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Propoxyphene and Acetaminophen (Propoxyphene Hydrochloride / Acetaminophen) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

Drug Interactions

The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. On the other hand, strong CYP3A4 inducers such as rifampin may lead to enhanced metabolite (norpropoxyphene) levels.

Propoxyphene is also thought to possess CYP3A4 and CYP2D6 enzyme inhibiting properties. Coadministration with a drug that is a substrate of CYP3A4 or CYP2D6, may result in higher plasma concentrations and increased pharmacologic or adverse effects of that drug.

OVERDOSAGE

Propoxyphene napsylate and acetaminophen is a combination product containing propoxyphene and acetaminophen. Overdose of propoxyphene napsylate and acetaminophen may present with the signs and symptoms of propoxyphene overdose, acetaminophen overdose or both. Fatalities within the first hour of overdosage are not uncommon.

In all cases of suspected overdosage, call your regional Poison Control Center to obtain the most up-to-date information about the treatment of overdose. This recommendation is made because, in general, information regarding the treatment of overdosage may change more rapidly than do package inserts.

Initial consideration should be given to the management of the CNS effects of propoxyphene overdosage. Resuscitative measures should be initiated promptly.

Propoxyphene Overdosage

Symptoms of Propoxyphene Overdosage

The manifestations of acute overdosage with propoxyphene are those of opioid 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 apnea may occur. Blood pressure and heart rate are usually normal initially, but blood pressure falls and cardiac performance deteriorates, which ultimately results in pulmonary edema 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 (hypercapnia) and to lactic acid formed during anaerobic glycolysis. Acidosis may be severe if large amounts of salicylates have also been ingested. Death may occur.

Treatment of Propoxyphene Overdosage

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 edema is present. The opioid antagonist naloxone will markedly reduce the degree of respiratory depression, and should be administered promptly, preferably intravenously. The duration of action of the antagonist may be brief. If no response is observed after 10 mg of naloxone have been administered, the diagnosis of propoxyphene toxicity should be questioned.

In addition to the use of an opioid antagonist, the patient may require careful titration with an anticonvulsant to control convulsions. Activated charcoal can adsorb a significant amount of ingested propoxyphene. Dialysis is of little value in poisoning due to propoxyphene. Efforts should be made to determine whether other agents, such as alcohol, barbiturates, tranquilizers, or other CNS depressants, were also ingested, since these increase CNS depression as well as cause specific toxic effects or death.

Acetaminophen Overdosage

Symptoms of Acetaminophen Overdosage

Overdose of acetaminophen may cause dose-dependent potentially fatal hepatic toxicity. Early symptoms within 24 hours after the overdose may include anorexia, nausea, vomiting, diaphoresis, general malaise, and abdominal pain. 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.

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-hour intervals.

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 overdose.

Treatment of Acetaminophen Overdosage

In all cases of suspected overdose, immediately call the Rocky Mountain Poison Center's toll-free number (800-525-6115) for assistance in diagnosis and for directions in the use of N-acetylcysteine as an antidote.

Patients' estimates of the quantity of a drug ingested are notoriously unreliable. Therefore, if an acetaminophen overdose is suspected, a serum acetaminophen 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.

CONTRAINDICATIONS

Propoxyphene napsylate and acetaminophen tablets are contraindicated in patients with known hypersensitivity to propoxyphene or acetaminophen.

Propoxyphene napsylate and acetaminophen tablets are contraindicated in patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe asthma or hypercarbia.

Propoxyphene napsylate and acetaminophen tablets are contraindicated in any patient who has or is suspected of having paralytic ileus.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Propoxyphene napsylate and acetaminophen is a Schedule IV narcotic under the U.S. Controlled Substances Act. Propoxyphene napsylate and acetaminophen can produce drug dependence of the morphine type, and therefore, has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration. Propoxyphene napsylate and acetaminophen should be prescribed and administered with the same degree of caution appropriate to the use of other narcotic-containing medications.

Abuse

Since propoxyphene napsylate and acetaminophen is a mu-opioid agonist, it may be subject to misuse, abuse, and addiction. Addiction to opioids prescribed for pain management has not been estimated. However, requests for opioids from opioid-addicted patients occur. As such, physicians should take appropriate care in prescribing propoxyphene napsylate and acetaminophen.

Dependence

Opioid analgesics may cause psychological and physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug after long term administration. Also, symptoms of withdrawal may be precipitated through the administration of drugs with mu-opioid antagonist activity, e.g., naloxone or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine, dezocine) (see OVERDOSAGE). Physical dependence usually does not occur to a clinically significant degree, until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required to produce the same degree of analgesia, is initially manifested by a shortened duration of an analgesic effect and subsequently, by decreases in the intensity of analgesia.

In chronic pain patients, and in opioid-tolerant cancer patients, the administration of propoxyphene napsylate and acetaminophen should be guided by the degree of tolerance manifested and the doses needed to adequately relieve pain.

The severity of the propoxyphene napsylate and acetaminophen abstinence syndrome may depend on the degree of physical dependence. Withdrawal is characterized by rhinitis, myalgia, abdominal cramping, and occasional diarrhea. Most observable symptoms disappear in 5 to 14 days without treatment; however, there may be a phase of secondary or chronic abstinence which may last for 2 to 6 months characterized by insomnia, irritability, and muscular aches. The patient may be detoxified by gradual reduction of the dose. Gastrointestinal disturbances or dehydration should be treated with supportive care.

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