Propoxyphene Napsylate and Acetaminophen (propoxyphene napsylate 100 mg acetaminophen 650 mg) Dailymed

Boxed Warning Section

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 and , and for further information). CLINICAL PHARMACOLOGY: Drug Interactions WARNINGS PRECAUTIONS DOSAGE AND ADMINISTRATION

Description

Propoxyphene hydrochloride and acetaminophen tablets, USP contain propoxyphene hydrochloride and acetaminophen.

Propoxyphene napsylate, USP 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 ,1 ) 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. S R -
C H NO •C H O S•H O _{22 29 2 10 8 3 2}
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.

Acetaminophen, USP, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste. The molecular formula for acetaminophen is C H NO and the molecular weight is 151.17. It may be represented by the following structural formula: _{8 9 2}
C H NO      MW 151.17 _{8 9 2}
Each tablet of propoxyphene napsylate and acetaminophen contains 100 mg (176.8 μmol) propoxyphene napsylate and 650 mg (4,300 μmol) of acetaminophen and the following inactive ingredients: D&C Red No. 30 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, sodium lauryl sulfate, sodium starch glycolate and titanium dioxide.

Clinical Pharmacology

Pharmacokinetics

Clinical Studies

The efficacy of propoxyphene in combination with acetaminophen was studied in seven single-dose, randomized, double-blind, placebo-controlled trials in patients with mild to severe postpartum pain. One of the studies demonstrated that both propoxyphene and acetaminophen in the combination contributed to a greater reduction in pain than acetaminophen and propoxyphene alone and that propoxyphene was superior to placebo.

There is insufficient information available to assess efficacy of propoxyphene in combination with acetaminophen in patients with chronic pain.

Indication

Propoxyphene napsylate and acetaminophen tablets are indicated for the relief of mild to moderate pain.

Contraindications

Propoxyphene napsylate and acetaminophen tablets are contraindicated in patients with known hypersensitivity to propoxyphene or acetaminophen.

Propoxyphene napsylate and acetaminophen tablets 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 napsylate and acetaminophen tablets are contraindicated in any patient who has or is suspected of having paralytic ileus.

Warnings

Precautions

Carcinogenesis, Mutagenesis, Impairment of Fertility

The mutagenic and carcinogenic potential of propoxyphene and acetaminophen alone and in combination have 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. Acetaminophen has not been studied in animals for effects on fertility and the effects on human fertility are unknown.

Pregnancy

Nursing Mothers

Propoxyphene, norpropoxyphene (major metabolite) and acetaminophen 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 breast-feeding infants for signs of sedation including poor feeding, somnolence or respiratory depression. Caution should be exercised when propoxyphene napsylate and acetaminophen is administered to a nursing woman.

Pediatric Patients

Safety and effectiveness in pediatric patients have not been established.

Adverse Reactions

During clinical trials, the most frequently reported adverse reactions 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 post-marketing 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 post-marketing surveillance include:

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

eye swelling, vision blurred Eye Disorder:

drug ineffective, drug interaction, drug tolerance, influenza type illness, drug withdrawal syndrome General Disorder and Administration Site Conditions:

gastrointestinal bleed, acute pancreatitis Gastrointestinal Disorder:

hepatic steatosis, hepatomegaly, hepatocellular injury Hepatobiliary Disorder:

hypersensitivity Immune System Disorder:

drug toxicity, hip fracture, multiple drug overdose, narcotic overdose Injury Poisoning and Procedural Complications:

blood pressure decreased, heart rate elevated/abnormal Investigations:

metabolic acidosis Metabolism and Nutrition Disorder:

ataxia, coma, dizziness, somnolence, syncope Nervous System Disorder:

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

respiratory depression, dyspnoea Respiratory, Thoracic and Mediastinal Disorders:

rash, itch Skin and Subcutaneous Tissue Disorder:

Liver dysfunction has been reported in association with both active components of propoxyphene napsylate and acetaminophen tablets. Propoxyphene therapy has been associated with abnormal liver function tests and, more rarely, with instances of reversible jaundice (including cholestatic jaundice). Hepatic necrosis may result from acute overdose of acetaminophen (see ). In chronic ethanol abusers, this has been reported rarely with short-term use of acetaminophen dosages of 2.5 to 10 g/day. Fatalities have occurred. OVERDOSAGE

There have also been post-marketing reports of renal papillary necrosis associated with chronic acetaminophen use, particularly when the dosage is greater than recommended and when combined with aspirin. Subacute painful myopathy has been reported following chronic propoxyphene overdosage.

Drug Abuse And Dependence

Controlled Substance

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

Abuse

Since propoxyphene napsylate and acetaminophen 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 napsylate and acetaminophen.

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 ). 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. OVERDOSAGE

In chronic pain patients, and in opioid-tolerant cancer patients, the administration of propoxyphene napsylate and acetaminophen should be guided by the degree of tolerance manifested and the doses needed to adequately relieve pain.

The severity of the propoxyphene napsylate and acetaminophen 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

Propoxyphene napsylate and acetaminophen tablets are a combination product containing propoxyphene and acetaminophen. Overdose of propoxyphene napsylate and acetaminophen may present with the signs and symptoms of propoxyphene overdose, acetaminophen overdose or both. 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.

Dosage And Administration

Propoxyphene napsylate and acetaminophen tablets 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.

Medication Guide

Read this Medication Guide before you start taking propoxyphene napsylate and acetaminophen tablets 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 napsylate and acetaminophen tablets?

Propoxyphene napsylate and acetaminophen tablets and other medicines that contain propoxyphene can cause serious side effects, including:

Overdoses with propoxyphene napsylate and acetaminophen may happen when it is taken by itself, or with alcohol or other medicines that can also decrease your breathing and make you very sleepy. Overdoses by accident or on purpose (intentional overdose).

• Many of the deaths that happen in people who take propoxyphene napsylate and acetaminophen tablets happen in those who: Death can happen within 1 hour of taking an overdose of propoxyphene napsylate and acetaminophen tablets.
  • 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 napsylate and acetaminophen tablets without talking to your doctor.
• Before taking propoxyphene napsylate and acetaminophen tablets 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 napsylate and acetaminophen tablets exactly as prescribed. Do not change your dose or stop taking propoxyphene napsylate and acetaminophen tablets  without first talking to your doctor.

• If you take propoxyphene napsylate and acetaminophen tablets, do not take more than tablets in one day. 6
• Before taking propoxyphene napsylate and acetaminophen tablets, tell your doctor about all the medicines you take. Propoxyphene napsylate and acetaminophen tablets 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 napsylate and acetaminophen tablets?”
• Do not drink grapefruit juice or eat grapefruit while you are taking propoxyphene napsylate and acetaminophen tablets. Grapefruit juice may interact with propoxyphene napsylate and acetaminophen tablets.
• Do not drink alcohol while using propoxyphene napsylate and acetaminophen tablets. Using alcohol with propoxyphene napsylate and acetaminophen tablets may increase your risk of having dangerous side effects.

What are propoxyphene napsylate and acetaminophen tablets?

• Propoxyphene napsylate and acetaminophen tablets are a prescription medicine that contains two medicines: propoxyphene and acetaminophen. Propoxyphene napsylate and acetaminophen tablets are used to relieve mild to moderate pain.

Boxed Warning section

• Propoxyphene napsylate and acetaminophen tablets are a federally controlled substance (C-IV) because it is a strong opioid pain medicine that can be abused by people who abuse prescription medicines or street drugs.
• Prevent theft, misuse or abuse. Keep propoxyphene napsylate and acetaminophen tablets in a safe place to protect it from being stolen. Propoxyphene napsylate and acetaminophen tablets can be a target for people who misuse or abuse prescription medicines or street drugs.
• Never give propoxyphene napsylate and acetaminophen tablets to anyone else, even if they have the same symptoms that you have. It may harm them or even cause death. Selling or giving away this medicine is against the law.

Propoxy Naps/apap 100/650mg(civ)