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Special Alerts
Propoxyphene: Withdrawal from the U.S. and Canadian Markets (Update)
December 2010
Xanodyne Pharmaceuticals Inc, the manufacturer of Darvon® (propoxyphene) and Darvocet® (propoxyphene and acetaminophen), in conjunction with the U.S. Food and Drug Administration (FDA), has agreed to withdraw both products from the U.S. market. This decision is the result of a recent safety study which demonstrated an increased risk of potentially serious and fatal cardiac rhythm abnormalities with propoxyphene. The FDA has requested that all generic manufacturers of propoxyphene-containing products also voluntarily withdraw their products from the market as well. Due to the same safety concerns prompting the U.S. withdrawal, Paladin Labs, Inc, in collaboration with Health Canada, is voluntarily withdrawing NDarvon-N® (dextropropoxyphene) from the Canadian market. Prescribers are advised to no longer prescribe propoxyphene-containing products. Patients should contact their healthcare provider to discuss alternative pain management.
For further details, please refer to:
U.S.: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm234389.htm
Canada: http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2010/darvon-n_hpc-cps-eng.php
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(proe POKS i feen)
Generic Available (U.S.)
Yes: Capsule
Index Terms
Controlled Substance
C-IV
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM187068.pdf, must be dispensed with this medication.
REMS Components
Medication Guide
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of mild-to-moderate pain
Pregnancy Risk Factor
C
Pregnancy Considerations
Adequate animal reproduction studies were not conducted by the manufacturer. Propoxyphene and norpropoxyphene cross the placenta. Respiratory depression and withdrawal symptoms may occur in the neonate following propoxyphene use during pregnancy. Teratogenic effects have also been noted in case reports.
Lactation
Enters breast milk/use caution (AAP rates “compatible”; AAP 2001 update pending)
Breast-Feeding Considerations
Propoxyphene and norpropoxyphene are excreted in breast milk. Based on limited data, a breast-feeding infant would receive ~2% of the maternal weight adjusted dose of propoxyphene. Norpropoxyphene clearance is decreased in neonates. Monitor infant for signs of sedation.
Contraindications
Hypersensitivity to propoxyphene or any component of the formulation; patients with paralytic ileus, acute/severe asthma, hypercarbia, or severe respiratory depression (unless patient is mechanically ventilated)
Warnings/Precautions
Boxed warnings:
• Overdose: See “Concerns related to adverse effects” below.
• High potential for interactions: See “Concurrent drug therapy issues” below.
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Overdose: [U.S. Boxed Warning]: Accidental and intentional overdose has occurred (including fatalities) when propoxyphene was used alone or in combination with other CNS depressants (including ethanol). Patients with a history of emotional disturbances or suicidal ideation/attempt or who are on concurrent sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs are at greatest risk of propoxyphene-related deaths.
• Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics).
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction; acute pancreatitis may cause constriction of sphincter of Oddi.
• CNS depression/coma: Use with caution in patients with CNS depression or coma.
• Depression: Should not be prescribed in patients who are severely depressed, suicidal, or have a history of suicidal ideation.
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with hepatic impairment; consider dosing adjustment.
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Renal impairment: Use with caution in patients with renal impairment; consider dosing adjustment.
• Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD, or other obstructive pulmonary disease; critical respiratory depression may occur, even at therapeutic dosages.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• High potential for interactions: [U.S. Boxed Warning]: Use with caution in patients taking strong CYP3A4 inhibitors (see Drug Interactions); monitor patients closely. Dosage adjustments may be needed.
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.
• Elderly: May be inappropriate in this age group due to adverse effects; has few advantages over acetaminophen for treating pain (Beers Criteria).
Other warnings/precaution:
• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.
• Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.
Adverse Reactions
Frequency not defined.
Central nervous system: Dizziness, dysphoria, euphoria, hallucinations, headache, lightheadedness, sedation
Dermatologic: Rash
Gastrointestinal: Abdominal pain, constipation, nausea, vomiting
Neuromuscular & skeletal: Weakness
Ocular: Visual disturbances
Postmarketing and/or case reports: Abnormal behavior, arrhythmia, ataxia, blurred vision, bradycardia, CHF, cholestatic jaundice (rare), coma, confusion, diarrhea, dyspnea, eye edema, GI bleed, hepatic steatosis, hepatomegaly, hepatocellular injury, histamine release, hypotension, hypersensitivity reaction, jaundice (rare, reversible), liver dysfunction, liver function tests abnormal, metabolic acidosis, MI, myopathy (associated with overdose), overdose (accidental/intentional), pancreatitis, pruritus, psychologic and physical dependence with prolonged use, respiratory arrest, respiratory depression, seizure, somnolence, suicide, syncope, tachycardia, withdrawal syndrome
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Inhibits CYP2C9 (weak), 2D6 (weak), 3A4 (weak)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification
Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy
Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy
Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy
Beta-Blockers: Propoxyphene may decrease the metabolism of Beta-Blockers. Exceptions: Atenolol; Carteolol; Carteolol (Ophthalmic); Levobunolol; Metipranolol; Nadolol. Risk C: Monitor therapy
CarBAMazepine: Propoxyphene may enhance the CNS depressant effect of CarBAMazepine. Propoxyphene may increase the serum concentration of CarBAMazepine. Management: Consider alternatives to propoxyphene. If this combination cannot be avoided, monitor carbamazepine concentrations and dose adjust as needed to maintain in the therapeutic range. Carefully monitor for signs/symptoms of carbamazepine toxicity. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: For patients being treated with hydroxyzine, a reduction in the dose of any other CNS depressants that are to be used in combination is recommended. With concurrent use, monitor patients closely for excessive response to the combination. Risk D: Consider therapy modification
MAO Inhibitors: Propoxyphene may enhance the adverse/toxic effect of MAO Inhibitors. Specifically, the risk of serotonin syndrome or other serotonergic adverse events may be increased. Risk X: Avoid combination
Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk D: Consider therapy modification
Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy
Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy
Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Tricyclic Antidepressants: Propoxyphene may enhance the CNS depressant effect of Tricyclic Antidepressants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Propoxyphene may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: May decrease rate of absorption, but may slightly increase bioavailability. Avoid grapefruit juice (may increase levels/effects of propoxyphene).
Storage
Store at controlled room temperature of 20°C to 25°C (68°F to 77°F).
Mechanism of Action
Propoxyphene is a weak narcotic analgesic which acts through binding to opiate receptors to inhibit ascending pain pathways. Propoxyphene, as with other narcotic (opiate) analgesics, blocks pain perception in the cerebral cortex by binding to specific receptor molecules (opiate receptors) within the neuronal membranes of synapses. This binding results in a decreased synaptic chemical transmission throughout the CNS thus inhibiting the flow of pain sensations into the higher centers. Mu and kappa are the two subtypes of the opiate receptor which propoxyphene binds to cause analgesia.
Pharmacodynamics/Kinetics
Onset of action: 0.5-1 hour
Duration: 4-6 hours
Distribution: Vd: 16 L/kg
Protein binding: ~80%
Metabolism: Hepatic via CYP3A4 to active metabolite (norpropoxyphene) and inactive metabolites; extensive first-pass effect
Half-life elimination: Adults: 6-12 hours, Elderly: 13-35 hours; Norpropoxyphene: Adults: 30-36 hours, Elderly: 22-41 hours
Time to peak, plasma: 2-2.5 hours
Excretion: Urine (~20% to 25%, primarily as metabolites)
Dosage
Oral: Mild-to-moderate pain:
Adults:
Hydrochloride: 65 mg every 4 hours as needed; maximum: 390 mg/day
Napsylate: 100 mg every 4 hours as needed; maximum: 600 mg/day
Elderly: Refer to adult dosing; consider decreasing total daily dose
Concurrent use with CYP3A4 inhibitors: Monitor closely; dosage adjustment may be necessary.
Discontinuation of therapy: In patients on prolonged therapy, gradually discontinue propoxyphene and acetaminophen by reducing dose by 25% to 50% daily and carefully monitor for signs/symptoms of withdrawal.
Dosing adjustment in renal impairment: Serum concentrations of propoxyphene may be increased or elimination may be delayed. Use with caution; dosage reduction should be considered; however, no specific dosing recommendations are available.
Not dialyzable (8%)
Dosing adjustment in hepatic impairment: Serum concentrations of propoxyphene may be increased or elimination may be delayed. Use with caution; dosage reduction should be considered; however, no specific dosing recommendations are available.
Administration: Oral
Food may decrease rate of absorption, but may slightly increase bioavailability.
Monitoring Parameters
Pain relief, respiratory and mental status, blood pressure
Test Interactions
False-positive methadone test
Dietary Considerations
May take with food if gastrointestinal distress occurs. Avoid grapefruit juice.
Patient Education
Do not use alcohol, other prescription or OTC sedatives, tranquilizers, antihistamines, or pain medications without consulting prescriber. May cause dizziness, drowsiness, impaired judgment, vomiting, loss of appetite, or constipation. Report suicide ideation, unresolved nausea or vomiting, respiratory difficulty or shortness of breath, or unusual weakness.
Geriatric Considerations
Elderly may be particularly susceptible to the CNS depressant and constipating effects of narcotics. Propoxyphene is not considered the analgesic of choice in the elderly when mild-to-moderate pain requires a narcotic analgesic. This is due to the higher incidence of adverse CNS effects seen in the elderly population. The potential for dependence is also a concern; avoid use, if possible. See Warnings/Precautions.
This medication is considered to be potentially inappropriate in this patient population (Beers Criteria severity: Low).
Additional Information
100 mg of napsylate = 65 mg of hydrochloride
Propoxyphene hydrochloride: Darvon®
Propoxyphene napsylate: Darvon-N®
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Equivalent dosing: 100 mg of propoxyphene napsylate = 65 mg of propoxyphene hydrochloride
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Dizziness, drowsiness, insomnia, and paradoxical excitement are common; may cause nervousness, restlessness, confusion; may rarely cause depression or hallucinations
Mental Health: Effects on Psychiatric Treatment
Concurrent use with psychotropics may produce additive sedation as well as increase their serum levels; monitor for altered clinical response or preferably, use a different analgesic
Nursing: Physical Assessment/Monitoring
Assess for suicide ideation. Monitor respiratory and CNS status at beginning of therapy and periodically thereafter. Assess patient's physical and/or psychological dependence. Discontinue slowly after prolonged use
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, oral, as hydrochloride: 65 mg [DSC]
Darvon®: 65 mg [DSC]
Tablet, oral, as napsylate:
Darvon-N®: 100 mg [DSC]
References
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
“Drugs for Pain,” Med Lett Drugs Ther, 2000, 42(1085):73-8.
Ferrell BA, “Pain Management in Elderly People,” J Am Geriatr Soc, 1991, 39(1):64-73.
Finkle BS, “Self-Poisoning With Dextropropoxyphene and Dextropropoxyphene Compounds: The USA Experience,” Hum Toxicol, 1984, 3(Suppl):115-34.
Hasday JD and Weintraub M, “Propoxyphene in Children With Iatrogenic Morphine Dependence,” Am J Dis Child, 1983, 137(8):745-8.
Lawson AA and Northridge DB, “Dextropropoxyphene Overdose. Epidemiology, Clinical Presentation, and Management,” Med Toxicol Adverse Drug Exp, 1987, 2(6):430-44.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Proudfoot AT, “Clinical Features and Management of Distalgesic Overdose,” Hum Toxicol, 1984, 3(Suppl):85-94.
Rathmell JP, Viscomi CM, and Ashburn MA, “Management of Nonobstetric Pain During Pregnancy and Lactation,” Anesth Analg, 1997, 85(5):1074-87.
Stork CM, Redd JT, Fine K, et al, “Propoxyphene-Induced Wide QRS Complex Dysrhythmia Responsive to Sodium Bicarbonate - A Case Report,” J Toxicol Clin Toxicol, 1995, 33(2):179-83.
Wetli CV and Bednarczyk LR, “Deaths Related to Propoxyphene Overdose: A Ten Year Assessment,” South Med J, 1980, 73(9):1205-9.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
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