. At or near therapeutic doses, this absorption difference is small when compared with that among subjects and among doses.
Because of this several hundredfold difference in solubility, the absorption rate of very large doses of the napsylate salt is significantly lower than that of equimolar doses of the hydrochloride.
Repeated doses of dextropropoxyphene at 6-hour intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 hours.
Dextropropoxyphene is metabolized 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.
Norpropoxyphene has substantially less central-nervous system depressant effect than dextropropoxyphene but a greater local anaesthetic effect, which is similar to that of amitriptyline and antiarrhythmic agents, such as lidocaine and quinidine.
In animal studies in which dextropropoxyphene and norpropoxyphene were continuously infused in large amounts, intracardiac conduction time (PR and QRS intervals) was prolonged. Any intracardiac conduction delay attributable to high concentrations of norpropoxyphene may be of relatively long duration.
Paracetamol is readily and completely absorbed from the small intestine after oral administration. Peak plasma levels occur 10-60 minutes after oral administration. Paracetamol is uniformly distributed throughout most body fluids with an apparent volume of distribution of 1 to 1.2L/kg. Food intake delays paracetamol absorption.
Paracetamol crosses the placenta and is present in breast milk. At usual therapeutic doses, plasma protein binding is negligible but increases with increasing concentrations.
Paracetamol is metabolized by the hepatic microsomal enzyme 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 metabolized to catechol derivatives and mercapturic acid compounds via oxidation. In infants and children paracetamol is metabolized differently to adults with the sulphate conjugate being predominant. A minor hydroxylated metabolite ( N-acetyl-p-benzoquinoneimine ) which is usually produced in very small amounts by mixed-function oxidases in the liver and kidney and which is usually detoxified by conjugation with glutathione may accumulate following paracetamol overdosage and cause tissue damage.
Paracetamol is excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. Within 24 hours of ingestion 85-90% of the dose is eliminated in urine. The elimination half life varies from 1 to 3 hours. The half life may be prolonged in acute overdose or severe liver disease.
PARADEX is indicated for the relief of chronic pain of moderate severity. PARADEX should only be prescribed to patients in whom treatment with therapeutic doses of alternative therapeutic groups, including combination products, have been used and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient.
PARADEX is given orally. The usual adult dose is 2 tablets every four hours as needed for pain.
The maximum recommended daily dose of Paradex is 8 tablets.
Consideration should be given to a reduced total daily dosage in patients with hepatic or renal impairment.
PARADEX is not recommended for administration to children
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. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of dextropropoxyphene products and alcohol because of 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 concomitant 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 disturbances or suicidal ideation or attempts as well as histories of misuse of anxiolytics, alcohol and other CNS-active medicines. 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 characterized 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 is qualitatively similar to that of codeine although quantitatively less, and 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 hepatic or renal impairment since higher serum concentrations or delayed elimination may occur.
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. Therefore, dextropropoxyphene should not be used in pregnant women unless, in the judgement of the physician, the potential benefits outweigh the possible hazards.
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.
Dextropropoxyphene is not recommended for use in children, because documented clinical experience has been insufficient to establish safety and a suitable dosage regiment in the paediatric age group.
The rate of dextropropoxyphene metabolism may be reduced in some patients. Increased dosing interval should be considered.
In a survey conducted in hospitalized patients, less than 1% of patients taking dextropropoxyphene hydrochloride at recommended doses experienced side effects. The most frequently reported were dizziness, sedation, nausea, and vomiting. Some of these adverse reactions may be alleviated if the patient lies down.
Other adverse reactions include constipation, abdominal pain, skin rashes, lightheadedness, headache, weakness, euphoria, dysphoria, hallucinations, and minor visual disturbances.
Liver dysfunction has been reported in association with both active components of PARADEX. 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 overdose of paracetamol (see Treatment of Overdosage). In chronic ethanol abusers, this has been reported rarely with short-term use of paracetamol dosages of 2.5 to 10g/day. Fatalities have occurred.
Renal papillary necrosis may result from chronic paracetamol use, particularly when the dosage is greater than recommended and when combined with aspirin.
Subacute painful myopathy has occurred following chronic dextropropoxyphene overdosage.
The CNS-depressant effect of dextropropoxyphene is additive with that of other CNS depressants, including alcohol. As is the case with many medicinal agents, dextropropoxyphene may slow the metabolism of a concomitantly administered medicine. Should this occur, the higher serum concentrations of that medicine may result in increased pharmacologic or adverse effects of that medicine. Such occurrences have been reported when dextropropoxyphene was administered to patients on anti-depressants, anticonvulsants, or warfarin-like medicines. Severe neurologic signs, including coma, have occurred with concurrent use of carbamazepine.
Initial consideration should be given to the management of the CNS effects of dextropropoxyphene overdosage. Resuscitative measures should be initiated promptly.
The manifestation of acute overdosage with dextropropoxyphene are those of narcotic overdosage. The patient is usually somnolent but may be stuporous 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 CO (hypercapnia) and to lactic acid formed during anaerobic clycolysis. Acidosis may be severe if large amounts of salicylates have also been ingested. 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 2.0mg should be administered promptly, preferably intravenously. If the desired degree of counteraction with improvement in respiratory functions is not obtained, naloxene may 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 hypercapnia eliminated, but lactic acidosis may require intravenous bicarbonate for prompt correction. Electrocardiographic monitoring is essential. Prompt correction of hypoxia, acidosis and electrolyte disturbances (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, vasopressorinotropic 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, anxiolytics, or other CNS depressants, were also ingested, since these increase NCS 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 10g and fatalities with less than 15g. 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. Shelf-life is 60 months
Controlled Drug C5.
PARADEX tablets: Pack of 500 tablets in 10 packets, each containing 50 tablets in 5 strips of 10 tablets.
Nil
PSM Healthcare Ltd trading as Healthcare Manufacturing Group
PO Box 76 401
Manukau City
Auckland
Phone 09-279-7979
April 06, 2006