Prescription Drugs

CLINICAL PHARMACOLOGY Propoxyphene is a centrally acting narcotic analgesic agent. Equimolar doses of propoxyphene hydrochloride or napsylate provide similar plasma concentrations. Following administration of 65, 130 or 195 mg of propoxyphene hydrochloride, the bioavailability of propoxyphene is equivalent to that of 100, 200, or 300 mg respectively of propoxyphene napsylate. Peak plasma concentrations of propoxyphene are reached in two to two and one-half hours. After a 65 mg oral dose of propoxyphene hydrochloride peak plasma levels of 0.05 to 0.1 mcg/ml are achieved. Repeated doses of propoxyphene at 6-hour intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 hours. Propoxyphene is metabolized in the liver to yield norpropoxyphene. Propoxyphene has a half-life of 6 to 12 hours whereas that of norpropoxyphene is 30 to 36 hours. Norpropoxyphene has substantially less central-nevous-system-depressant effect than propoxyphene but a greater local anesthetic effect, which is similar to that of amitriptyline and antiarrhythmic agents, such as lidocaine and quinidine. In animal studies in which propoxyphene and norpropoxyphene were continuously infused in large amounts, intracardiac conduction time (P-R and QRS intervals) was prolonged. Any intracardiac conduction delay attributable to high concentrations of norpropoxyphene may be of relatively long duration. Actions Propoxyphene is a mild narcotic analgesic structurally related to methadone. The potency of propoxyphene hydrochloride is from two-thirds to equal that of codeine. The combination of propoxyphene with a mixture of aspirin and caffeine produces greater analgesia than that produced by either propoxyphene, aspirin, and caffeine administered alone.

DESCRIPTION PROPOXYPHENE COMPOUND 65 mg CAPSULES (Propoxyphene Hydrochloride, Aspirin, and Caffeine Capsules,USP) Propoxyphene hydrochloride is an odorless, white crystalline powder with a bitter taste. It is freely soluble in water. Chemically, it is alpha (+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl-2-butanol Propionate Hydrochloride. Each Pulvule¨ contains 65 mg (172.9 µmol) propoxyphene hydrochloride, 389 mg (2,159 µmol) aspirin, and 32.4 mg (166.8 µmol) caffeine. It also contains F D & C Red No. 3, F D & C Yellow No. 6, gelatin, glutamic acid hydrochloride, iron oxide, kaolin, silicone, titanium dioxide, and other inactive ingredients.

INDICATIONS This product is indicated for the relief of mild to moderate pain, either when pain is present alone or when it is accompanied by fever. DOSAGE AND ADMINISTRATION This product is given orally. The usual dosage is 65 mg propoxyphene hydrochloride, 389 mg aspirin and 32.4 mg caffeine (one capsule) every 4 hours as needed for pain. The maximum recommended dose of propoxyphene hydrochloride is 390 mg per day. Consideration should be given to a reduced total daily dosage in patients with hepatic or renal impairment. HOW SUPPLIED Darvon® Compound 65 Pulvules® are available in: The 65 mg parabolic-shaped capsules are imprinted with the script "Darvon Comp 65" on the opaque red body in axial print, using edible black ink. There are available as follows: Bottles of 100 NDC 66591-612-41 Bottles of 500 NDC 66591-612-51 Store at controlled room temperature 15°-30°C (59°-86°F). Dispense with child-resistant closure (as required) and in a tight, light-resistant container as defined in the USP CAUTION: Federal law prohibits dispensing without prescription. Darvon, Darvon-N, Darvocet-N are registered trademarks of aaiPharma LLC. Darvocet is a trademark of aaiPharma Inc. © 2003 aaiPharma LLC Manufactured by: AAI Development Services An aaiPharma¨ Company 1726 North 23rd St. Wilmington, NC 28405 Manufactured for: aaiPharama® Wilmington, NC 28405

PATIENT INFORMATION Products containing propoxyphene are used to relieve pain. LIMIT YOUR INTAKE OF ALCOHOL WHILE TAKING THIS DRUG. Make sure your doctor knows if you are taking tranquilizers sleep aids, anti-depressants, antihistamines or any other drugs that make you sleepy. Combining propoxyphene with alcohol or these drugs in excessive doses is dangerous. Use care while driving a car or using machines until you see how the drug affects you because propoxyphene can make you sleepy. Do not take more of the drug than your doctor prescribed. Dependence has occurred when patients have taken propoxyphene for a long period of time at doses greater than recommended. The rest of this leaflet gives you more information about propoxyphene. Please read it and keep it for future use. Uses of Propoxyphene Products containing propoxyphene are used for the relief of mild to moderate pain. Products that contain propoxyphene plus aspirin or acetaminophen are prescribed for the relief of pain or pain associated with fever. Before Taking Propoxyphene Make sure your doctor knows if you have ever had an allergic reaction to propoxyphene, aspirin or acetaminophen. Some forms of propoxyphene products contain aspirin to help relieve the pain. Your doctor should be advised if you have a history of ulcers or if you are taking an anticoagulant (''blood thinner"). The aspirin may irritate the stomach lining and may cause bleeding particularly if an ulcer is present. Also bleeding may occur if you are taking an anticoagulant. In a small group of people aspirin may cause an asthma attack. If you are one of these people be sure your drug does not contain aspirin. The effect of propoxyphene in children under 12 has not been studied. Therefore use of the drug in this age group is not recommended. Also due to the possible association between aspirin and Reyes Syndrome, those propoxyphene products containing aspirin should not be given to children including teenagers, with chicken pox or flu unless prescribed by a physician. The following propoxyphene product contains aspirin: Propoxyphene Compound 65 mg Capsules (Propoxyphene Hydrochloride, Aspirin, and Caffeine, USP). How to Take Propoxyphene Follow your doctor's directions exactly. Do not increase the amount you take without your doctor's approval. If you miss a dose of the drug do not take twice as much the next time. Pregnancy Do not take propoxyphene during pregnancy unless your doctor knows you are pregnant and specifically recommends its use. Cases of temporary dependence in the new-born have occurred when the mother has taken propoxyphene consistently in the weeks before delivery. IT IS ESPECIALLY IMPORTANT NOT TO USE DARVON COMPOUND (propoxyphene, aspirin, and caffeine) -65 DURING THE LAST 3 MONTHS OF PREGNANCY UNLESS SPECIFICALLY DIRECTED TO DO SO BY A DOCTOR BECAUSE ASPIRIN MAY CAUSE PROBLEMS IN THE UNBORN CHILD OR COMPLICATIONS DURING DELIVERY. As a general principle, no drug should be taken during pregnancy unless it is clearly necessary. General Cautions Heavy use of alcohol with propoxyphene is hazardous and may lead to overdosage symptoms (see Overdose below). THEREFORE LIMIT YOUR INTAKE OF ALCOHOL WHILE TAKING PROPOXYPHENE. Combinations of excessive doses of propoxyphene, alcohol, and tranquilizers are dangerous. Make sure your doctor knows if you are taking tranquilizers, sleep aids, antidepressant drugs, antihistamines, or any other drugs that make YOU Sleepy. The use of these drugs with propoxyphene increases their sedative effects and may lead to Overdosage symptoms, including death (see Overdose below) Propoxyphene may cause drowsiness or impair your mental and/or physical abilities; therefore, use caution when driving a vehicle. Do NOT perform any hazardous task until you have seen your response to this drug. Propoxyphene may increase the concentration in the body of Medications such as anticoagulants ("blood thinners"), antidepressants, or drugs used for epilepsy. The result may be excessive or adverse effects of these medications. Make sure your doctor knows if you are taking any of these medications. Dependence You can become dependent on propoxyphene if you take it in higher than recommended doses over a long period of time. Dependence is a feeling of need for the drug and a feeling that you cannot perform normally without it. Overdose An overdose of propoxyphene, alone or in combination with other drugs, including alcohol, may cause weakness, difficulty in breathing, confusion, anxiety, and more severe drowsiness and dizziness. Extreme overdosage may lead to unconsciousness and death. If the propoxyphene product contains acetaminophen, the overdosage symptoms include nausea vomiting, lack of appetite and abdominal pain. Liver damage; may occur. When the propoxyphene product contains aspirin, symptoms of taking too much of the drug are headache, dizziness, ringing in the ears, difficulty in hearing, dim vision, confusion, drowsiness, sweating, thirst, rapid breathing, nausea, vomiting, and occasionally, diarrhea. In any suspected overdosage situation contact your doctor or nearest hospital emergency room. GET EMERGENCY HELP IMMEDIATELY. KEEP THIS DRUG AND ALL DRUGS OUT OF THE REACH OF CHILDREN. Possible Side Effects When propoxyphene is taken as directed, side effects are infrequent. Among those reported are drowsiness, dizziness, nausea, and vomiting. If these effects occur it may help if you lie down and rest. Less frequently reported side effects are constipation, abdominal pain, skin rashes, lightheadedness, headache, weakness, hallucinations, minor visual disturbances, and feelings of elation or discomfort. If side effects occur and concern you, contact your doctor. Other INFORMATION The safe and effective use of propoxyphene depends on your taking it exactly as directed. This drug has been prescribed specifically for you and your present condition. Do not give this drug to others who may have similar symptoms. Do not use it for any other reason. If you would like more information about propoxyphene, ask your doctor or pharmacist. They have a more technical leaflet (professional labeling) you may read.

OVERDOSE In all cases of suspected over-dosage, 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 OVERDOSE 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 (hypercapnea) 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 at Propoxyphene OVERDOSE Attention should be directed first to establishing a patent airway and to restoring ventilation. Mechanically assisted ventilation with or without oxygen may be required, and positive pressure respiration may be desirable if pulmonary edema is present. The narcotic antagonist naloxone will markedly reduce the degree of respiratory depression, and 0.4 mg to 2 mg should be administered promptly, preferably intravenously. If the desired degree of counteraction with improvement in respiratory functions is not obtained, naloxone should be repeated at 2 to 3-minute intervals. The duration of action of the antagonist may be brief. If no response is observed after 10 mg of naloxone have been administered, the diagnosis of propoxyphene toxicity should be questioned. Naloxone may also be administered by continuous intravenous infusion. Treatment of Propoxyphene Overdosage in Pediatric Patients The usual initial dose of naloxone in children is 0.01 mg/kg body weight given intravenously. If this dose does not result in the desired degree of clinical improvement, a subsequent increased dose of 0.1 mg/kg body weight may be administered. If an IV route of administration is not available naloxone may be administered IM or subcutaneously in divided doses. If necessary, naloxone can be diluted with sterile water for injection. Blood gases, pH, and electrolytes should be monitored in order that acidosis and any electrolyte disturbance present may be corrected promptly. Acidosis, hypoxia, and generalized CNS depression predispose to the development of cardiac arrhythmias. Ventricular fibrillation or cardiac arrest may occur and necessitate the full complement of cardiopulmonary resuscitation (CPR) measures. Respiratory acidosis rapidly subsides as ventilation is restored and hypercapnea eliminated, but lactic acidosis may require intravenous bicarbonate for prompt correction. Electrocardiographic monitoring is essential. Prompt correction of hypoxia, acidosis and electrolyte disturbance (when present) will help prevent these cardiac complications and will increase the effectiveness of agents administered to restore normal cardiac function. In addition to the use of a narcotic antagonist the patient may require careful titration with an anticonvulsant to control convulsions. Analeptic drugs (for example, caffeine or amphetamine) should not be used because of their tendency to precipitate convulsions. General supportive measures in addition to oxygen include, when necessary, intravenous fluids, vasopressor-inotropic compounds and when infection is likely anti-infective agents. Gastric lavage may be useful and 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. Symptoms of Salicylate OVERDOSE Such symptoms include central nausea and vomiting tinnitus and deafness, vertigo and headaches, mental dullness and confusion, diaphoresis, rapid pulse and increased respiration and respiratory alkalosis. Treatment of Salicylate OVERDOSE When propoxyphene with aspirin and caffeine has been ingested the clinical picture may be complicated by salicylism. The treatment of acute salicylate intoxication includes minimizing drug absorption, promoting elimination through the kidneys, and correcting metabolic derangements affecting body temperature, hydration, acid-base balance, and electrolyte balance. The technique to be employed for eliminating salicylate from the bloodstream depends on the degree of drug intoxication. If the patient is seen within 4 hours of ingestion the stomach should be emptied by inducing vomiting or by gastric lavage as soon as possible. The nomogram of Done is a useful prognostic guide in which the expected severity of salicylate intoxication is based on serum salicylate levels and the time interval between ingestion and taking the blood sample. Exchange transfusion is most feasible for a small infant. Intermittent peritoneal dialysis is useful for cases of moderate severity in adults. Intravenous fluids alkalinized by the addition of sodium bicarbonate or potassium citrate are helpful. Hemodialysis with the artificial kidney is the most effective means of removing salicylate and is indicated for the very severe cases of salicylate intoxication. CONTRAINDICATIONS Hypersensitivity to propoxyphene, aspirin, or caffeine.

SIDE EFFECTS In a survey conducted in hospitalized patients less than 1% of patients taking propoxyphene hydrochloride at recommended doses experienced side effects. The most frequently reported were dizziness, sedation, nausea and vomiting. Some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include constipation, abdominal pain, skin rashes, lightheadedness, headache, weakness, euphoria, dysphoria hallucinations, and minor visual disturbances. Propoxyphene therapy has been associated with abnormal liver function tests and more rarely with instances of reversible jaundice (including cholestatic jaundice). Renal papillary necrosis may result from chronic aspirin use, particularly when the dosage is greater than recommended and when combined with acetaminophen. Subacute painful myopathy has occurred following chronic propoxyphene overdosage. DRUG INTERACTIONS The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol. Salicylates may enhance the effect of anticoagulants and inhibit the uric-casework effect of uricosuric agents. As is the case with many medicinal agents propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on antidepressants, anticonvulsants, or warfarin-like drugs. Severe neurologic signs, including coma have occurred with concurrent use of carbamazepine.

WARNINGS Do not prescribe propoxyphene for patients who are suicidal or addiction-prone. Prescribe propoxyphene with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcohol in excess. Tell your patients not to exceed the recommended dose and to limit their intake of alcohol. Propoxyphene products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. In a survey of deaths due to overdosage conducted in 1975, in approximately 20% of the fatal cases, death occurred within the first hour (5% occurred within 15 minutes). Propoxyphene should not be taken in doses higher than those recommended by the physician. The judicious prescribing of propoxyphene is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of propoxyphene products and alcohol because of potentially serious CNS-additive effects of these agents. 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. Patients should be advised of the additive depressant effects of these combinations. Many of the propoxyphene-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of propoxyphene alone or in combination with other drugs. Patients taking propoxyphene should be warned not to exceed the dosage recommended by the physician. Drug Dependence Propoxyphene, when taken in higher-than-recommended doses over long periods of time, can produce drug dependence characterized by psychic dependence and, less frequently, physical dependence and tolerance. Propoxyphene will only partially suppress the withdrawal syndrome in individuals physically dependent on morphine or other narcotics. The abuse liability of propoxyphene is qualitatively similar to that of codeine although quantitatively less, and propoxyphene should be prescribed with the same degree of caution appropriate to the use of codeine. 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. Warning: Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease. PRECAUTIONS General Salicylates should be used with extreme caution in the presence of peptic ulcer or coagulation abnormalities. Propoxyphene should be administered with caution to patients with hepatic or renal impairment since higher serum concentrations or delayed elimination may occur. Usage In Pregnancy Safe use in pregnancy has not been established relative to possible adverse effects on fetal development. Instances of withdrawal symptoms in the neonate have been reported following usage during pregnancy. Therefore, propoxyphene should not be used in pregnant women unless in the judgment of the physician the potential benefits outweigh the possible hazards. Aspirin does not appear to have teratogenic effects. However, prolonged pregnancy and labor with increased bleeding before and after delivery, decreased birth weight, and increased rate of stillbirth were reported with high blood salicylate levels. Because of possible adverse effects on the neonate and the potential for increased maternal blood loss, aspirin should be avoided during the last 3 months of pregnancy. Usage In Nursing Mothers Low levels of propoxyphene have been detected in human milk. In postpartum studies involving nursing mothers who were given propoxyphene no adverse effects were noted in infants receiving mother's milk. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Usage in the Elderly The rate of propoxyphene metabolism may be reduced in some patients. Increased dosing interval should be considered.