Propoxyphene Hydrochloride

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.

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.

PROPOXYPHENE HYDROCHLORIDE INDICATIONS AND USAGE

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

PROPOXYPHENE HYDROCHLORIDE 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.

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.)

• 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 propoxyphene without consulting the prescribing professional.
• 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).
• 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.
• 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.
• 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 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.
• 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).

PROPOXYPHENE HYDROCHLORIDE 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.

PROPOXYPHENE HYDROCHLORIDE 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.

PROPOXYPHENE HYDROCHLORIDE CAPSULES, USP CIV

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.

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:

• 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:

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

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use propoxyphene hydrochloride capsules, USP for a purpose for which they were not prescribed. Do not give propoxyphene hydrochloride capsules, USP to others even if they have the same symptoms you have. They may harm them and is against the law.

This Medication Guide summarizes the most important information about propoxyphene hydrochloride capsules. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about propoxyphene hydrochloride capsules, USP that is written for health professionals. For more information, call 1-888-838-2872, MEDICAL AFFAIRS.

What are the ingredients in propoxyphene hydrochloride capsules, USP?

Active ingredient: propoxyphene hydrochloride

Inactive ingredients: corn starch, gelatin, lactose monohydrate, magnesium stearate, titanium dioxide, FD&C yellow #6, and D&C red #33.

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Iss. 10/2009

Propoxyphene HCL 65mg (CIV) Caps.