DailyMed Label: Darvon-N

DailyMed Label: Darvon-N

2009

DailyMed Prescription

Darvon-N

propoxyphene napsylate

Stat Rx USA

NDC: 16590-874

NDC: 16590-874

DESCRIPTION Darvon-N contains propoxyphene napsylate, USP which is an odorless, white crystalline powder with a bitter taste. It is very slightly soluble in water and soluble in methanol, ethanol, chloroform, and acetone. Chemically, it is (α S ,1 R )-α-[2-(Dimethylamino)-1-methylethyl]-α-phenylphenethyl propionate compound with 2-naphthalenesulfonic acid (1:1) monohydrate, which can be represented by the accompanying structural formula. Its molecular weight is 565.72 Propoxyphene napsylate differs from propoxyphene hydrochloride in that it allows more stable liquid dosage forms and tablet formulations. Because of differences in molecular weight, a dose of 100 mg (176.8 μmol) of propoxyphene napsylate is required to supply an amount of propoxyphene equivalent to that present in 65 mg (172.9 μmol) of propoxyphene hydrochloride. Each tablet of Darvon-N contains 100 mg (176.8 μmol) propoxyphene napsylate. The tablet also contains cellulose, cornstarch, iron oxides, lactose, magnesium stearate, silicon dioxide, stearic acid, and titanium dioxide. STRUCTURE

INDICATION Darvon-N is indicated for the relief of mild to moderate pain.

DOSAGE AND ADMINISTRATION Darvon-N is 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. Darvon-N is given orally. The usual dosage is one 100 mg propoxyphene napsylate tablet every 4 hours as needed for pain. The maximum dose of Darvon-N 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 Darvon-N on a regular basis for a period of time, when therapy with Darvon-N is no longer needed for the treatment of their pain, it may be useful to gradually discontinue the Darvon-N 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.

CONTRAINDICATIONS Darvon-N is contraindicated in patients with known hypersensitivity to propoxyphene. Darvon-N is 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. Darvon-N is 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. Darvon-N 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 pre-existing respiratory depression. In such patients, even usual therapeutic doses of Darvon-N 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 Darvon-N, 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. Darvon-N may produce orthostatic hypotension in ambulatory patients. Darvon-N, 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 pre-existing 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 Darvon-N is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur (see Drug Abuse and Dependance). If signs and symptoms of withdrawal occur, patients should be treated by reinstitution of opioid therapy followed by gradual tapered dose reduction of Darvon-N combined with symptomatic support (see Dosage and Administration: Cessation of Therapy). Use in Pancreatic/Biliary Tract Disease Darvon-N 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 Darvon-N 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 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. Patients should be advised not to adjust the dose of Darvon-N without consulting the prescribing professional. Patients should be advised that Darvon-N may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). Patients should not combine Darvon-N with central nervous system depressants (e.g., sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur. Patients should be instructed not to consume alcoholic beverages, including prescription and over-the-counter medications that contain alcohol, while using Darvon-N because of risk of serious adverse events including death. 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. Patients should be advised that Darvon-N 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. Patients should be advised that if they have been receiving treatment with Darvon-N for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the Darvon-N 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 Darvon-N. 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 Darvon-N. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of Darvon-N 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 Darvon-N 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/m 2 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 Darvon-N is administered to a nursing woman. Pediatric Patients Safety and effectiveness in pediatric patients have not been established. Elderly Patients Clinical studies of Darvon-N 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).

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.

HOW SUPPLIED Darvon-N Tablets are available in: The 100 mg tablets are buff colored, elliptical shaped, film coated, and imprinted with the script “DARVON-N 100” on one side of the tablet, using edible black ink. They are available as follows: Bottles of 100 NDC 66479-512-10 Store at 25°C (77°F); excursions are permitted to 15°- 30°C (59°- 86°F) [see USP Controlled Room Temperature]. Inform patients of the availability of a Medication Guide for Darvon/Darvon-N that accompanies each prescription dispensed. Instruct patients to read the Darvon/Darvon-N Medication Guide prior to using Darvon. Darvon, Darvon-N, Darvocet, and Darvocet-N are registered trademarks of Xanodyne Pharmaceuticals, Inc. © 2009 Xanodyne Pharmaceuticals, Inc. Marketed by: Xanodyne Pharmaceuticals, Inc. Newport, KY 41071 PI-512-A REV. 09-2009

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 μg/mL for propoxyphene and 0.1 to 0.2 μg/mL for norpropoxyphene (major metabolite) are achieved. Repeated doses of propoxyphene at 6 h intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 h. Propoxyphene has a half-life of 6 to 12 h, whereas that of norpropoxyphene is 30 to 36 h. 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 (70-78 years), much longer half-lives of propoxyphene and norpropoxyphene have been reported (propropoxyphene 13 to 35 h, norpropoxyphene 22 to 41 h). In addition, the AUC was an average of 3-fold higher and the Cmax was an average of 2.5-fold higher in the elderly when compared to a younger (20-28 years) population. Longer dosage intervals may be considered in the elderly because the metabolism of propoxyphene may be reduced in this patient population. After multiple oral doses of propoxyphene in elderly patients (70-78 years), the Cmax of the metabolite (norpropoxyphene) was increased 5-fold. Pediatric Patients 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.

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