Propoxyphene Napsylate

Class: Opiate Agonists
Note: This monograph also contains information on Propoxyphene Hydrochloride
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

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 ().

• 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 Napsylate

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

Propoxyphene Napsylate 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 Napsylate

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 C^{101 102 103 d} (category D, if used for prolonged periods^d ).

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 Napsylate

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 Napsylate 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

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, 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.

Propoxyphene Capsules

Generic Name: propoxyphene hydrochloride

Dosage Form: capsule
PROPOXYPHENE HYDROCHLORIDE CAPSULES, USP

0741

CIV

Rx only

WARNINGS

 

• There have been numerous cases of accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol. Fatalities within the first hour of overdosage are not uncommon. Many of the propoxyphene-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation.


• 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. Patients receiving propoxyphene and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see CLINICAL PHARMACOLOGY, Drug Interactions; WARNINGS; PRECAUTIONS;  and DOSAGE AND ADMINISTRATION for further information).

Propoxyphene Capsules Description

Propoxyphene hydrochloride is an odorless, white crystalline powder with a bitter taste. It is freely soluble in water. Chemically, it is (2S,3R)-(+)-4-(dimethylamino)-3-methyl-1,2- diphenyl-2-butanol propionate (ester) hydrochloride, which can be represented by the following structural formula:

C22H29NO2•HCl M.W. 375.94

Each capsule, for oral administration, contains 65 mg propoxyphene hydrochloride. Propoxyphene hydrochloride capsules, USP contain the inactive ingredients corn starch, gelatin, lactose monohydrate, magnesium stearate, titanium dioxide, FD&C yellow #6, and D&C red #33.

Propoxyphene Capsules - 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.

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 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.

Distribution

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

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.

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.

SPECIAL POPULATIONS

Geriatric Patients

After oral administration of propoxyphene in elderly patients (70 to 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 to 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 to 78 years), the Cmax of the metabolite (norpropoxyphene) was increased 5 fold.

Pediatric Patients

Propoxyphene has not been studied in pediatric patients.

Hepatic Impairment

No formal pharmacokinetic study of propoxyphene 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).

Renal Impairment

No formal pharmacokinetic study of propoxyphene 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.

Indications and Usage for Propoxyphene Capsules

This product is indicated for the relief of mild to moderate pain.

Contraindications

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.

Warnings

Risk of Overdose

There have been numerous cases of accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol. Fatalities within the first hour of overdosage are not uncommon. Many of the propoxyphene-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation.

Respiratory Depression

Respiratory depression is the chief hazard from all opioid agonist preparations. Respiratory depression occurs most frequently in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration. Propoxyphene should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. In such patients, even usual therapeutic doses of propoxyphene may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Hypotensive Effect

Propoxyphene, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Propoxyphene may produce orthostatic hypotension in ambulatory patients. Propoxyphene, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.

Drug Interactions

The concomitant use of propoxyphene and CNS depressants, including alcohol, can result in potentially serious adverse events including death. Because of its added depressant effects, propoxyphene should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs.

Usage in Ambulatory Patients

Propoxyphene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly.

Use With Alcohol

Patients should be cautioned about the concomitant use of propoxyphene products and alcohol because of potentially serious CNS-additive effects of these agents that can lead to death.

Precautions

Tolerance and Physical Dependence

Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION, Cessation of Therapy).

If propoxyphene is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur (see DRUG ABUSE AND DEPENDENCE). If signs and symptoms of withdrawal occur, patients should be treated by reinstitution of opioid therapy followed by gradual tapered dose reduction of propoxyphene combined with symptomatic support (see DOSAGE AND ADMINISTRATION, Cessation of Therapy).

Use in Pancreatic/Biliary Tract Disease

Propoxyphene may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like propoxyphene may cause increases in the serum amylase level.

Hepatic or Renal Impairment

Insufficient information exists to make appropriate dosing recommendations regarding the use of either propoxyphene in patients with hepatic or renal impairment as a function of degree of impairment. Higher plasma concentrations and/or delayed elimination may occur in case of impaired hepatic function and/or impaired renal function (see CLINICAL PHARMACOLOGY).

If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of propoxyphene metabolites.

Information for Patients/Caregivers

(Also see Medication Guide.)

1. Patients should be advised to report pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.


2. Patients should be advised not to adjust the dose of propoxyphene without consulting the prescribing professional.


3. Patients should be advised that propoxyphene may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).


4. Patients should not combine propoxyphene with central nervous system depressants (e.g., sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur.


5. Patients should be instructed not to consume alcoholic beverages, including prescription and over-the-counter medications that contain alcohol, while using propoxyphene because of risk of serious adverse events including death.


6. Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.


7. Patients should be advised that propoxyphene is a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.


8. Patients should be advised that if they have been receiving treatment with propoxyphene for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the propoxyphene dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.

Drug Interactions With Propoxyphene

Propoxyphene is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when propoxyphene is administered concurrently with agents that affect CYP3A4 activity.

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. Coadministration with agents that induce CYP3A4 activity may reduce the efficacy of propoxyphene. 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 and coadministration with drugs that rely on either of these enzymes for metabolism may result in increased pharmacologic or adverse effects of that drug. Severe neurologic signs, including coma, have occurred with concurrent use of carbamazepine (metabolized by CYP3A4).

Increased risk of bleeding has been observed with warfarin-like agents when given along with propoxyphene; however, the mechanistic basis of this interaction is unknown.

CNS Depressants

Patients receiving narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with propoxyphene may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dosage of propoxyphene. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as propoxyphene. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of propoxyphene and/or may precipitate withdrawal symptoms in these patients.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant depression of respiration or coma. The use of propoxyphene is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The mutagenic and carcinogenic potential of propoxyphene has not been evaluated.

In animal studies there was no effect of propoxyphene on mating behavior, fertility, duration of gestation, or parturition when rats were fed propoxyphene as a component of their daily diet at estimated daily propoxyphene intake up to 8 fold greater than the maximum human equivalent dose (HED) based on body surface area comparison. At this highest dose, fetal weight and survival on postnatal day 4 was reduced.

Pregnancy

Risk Summary

Pregnancy category C

There are no adequate and well-controlled studies of propoxyphene in pregnant women. While there are limited data in the published literature, adequate animal reproduction studies have not been conducted with propoxyphene. Therefore, it is not known whether propoxyphene can affect reproduction or cause fetal harm when administered to a pregnant woman. Propoxyphene should be given to a pregnant woman only if clearly needed.

Clinical Considerations

Propoxyphene and its major metabolite, norpropoxyphene, cross the human placenta. Neonates whose mothers have taken opiates chronically may exhibit respiratory depression or withdrawal symptoms.

Data

In published animal reproduction studies, no teratogenic effects occurred in offspring born to pregnant rats or rabbits that received propoxyphene during organogenesis. Pregnant animals received propoxyphene doses approximately 10 fold (rats) and 4 fold (rabbits) the maximum recommended human dose (based on mg/m2 body surface area comparison).

Nursing Mothers

Propoxyphene, norpropoxyphene (major metabolite), are excreted in human milk. Published studies of nursing mothers using propoxyphene detected no adverse effects in nursing infants. Based on a study of six mother-infant pairs, an exclusively breastfed infant receives approximately 2% of the maternal weight-adjusted dose. Norpropoxyphene is renally excreted, and renal clearance is lower in neonates than in adults. Therefore, it is possible that prolonged maternal propoxyphene use could result in norpropoxyphene accumulation in a breastfed infant. Watch breastfeeding infants for signs of sedation including poor feeding, somnolence, or respiratory depression. Caution should be exercised when propoxyphene is administered to a nursing woman.

Pediatric Patients

Safety and effectiveness in pediatric patients have not been established.

Elderly Patients

Clinical studies of propoxyphene did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, postmarketing reports suggest that patients over the age of 65 may be more susceptible to CNS-related side effects. Therefore, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Decreased total daily dosage should be considered (see DOSAGE AND ADMINISTRATION).

Adverse Reactions

In hospitalized patients, the most frequently reported were dizziness, sedation, nausea, and vomiting. Other adverse reactions include constipation, abdominal pain, skin rashes, lightheadedness, headache, weakness, euphoria, dysphoria, hallucinations, and minor visual disturbances.

The most frequently reported postmarketing adverse events have included completed suicide, accidental and intentional overdose, drug dependence, cardiac arrest, coma, drug ineffective, drug toxicity, nausea, respiratory arrest, cardio-respiratory arrest, death, vomiting, dizziness, convulsion, confusional state, and diarrhea.

Additional adverse experiences reported through postmarketing surveillance include:

Cardiac disorders: arrhythmia, bradycardia, cardiac/respiratory arrest, congestive arrest, congestive heart failure (CHF), tachycardia, myocardial infarction (MI)

Eye disorder: eye swelling, vision blurred

General disorder and administration site conditions: drug interaction, drug tolerance, drug withdrawal syndrome

Gastrointestinal disorder: gastrointestinal bleed, acute pancreatitis

Hepatobiliary disorder: hepatic steatosis, hepatomegaly, hepatocellular injury

Immune system disorder: hypersensitivity

Injury poisoning and procedural complications: drug toxicity, hip fracture, multiple drug overdose, narcotic overdose

Investigations: blood pressure decreased, heart rate elevated/abnormal

Metabolism and nutrition disorder: metabolic acidosis

Nervous system disorder: ataxia, coma, dizziness, somnolence, syncope

Psychiatric: abnormal behavior, confusional state, hallucinations, mental status change

Respiratory, thoracic, and mediastinal disorders: respiratory depression, dyspnoea

Skin and subcutaneous tissue disorder: rash, itch

Liver dysfunction has been reported in association with propoxyphene. Propoxyphene therapy has been associated with abnormal liver function tests and, more rarely, with instances of reversible jaundice (including cholestatic jaundice).

Subacute painful myopathy has been reported following chronic propoxyphene overdosage.

Drug Abuse and Dependence

Controlled Substance

Propoxyphene is a Schedule IV narcotic under the U.S. Controlled Substances Act. Propoxyphene 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 should be prescribed and administered with the same degree of caution appropriate to the use of other narcotic-containing medications.

Abuse

Since propoxyphene 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.

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 should be guided by the degree of tolerance manifested and the doses needed to adequately relieve pain.

The severity of the propoxyphene 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.

Overdosage

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.

Propoxyphene Capsules Dosage and Administration

Propoxyphene hydrochloride capsules, USP are intended for the management of mild to moderate pain. The dose should be individually adjusted according to severity of pain, patient response and patient size.

Propoxyphene hydrochloride capsules, USP are given orally. The usual dosage is one 65 mg propoxyphene hydrochloride capsule, USP every 4 hours as needed for pain. The maximum dose of propoxyphene hydrochloride capsules, USP is 6 tablets per day. Do not exceed the maximum daily dose.

Patients receiving propoxyphene and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted.

Consideration should be given to a reduced total daily dosage in elderly patients and in patients with hepatic or renal impairment.

Cessation of Therapy

For patients who used propoxyphene hydrochloride capsules, USP on a regular basis for a period of time, when therapy with propoxyphene hydrochloride capsules, USP is no longer needed for the treatment of their pain, it may be useful to gradually discontinue the propoxyphene hydrochloride capsules, USP over time to prevent the development of an opioid abstinence syndrome (narcotic withdrawal). In general, therapy can be decreased by 25% to 50% per day with careful monitoring for signs and symptoms of withdrawal (see DRUG ABUSE AND DEPENDENCE for description of the signs and symptoms of withdrawal). If the patient develops these signs or symptoms, the dose should be raised to the previous level and titrated down more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.

How is Propoxyphene Capsules Supplied

Propoxyphene hydrochloride capsules, USP, 65 mg, available in bottles of 100 and 1000. The #3 pink capsule is imprinted "93" - "741".

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense contents with a child-resistant closure (as required) and in a tight, light-resistant container as defined in the USP/NF.

Inform patients of the availability of a Medication Guide for propoxyphene hydrochloride capsules, USP that accompanies each prescription dispensed. Instruct patients to read the propoxyphene hydrochloride capsules, USP Medication Guide prior to using propoxyphene hydrochloride capsules, USP.

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. O 10/2009

MEDICATION GUIDE

PROPOXYPHENE HYDROCHLORIDE CAPSULES, USPCIV

Rx only

Read this Medication Guide before you start taking propoxyphene hydrochloride capsules, USP, and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is the most important information I should know about propoxyphene hydrochloride capsules, USP?

Propoxyphene hydrochloride capsules, USP, and other medicines that contain propoxyphene can cause serious side effects, including:

Overdoses by accident or on purpose (intentional overdose). Overdoses with propoxyphene hydrochloride capsules, USP may happen when they are taken by themselves, or with alcohol or other medicines that can also decrease your breathing and make you very sleepy.

• Death can happen within 1 hour of taking an overdose of propoxyphene hydrochloride capsules, USP.
  
  Many of the deaths that happen in people who take propoxyphene hydrochloride capsules, USP happen in those who:
  
  • have emotional problems
  
  
  • have thoughts of suicide or attempted suicide, or
  
  
  • also take antidepressants, sedatives, tranquilizers, muscle relaxants, or other medicines that affect your breathing and make you very sleepy. You should not use any of these medicines with propoxyphene hydrochloride capsules, USP without talking to your doctor.
  
  


• Before taking propoxyphene hydrochloride capsules, USP tell your doctor if you:
  
  • have a lung problem, such as COPD or cor pulmonale
  
  
  • have liver or kidney problems
  
  
  • have problems with your pancreas or gallbladder
  
  
  • have a history of head injury
  
  
  • are over age 65
  
  
  • have a history of drug or alcohol abuse or addiction
  
  

Take propoxyphene hydrochloride capsules, USP exactly as prescribed. Do not change your dose or stop taking propoxyphene hydrochloride capsules, USP without first talking to your doctor.

• If you take propoxyphene hydrochloride capsules, USP, do not take more than 6 capsules in one day.


• Before taking propoxyphene hydrochloride capsules, USP, tell your doctor about all the medicines you take. Propoxyphene hydrochloride capsules, USP and many other medicines may interact with each other and may cause serious side effects. Certain medicines can affect how your liver breaks down other medicines. See “What should I tell my doctor before taking propoxyphene hydrochloride capsules, USP?”


• Do not drink grapefruit juice or eat grapefruit while you take propoxyphene hydrochloride capsules, USP. Grapefruit juice may interact with propoxyphene hydrochloride capsules, USP.


• Do not drink alcohol while using propoxyphene hydrochloride capsules, USP. Using alcohol with propoxyphene hydrochloride capsules, USP may increase your risk of having dangerous side effects.

What are propoxyphene hydrochloride capsules, USP?

• Propoxyphene hydrochloride capsules, USP are a prescription medicine used to treat mild to moderate pain.

• Propoxyphene hydrochloride capsules, USP are a federally controlled substance (C-IV) because they are strong opioid pain medicines that can be abused by people who abuse prescription medicines or street drugs.


• Prevent theft, misuse or abuse. Keep propoxyphene hydrochloride capsules,USP in a safe place to protect them from being stolen. Propoxyphene hydrochloride capsules, USP can be a target for people who misuse or abuse prescription medicines or street drugs.


• Never give propoxyphene hydrochloride capsules, USP to anyone else, even if they have the same symptoms that you have. They may harm them or even cause death. Selling or giving away this medicine is against the law.

It is not known if propoxyphene hydrochloride capsules, USP are safe and effective in children younger than age 18.

Who should not take propoxyphene hydrochloride capsules, USP?

Do not take propoxyphene hydrchloride capsules, USP if you:

• are allergic to propoxyphene. Ask your doctor if you are not sure. See the end of this Medication Guide for a list of the ingredients in propoxyphene hydrochloride capsules, USP.


• are having an asthma attack or have severe asthma, trouble breathing, or have a lung problem


• have a bowel blockage called paralytic ileus
  

What should I tell my doctor before taking propoxyphene hydrochloride capsules, USP?

Before you take propoxyphene hydrochloride capsules, USP, tell your doctor:

• if you have any of the conditions listed in the section “What is the most important information I should know about propoxyphene hydrochloride capsules, USP?”


• if you are allergic to propoxyphene


• if you plan to have surgery with general anesthesia


• if you are pregnant or plan to become pregnant.


• if you take propoxyphene hydrochloride capsules, USP regularly before your baby is born, your newborn baby may have withdrawal symptoms because their body has become used to the medicine.

Symptoms of withdrawal in a newborn baby may include:

irritability	crying more than usual
shaking (tremors)	diarrhea or more stools than normal
jitteriness	vomiting
breathing faster than normal	fever

• if you take propoxyphene hydrochloride capsules, USP right before your baby is born, your baby could have breathing problems.


• if you are breast-feeding or plan to breast-feed. Some propoxyphene hydrochloride passes into breast milk.

Tell your doctor about all the medicines you take, including prescription, and non-prescription medicines, vitamins, and herbal supplements. Propoxyphene hydrochloride capsules, USP interact with many medicines and may lead to serious side effects. The doses of certain medicines may need to be changed.

Especially tell your doctor if you take:

See “What is the most important information I should know about propoxyphene hydrochloride capsules, USP?”

• certain medicines that can affect how your liver breaks down other medicines


• a monoamine oxidase inhibitor (MAOI) medicine


• other medicines that make you sleepy, such as: other medicines for pain, including other opioid medicines, anti-depressant medicines, sleeping pills, anti-anxiety medicines, muscle relaxants, anti-nausea medicines, or tranquilizers


• a blood pressure medicine


• a blood-thinner medicine. You may have an increased risk of bleeding while also taking propxyphene hydrochloride capsules, USP.

Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

Know the medicines you take. Keep a list of them to show to your doctor and pharmacist when you get a new medicine.

How should I take propoxyphene hydrochloride capsules, USP?

See “What is the most important information I should know about propoxyphene hydrochloride capsules, USP?”

• Take propoxyphene hydrochloride capsules, USP exactly as prescribed.


• If you take too many propoxyphene hydrochloride capsules, USP, or take them with alcohol or other medicines, you may overdose. See “What is the most important information I should know about propoxyphene hydrochloride capsules, USP?” You will need medical help right away if you think you have taken an overdose of propoxyphene hydrochloride capsules, USP. A large overdose could cause you to become unconscious and die.

Signs and symptoms of an overdose of propoxyphene hydrochloride capsules, USP include:

• you are very sleepy or do not respond to others


• confusion


• have trouble breathing or stop breathing


• changes in blood pressure and heart rate

What are the possible side effects of propoxyphene hydrochloride capsules, USP?

Propoxyphene hydrochloride capsules, USP can cause serious side effects, including:

See “What is the most important information I should know about propoxyphene hydrochloride capsules, USP?”

• Serious breathing problems that can become life-threatening. This is especially true if you already have a serious lung or breathing problem, or your body is not used to opioid pain medicines. This can happen even if you take propoxyphene hydrochloride capsules, USP exactly as prescribed by your doctor. Call your doctor or get medical help right away if: 
  
  • your breathing slows down
  
  
  • you have shallow breathing (little chest movement with breathing)
  
  
  • you feel faint, dizzy, confused, or
  
  
  • you have any other unusual symptoms
  
  


• Propoxyphene hydrochloride capsules, USP can cause your blood pressure to drop. This can make you feel dizzy and faint if you get up too fast from sitting or lying down. Low blood pressure is also more likely to happen if you take other medicines that can also lower your blood pressure. Severe low blood pressure can happen if you lose blood or take certain other medicines.


• Sleepiness. Propoxyphene hydrochloride capsules, USP can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do other dangerous activities until you know how propoxyphene hydrochloride capsules, USP affect you.


• Propoxyphene hydrochloride capsules, USP can cause physical dependence if you take them for more than a few weeks. Do not stop taking propoxyphene hydrochloride capsules, USP all of a sudden. You could become sick with uncomfortable withdrawal symptoms (for example, nausea, vomiting, diarrhea, anxiety, and shivering) because your body has become used to the medicine. Physical dependence is not the same as drug addiction. Your doctor can tell you more about the differences between physical dependence and drug addiction.

Tell your doctor if you have any of these withdrawal symptoms while you slowly stop taking propoxyphene hydrochloride capsules, USP. You may need to stop propoxyphene hydrochloride capsules, USP more slowly.

Common side effects of propoxyphene hydrochloride capsules, USP include:

dizziness	weakness
feeling sleepy	feeling of excitement (elation) or discomfort
nausea and vomiting	seeing, hearing, or sensing things that are not really there (hallucinations)
constipation	blurred vision
stomach area (abdominal) pain
skin rashes
lightheadedness
headache

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to TEVA USA, PHARMACOVIGILANCE at 1-888-838-2872, X6351.

How should I store propoxyphene hydrochloride capsules, USP?

• Store propoxyphene hydrochloride capsules, USP at 20° to 25°C (68° to 77°F).

Keep propoxyphene hydrochloride capsules, USP and all medicines out of the reach of children.

General information about propoxyphene hydrochloride capsules, USP