Propoxyphene

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing. /Propoxyphene hydrochloride/

Water spray, dry chemical, carbon dioxide or foam as appropriate for surrounding fire and materials. /Propoxyphene hydrochloride/

Wear approved respiratory protection, chemically compatible gloves and protective clothing. Wipe up spillage or collect spillage using a high efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labelled container for disposal. Wash spill site. /Propoxyphene hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling. /Propoxyphene hydrochloride/

As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity. /Propoxyphene hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. The completeness of the cleaning procedures should be considered before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at the end of shift, but should remain at employee's place of work for cleaning.

SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.

Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used. Gloves: Chemically compatible Eye Protection: Safety glasses or goggles Protective Clothing: Protect exposed skin. /Propoxyphene hydrochloride/

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 narcotic antagonist naloxone will markedly reduce the degree of respiratory depression, and 0.4 to 2 mg 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 10 mg of naloxone have been administered, the diagnosis of propoxyphene toxicity should be questioned. Naloxone may also be administered by continuous intravenous infusion. (L1712)

The effect of ethanol (0.5 and 1.0 g/kg) on gastrointestinal absorption and presystemic biotransformation of propoxyphene (4 mg/kg) was studied in dogs in a crossover design. Low ethanol doses (0.5 g/kg) had no effect on the bioavailability of propoxyphene. High ethanol doses (1.0 g/kg) enhanced the bioavailability of orally administered propoxyphene significantly (p less than 0.05). With this dose of ethanol, the area under the blood concentration versus time curve (AUC)0-5 hr of propoxyphene was approximately 200% of the control value. The level of norpropoxyphene, a major metabolite of propoxyphene, was significantly decreased (p less than 0.05) after administration of high ethanol doses. In all blood samples, after propoxyphene administration, an unidentified metabolite of propoxyphene was found, which formation was dose dependently inhibited by ethanol.

Because additive CNS depression may occur when propoxyphene is used concomitantly with other CNS depressants (including opiate agonists, general anesthetics, phenothiazines, tranquilizers, sedatives and hypnotics, muscle relaxants, antidepressants, and alcohol), propoxyphene should be used with great caution in conjunction with such drugs. Concomitant use of propoxyphene and other CNS depressants, including alcohol, can result in potentially serious adverse effects, including death. Because respiratory depression, hypotension, profound sedation, or coma may result if CNS depressants are taken in combination with usual dosages of propoxyphene, the dosage of one or both agents should be reduced in patients who require such combined therapy. Patients receiving propoxyphene should be advised not to consume alcohol (including alcohol-containing prescription and nonprescription drugs) concomitantly.

Three cases are presented of patients who experienced potentiation of propoxyphene's effects by different antihistamines. These included increased analgesia and mild euphoria as well as moderately severe symptoms of opiate withdrawal at therapeutic doses of propoxyphene. In one case, withdrawal symptoms were blocked with clonidine, an alpha-2 agonist. Since the specific antihistamine-opiate combination, pentazocine and tripelennamine, is associated with increased lethality, physicians are cautioned to avoid combining propoxyphene with antihistamines.

Propoxyphene (Darvon, Darvocet-N) appears to inhibit the hepatic metabolism of phenobarbital. In four epileptic patients on chronic phenobarbital, propoxyphene (65 mg 3 times a day) increased mean phenobarbital levels by 20% after 1 week.

For more Interactions (Complete) data for (d)-PROPOXYPHENE (20 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8.1X10+4(SRC), determined from a log Kow of 4.18(2) suggest that (d)-propoxyphene is expected to be immobile in soil(SRC). Volatilization of (d)-propoxyphene from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.3X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(4). (d)-Propoxyphene is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.02X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). (d)-Propoxyphene was classified as non-biodegradable in sewage treatment(6), indicating that biodegradation is not expected to be an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8.1X10+4(SRC), determined from a log Kow of 4.18(2) and a regression-derived equation(3), indicates that (d)-propoxyphene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 2.3X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 260(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is high(SRC). (d)-Propoxyphene was classified as non-biodegradable in sewage treatment(7), indicating that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), (d)-propoxyphene, which has an estimated vapor pressure of 2.1X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase (d)-propoxyphene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1.4 hrs(SRC), calculated from its rate constant of 9.9X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase (d)-propoxyphene may be removed from the air by wet or dry deposition(SRC).(d)-Propoxyphene contains chromophores that absorb at wavelengths >290 nm(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

EXPERIMENTAL: Propoxyphene (P) and norpropoxyphene (NP) excretion in breast milk was studied in six healthy nursing mothers. Concentrations of P and NP in breast milk and plasma were quantitated by an HPLC method. Plasma P half-lives in mothers averaged 4.40 hr. P and NP breast milk concentrations generally followed plasma levels. NP/P averaged 2.69 in plasma and 2.73 in breast milk. While there was substantial inter- and intrasubject variability, the ratio of drug in the milk and plasma averaged 0.417 and 0.382 for P and NP. These similarities in distribution in breast milk were also reflected in elimination. Clearances of P and NP in milk were of the same order (3.97 mL/hr) as were elimination half-lives in milk in most subjects (mean = 3.68 hr for P and 5.49 hr for NP). Approximately twice as much NP was excreted in the milk, primarily because of the higher NP levels in plasma. Clearance of P and NP in breast milk also correlated strongly with breast milk volume. While little information is available concerning P and NP disposition in neonates, dosage estimates based on kinetic and pharmacologic assumptions suggest that the estimated amounts consumed by the neonate after the mother is given the recommended dose of the drug are not likely to result in toxic plasma levels.

Propoxyphene acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Propoxyphene primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is inhibited. Opioids such as propoxyphene also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

The Koc of (d)-propoxyphene is estimated as 8.1X10+4(SRC), using a log Kow of 4.18(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that (d)-propoxyphene is expected to be immobile in soil.

/SIGNS AND SYMPTOMS/ Toxicity is similar to other opioids but also includes echocardiogram effects, ototoxicity, delusions, hallucinations, confusion, and seizures at high doses. Absorption is rapid, and clinical deterioration may occur within 1 hour of overdose. Prolongation of QRS and QTc duration, heart block, and hypotension are common after significant overdose.

/SIGNS AND SYMPTOMS/ Acute toxicity from propoxyphene overdosage results in symptoms similar to those of acute opiate intoxication and may include coma, respiratory depression, circulatory collapse, and pulmonary edema. Seizures occur more frequently in patients with propoxyphene intoxication than in those with opiate intoxication. Nephrogenic diabetes insipidus and ECG abnormalities such as transient right heart block, bigeminy, and prolongation of the QRS complex associated with ST-T wave changes may also occur. Death may occur within the first hour; up to 5% of fatalities in one survey reportedly occurred within the first 15 minutes. When combination products containing aspirin have been ingested, the clinical picture may be complicated by salicylism.

/SIGNS AND SYMPTOMS/ Propoxyphene overdose may produce acute central nervous system toxicity that usually manifests as seizures. In one study of propoxyphene-overdosed patients, 10% of the subjects developed seizures.

/SIGNS AND SYMPTOMS/ A small number of cases of propoxyphene-induced cholestasis have been reported; these are thought to be the result of hypersensitivity.

For more Human Toxicity Excerpts (Complete) data for (d)-PROPOXYPHENE (16 total), please visit the HSDB record page.

(d)-Propoxyphene's production and use as an analgesic(1) may result in its release to the environment through various waste streams(SRC). On November 19, 2010, the U.S. Food and Drug Administration announced that it intends to withdraw propoxyphene from the US market, because new data indicate this drug may cause serious toxicity to the heart, even when used at therapeutic doses(2).

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Narcotic drugs: Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation containing any of the following narcotic drugs, or their salts calculated as the free anhydrous base or alkaloid, in limited quantities as set forth below: Dextropropoxyphene (alpha-(+)-4-dimethylamino-1,2-diphenyl-3-methyl-2-propionoxybutane) (DEA Code Number: 9278) is included on this list.

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Unless specifically excepted or unless in another schedule any of the following opiates, including its isomers, esters, ethers, salts and salts of isomers, esters and ethers whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation, dextrorphan and levopropoxyphene excepted: Bulk dextropropoxyphene (non-dosage forms) (DEA Code Number: 9273) is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including propoxyphene hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Propoxyphene hydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including propoxyphene napsylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Propoxyphene napsylate/

Schedule II controlled substance: Bulk dextropropoxyphene (non-dosage forms) (DEA Code Number: 9273).

Schedule IV controlled substance: Dextropropoxyphene (alpha-(+)-4-dimethylamino-1,2-diphenyl-3-methyl-2-propionoxybutane) (DEA Code Number: 9278).

The alpha diasterioisomers are optically active and are preferred for their greater pain-relieving ability. The drug has about the same analgesic effect as codeine. Abuse can cause addiction, and overdose can be fatal. Its use has been restricted by FDA.

THERAPEUTIC CATEGORY: Analgesic (narcotic)

For more Uses (Complete) data for (d)-PROPOXYPHENE (6 total), please visit the HSDB record page.

For the relief of mild to moderate pain

The Mannich base formed by condensation of propiophenone and dimethylamine with formaldehyde is grignardized with benzyl magensium chloride to produce a mixture of the racemates of the two diasteeoisomers (designated commercially as alpha and beta) of the alcohol. The desired alpha-dl form is isolated by fractional crystrallization and resolved by means of d-camphorsulfonic acid. The desired alpha-d enantiomorph is propionylated with propionic acid in the presence of trimethylamine to form propoxyphene, which adds an equivalent of HCl in forming the hydrochloride.

Propiophenone + formaldehyde + dimethylamine + benxyl chloride + propionyl chloride (Mannich reaction/Grignard reaction/racemate separation/esterification)

Distalgesic (UK) tablets: dextropropoxyphene hydrochloride, 32.5 mg; acetaminophen, 325 mg. /Dextropropoxyphene hydrochloride/

ALGAFAN /ALPHA-D-PROPOXYPHENE HYDROCHLORIDE/

Darvon, Deprancol, Develin /Propoxyphene hydrochloride/

Darvon-N /Napsylate monohydrate/

For more Formulations/Preparations (Complete) data for (d)-PROPOXYPHENE (10 total), please visit the HSDB record page.

On November 19, 2010, the U.S. Food and Drug Administration (FDA) announced that it intends to withdraw propoxyphene from the United States market, because new data indicate this drug may cause serious toxicity to the heart, even when used at therapeutic doses.

Propoxyphene /is/ a synthetic chemical ...

Of the four stereoisomers, only the alpha racemate, known as propoxyphene, has analgesic activity. Its analgesic effect resides in the dextro isomer, d-propoxyphene (dextropropoxyphene). However, levopropoxyphene seems to have some antitussive activity.

By 1970, it was concluded that propoxyphene was no more effective than aspirin or codeine and was probably inferior to these analgesics. Nevertheless, the product was commercially successful.

For more General Manufacturing Information (Complete) data for (d)-PROPOXYPHENE (6 total), please visit the HSDB record page.