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

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 hours, 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

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. Propoxyphene 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 preexisting respiratory depression. In such patients, even usual therapeutic doses of propoxyphene 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

Propoxyphene, 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. Propoxyphene may produce orthostatic hypotension in ambulatory patients. Propoxyphene, 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 preexisting 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.

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

1.

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.

2.

Patients should be advised not to adjust the dose of propoxyphene without consulting the prescribing professional.

3.

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).

4.

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.

5.

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.

6.

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.

7.

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.

8.

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.

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

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 breast-feeding 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 Use

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, post-marketing 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).

Controlled Substance

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

Abuse

Since propoxyphene 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.

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 OVERDOSAGE). 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.

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

The severity of the propoxyphene 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.

Symptoms of Propoxyphene Overdosage

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 (hypercapnia) 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 of Propoxyphene Overdosage

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 opioid antagonist naloxone will markedly reduce the degree of respiratory depression, and should be administered promptly, preferably intravenously. 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.

In addition to the use of an opioid antagonist, the patient may require careful titration with an anticonvulsant to control convulsions. 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 or death.

Cessation of Therapy

For patients who used propoxyphene hydrochloride capsules on a regular basis for a period of time, when therapy with propoxyphene hydrochloride capsules is no longer needed for the treatment of their pain, it may be useful to gradually discontinue the propoxyphene hydrochloride capsules 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.

It is not known if propoxyphene hydrochloride capsules are safe and effective in children younger than age 18.

Who should not take propoxyphene hydrochloride capsules?

Do not take propoxyphene hydrochloride capsules 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.

•

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?

Before you take propoxyphene hydrochloride capsules, 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?”

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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 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:

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irritability

•

shaking (tremors)

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jitteriness

•

breathing faster than normal

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crying more than usual

•

diarrhea or more stools than normal

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vomiting

•

fever

•

if you take propoxyphene hydrochloride capsules 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 capsules passes into breast milk.
 

Tell your doctor about all the medicines you take, including prescription, and nonprescription medicines, vitamins and herbal supplements. Propoxyphene hydrochloride capsules 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?”

•

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, antidepressant 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 propoxyphene hydrochloride capsules.

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?

See “What is the most important information I should know about propoxyphene hydrochloride capsules?”

•

Take propoxyphene hydrochloride capsules exactly as prescribed.

•

If you take too much propoxyphene hydrochloride capsules, or take it with alcohol or other medicines, you may overdose. See “What is the most important information I should know about propoxyphene hydrochloride capsules?” You will need medical help right away if you think you have taken an overdose of propoxyphene hydrochloride capsules. A large overdose could cause you to become unconscious and die.

Signs and symptoms of an overdose of propoxyphene hydrochloride capsules 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?

Propoxyphene hydrochloride capsules can cause serious side effects, including:

See “What is the most important information I should know about propoxyphene hydrochloride capsules?”

•

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 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 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 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 affects you.

•

Propoxyphene hydrochloride capsules can cause physical dependence if you take it for more than a few weeks. Do not stop taking propoxyphene hydrochloride capsules 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. You may need to stop propoxyphene hydrochloride capsules more slowly.

Common side effects of propoxyphene hydrochloride capsules include:

•

dizziness

•

feeling sleepy

•

nausea and vomiting

•

constipation

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stomach area (abdominal) pain

•

skin rashes

•

lightheadedness

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headache

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weakness

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feeling of excitement (elation) or discomfort

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seeing, hearing or sensing things that are not really there (hallucinations)

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blurred vision

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 Mylan Pharmaceuticals, Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

How should I store propoxyphene hydrochloride capsules?

•

Store propoxyphene hydrochloride capsules at 20oC to 25oC (68oF to 77oF).

Keep propoxyphene hydrochloride capsules and all medicines out of the reach of children.

General information about propoxyphene hydrochloride capsules

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use propoxyphene hydrochloride capsules  for a purpose for which it was not prescribed. Do not give propoxyphene hydrochloride capsules  to others even if they have the same symptoms you have. It 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  that is written for health professionals. For more information, call Mylan Pharmaceuticals, Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in propoxyphene hydrochloride capsules, USP?

Active ingredient: propoxyphene hydrochloride, USP

Inactive ingredients: anhydrous lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch and sodium lauryl sulfate. The empty hard-shell hypromellose capsule shells contain carnauba wax, carrageenan, hypromellose, potassium chloride, synthetic red iron oxide and titanium dioxide. In addition, the imprinting ink contains black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

OCTOBER 2009
MG:PHCL:R1