Effects on the Central Nervous System

Pentazocine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Pentazocine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Pentazocine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Pentazocine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of pentazocine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing pentazocine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions see Dosage and Administration].

Opioid Antagonist Effects

Pentazocine weakly antagonizes the analgesic effects of morphine, meperidine, and phenazocine; in addition, it produces incomplete reversal of cardiovascular, respiratory, and behavioral depression induced by morphine and meperidine. Pentazocine has about 1/50 the antagonistic activity of nalorphine. It also has sedative activity.

Naloxone when administered orally at 0.5 mg has no pharmacologic activity. Naloxone hydrochloride administered parenterally at the same dose is an antagonist to pentazocine and a pure antagonist to narcotic analgesics.

Pentazocine and Naloxone Tablets are a potent analgesic when administered orally. However, the presence of naloxone in Pentazocine and Naloxone Tablets is intended to prevent the effect of pentazocine if the product is misused by injection.

Studies in animals indicate that the presence of naloxone does not affect pentazocine analgesia when the combination is given orally. If the combination is given by injection the action of pentazocine is neutralized.

Pharmacokinetics

Onset of significant analgesia usually occurs between 15 and 30 minutes after oral administration, and duration of action is usually three hours or longer.

Pentazocine is well absorbed from the gastrointestinal tract. Concentrations in plasma coincide closely with the onset, duration, and intensity of analgesia. The time to mean peak concentration in 24 normal volunteers was 1.7 hours (range 0.5 to 4 hours) after oral administration and the mean plasma elimination half-life was 3.6 hours (range 1.5 to 10 hours).

Pentazocine is metabolized in the liver and excreted primarily in the urine. The products of the oxidation of the terminal methyl groups and glucuronide conjugates are excreted by the kidney. Elimination of approximately 60% of the total dose occurs within 24 hours. Pentazocine passes into the fetal circulation.

Addiction, Abuse, and Misuse

Pentazocine and Naloxone Tablets contain pentazocine, a Schedule IV controlled substance. As an opioid, Pentazocine and Naloxone Tablets expose users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Pentazocine and Naloxone Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Pentazocine and Naloxone Tablets, and monitor all patients receiving Pentazocine and Naloxone Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Pentazocine and Naloxone Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Pentazocine and Naloxone Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Pentazocine and Naloxone Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see PRECAUTIONS; Information for Patients]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

•

Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.

•

Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.

•

Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.

•

Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Pentazocine and Naloxone Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Pentazocine and Naloxone Tablets.

To reduce the risk of respiratory depression, proper dosing and titration of Pentazocine and Naloxone Tablets are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the Pentazocine and Naloxone Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of Pentazocine and Naloxone Tablets, especially by children, can result in respiratory depression and death due to an overdose of pentazocine.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Pentazocine and Naloxone Tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS; Information for Patients, Pregnancy].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Pentazocine and Naloxone Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see PRECAUTIONS, Drug Interactions].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Pentazocine and Naloxone Tablets is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see PRECAUTIONS; Information for Patients, Drug Interactions].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Pentazocine and Naloxone Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: Pentazocine and naloxone-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Pentazocine and Naloxone Tablets [see WARNINGS].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS].

Monitor such patients closely, particularly when initiating and titrating Pentazocine and Naloxone Tablets and when Pentazocine and Naloxone Tablets are given concomitantly with other drugs that depress respiration [see WARNINGS]. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

Pentazocine and Naloxone Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see PRECAUTIONS; Information for Patients]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Pentazocine and Naloxone Tablets. In patients with circulatory shock, Pentazocine and Naloxone Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Pentazocine and Naloxone Tablets in patients with circulatory shock.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Pentazocine and Naloxone Tablets may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Pentazocine and Naloxone Tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Pentazocine and Naloxone Tablets in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

Pentazocine and Naloxone Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The administration of Pentazocine and Naloxone Tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Pentazocine and Naloxone Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Withdrawal

The use of Pentazocine and Naloxone Tablets, a mixed agonist/antagonist opioid analgesic, in patients who are receiving a full opioid agonist analgesic may reduce the analgesic effect and/or precipitate withdrawal symptoms. Avoid concomitant use of Pentazocine and Naloxone Tablets with a full opioid agonist analgesic.

When discontinuing Pentazocine and Naloxone Tablets, gradually taper the dosage (see DOSAGE AND ADMINISTRATION). Do not abruptly discontinue Pentazocine and Naloxone Tablets (see DRUG ABUSE AND DEPENDENCE)

Risks of Driving and Operating Machinery

Pentazocine and Naloxone Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Pentazocine and Naloxone Tablets and know how they will react to the medication.

Acute CNS Manifestations

Patients receiving therapeutic doses of Pentazocine and Naloxone Tablets have experienced hallucinations (usually visual), disorientation, and confusion which have cleared spontaneously within a period of hours. The mechanism of this reaction is not known. Such patients should be very closely observed and vital signs checked. If the drug is reinstituted, it should be done with caution since these acute CNS manifestations may recur.

The amount of naloxone present in Pentazocine and Naloxone Tablets (0.5 mg per tablet) has no action when taken orally and will not interfere with the pharmacologic action of pentazocine. However, this amount of naloxone given by injection has profound antagonistic action to narcotic analgesics.

Severe, even lethal, consequences may result from misuse of tablets by injection either alone or in combination with other substances, such as pulmonary emboli, vascular occlusion, ulceration and abscesses, and withdrawal symptoms in narcotic dependent individuals.

Increased Risk of Seizures in Patients with Seizure Disorders

The pentazocine in Pentazocine and Naloxone Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Pentazocine and Naloxone Tablets therapy.

Risks of Driving and Operating Machinery

Pentazocine and Naloxone Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Pentazocine and Naloxone Tablets and know how they will react to the medication [see Patient Counseling Information].

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse

Inform patients that the use of Pentazocine and Naloxone Tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS]. Instruct patients not to share Pentazocine and Naloxone Tablets with others and to take steps to protect Pentazocine and Naloxone Tablets from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Pentazocine and Naloxone Tablets or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS]. Advise

patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS]. Instruct patients to take steps to store Pentazocine and Naloxone Tablets securely and to dispose of unused Pentazocine and Naloxone Tablets by consulting their pharmacist for proper disposal instructions.

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Pentazocine and Naloxone Tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these drugs concomitantly unless supervised by a healthcare provider [see WARNINGS, PRECAUTIONS; Drug Interactions].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS].

Important Administration Instructions

Instruct patients how to properly take Pentazocine and Naloxone Tablets.

•

Advise patients not to adjust the dose of Pentazocine and Naloxone Tablets without consulting with a physician or other healthcare professional.

•

If patients have been receiving treatment with Pentazocine and Naloxone Tablets for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abruptly discontinuation of the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication. [see DOSAGE AND ADMINISTRATION]

Hypotension

Inform patients that Pentazocine and Naloxone Tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see WARNINGS].

Anaphylaxis

Inform patients that anaphylaxis have been reported with ingredients contained in Pentazocine and Naloxone Tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications, Adverse Reactions].

Pregnancy

 

Neonatal Opioid Withdrawal Syndrome

 

Inform female patients of reproductive potential that prolonged use of Pentazocine and Naloxone Tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS, PRECAUTIONS; Pregnancy]

 

Embryo-Fetal Toxicity

 

Inform female patients of reproductive potential that Pentazocine and Naloxone Tablets can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see PRECAUTIONS; Pregnancy].

Lactation

Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see PRECAUTIONS; Nursing Mothers].

Driving or Operating Heavy Machinery

Inform patients that Pentazocine and Naloxone Tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see PRECAUTIONS].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY).

Disposal of Unused Pentazocine and Naloxone Tablets

Advise patients to properly dispose of unused Pentazocine and Naloxone Tablets. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in accordance with local state guidelines and/or regulations.

Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies have not been completed to evaluate the carcinogenic potential of the combination or individual components of pentazocine and naloxone.

Mutagenesis

Studies to evaluate the mutagenic potential of the components of pentazocine and naloxone have not been conducted.

Impairment of Fertility

Studies in animals to evaluate the impact of pentazocine and naloxone on fertility have not been completed.

The daily administration of 4 mg/kg to 20 mg/kg pentazocine subcutaneously to female rats during a 14 day pre-mating period and until the 13th day of pregnancy did not have any adverse effects on the fertility rate.

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with Pentazocine and Naloxone Tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, pentazocine administered subcutaneously to pregnant hamsters during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 2.6 times the maximum daily dose (MDD). In pregnant rats administered pentazocine:naloxone during organogenesis, there were increased incidences of resorptions and extra ribs at 0.2 times the MDD. There was no evidence of malformations in rats or rabbits [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Pentazocine and Naloxone Tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Pentazocine and Naloxone Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data

In a published report, a single dose of pentazocine administered to pregnant hamsters on Gestation Day 8 increased the incidence of neural tube defects (exencephaly and cranioschisis) at a dose of 196 mg/kg, SC (2.6-times the maximum daily human dose (MDD) of 600 mg/day pentazocine (12 tablets) on a mg/m2 basis). No evidence of neural tube defects were reported following a dose of 98 mg/kg (1.3 times the MDD).

Animal reproduction studies testing the combination of pentazocine and naloxone during organogenesis have been completed in rats and rabbits. In rats, a pentazocine:naloxone dose of 64 mg/kg:0.64 mg/kg via oral gavage from Gestation Day 6 to 15 increased the incidences of resorptions and extra ribs (0.2 times the maximum daily human dose of pentazocine via 12 tablets on a mg/m2 basis). There were no clear treatment related effects in rabbits treated from Gestation Day 6 to 18 with a pentazocine:naloxone dose of up to 64 mg/kg:0.64 mg/kg via oral gavage (0.3-times the maximum daily human dose of pentazocine via 12 tablets on a mg/m2 basis).

Lactation

Risk Summary

Pentazocine is excreted in human milk. Caution should be exercised when Pentazocine and Naloxone Tablets are administered to a nursing woman.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Pentazocine and Naloxone Tablets and any potential adverse effects on the breastfed infant from Pentazocine and Naloxone Tablets or from the underlying maternal condition.

Clinical Considerations

Infants exposed to pentazocine and naloxone through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to Pentazocine and Naloxone Tablets. In general, use caution when selecting a dosage for an elderly patient, 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.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Pentazocine and Naloxone Tablets slowly in geriatric patients [see WARNINGS].

Pentazocine and naltrexone are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Controlled Substance

Pentazocine and Naloxone Tablets contain pentazocine, a Schedule IV controlled substance.

Abuse

Pentazocine and Naloxone Tablets contain pentazocine, a substance with a high potential for abuse similar to other opioids including tramadol. Pentazocine and Naloxone Tablets can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS].

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Pentazocine and Naloxone Tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Pentazocine and Naloxone Tablets

Pentazocine and Naloxone Tablets is for oral use only. Abuse of Pentazocine and Naloxone Tablets poses a risk of overdose and death. The risk is increased with concurrent use of Pentazocine and Naloxone Tablets with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. 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). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Pentazocine and Naloxone Tablets should not be abruptly discontinued in a physically-dependent patient [see DOSAGE AND ADMINISTRATION]. If Pentazocine and Naloxone Tablets are abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and 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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see PRECAUTIONS; Pregnancy].

Important Dosage and Administration Instructions

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS].

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS].

Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Pentazocine and Naloxone Tablets and adjust the dosage accordingly [see WARNINGS].

Initial Dosage

Use of Pentazocine and Naloxone Tablets as the First Opioid Analgesic

Initiate treatment with pentazocine hydrochloride and naloxone hydrochloride tablets, USP in a dosing range of 1 tablet every three to four hours. This may be increased to 2 tablets when needed. Total daily dosage should not exceed 12 tablets.

Conversion from Other Opioids to Pentazocine and Naloxone Tablets

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Pentazocine and Naloxone Tablets. It is safer to underestimate a patient’s 24-hour Pentazocine and Naloxone Tablets dosage than to overestimate the 24-hour Pentazocine and Naloxone Tablets dosage and manage an adverse reaction due to overdose.

Titration and Maintenance of Therapy

Individually titrate Pentazocine and Naloxone Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Pentazocine and Naloxone Tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see WARNINGS]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Pentazocine and Naloxone Tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Discontinuation of Pentazocine and Naloxone Tablets

When a patient who has been taking Pentazocine and Naloxone Tablets regularly and may be physically dependent no longer require therapy with Pentazocine and Naloxone Tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Pentazocine and Naloxone Tablets in a physically-dependent patient [see WARNINGS, DRUG ABUSE AND DEPENDENCE].