Propoxyphene Capsules

Pharmacology

Propoxyphene is a centrally acting opiate analgesic. In vitro studies demonstrated propoxyphene and the metabolite norpropoxyphene inhibit sodium channels (local anesthetic effect) with norpropoxyphene being approximately 2 fold more potent than propoxyphene and propoxyphene approximately 10 fold more potent than lidocaine. Propoxyphene and norpropoxyphene inhibit the voltage-gated potassium current carried by cardiac rapidly activating delayed rectifier (hERG) channels with approximately equal potency. It is unclear if the effects on ion channels occur within therapeutic dose range.

Pharmacokinetics

Peak plasma concentrations of propoxyphene are reached in 2 to 2.5 h. After a 65 mg oral dose of propoxyphene hydrochloride, peak plasma levels of 0.05 to 0.1 mcg/mL for propoxyphene and 0.1 to 0.2 mcg/mL for norpropoxyphene (major metabolite) are achieved. Repeated doses of propoxyphene at 6 h intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 h. Propoxyphene has a half-life of 6 to 12 h, whereas that of norpropoxyphene is 30 to 36 h.

Propoxyphene is about 80% bound to proteins and has a large volume of distribution, 16 L/kg.

Propoxyphene undergoes extensive first-pass metabolism by intestinal and hepatic enzymes. The major route of metabolism is cytochrome CYP3A4 mediated N-demethylation to norpropoxyphene, which is excreted by the kidneys. Ring hydroxylation and glucuronide formation are minor metabolic pathways.

In 48 h, approximately 20 to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene. The renal clearance rate of propoxyphene is 2.6 L/min.

Propoxyphene hydrochloride capsules are contraindicated in patients with known hypersensitivity to propoxyphene.

Propoxyphene hydrochloride capsules 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 hydrochloride capsules are contraindicated in any patient who has or is suspected of having paralytic ileus.

Overdose of propoxyphene may present with the signs and symptoms of propoxyphene overdose. 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.

Symptoms of Propoxyphene Overdosage

The manifestations of acute overdosage with propoxyphene 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 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.

Do not drink alcohol while you are taking propoxyphene. Dangerous side effects or death can occur when alcohol is combined with a narcotic pain medicine. Check your food and medicine labels to be sure these products do not contain alcohol. propoxyphene can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Grapefruit and grapefruit juice may interact with propoxyphene and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

Usual Adult Dose for Pain:

65 mg (HCl) orally every 4 hours as needed or
100 mg (Napsylate) orally every 4 hours as needed.

Do not take propoxyphene with other narcotic pain medications, sedatives, tranquilizers, muscle relaxers, or other medicines that can make you sleepy or slow your breathing. Dangerous side effects may result.

Before taking propoxyphene, tell your doctor if you are using any of the following drugs:

• amiodarone (Cordarone, Pacerone);

• aprepitant (Emend);

• bosentan (Tracleer);

• conivaptan (Vaprisol);

• dexamethasone (Decadron, Hexadrol);

• imatinib (Gleevec);

• isoniazid (for treating tuberculosis);

• St. John's wort;

• an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), rifampin (Rifadin, Rifater, Rifamate), or telithromycin (Ketek);

• antifungal medication such as clotrimazole (Mycelex Troche), fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), or voriconazole (Vfend);

• an antidepressant such as nefazodone;

• a barbiturate such as butabarbital (Butisol), secobarbital (Seconal), pentobarbital (Nembutal), or phenobarbital (Solfoton);

• a blood thinner such as warfarin (Coumadin);

• heart or blood pressure medication such as diltiazem (Cartia, Cardizem), felodipine (Plendil), nifedipine (Nifedical, Procardia), verapamil (Calan, Covera, Isoptin, Verelan), and others;

• HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), saquinavir (Invirase), or ritonavir (Norvir);

• medicines to treat narcolepsy, such as armodafanil (Nuvigil) or modafanil (Progivil); or

• seizure medication such as carbamazepine (Carbatrol, Tegretol), felbamate (Felbatol), oxcarbazepine (Trileptal), or phenytoin (Dilantin), or primidone (Mysoline).

This list is not complete and there may be other drugs that can interact with propoxyphene. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Data not available

Initial dose: 50 mg of propoxyphene napsylate orally once.

Because of the risk of accumulation of propoxyphene in patients with liver disease and because patients with liver disease may be particularly sensitive to the sedative properties of this drug, use of multiple doses of propoxyphene is not recommended.

If this patient has hepatic failure, use of propoxyphene is not recommended.

Because the elimination of propoxyphene is significantly impaired in patients with liver disease, and because dosage forms of propoxyphene hydrochloride do not readily accommodate small doses, use of propoxyphene hydrochloride is not recommended for the treatment of this patient."

Propoxyphene is not dialyzable.