BOXED WARNING SECTION.
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DE PRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME ; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse Pentazocine and Naloxone Tablets expose s patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patients risk prior to prescribing Pentazocine and Naloxone Tablets , and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS ]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Pentazocine and Naloxone Tablets . Monitor for respiratory depression, especially during initiation of Pentazocine and Naloxone Tablets or following a dose increase [see WARNINGS ]. Accidental Ingestion Accidental ingestion of Pentazocine and Naloxone Tablets , especially by children, can result in a fatal overdose of P entazocine [see WARNINGS ]. Neonatal Opioid Withdrawal Syndrome 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, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see WARNINGS ]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see WARNINGS , PRECAUTIONS; Drug Interactions ]. Reserve concomitant prescribing of Pentazocine and Naloxone Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.
Principal Display Panel NDC 43063-142-20 CIV Pentazocine and Naloxone Tablets, USP 50 mg*/0.5 mg* 20 Tablets Rx Only
ADVERSE REACTIONS SECTION.
ADVERSE REACTIONS The following adverse reactions associated with theuseofpentazocine and naltrexonewere identified in clinical studies orpostmarketingreports. Becausesomeofthese reactions were reported voluntarilyfrom apopulation ofuncertain size, it is not always possibleto reliably estimatetheir frequencyor establish a causal relationship to drugexposure. Cardiovascular - Hypertension, hypotension, circulatory depression, tachycardia, syncope. Respiratory - Rarely, respiratory depression. Acute CNS Manifestations - Hallucinations (usually visual), disorientation, and confusion. Other CNS Effects - Grand mal convulsions, increase in intracranial pressure, dizziness, lightheadedness, hallucinations, sedation, euphoria, headache, confusion, disorientation; infrequently weakness, disturbed dreams, insomnia, syncope, and depression; and rarely tremor, irritability, excitement, tinnitus. Autonomic -Sweating; infrequently flushing; and rarely chills. Gastrointestinal -Nausea, vomiting, constipation, diarrhea, anorexia, dry mouth, biliary tract spasm, and rarely abdominal distress. Allergic -Edema of the face; anaphylactic shock; dermatitis, including pruritus; flushed skin, including plethora; infrequently rash, and rarely urticaria. Ophthalmic -Visual blurring and focusing difficulty, miosis. Hematologic -Depression of white blood cells (especially granulocytes), with rare cases of agranulocytosis, which is usually reversible, moderate transient eosinophilia. Dependence and Withdrawal Symptoms -(See WARNINGS , PRECAUTIONS , and DRUG ABUSE AND DEPENDENCE Sections). Other -Urinary retention, paresthesia, serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome toxic epidermal necrolysis, and alterations in rate or strength of uterine contractions during labor. S er otonin s y nd r om e: Cases ofserotonin syndrome, apotentiallylife-threatening condition, havebeenreported duringconcomitantuseofopioids with serotonergicdrugs. Ad re n a l insu ff i c i e n c y: Cases of adrenal insufficiencyhavebeen reportedwith opioid use, moreoften following greaterthan onemonth ofuse. An a p h y l a x is: Anaphylaxis has been reported withingredients contained inPentazocine and NaloxoneTablets. And r o g e n d e f i c i e n cy: Cases of androgen deficiencyhaveoccurred with chronicuseof opioids[see Clinical Pharmacology].
INDICATIONS & USAGE SECTION.
INDICATIONS AND USAGE Pentazocine and NaloxoneTablets are indicated for the management of painsevere enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses, reserve Pentazocine and Naloxone Tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics] Have not been tolerated, or are not expected to be tolerated, Have not provided adequate analgesia, or are not expected to provide adequate analgesia.
DRUG ABUSE AND DEPENDENCE SECTION.
DRUG ABUSE AND DEPENDENCE 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 includingtramadol. Pentazocine and Naloxone Tabletscan 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 NaloxoneTablets is fororal useonly. AbuseofPentazocine and Naloxone Tablets poses a risk ofoverdose and death. Therisk is increased with concurrent useof Pentazocine and NaloxoneTablets with alcohol and other central nervous system depressants. Parenteral drugabuseiscommonlyassociated with transmission ofinfectious 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 Tabletsshould not be abruptly discontinued in aphysically-dependent patient [see DOSAGE AND ADMINISTRATION ] . If Pentazocine and Naloxone Tabletsare 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 ].
DOSAGE & ADMINISTRATION SECTION.
DOSAGE AND ADMINISTRATION Important Dosage and Administration Instructions Usethelowest effectivedosage fortheshortest duration consistent with individual patient treatmentgoals [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 Tabletsand adjust the dosage accordingly [see WARNINGS ]. Initial Dosage Use of P e nt a z o c ine a nd N a lo x one T a bl e ts a s the F i r st Opioid An a l g e sic Initiatetreatment with Pentazocine and NaloxoneTabletsin a dosingrangeof1 tableteverythreeto fourhours.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 patients 24-hour Pentazocine and NaloxoneTabletsdosage than to overestimate the 24-hour Pentazocine and Naloxone Tabletsdosage and manage an adverse reaction due to overdose. Titration and Maintenance of Therapy Individually titrate Pentazocine and Naloxone Tabletsto a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Pentazocine and NaloxoneTabletsto 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 Tabletsregularly and may be physically dependent no longer require therapy with Pentazocine and Naloxone Tablets, taperthe dosegradually, by25%to 50% every2 to 4 days,whilemonitoringcarefullyforsignsand symptoms ofwithdrawal.Ifthepatient develops thesesigns orsymptoms, raisethedoseto the previous level and tapermoreslowly,eitherbyincreasingtheinterval between decreases, decreasingthe amount ofchangein dose, orboth. Do not abruptlydiscontinuePentazocine and NaloxoneTablets in aphysically-dependent patient [see WARNINGS , DRUG ABUSE AND DEPENDENCE ].
SPL UNCLASSIFIED SECTION.
Pentazocine and Naloxone Tablets , USP CIV Revised: December 2016 Analgesic for Oral Use Only
HOW SUPPLIED SECTION.
HOW SUPPLIED Pentazocine and Naloxone Tablets, USP are light green, scored, capsule shaped tablets debossed 395 to the left of the score, 50 over 0.5 to the right of the score and WATSON on the reverse side supplied in bottles of 100. Bottles of 20..NDC 43063-142-20 Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.
DESCRIPTION Pentazocine and Naloxone Tablets, USP contain pentazocine hydrochloride, USP, apartial opioid agonist, equivalent to 50 mg base and is a member of the benzazocine series (also known as the benzomorphan series), and naloxone hydrochloride, USP, an opioid antagonist equivalent to 0.5 mg base. Pentazocine and Naloxone Tablets, USPare an analgesic for oral administration. Chemically, pentazocine hydrochloride, USP is (2 R*,6 R*,11 R*)-1,2,3,4,5,6-Hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride, a white, crystalline substance soluble in acidic aqueous solutions, and has the following structural formula: C 19H 27NOHCl Molecular Weight: 321.88 Chemically, naloxone hydrochloride, USP is Morphinan-6-one,4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-, hydrochloride, (5)-. It is a slightly off-white powder, and is soluble in water and dilute acids, and has the following structural formula: C 19H 21NO 4HCl Molecular Weight: 363.84 Inactive Ingredients: colloidal silicon dioxide, dibasic calcium phosphate, D&C Yellow No. 10 Al-lake, FD&C Blue No. 1 Al-lake, FD&C Yellow No. 6 Al-lake, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium lauryl sulfate.
OVERDOSAGE Clinical Presentation Acute overdose with Pentazocine and Naloxone Tabletscan be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Forpentazocinealoneinsingledosesabove60 mgtherehavebeenreportsoftheoccurrenceof nalorphine-likepsychotomimetic effects such as anxiety, nightmares, strangethoughts, and hallucinations. Somnolence, marked respiratorydepression associatedwith hypertension and tachycardiahave also resulted as haveseizures, hypotension, dizziness, nausea, vomiting, lethargy, and paresthesias. The respiratorydepression is antagonized bynaloxone (see Treatment ). Circulatoryfailure and deepeningcomamayoccurin moreseverecases, particularly in patients who have alsoingested otherCNSdepressants such as alcohol, sedative/hypnotics, or antihistamines. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to pentazocine overdose, administer an opioid antagonist. As pentazocineis amixed opioid agonist/antagonist, largerdoses ofnaloxoneornalmefenemaybeneeded to reversethe effects of an overdose. Opioid antagonists should not be administered in the absenceofclinicallysignificantrespiratory or circulatorydepression secondaryto pentazocineoverdose. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
PRECAUTIONS Porphyria Particular caution should be exercised in administering pentazocine to patients with porphyria since it may provoke an acute attack in susceptible individuals. Cardiovascular Disease Pentazocine can elevate blood pressure, possibly through the release of endogenous catecholamines. Particular caution should be exercised in conditions where alterations in vascular resistance and blood pressure might be particularly undesirable, such as in the acute phase of myocardial infarction. Pentazocine and Naloxone Tabletsshould be used with caution in patients with myocardial infarction who have nausea or vomiting. Imp aired Renal or Hepatic Function Decreased metabolism of pentazocine by the liver in extensive liver disease may predispose to accentuation of side effects. Although laboratory tests have not indicated that pentazocine causes or increases renal or hepatic impairment, the drug should be administered with caution to patients with such impairment. Biliary Surge ry Narcotic drug products are generally considered to elevate biliary tract pressure for varying periods following their administration. Some evidence suggests that pentazocine may differ from other marketed narcotics in this respect (i.e., it causes little or no elevation in biliary tract pressures). The clinical significance of these findings, however, is not yet known. Information for Patients Advisethepatient 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 Tabletswith others and to take steps to protect Pentazocine and Naloxone Tabletsfrom 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 Tabletsor 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 Tabletssecurely and to dispose of unused Pentazocine and Naloxone Tabletsby consulting their pharmacist for proper disposal instructions. Interaction s with Benzodiazepine s and Other CNS Depressants Informpatientsandcaregiversthatpotentiallyfataladditiveeffectsmayoccurif Pentazocine and Naloxone Tabletsareused withbenzodiazepinesor otherCNS depressants,includingalcohol,and nottouse thesedrugs concomitantlyunless supervisedby ahealthcareprovider[see WARNINGS , PRECAUTIONS;DrugInteractions ]. 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 healthcareproviderif 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 ]. I mpo r t a nt Administ ra tion I nst r u c tions Instruct patients how to properlytakePentazocineand NaloxoneTablets. Advisepatients not to adjust thedoseofPentazocine and NaloxoneTabletswithout consultingwith aphysician orotherhealthcareprofessional. Ifpatients havebeenreceivingtreatment with Pentazocine and NaloxoneTablets formore than a fewweeksand cessation oftherapyis indicated, counsel them on theimportanceof safelytaperingthedoseasabruptlydiscontinuation ofthemedication couldprecipitate withdrawal symptoms. Provideadosescheduletoaccomplish agradual discontinuation of themedication. [see DOSAGEAND ADMINISTRATION ] H y pot e nsion Inform patients that Pentazocine and NaloxoneTablets maycauseorthostatichypotensionand syncope. Instruct patients how to recognizesymptoms oflow blood pressure and how to reduce the risk ofserious consequences should hypotension occur(e.g., sit orliedown, carefullyrise from asittingorlyingposition)[see WARNINGS ]. An a p h y l a x is Inform patients that anaphylaxis havebeen reported with ingredients contained in Pentazocine and NaloxoneTablets. Advisepatients how to recognizesucha reaction and when to seek medical attention [see CONTRAINDICATIONS , ADVERSEREACTIONS ]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform femalepatients ofreproductivepotential that prolonged use of Pentazocine and Naloxone Tabletsduring 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 Tabletscan cause fetal harm and to inform the healthcareproviderof 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]. D r iving or Op e r a ting H e a v y M ac hin e r y Inform patients that Pentazocine and NaloxoneTablets mayimpairtheabilityto perform potentiallyhazardousactivities such as drivinga caroroperatingheavymachinery. Advise patients not to perform such tasks until theyknowhow theywill react to themedication [see PRECAUTIONS ]. C onstip a tion Advisepatients ofthepotential forsevere constipation, includingmanagement instructions and when to seek medical attention [see ADVERSEREACTIONS , CLINICAL PHARMACOLOGY ]. Disposal of Unused Pentazocine and Naloxone Tablets Advisepatients to properlydisposeofunused Pentazocine and NaloxoneTablets. Advise patients to throw thedrugin thehousehold trash followingthesesteps. 1)Removethem from theiroriginal containersand mixthem with an undesirablesubstance, suchas used coffee grounds orkittylitter (this makes thedrugless appealingtochildren and pets, and unrecognizableto peoplewho mayintentionallygo through thetrash seekingdrugs). 2)Placethe mixturein asealablebag, emptycan, orother containerto prevent thedrug from leakingor breakingout ofagarbagebag, orto disposeofin accordancewith local stateguidelines and/or regulations. Drug Interactions Benzodiazepine s and Other Centra l Nervous Syste m (CNS) Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserveconcomitantprescribingof thesedrugs for use inpatientsfor whom alternativetreatment optionsareinadequate.Limitdosages anddurationstotheminimumrequired.Followpatients closelyforsigns of respiratorydepressionandsedation[see WARNINGS ] . Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT 3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome. [see PRECAUTIONS; Information for Patients ]. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Pentazocine and Naloxone Tabletsif serotonin syndrome is suspected. Monoa mine Oxidase Inhibitors (MAOIs) Concomitant use of monoamine oxidase inhibitors (MAOIs) with Pentazocine and Naloxone Tabletsmay cause CNS excitation and hypertension through their respective effects on catecholamines. Caution should therefore be observed in administering Pentazocine and Naloxone Tabletsto patients who are currently receiving MAOIs or who have received them within the preceding 14 days Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics such as butorphanol,nalbuphine, pentazocine,buprenorphine, mayreducethe analgesiceffect ofPentazocine and NaloxoneTablets and/orprecipitatewithdrawal symptoms. Avoid concomitant useofthesedrugs. Muscle Relaxants TheConcomitant useofopioids and muscle relaxants mayenhancetheneuromuscularblocking action ofskeletal musclerelaxants and produceanincreased degreeofrespiratorydepression. Monitorpatients forsigns of respiratorydepression that maybegreaterthan otherwise expected and decreasethedosageofPentazocine and NaloxoneTablets and/orthemuscle relaxant as necessary. Diuretics Opioids can reducetheefficacyofdiuretics byinducingthereleaseofantidiuretichormone. Monitorpatients forsigns ofdiminished diuresisand/oreffectson bloodpressure andincreasethe dosageofthediuretic asneeded. Anticholinergic Drugs The concomitant useofanticholinergicdrugs mayincrease risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitorpatients forsigns ofurinaryretentionorreduced gastricmotilitywhenPentazocine and NaloxoneTablets is used concomitantlywith anticholinergicdrugs. Tobacco Smoking tobacco could enhance the metabolic clearance rate of pentazocine reducing the clinical effectiveness of a standard dose of pentazocine. Carcinogenesis, Mutagenesis, Impa irment of Fertility Carcinogenesis Long-term animal studies havenot beencompleted to evaluatethecarcinogenicpotential ofthe combination orindividual components of Pentazocine and Naloxone Tablets. Mutagenesis Studies to evaluate the mutagenic potential of the components of Pentazocine and Naloxone Tablets have not been conducted. Impairment ofFertility Studies in animals to evaluatetheimpact ofPentazocine and Naloxone Tablets on fertilityhavenot been completed. Thedailyadministration of4 mg/kgto 20 mg/kgpentazocinesubcutaneouslyto femalerats duringa14 daypre-matingperiod and until the13th dayofpregnancydidnot have anyadverse effects on the fertilityrate. Pregnancy Risk Summary Prolonged useofopioid analgesics duringpregnancycancauseneonatal opioid withdrawal syndrome[see WARNINGS ]. Therearenoavailabledatawith Pentazocine and NaloxoneTablets in pregnant women to inform adrug-associated riskformajorbirth defects and miscarriage. Inanimal reproduction studies, pentazocine administeredsubcutaneouslyto pregnant hamsters during the early gestational period produced neural tubedefects (i.e., exencephalyandcranioschisis) at 2.6 times themaximum dailydose (MDD). In pregnant rats administered pentazocine:naloxoneduringorganogenesis, therewereincreased incidences of resorptions and extra ribsat 0.2 times theMDD. Therewas no evidenceofmalformations in rats or rabbits [ s e e Data ]. Based on animal data, advisepregnant women ofthepotential risk to a fetus. The estimated backgroundrisk ofmajorbirth defects and miscarriage fortheindicated population is unknown. All pregnancies haveabackground risk ofbirth defect, loss, orother adverseoutcomes. In theU.S. general population,the estimated background risk ofmajorbirth defectsand miscarriagein clinicallyrecognized pregnancies is 2 to 4% and 15 to 20%, respectively. C lini ca l C onsid era tions F e tal/ N e onatal Ad ve rse R e a c tions Prolonged useofopioid analgesics duringpregnancyformedical ornonmedical purposescan result in physical dependencein theneonate and neonatal opioid withdrawal syndromeshortly afterbirth. Neonatal opioid withdrawal syndromepresents as irritability, hyperactivityandabnormal sleep pattern, high pitched cry,tremor, vomiting, diarrhea and failuretogain weight. Theonset, duration, and severityofneonatal opioid withdrawal syndromevarybased on thespecificopioid used, duration ofuse, timingandamount oflast maternal use,and rateof elimination ofthedrug bythenewborn. Observenewborns forsymptomsofneonatal opioid withdrawal syndromeand manageaccordingly[see WARNINGS ]. Labor or Delivery Opioids cross theplacenta and mayproducerespiratorydepression and psycho-physiologiceffects in neonates. An opioid antagonist, such asnaloxone, must be available for reversal of opioid-induced respiratorydepression in theneonate. Pentazocine and NaloxoneTablets arenot recommendedforuseinpregnant women during orimmediatelypriorto labor, when other analgesictechniques aremore appropriate. Opioidanalgesics, includingPentazocine and NaloxoneTablets, can prolonglaborthroughactions which temporarilyreducethestrength, duration, and frequencyofuterine contractions. However, this effect is not consistent and maybe offset byan increased rateof cervical dilation, which tends to shorten labor. Monitorneonates exposed to opioid analgesics duringlabor forsigns of excess sedation and respiratorydepression. 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/m 2 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/m 2 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/m 2 basis). Lactation R isk S umm a r y Pentazocineis excreted in human milk. Caution should be exercised whenPentazocine andNaloxone Tablets are administered to a nursing woman. Thedevelopmentaland health benefits ofbreastfeedingshould beconsidered alongwith the mothers clinical need forPentazocine and NaloxoneTablets andanypotential adverseeffects on thebreastfed infant from Pentazocine and NaloxoneTablets or from theunderlyingmaternal condition. C lini ca l C onsid era tions Infants exposed to pentazocine and naloxonethrough breast milk should bemonitored for excess sedation and respiratorydepression. Withdrawal symptoms can occurin breastfed infants when maternal administrationof an opioid analgesicisstopped, orwhen breast-feedingis 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 NaloxoneTablets. 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 Tabletsslowly in geriatric patients [see WARNINGS ]. Pentazocine and naltrexone areknown to besubstantiallyexcreted bythekidney,and the risk of adversereactions to this drugmaybegreaterin patients with impaired renal function. Because elderlypatients aremorelikelyto havedecreased renal function, careshould betaken in dose selection, and it maybeuseful to monitor renal function
SPL MEDGUIDE SECTION.
Medication Guide Pentazocine and Naloxone ( pen taz oh seen and nal ox one ) T ablets, USP CIV Pentazocine and Naloxone Tablets are: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage moderate to severe pain, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about Pentazocine and Naloxone Tablets : Get emergency help right away if you take too many Pentazocine and Naloxone Tablets (overdose). When you first start taking Pentazocine and Naloxone Tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.TakingPentazocine and Naloxone Tabletswithotheropioidmedicines,benzodiazepines,alcohol,or other centralnervous systemdepressants(includingstreetdrugs)cancauseseveredrowsiness, decreasedawareness,breathingproblems,coma,anddeath. Never give anyone else your Pentazocine and Naloxone Tablets. They could die from taking them. Store Pentazocine and Naloxone Tabletsaway from children and in a safe place to prevent stealing or abuse. Selling or giving away Pentazocine and Naloxone Tabletsare against the law. Do not take Pentazocine and Naloxone Tablets if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. previouslyhad anallergicreaction to pentazocine ornaloxone. known orsuspectedgastrointestinal obstruction, includingparalyticileus. Before taking Pentazocine and Naloxone Tablets , tell your healthcare provider if you have a history of: head injury, seizures liver, kidney, thyroid problems problems urinating pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, or mental health problems. Tell your healthcare provider if you are: pregnant or planning to become pregnant. Prolonged use of Pentazocine and Naloxone Tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding.Pentazocine and naloxone passes into breast milk and may harm your baby. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Pentazocine and Naloxone Tabletswith certain other medicines can cause serious side effects that could lead to death. When taking Pentazocine and Naloxone Tablets : Do not change your dose. Take Pentazocine and Naloxone Tabletsexactly as prescribed by your healthcare provider.Usethelowest dosepossible fortheshortest timeneeded. Take your prescribed dose every 3 or 4 hoursat the same time every day. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. Call your healthcare provider if the dose you are taking does not control your pain. If you have been taking Pentazocine and Naloxone Tabletsregularly, do not stop taking Pentazocine and Naloxone Tabletswithout talking to your healthcare provider. Advisepatients to properlydisposeofunused Pentazocine and NaloxoneTablets. Advise patients to throw thedrugin thehousehold trash followingthesesteps. 1)Removethem from theiroriginal containersand mixthem with an undesirablesubstance, suchas used coffee grounds orkittylitter (this makes thedrugless appealingtochildren and pets, and unrecognizableto peoplewho mayintentionallygo through thetrash seekingdrugs). 2)Place themixturein asealablebag,emptycan, orothercontainerto prevent thedrug from leaking orbreakingout ofagarbagebag, orto disposeofin accordancewith localstateguidelines and/or regulations. While taking Pentazocine and Naloxone Tablets DO NOT: Drive or operate heavy machinery, until you know how Pentazocine and Naloxone Tabletsaffect you. Pentazocine and Naloxone Tabletscan make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Pentazocine and Naloxone Tabletsmay cause you to overdose and die. The possible side effects of Pentazocine and Naloxone Tablets: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of Pentazocine and Naloxone Tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. For more information call Actavis at 1-800-272-5525. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: ActavisPharma, Inc. Parsippany, NJ 07054 USA Revised: November 2016 224426-4
CLINICAL PHARMACOLOGY SECTION.
CLINICAL PHARMACOLOGY Mechanism of Action Pentazocineis amixed agonist-antagonist at opioid receptors. Pentazocineis apartial agonist at themu opioid receptorand an agonist at thekappaopioid receptor. Naloxoneis an opioid antagonist. Pharmacodynamics E f f ect s on t h e C e n tr al N er vo u s S ys t e m Pentazocineproduces respiratorydepression bydirect action on brain stemrespiratorycenters. The respiratorydepression involves a reduction inthe responsiveness ofthebrain stem respiratorycenters to both increases in carbon dioxidetension and electrical stimulation. Pentazocine causes miosis, even in total darkness.Pinpoint pupils areasignofopioid overdose but arenot pathognomonic (e.g., pontinelesions ofhemorrhagicorischemicorigins may producesimilar findings). Marked mydriasis ratherthan miosis maybeseen dueto hypoxiain overdosesituations. E f f ect s on t h e G as t r oi n te s t i n al T r a ct a n d O t h er S m oo t h M u s c le Pentazocine causesa reduction in motilityassociated with an increasein smooth muscletonein the antrum ofthestomach and duodenum. Digestion of food in thesmall intestineis delayed and propulsive contractions aredecreased. Propulsiveperistalticwaves in the colon aredecreased, whiletonemaybeincreased to thepoint ofspasm, resultingin constipation.Otheropioid-induced effects mayincludea reduction in biliaryand pancreaticsecretions, spasm ofsphincter ofOddi, and transient elevations in serum amylase. E f f ect s on t h e Ca r d iovas c u lar S ys t e m Pentazocineproduces peripheral vasodilation which mayresult in orthostatichypotension or syncope. Manifestations ofhistamine release and/orperipheral vasodilation mayincludepruritus, flushing, red eyes, sweating, and/ororthostatichypotension. E f f ect s on t h e End o cr i n e S ys t e m Opioids inhibit thesecretion of adrenocorticotropichormone (ACTH), cortisol, and luteinizing hormone(LH)in humans [see ADVERSEREACTIONS ]. Theyalso stimulateprolactin, growth hormone (GH)secretion,and pancreaticsecretion ofinsulin and glucagon. Chronicuseofopioids mayinfluencethehypothalamic-pituitary-gonadal axis,leadingto androgen deficiencythatmaymanifest as low libido, impotence, erectiledysfunction, amenorrhea, orinfertility. The causal roleofopioids in the clinical syndromeofhypogonadism is unknown becausethevarious medical, physical, lifestyle, and psychological stressors that may influencegonadal hormonelevels havenot been adequatelycontrolledforin studies conducted to date[see ADVERSEREACTIONS ]. E f f ects on t h e I m m un e S ys t e m Opioids havebeen shown to haveavarietyofeffects on components oftheimmunesystem. The clinical significanceofthese findings is unknown. Overall, theeffects ofopioids appearto be modestlyimmunosuppressive. Co n ce n tr a t io n E ff i c a c y R e la t io n s h i p s Theminimum effective analgesic concentration will varywidelyamongpatients, especially amongpatients who havebeen previouslytreatedwith potent agonist opioids. Theminimum effective analgesic concentration ofpentazocinefor anyindividual patient mayincreaseover timedueto an increasein pain, thedevelopmentofanew pain syndrome,and/orthe development of analgesictolerance[see DOSAGEANDADMINISTRATION ]. Co n ce n tr a t io n A d v er s e R e a ct ion R e la t io n s h i p s Thereis arelationship between increasingpentazocineplasma concentration and increasing frequencyofdose-relatedopioid adversereactionssuch as nausea, vomiting, CNSeffects, and respiratorydepression. In opioid-tolerant patients, thesituation maybealtered bythe development oftoleranceto opioid-related adversereactions [see DOSAGEANDADMINISTRATION ]. O p ioid A n t ago n ist E ff e ct s Pentazocineweaklyantagonizes the analgesic effects ofmorphine, meperidine, and phenazocine;in addition, it produces incomplete reversal ofcardiovascular, respiratory,and behavioral depression induced bymorphine and meperidine.Pentazocinehas about 1/50 the antagonistic activityofnalorphine.Italso has sedativeactivity. Naloxonewhen administered orallyat 0.5 mghasno pharmacologicactivity. Naloxone hydrochloride administered parenterallyat thesamedoseis an antagonistto pentazocine and a pure antagonist to narcotic analgesics. Pentazocine and NaloxoneTablets areapotentanalgesicwhen administeredorally. However, thepresenceofnaloxonein Pentazocine and NaloxoneTablets is intended to prevent theeffect ofpentazocineiftheproduct is misused byinjection. Studies in animals indicatethat thepresenceofnaloxonedoes not affect pentazocine analgesia when the combination is given orally.Ifthecombination is given byinjection the action of pentazocineis 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.
CONTRAINDICATIONS Pentazocine and Naloxone Tabletsare contraindicated in patients with: Significant respiratory depression [see WARNINGS ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS ] Patientswithknown orsuspected gastrointestinal obstruction, includingparalyticileus[see WARNINGS ] Patientswithhypersensitivitytoeitherpentazocine,naloxone,oranyoftheformulation excipients (e.g.,anaphylaxis)[see WARNINGS ].
WARNINGS 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 patients 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 andproper 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. 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 patients clinical status [see OVERDOSAGE ]. Carbon dioxide (CO 2) 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 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. Observenewborns forsigns ofneonatal opioid withdrawal syndromeand manageaccordingly. Advisepregnant women usingopioids 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,respiratorydepression,coma,anddeathmayresultfromtheconcomitantuse of Pentazocine and Naloxone Tablets withbenzodiazepinesorotherCNS depressants(e.g.,non-benzodiazepine sedatives/hypnotics,anxiolytics,tranquilizers,musclerelaxants,generalanesthetics, antipsychotics,otheropioids,alcohol).Becauseof theserisks, reserveconcomitantprescribingof thesedrugs for use inpatientsforwhom alternativetreatmentoptionsareinadequate. Observationalstudieshavedemonstratedthatconcomitantuseof opioidanalgesicsand benzodiazepinesincreasestherisk of drug-relatedmortalitycomparedto use of opioidanalgesics alone.Becauseof similarpharmacologicalproperties,itisreasonabletoexpectsimilarrisk with theconcomitantuse of otherCNS depressantdrugs withopioidanalgesics[see PRECAUTIONS; Drug Interactions ]. If thedecisionismadetoprescribeabenzodiazepineor otherCNS depressantconcomitantly with anopioidanalgesic,prescribethelowesteffectivedosages andminimumdurationsof concomitantuse. In patientsalreadyreceivinganopioidanalgesic,prescribealowerinitialdose of thebenzodiazepineor otherCNS depressantthanindicatedintheabsenceof anopioid,and titratebasedon clinicalresponse. If anopioidanalgesicisinitiatedinapatientalreadytakinga benzodiazepineor otherCNS depressant,prescribealowerinitialdose of theopioidanalgesic, andtitratebasedon clinicalresponse.Followpatientscloselyfor signs andsymptomsof respiratorydepressionandsedation. Advise bothpatientsandcaregiversabouttherisks of respiratorydepressionandsedationwhen Pentazocine and Naloxone Tabletsareused withbenzodiazepinesor otherCNS depressants(includingalcoholand illicitdrugs). Advise patientsnottodriveor operateheavymachineryuntiltheeffectsof concomitantuse of thebenzodiazepineor otherCNS depressanthavebeendetermined.Screen patientsfor risk ofsubstanceuse disorders, includingopioidabuseandmisuse,andwarn themof therisk for overdoseanddeathassociatedwiththeuseof additionalCNS depressantsincluding alcoholandillicitdrugs [see PRECAUTIONS ; Information forPatients , 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 Tabletsin 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, Cache c tic, 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 Tabletsare 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 NaloxoneTablets maycauseseverehypotension including orthostatic hypotension and syncopein ambulatorypatients. Thereis increasedrisk in patients whose abilityto maintain blood pressurehas alreadybeen compromised bya reduced blood volumeor concurrent administration of certain CNSdepressant drugs(e.g., phenothiazines orgeneral anesthetics)[see PRECAUTIONS;InformationforPatients ] . Monitorthesepatients forsigns ofhypotension afterinitiatingortitratingthedosageofPentazocine and NaloxoneTablets.In patients with circulatoryshock, Pentazocine andNaloxoneTablets maycausevasodilation that can furtherreducecardiacoutput and blood pressure. Avoid theuseofPentazocine and NaloxoneTablets in patients with circulatoryshock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who maybesusceptibleto theintracranial effects ofCO 2retention (e.g., thosewith evidenceofincreased intracranial pressureorbrain tumors), Pentazocineand NaloxoneTablets mayreduce respiratorydrive, and theresultant CO 2retention canfurtherincreaseintracranial pressure. Monitorsuch patients forsigns ofsedation and respiratorydepression, particularly when initiatingtherapywith Pentazocine and NaloxoneTablets. Opioids mayalso obscurethe clinical coursein apatient with ahead injury. Avoid theuseof Pentazocine and NaloxoneTablets in patients with impaired consciousnessor coma. Risks of Use in Patients with Gastrointestinal Conditions Pentazocine and NaloxoneTablets are contraindicated in patients with known orsuspected gastrointestinal obstruction, includingparalyticileus. The administration ofPentazocine and NaloxoneTablets orotheropioidsmayobscurethe diagnosis orclinical coursein patients with acuteabdominal conditions. Pentazocine and NaloxoneTablets maycausespasm ofthesphincterofOddi. Opioids maycause increases in serum amylase. Monitorpatients with biliarytract disease, includingacute pancreatitis, forworseningsymptoms. Withdrawal TheuseofPentazocine and NaloxoneTablets, amixed agonist/antagonistopioid analgesic, in patients who arereceivingafull opioid agonist analgesicmayreducethe analgesic effectand/or precipitatewithdrawal symptoms. Avoid concomitant useofPentazocine and NaloxoneTablets with a full opioid agonistanalgesic. When discontinuingPentazocine and NaloxoneTablets, graduallytaperthedosage [see DOSAGE AND ADMINISTRATION ]. Do not abruptlydiscontinuePentazocine and Naloxone Tablets [see DRUG ABUSE AND DEPENDENCE ]. Risks of Driving and Operating Machinery Pentazocine and NaloxoneTablets mayimpairthemental orphysical abilities needed to perform potentiallyhazardousactivities such as drivinga caroroperatingmachinery. Warn patients not to driveoroperatedangerous machineryunless theyaretolerant to theeffects ofPentazocine and NaloxoneTablets and know how theywill react to themedication. Acute CNS Manifestations Patients receiving therapeutic doses of Pentazocine and NaloxoneTabletshave 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 ofnaloxonepresent in Pentazocine and NaloxoneTablets (0.5 mgpertablet)has no action when taken orallyand will not interferewith thepharmacologicaction ofpentazocine. However, this amount ofnaloxonegiven byinjection has profound antagonistic action to narcotic analgesics. Severe, even lethal, consequences mayresult from misuseoftablets byinjection either aloneor in combination with othersubstances, suchas pulmonaryemboli, vascularocclusion, ulceration and abscesses, and withdrawal symptoms in narcoticdependent individuals. Increased Risk of Seizures in Patients with Seizure Disorders Thepentazocinein Pentazocine and NaloxoneTablets mayincreasethe frequencyofseizures in patients with seizuredisorders, and mayincreasethe risk ofseizures occurringin other clinical settings associated with seizures. Monitorpatients with ahistoryofseizuredisorders for worsened seizure controlduringPentazocineandNaloxoneTablets therapy. Infertility C h r o n ic u se of o p i o i d s m ay c a u se re du ce d f ert i li t y in f e m al e s a n d m al e s of re p r o du ct ive p o te n t ial. It is n ot kn o wn w h et h e r t h e se e ff ect s on f ert ili t y a r e re v er si b le [ s e e ADVERSE REACTIONS ] .