Propoxyphene Hydrochloride

Pronunciation

Class: Opiate Agonists
Note: This monograph also contains information on Propoxyphene Napsylate
VA Class: CN101
Chemical Name: (2S,3R)-(+)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propionate (ester), hydrochloride
CAS Number: 1639-60-7
Brands: Darvocet, Darvon, Darvon-N

Warning(s)

Special Alerts:

On November 19, 2010, Xanodyne announced a voluntary withdrawal of propoxyphene-containing preparations (Darvon, Darvocet) from the US market.109 112 The withdrawal was requested by FDA following review of new data on cardiac risk.108 109 (See Cardiac Effects under Cautions.) FDA requested that manufacturers of generic propoxyphene-containing preparations also voluntarily withdraw these preparations from the US market.108 109

[Posted 01/13/2011] ISSUE: FDA notified healthcare professionals that it has asked drug manufacturers to limit the strength of acetaminophen in prescription drug products, predominantly combinations of acetaminophen and opioids, to 325 mg per tablet, capsule, or other dosage unit, making these products safer for patients. This action will help to reduce the risk of severe liver injury and allergic reactions associated with acetaminophen. A Boxed Warning highlighting the potential for severe liver injury and a Warning highlighting the potential for allergic reactions (swelling of the face, mouth, and throat, difficulty breathing, itching, or rash) will be added to the label of all prescription drug products that contain acetaminophen.

BACKGROUND: Acetaminophen, one of the most commonly used drugs in the United States, is widely and effectively used in both prescription and over-the-counter (OTC) products to reduce pain and fever. Examples of prescription products that contain acetaminophen include hydrocodone with acetaminophen (Vicodin, Lortab), and oxycodone with acetaminophen (Tylox, Percocet). OTC products containing acetaminophen (e.g., Tylenol) are not affected by this action. Information about the potential for liver injury is already required on the label for OTC products containing acetaminophen. FDA is continuing to evaluate ways to reduce the risk of acetaminophen related liver injury from OTC products. No drug shortages are expected, because the 3-year implementation period should permit adequate time for necessary reformulations.

RECOMMENDATION: Healthcare professionals were reminded to advise patients not to exceed the acetaminophen maximum total daily dose (4 grams/day), and not to drink alcohol while taking acetaminophen-containing medications.

Healthcare professionals were encouraged to inform patients that there is no immediate danger to patients who take these combination pain medications, and patients should continue to take them as directed by their health care provider. The Drug Safety Communication provides additional information for healthcare professionals, information for patients, a data summary and a list of all affected products. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for propoxyphene to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of propoxyphene and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Warning(s)

  • Risk of Fatal Overdosage
  • Numerous reports of intentional or accidental overdose of propoxyphene preparations, alone or in combination with other CNS depressants (e.g., alcohol); death may occur within 1 hour of overdose.101 102 103 a c

  • Many of the deaths have occurred in patients with a history of emotional disturbances or suicidal ideation or attempts and/or with concomitant use of CNS depressants (e.g., sedatives, tranquilizers, skeletal muscle relaxants, antidepressants, alcohol).101 102 103 a c

  • Do not use in patients who are suicidal or have a history of suicidal ideation.101 102 103 a c

  • Interactions with CYP3A4 Inhibitors
  • Concomitant use of potent CYP3A4 inhibitors (e.g., amiodarone, aprepitant, clarithromycin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin, verapamil) may increase plasma concentrations of propoxyphene.101 102 103 c

  • Monitor patients receiving any CYP3A4 inhibitor concomitantly with propoxyphene carefully for an extended period of time and adjust dosage if needed.101 102 103 c

Introduction

Synthetic analgesic; structurally related to methadone.101 102 103 a c

Uses for Propoxyphene Hydrochloride

Pain

Relief of mild to moderate pain.101 102 103 c Therapy in combination with acetaminophen or aspirin or with aspirin and caffeine may result in greater analgesia; however, some studies have shown no difference in analgesia.a

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Propoxyphene Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally.101 102 103 c

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as propoxyphene hydrochloride and propoxyphene napsylate; dosage expressed in terms of the salt.101 102 103 c

Propoxyphene napsylate 100 mg is equivalent to propoxyphene hydrochloride 65 mg.101 103 a c

Adults

Pain
Oral

Propoxyphene hydrochloride: Usual dosage is 65 mg every 4 hours as needed.102 a Doses <65 mg have questionable efficacy.a

Propoxyphene napsylate: Usual dosage is 100 mg every 4 hours as needed.101 103 a c

Adjust dosage according to severity of pain and response and size of the patient.101 102 103 c

If used concomitantly with another CNS depressant, reduce dosage of one or both agents.101 102 103 c (See Specific Drugs and Foods under Interactions.)

To discontinue therapy following extended, regular use (e.g., for several weeks or longer), gradually taper dosage (e.g., by 25–50% daily) to avoid signs and symptoms associated with abrupt withdrawal.101 102 103 c

Prescribing Limits

Adults

Pain
Oral

Propoxyphene hydrochloride: Maximum 390 mg daily.102 a

Propoxyphene napsylate: Maximum 600 mg daily.101 103 a c

Special Populations

Hepatic Impairment

Consider dosage reduction.101 102 103 a c

Renal Impairment

Consider dosage reduction.101 102 103 a c

Geriatric Patients

Consider dosage reduction.101 102 103 a c Consider increase in dosing interval because of reduced metabolism.101 102 103 c

Cautions for Propoxyphene Hydrochloride

Contraindications

  • Acute or severe asthma or hypercarbia.101 102 103 c

  • Substantial respiratory depression in unmonitored settings or in the absence of resuscitative equipment.101 102 103 c

  • Known or suspected paralytic ileus.101 102 103 c

  • Known hypersensitivity to propoxyphene or any ingredient in the formulation.101 102 103 c

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Cardiac Effects

Prolongation of QT and PR intervals and widening of QRS complex observed in healthy individuals receiving propoxyphene napsylate 600 or 900 mg daily.108 110 Largest mean changes in QT interval exceeded value thought to be associated with substantial increase in risk of proarrhythmic activity.108 110

Based on these data indicating potential for serious cardiac effects at therapeutic dosages, FDA concluded that the drug’s analgesic benefits no longer outweigh its risks at recommended dosages and requested that manufacturers withdraw all propoxyphene-containing preparations from the US market.108 (See Preparations.)

Geriatric patients and individuals with renal impairment may be at particular risk due to impaired elimination of norpropoxyphene (a cardiotoxic metabolite).108 110 (See Elimination under Pharmacokinetics.)

Risk of adverse events in individual patients may change as a result of small changes in health status (e.g., dehydration, decrease in renal function, change in drug therapy).109

FDA has advised health care professionals to stop prescribing and dispensing the drug, to assess propoxyphene-treated patients for cardiac conduction abnormalities if they exhibit signs or symptoms suggestive of arrhythmias, and to contact patients currently taking the drug to inform them of the drug’s cardiac risks, advise them to stop taking the drug (see Pain under Dosage and Administration), and discuss alternative analgesic therapy.108

Acute Toxicity

Propoxyphene preparations alone or in combination with other CNS depressants (e.g., alcohol) are a major cause of drug-related deaths; overdoses may be intentional or accidental.101 102 103 a c (See Risk of Fatal Overdosage in Boxed Warning.)

Respiratory Depression

The major toxicity associated with opiate agonists.101 102 103

Occurs most frequently in geriatric and debilitated patients, usually following large initial doses in nontolerant patients, or when given concomitantly with drugs that depress respiration.101 102 103

Use propoxyphene with extreme caution in patients with COPD or cor pulmonale, and in those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.101 102 103 Further decreased respiratory drive or apnea may occur at therapeutic dosages.101 102 103 (See Contraindications under Cautions.)

Hypotensive Effects

Like all opiate analgesics, may cause severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs (e.g., phenothiazines, general anesthetics).101 102 103

May produce orthostatic hypotension in ambulatory patients.101 102 103

Use with caution in patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP.101 102 103

Head Injury and Increased Intracranial Pressure

Respiratory depressant effects of opiates and their capacity to elevate CSF pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure.101 102 103

May interfere with evaluation of CNS function.101 102 103

Opiate Withdrawal

Caution in patients dependent on opiates.a Will not support morphine dependence; sudden substitution of usual propoxyphene dosage for opiates may result in acute opiate withdrawal symptoms.a Avoid withdrawal symptoms by gradually reducing dosage of prior opiate as propoxyphene is substituted.a

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.101 102 103 c

Concurrent use of other CNS depressants (including alcohol) may potentiate CNS depression.101 102 103 c (See Specific Drugs and Foods under Interactions.)

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Dependence, Tolerance, and Abuse

Possible tolerance, psychologic dependence, and physical dependence.101 102 103 c

Abuse potential exists.101 102 103

Abrupt cessation of therapy after prolonged use may result in withdrawal symptoms.101 102 103 After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.101 102 103

Pancreatic and Biliary Disease

May cause spasm of the sphincter of Oddi.101 102 103 Use with caution in patients with biliary tract disease, including acute pancreatitis.101 102 103 Opiates may increase serum amylase concentrations.101 102 103

Use of Fixed Combinations

When used in fixed combination with actetaminophen, consider the cautions, precautions, and contraindications associated with actetaminophen.103 a

Specific Populations

Pregnancy

Category C101 102 103 d (category D, if used for prolonged periodsd ).

Cases of respiratory depression or withdrawal symptoms in neonates reported following opiate use during pregnancy.101 102 103 a c

Lactation

Propoxyphene and its major metabolite, norpropoxyphene, are distributed into milk.101 102 103 a Use with caution; however, in postpartum studies involving nursing women who received propoxyphene, no adverse effects observed in breast-fed infants.101 102 103 c

Limited data suggest that exclusively breast-fed infants receive approximately 2% of the maternal weight-adjusted dose of propoxyphene.101 102 103 Prolonged maternal propoxyphene use potentially could result in norpropoxyphene accumulation in breast-fed infants.101 102 103 If a woman receiving propoxyphene breast-feeds, observe the infant for signs of sedation (e.g., poor feeding, somnolence) and respiratory depression.101 102 103

Pediatric Use

Safety and efficacy not established.101 102 103 c

Geriatric Use

Potential for reduced rate of propoxyphene metabolism.101 102 103 c (See Geriatric Patients under Dosage and Administration and also see Absorption: Special Populations and Elimination: Special Populations under Pharmacokinetics.)

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.101 102 103 However, postmarketing reports suggest that patients >65 years of age may be more susceptible to adverse CNS effects.101 102 103 Also may be more susceptible to adverse cardiac effects due to impaired elimination of norpropoxyphene.108 110 (See Cardiac Effects under Cautions.)

Select dosage with caution, usually starting at the low end of the dosing range; consider the greater frequency of decreased renal, hepatic, and/or cardiac function and of concomitant disease and drug therapy.101 102 103

Hepatic Impairment

Use with caution; serum concentrations of propoxyphene may be increased or elimination may be delayed.101 102 103 a c (See Hepatic Impairment under Dosage and Administration and see Absorption: Special Populations and also Elimination under Pharmacokinetics).

Renal Impairment

Use with caution; serum concentrations of the drug may be increased or elimination may be delayed.101 102 103 a c (See Renal Impairment under Dosage and Administration and see Absorption: Special Populations and also Elimination under Pharmacokinetics). May be more susceptible to adverse cardiac effects due to impaired elimination of norpropoxyphene.108 110 (See Cardiac Effects under Cautions.)

Common Adverse Effects

Dizziness, sedation, nausea, vomiting.101 102 103 a c

Interactions for Propoxyphene Hydrochloride

Extensively metabolized, mainly by CYP3A4.101 102 103

Propoxyphene is thought to inhibit CYP3A4 and CYP2D6.101 102 103

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: When used concomitantly with potent CYP3A4 inhibitors, possible increased plasma propoxyphene concentrations.101 102 103 Carefully monitor patients receiving any CYP3A4 inhibitor concomitantly with propoxyphene for an extended period of time and adjust dosage if needed.101 102 103

CYP3A4 inducers: Possible reduced efficacy of propoxyphene.101 102 103 When used concomitantly with potent CYP3A4 inducers, possible increased concentrations of the norpropoxyphene metabolite.101 102 103

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4 or CYP2D6: Potential for higher plasma concentrations and increased pharmacologic or adverse effects of the CYP3A4 or CYP2D6 substrate.101 102 103

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

Possible increased plasma propoxyphene concentrations101 102 103

Monitor carefully for an extended period of time; adjust dosage if needed101 102 103

Anticonvulsants (e.g., carbamazepine)

Severe neurologic signs (e.g., coma) reported with concomitant use of carbamazepine101 102 103 c

 

Anticoagulants, oral

Increased risk of bleeding; however, mechanism not determined101 102 103

 

Antifungal agents, azoles (fluconazole, itraconazole, ketoconazole)

Possible increased plasma propoxyphene concentrations101 102 103

Monitor carefully for an extended period of time; adjust dosage if needed101 102 103

Aprepitant

Possible increased plasma propoxyphene concentrations101 102 103

Monitor carefully for an extended period of time; adjust dosage if needed101 102 103

Calcium-channel blocking agents (diltiazem, verapamil)

Possible increased plasma propoxyphene concentrations101 102 103

Monitor carefully for an extended period of time; adjust dosage if needed101 102 103

CNS depressants (e.g., alcohol, sedatives and hypnotics, tranquilizers, opiate agonists, general anesthetics, phenothiazines, muscle relaxants, antidepressants)

Additive CNS depressant effects; can result in serious adverse effects, including death101 102 103 c

Use with caution;101 102 103 c if concomitant use is necessary, reduce dosage of one or both agents101 102 103 c

Avoid concomitant ingestion of alcohol, including alcohol-containing prescription and OTC drugs101 102 103

Grapefruit or grapefruit juice

Possible increased plasma propoxyphene concentrations101 102 103

Avoid concomitant use101 102 103

HIV protease inhibitors (amprenavir, fosamprenavir, nelfinavir, ritonavir)

Possible increased plasma propoxyphene concentrations101 102 103

Monitor carefully for an extended period of time; adjust dosage if needed101 102 103

Macrolide antibiotics (clarithromycin, erythromycin, troleandomycin)

Possible increased plasma propoxyphene concentrations101 102 103

Monitor carefully for an extended period of time; adjust dosage if needed101 102 103

MAO inhibitors

MAO inhibitors reported to enhance effects of opiate agonists, resulting in anxiety, confusion, respiratory depression, and coma101 102 103

Avoid use of propoxyphene during and within 14 days following discontinuance of MAO inhibitor therapy101 102 103

Nefazodone

Possible increased plasma propoxyphene concentrations101 102 103

Monitor carefully for an extended period of time; adjust dosage if needed101 102 103

Opiate partial agonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine)

May reduce analgesic effect of propoxyphene and/or precipitate withdrawal symptoms101 102 103

Use caution101 102 103

Rifampin

Possible reduced efficacy of propoxyphene; possible increased norpropoxyphene concentrations101 102 103

Propoxyphene Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Absorbed principally in the upper small intestine following oral administration.a Peak plasma concentrations usually achieved within 2–2.5 hours (propoxyphene hydrochloride)102 a or 3 hours (propoxyphene napsylate).a

In large doses, the napsylate salt appears to be absorbed more gradually than the hydrochloride salt.a

Onset

Analgesic effect occurs within 0.25–1 hour.a

Duration

Analgesic effect persists for 4–6 hours.a

Special Populations

Propoxyphene AUC and peak plasma concentrations averaged 3- and 2.5-fold higher in geriatric patients (70–78 years of age) than in young adults.101 102 103 Following multiple doses, peak plasma norpropoxyphene concentrations were fivefold higher in geriatric patients.101 102 103

Patients with cirrhosis may have substantially increased plasma propoxyphene concentrations and substantially decreased norpropoxyphene concentrations (presumably because of decreased first-pass metabolism).101 102 103

In anephric patients, AUC and peak plasma concentrations of the drug were increased by 76% and 88%, respectively.101 102 103

Distribution

Extent

Distributed into CSF.a Propoxyphene and its norpropoxyphene metabolite cross the placental barrier and are distributed into milk.101 102 103 a c

Plasma Protein Binding

About 80%.101 102 103

Elimination

Metabolism

Undergoes extensive first-pass metabolism by intestinal and hepatic enzymes.101 102 103 Metabolized mainly via N-demethylation (mediated by CYP3A4) to form norpropoxyphene.101 102 103 Ring hydroxylation and glucuronide formation appear to be minor metabolic pathways.101 102 103

Elimination Route

Propoxyphene and norpropoxyphene are excreted in urine.a Approximately 20–25% of an orally administered 65-mg dose of propoxyphene hydrochloride may be recovered in urine as unchanged drug (trace amount) and free or conjugated norpropoxyphene within 48 hours.101 102 103 a

Half-life

Propoxyphene: 6–12 hours.101 102 103 c

Norpropoxyphene: 30–36 hours.101 102 103 c

Special Populations

In geriatric patients (70–78 years of age), elimination half-lives of propoxyphene and norpropoxyphene reportedly were 13–35 and 22–41 hours, respectively.101 102 103

Not appreciably removed by dialysis.101 102 103

Stability

Storage

Oral

Capsules

Tight, light resistant container at 20–25°C.102 c

Tablets

Room temperature; consult product information for specific recommendations.101 103 c

Actions

  • Mild analgesic effects at usual dosages.a

  • No antipyretic action and little or no antitussive activity.a

  • Local anesthetic effect demonstrated in vitro, with norpropoxyphene being approximately twofold more potent than propoxyphene and propoxyphene being approximately tenfold more potent than lidocaine.101 102 103

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Provide manufacturer’s patient information (i.e., medication guide) to the patient each time propoxyphene is dispensed.101 102 103

  • Potential for propoxyphene to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.101 102 103 a c

  • Potential for severe or fatal respiratory depression following overdosage or use in conjunction with other CNS depressants.101 102 103

  • Importance of taking exactly as prescribed. Do not exceed recommended dosage; do not adjust dosage without consulting clinician.101 102 103 a c

  • Risk of additive depressant effects if combined with other CNS depressants (e.g., sedatives and hypnotics, tranquilizers, alcohol); do not consume alcohol (including alcohol-containing prescription and OTC drugs) during propoxyphene therapy.101 102 103

  • Importance of avoiding grapefruit and grapefruit juice during propoxyphene therapy.101 102 103

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.101 102 103 a

  • Importance of informing patients that propoxyphene is a potential drug of abuse.101 102 103 Instruct patients to keep the drug in a secure place to prevent theft or misuse.101 102 103

  • Importance of not abruptly discontinuing propoxyphene following prolonged (more than several weeks) therapy.101 102 103

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.101 102 103 a

  • Importance of informing patients of other important precautionary information.101 102 103 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as schedule IV (C-IV) drugs.a

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

On November 19, 2010, Xanodyne announced a voluntary withdrawal of propoxyphene-containing preparations (Darvon, Darvocet) from the US market.109 112 The withdrawal was requested by FDA following review of new data on cardiac risk.108 109 (See Cardiac Effects under Cautions.) FDA requested that manufacturers of generic propoxyphene-containing preparations also voluntarily withdraw these preparations from the US market.108 109

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Propoxyphene Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

65 mg*

Darvon Pulvules (C-IV)

Xanodyne

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Propoxyphene Hydrochloride and Acetaminophen

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

65 mg Propoxyphene Hydrochloride and Acetaminophen 650 mg*

Propoxyphene Napsylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

100 mg

Darvon-N (C-IV)

Xanodyne

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Propoxyphene Napsylate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg with Acetaminophen 325 mg*

Darvocet-N 50 (C-IV)

Xanodyne

100 mg with Acetaminophen 500 mg

Darvocet A500 (C-IV)

Xanodyne

100 mg with Acetaminophen 650 mg*

Darvocet-N 100 (C-IV)

Xanodyne

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

101. Xanodyne Pharmaceuticals, Inc. Darvon-N (propoxyphene napsylate) tablets prescribing information. Newport, KY; 2009 Sep.

102. Xanodyne Pharmaceuticals, Inc. Darvon Pulvules (propoxyphene hydrochloride capsules) prescribing information. Newport, KY; 2009 Sep.

103. Xanodyne Pharmaceuticals, Inc. Darvocet-N 50 and Darvocet-N 100 (propoxyphene napsylate and acetaminophen) tablets prescribing information. Newport, KY; 2009 Sep.

104. US Food and Drug Administration. Propoxyphene questions and answers. From FDA website. Accessed 2009 Oct 5.

105. US Food and Drug Administration. FDA takes actions on Darvon, other pain medications containing propoxyphene. Rockville, MD; 2009 Jul 7. Press release from FDA website.

106. Woodcock J. Letter to SM Wolfe, D Suzman, U Jonasson, and B Jonasson: Response to citizen petition (re: Docket No. FDA-2006-P-0270). Rockville, MD: US Food and Drug Administration; 2009. From FDA website. Accessed 2009 Oct 5.

107. Final summary minutes: Joint meeting of the Anesthetic and Life Support Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, January 30, 2009. From FDA website. Accessed 2009 Oct 8.

108. US Food and Drug Administration. Drug safety communication: FDA recommends against the continued use of propoxyphene. Rockville, MD; 2010 Nov 19. From FDA website.

109. US Food and Drug Administration. Xanodyne agrees to withdraw propoxyphene from the U.S. market. Rockville, MD; 2010 Nov 19. News release from FDA website.

110. Balakrishnan SM, Dang Q, Zhang J et al. Interdisciplinary review team for QT studies consultation: multiple ascending dose (MAD) study review. Available at FDA website. Accessed 2011 Feb 8.

111. Dal Pan GJ. Memorandum to Dr. Woodcock and Dr. Jenkins: Updated epidemiological review of propoxyphene safety. 2010 Nov 19. From FDA website.

112. Xanodyne Pharmaceuticals, Inc. Xanodyne Pharmaceuticals, Inc. to voluntarily withdraw Darvon and Darvocet-N products. Newport, KY; 2010 Nov 19. Press release from website.

113. Hertz S, Avigan M. Memorandum to Dr. Woodcock: Recommendation on a regulatory decision for propoxyphene-containing products. 2010 Nov 18. From FDA website.

a. AHFS Drug Information 2010. McEvoy, GK, ed. Propoxyphene. Bethesda, MD: American Society of Health-System Pharmacists; 2010:

c. Xanodyne Pharmaceuticals, Inc. Darvocet A500 (propoxyphene napsylate and acetaminophen) 100 mg/500 mg tablets prescribing information. Newport, KY; 2009 Nov.

d. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and lactation. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:1544-6.

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