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Darvocet-N

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Darvocet-N

CLINICAL PHARMACOLOGY

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.

Acetaminophen is a non-opiate, non-salicylate analgesic and antipyretic. The site and mechanism for the analgesic effect of acetaminophen has not been determined. The antipyretic effect of acetaminophen is mediated through activity in the hypothalamic heat-regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

Pharmacokinetics

Absorption

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 µg/mL for propoxyphene and 0.1 to 0.2 µg/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.

Acetaminophen is absorbed from the gastrointestinal tract and has a plasma half-life of 1.25 to 3 h, which may be increased by liver damage and following overdosage.

Distribution

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

Acetaminophen is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; only 20% to 50% may be bound at the concentrations encountered during acute intoxication.

Metabolism

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.

Acetaminophen is extensively metabolized in the liver. Less than 5% of acetaminophen dose is excreted unchanged in the kidney. About 85% of an acetaminophen dose is metabolized by conjugation, mainly glucuronidation via UDP-glucuronosyltransferase (mainly UGT1A6) and to a lesser extent sulfation via sulfotransferase (mainly SLT1A1 and SLT1A3). The glucuronide and sulfate conjugates are nontoxic and are largely excreted in the urine and bile. About 8-10% of an acetaminophen dose is oxidized by cytochrome CYP2E1 to form the toxic reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is further metabolized via glutathione (GSH) conjugation, yielding non-toxic thiol metabolites including cysteine, mercapturate, methylthioacetaminophen, and methanesulfinylacetaminophen that are excreted in the urine. Acetaminophen is also oxidized at a low percentage by cytochrome CYP2A6 to form inert catechols (e.g., methoxyacetaminophen).

Excretion

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.

Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

Special Populations

Geriatric Patients

After oral administration of propoxyphene in elderly patients (70-78 years), much longer half-lives of propoxyphene and norpropoxyphene have been reported (propropoxyphene 13 to 35 h, norpropoxyphene 22 to 41 h). In addition, the AUC was an average of 3-fold higher and the Cmax was an average of 2.5-fold higher in the elderly when compared to a younger (20-28 years) population. Longer dosage intervals may be considered in the elderly because the metabolism of propoxyphene may be reduced in this patient population. After multiple oral doses of propoxyphene in elderly patients (70-78 years), the Cmax of the metabolite (norpropoxyphene) was increased 5-fold.

Pediatric Patients

Neither propoxyphene alone nor in combination with acetaminophen has been studied in pediatric patients.

Hepatic Impairment

No formal pharmacokinetic study of either propoxyphene alone or in combination with acetaminophen has been conducted in patients with mild, moderate or severe hepatic impairment.

After oral administration of propoxyphene in patients with cirrhosis, plasma concentrations of propoxyphene were considerably higher and norpropoxyphene concentrations were much lower than in control patients. This is presumably because of a decreased first-pass metabolism of orally administered propoxyphene in these patients. The AUC ratio of norpropoxyphene: propoxyphene was significantly lower in patients with cirrhosis (0.5 to 0.9) than in controls (2.5 to 4).

Compared to healthy subjects, acetaminophen had a lower total clearance and longer half-life in patients with liver disease. Decreased metabolite formation clearance (8-42 %) was observed in subjects with liver disease compared to healthy subjects after both single and multiple-doses (at steady state). In addition, there is an increase in the amount of acetaminophen excreted unchanged in the urine (4.7% vs. 2.5%) in patients with liver disease compared to healthy subjects after repeat doses, suggesting that more acetaminophen was excreted by renal elimination in the liver disease state.

Renal Impairment

No formal pharmacokinetic study of either propoxyphene alone or in combination with acetaminophen has been conducted in patients with mild, moderate or severe renal impairment.

After oral administration of propoxyphene in anephric patients, the AUC and Cmax values were an average of 76% and 88% greater, respectively. Dialysis removes only insignificant amounts (8%) of administered dose of propoxyphene.

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.

Clinical Studies

The efficacy of propoxyphene in combination with acetaminophen was studied in seven single-dose, randomized, double-blind, placebo-controlled trials in patients with mild to severe postpartum pain. One of the studies demonstrated that both propoxyphene and acetaminophen in the combination contributed to a greater reduction in pain than acetaminophen and propoxyphene alone and that propoxyphene was superior to placebo.

There is insufficient information available to assess efficacy of propoxyphene in combination with acetaminophen in patients with chronic pain.

Last reviewed on RxList: 10/9/2009
This monograph has been modified to include the generic and brand name in many instances.

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