DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Capsules: Butalbital, 50 mg, Aspirin, 325 mg, Caffeine, 40 mg, Codeine Phosphate, 30 mg Blue cap with a yellow body. Cap is imprinted twice with FIORINAL and CODEINE in red. Body is imprinted twice with WATSON 956 in red. Capsules: 50 mg butalbital, 325 mg aspirin, 40 mg caffeine, and 30 mg codeine phosphate(3)

BOXED WARNING SECTION.


WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAW A L SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES Addiction, Abuse, and Misuse FIORINAL with CODEINE exposes 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 FIORINAL with CODEINE, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of FIORINAL with CODEINE. Monitor for respiratory depression, especially during initiation of FIORINAL with CODEINE or following a dose increase [see Warnings and Precautions ( 5.2 )]. Accidental Ingestion Accidental ingestion of even one dose of FIORINAL with CODEINE, especially by children, can result in a fatal overdose of FIORINAL with CODEINE [see Warnings and Precautions ( 5.2 )]. 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 and Precautions ( 5.3 ), Drug Interactions ( 7 )]. Reserve concomitant prescribing of FIORINAL with CODEINE 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. Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occu r red following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. [see Warnings and Precautions ( 5.4 )]. FIORINAL with CODEINE is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )]. Avoid the use of FIORINAL with CODEINE in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Neonatal Opioid Withdrawal Syndrome Prolonged use of FIORINAL with CODEINE 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 and Precautions ( 5.5 )]. Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with FIORINAL with CODEINE requires careful consideration of the effects on codeine, and the active metabolite, morphine [see Warnings and Precautions ( 5.6 ) Drug Interactions ( 7 )]. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS;ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN ; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES See full prescribing information for complete boxed warning. FIORINAL with CODEINE exposes users to the risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patients risk before prescribing and monitor regularly for these behaviors and conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.2 ) Accidental ingestion of FIORINAL with CODEINE, especially by children, can result in fatal overdose. ( 5.2 ) Concomitant use of opioids or a barbiturate with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.3 , 7 ) Life-threatening r espiratory depression and death have occurred in children who received codeine ; most cases follow ed tonsillectomy and/or adenoidectomy , and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism . ( 5.4 ) FIORINAL with CODEINE is contraindicated in ch ildren younger than 12 years of age and in children younger than 18 years of age foll owing tonsillectomy and/or adenoidectomy ( 4 ). Avoid the use of FIORINAL with CODEINE in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.5 ) The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with FIORINAL with CODEINE requires careful consideration of the effects on codeine, and the active metabolite, morphine . ( 5.6 , 7 )

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL NDC 0023-6010-01 Fiorinal with Codeine 100 Capsules Rx Only

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Interactions with BenzodiazepinesorOtherCNSDepressants [s e e W arni n gs and Pr ec autions ( 5.3 )] Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.4 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.5 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.9 )] Severe Hypotension [see Warnings and Precautions ( 5.10 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Withdrawal [see Warnings and Precautions ( 5.14 )] Coagulation Abnormalities and Bleeding [see Warnings and Precautions ( 5.16 )] Reyes Syndrome [see Warnings and Precautions ( 5.17 )] Allergy [see Warnings and Precautions ( 5.18 )] Most common adverse reactions (incidence > 1%) are nausea and/or abdominal pain, drowsiness, and dizziness. (6) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observedin practice. Incidence in Controlled Clinical Trials Thefollowingtablesummarizestheincidenceratesoftheadverseevents reportedbyatleast1%oftheFIORINALwithCODEINEtreatedpatientsincontrolledclinicaltrials comparing FIORINALwithCODEINEtoplacebo,andprovidesacomparisontotheincidence rates reportedby theplacebo-treatedpatients. Theprescribershouldbeaware thatthesefigurescannotbeusedtopredictthe incidenceofsideeffectsinthe courseofusualmedicalpracticewhere patient characteristicsandotherfactors differfromthosethatprevailedinthe clinicaltrials.Similarly,the citedfrequenciescannot becomparedwithfigures obtainedfromother clinicalinvestigationsinvolvingdifferent treatments,uses,andinvestigators. Adverse Events Reported by at Least 1% of FIORINAL with CODEINE Treated Patients During Placebo Controlled Clinical Trials Incidence Rate of Adverse Events Body System/Adverse Event FIORINAL with CODEINE (N=382) Placebo (N =377) Central Nervous Drowsiness 2.4% 0.5% Dizziness/Lightheadedness 2.6% 0.5% Intoxicated Feeling 1.0% 0% Gastrointestinal Nausea/Abdominal Pain 3.7% 0.8% Othe r Advers e Event s Reporte d Durin g Controlle d Clinica l Trials Thelisting thatfollowsrepresentsthe proportionofthe 382patientsexposedtoFIORINALwithCODEINEwhileparticipatinginthe controlledclinicaltrialswhoreported, on atleastoneoccasion,an adverseevent of thetypecited. Allreportedadverseevents,exceptthose alreadypresentedin theprevioustable, areincluded.Itis importantto emphasizethat,althoughtheadverseeventsreporteddidoccur while thepatientwasreceivingFIORINALwithCODEINE,theadverseeventswerenot necessarilycaused byFIORINALwithCODEINE. Adverseeventsare classifiedbybodysystemandfrequency.Frequentisdefinedasanadverseeventwhich occurredinatleast1/100 (1%)ofthe patients;all adverseeventslistedinthe previoustableare frequent.Infrequentisdefinedas an adverseevent thatoccurredin lessthan1/100patientsbutatleast1/1000patients. All adverseevents tabulatedbeloware classifiedasinfrequent. Centra l Nervous:headache,shakyfeeling,tingling,agitation,fainting,fatigue,heavyeyelids,high energy,hotspells,numbness,andsluggishness. Autonomic Nervous:dry mouth and hyperhidrosis. Gastrointestinal:vomiting, difficulty swallowing, and heartburn. Cardiovascular:tachycardia. Musculoskeletal: leg pain and muscle fatigue. Genitourinary:diuresis. Miscellaneous: pruritus, fever, earache, nasal congestion, and tinnitus. Thefollowingadversedrugreactions have been reported with the components ofFIORINALwithCODEINE.Potentialeffects ofhighdosage are listedin the[see OVERDOSAG E ( 10 )] section ofthisinsert. Aspirin:occultbloodloss,hemolyticanemia,irondeficiencyanemia,gastric distress,heartburn,nausea,pepticulcer,prolongedbleedingtime,acuteairway obstruction,renaltoxicitywhentakeninhighdosesfor prolongedperiods,impairedurateexcretion,hepatitis. Caffeine:cardiac stimulation,irritability,tremor, dependence,nephrotoxicity,hyperglycemia. Codeine:nausea, vomiting,drowsiness,lightheadedness,constipation,pruritus. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of FIORINAL with CODEINE. Because these reactions are reported voluntarily froma population of uncertain size, itis not always possible to reliably estimate their frequency or establisha causal relationship to drug exposure. Centra l Nervous:abuse, addiction,anxiety,depression,disorientation,hallucination,hyperactivity,insomnia,libidodecrease,nervousness,neuropathy,psychosis, sedation,sexual activityincrease,slurred speech,twitching,unconsciousness,vertigo. Autonomic Nervous:epistaxis, flushing,miosis,salivation. Gastrointestinal:anorexia,appetiteincreased,constipation,diarrhea,esophagitis,gastroenteritis,gastrointestinalspasm, hiccup,mouth burning,pyloriculcer. Cardiovascular:chestpain,hypotensivereaction,palpitations,syncope. Skin:erythema,erythemamultiforme,exfoliativedermatitis,hives,rash,toxicepidermalnecrolysis. Urinary:kidneyimpairment,urinarydifficulty. Miscellaneous:allergic reaction,anaphylacticshock,cholangiocarcinoma,druginteractionwitherythromycin(stomachupset),edema. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis:Anaphylaxis has been reported with ingredients contained in FIORINAL with CODEINE. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )].

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE FIORINAL with CODEINE is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when non-opioid analgesic and alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids and butalbital, even at recommended doses [see Warnings and Precautions ( 5.1 )], reserve FIORINAL with CODEINE for use in patients for whom alternative treatment options (e.g., non-opioid, non-barbiturate 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 FIORINAL with CODEINE is a combination of butalbital, abarbiturate,aspirin, a nonsteroidal anti-inflammatory drug, caffeine, a methylxanthine, and codeine phosphate, an opioid agonist, and is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when other non-opioid analgesics and alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve FIORINAL with CODEINE for use in patients for whom alternative treatment options (e.g., non-opioid analgesics)(5.1): 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.


9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance FIORINAL with CODEINE containscodeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance. 9.2 Abuse FIORINAL with CODEINE contains codeine, a substance witha high potential for abusesimilar to other opioids, including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. FIORINAL with CODEINE can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.1 ) ] . All patients treated with opioids require careful monitoring for signs of abuse and addiction, becauseuse 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 prescriptiondrug, 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 controllingits use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increasedtolerance,andsometimes a physical withdrawal. Drug-seeking behavior is very common in persons with substance use disorders.Drug-seekingtacticsinclude emergency calls or visits near theend 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 healthcare provider(s). Doctor shopping (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation withachieving adequate pain relief can beappropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence andtolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance andsymptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. FIORINAL with CODEINE, like other opioids, can be diverted for non-medical use intoillicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federallaw, is strongly advised. Proper assessment of thepatient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help tolimit abuse of opioid drugs. Risks Specific to Abuse of FIORINAL with CODEINE FIORINAL with CODEINE is for oral use only. Abuse of FIORINAL with CODEINE poses a risk of overdose and death. The risk is increased with concurrent abuse of FIORINAL with CODEINE with alcohol and other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Butalbital Barbiturates may be habit-forming. Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. The average daily dose for the barbiturate addict is usually about 1,500 mg. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. As this occurs, the margin between an intoxication dosage and fatal dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can bewithdrawn by using a number of different withdrawal regimens. One method involves initiating treatment at the patients regular dosage level and gradually decreasing the daily dosage as tolerated by the patient. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioidtherapy. Tolerance is the need for increasing doses of opioids to maintain a defined effectsuch as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired andundesired 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., pentazocine, butorphanol, nalbuphine), or partialagonists(e.g., buprenorphine).Physical dependence may not occurto a clinically significant degree until after several days to weeks ofcontinued opioid usage. FIORINAL with CODEINE should not beabruptly discontinued in a physically-dependent patient [see Dosage and Administration ( 2.3 ) ] . If FIORINAL with CODEINE is 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 Use in Specific Populations ( 8.1 , 8.2 ) ].

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (2.1). Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse(2.1). Initiate treatment with one or twocapsules every 4 hours. Total daily dosage should not exceed 6capsules. Do not stopFIORINAL with CODEINEabruptly in a physically dependent patient(2.3). 2.1 Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )]. 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 and Precautions ( 5.1 )]. 2.2 Dosing Information One or two capsules every 4 hours. Total daily dosage should not exceed 6 capsules. 2.3 Discontinuation of FIORINAL with CODEINE While not indicated for around-the-clock therapy,when a patient who has been taking FIORINAL with CODEINE regularly and may be physically dependent no longer requires therapy with FIORINAL with CODEINE, 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 FIORINAL with CODEINE in a physically-dependent patient [see Warnings and Precautions ( 5.14 ), Drug Abuse and Dependence ( 9.3 )].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING FIORINAL with CODEINE (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) Blue cap with a yellow body. Cap is imprinted twice with FIORINAL and CODEINE in red. Body is imprinted twice with WATSON 956 in red. High density polyethylene bottles of 100 capsules are supplied with child-resistant closures. (NDC 0023-6010-01) Store and Dispense Below 25C (77F)tightcontainer.Protectfrommoisture. Rx only

DESCRIPTION SECTION.


11 DESCRIPTION FIORINAL with CODEINE (butalbital, aspirin, caffeine, and codeine phosphate, USP) is supplied in capsule form for oral administration. Each capsule contains the following active ingredients: Butalbital, USP..50mg Aspirin, USP..325mg Caffeine, USP40mg Codeine phosphate, USP...30mg Butalbital (5-allyl-5-isobutylbarbituricacid)isashort-tointermediate-actingbarbiturate.Ithas thefollowingstructuralformula: Aspirin(benzoicacid,2-(acetyloxy)-)isa nonsteroidal anti-inflammatory drug..Ithasthefollowing structural formula: Caffeine(1,3,7-trimethylxanthine), a methylxanthine,isacentralnervoussystemstimulant.Ithas thefollowingstructuralformula: Codeinephosphate(7,8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-olphosphate(1:1)(salt)hemihydrate)isan opioid agonist.It hasthefollowing structural formula: c Ingredients: microcrystallinecellulose,pregelatinizedstarch,talc.GelatincapsulescontainD&C YellowNo.10,FD&CBlueNo.1, FD&CRedNo.3, FD&C YellowNo.6,gelatin,titaniumdioxide.Thecapsulesare printedwithedibleink containingred ironoxide.

OVERDOSAGE SECTION.


10 OVERDOSAGE Clinical Presentation Acute overdose with FIORINAL with CODEINE can be manifested by respiratory depression, somnolenceprogressingto stupororcoma,skeletalmuscle 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 [ see Clinic a l Pharmacology ( 12.2 ) ]. Signs and Symptoms Acute Barbiturate Poisoning: Symptomsincludedrowsiness,confusion,andcoma;respiratorydepression;hypotension;hypovolemicshock. Acute Aspirin Poisoning: Symptomsinclude hyperpnea;acid-basedisturbanceswithdevelopmentofmetabolicacidosis;vomitingand abdominalpain; tinnitus,hyperthermia;hypoprothrombinemia;restlessness;delirium; convulsions. AcuteCaffeinePoisoning: Symptomsincludeinsomnia,restlessness,tremor, anddelirium; tachycardiaandextrasystoles. Codeine: Acute overdose with codeine can 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 [see Clinical Pharmacology ( 12.2 )]. Treat m ent of Overdose In case of overdose, priorities are the reestablishment ofa patent and protected airwayand institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management ofcirculatory shock and pulmonary edema as indicated.Cardiac arrest or arrhythmias will require advanced life-support techniques. The opioid antagonists, naloxone or nalmefene, are specificantidotestorespiratorydepression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to codeine phosphate overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratoryorcirculatorydepression secondary to codeine overdose. Because the duration of opioid reversal is expected to be lessthan the duration of action of codeine in FIORINAL with CODEINE, carefully monitor the patient until spontaneous respiration is reliably re-established. Ifthe response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the products prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. Theseverity 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 seriousrespiratory depression in the physicallydependent patient,administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. Treatment consists primarily of management of barbiturate intoxication, reversal of the effects of codeine, and the correction of the acid-base imbalance due to salicylism. Vomiting should be induced mechanically or with emetics in the conscious patient. Gastric lavage may be used if the pharyngeal and laryngeal reflexes are present and if less than 4 hours have elapsed since ingestion. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and when necessary to provide assisted respiration. Diuresis, alkalinization of the urine, and correction of electrolyte disturbances should be accomplished through administration of intravenous fluids such as1% sodium bicarbonate and 5% dextrose in water. Meticulous attention should be given to maintaining adequate pulmonary ventilation. The value of vasopressor agents such as Norepinephrine or Phenylephrine Hydrochloride in treating hypotension is questionable since they increase vasoconstriction and decrease blood flow. However, if prolonged support of blood pressure is required, Norepinephrine Bitartrate (Levophed) may be given I.V. with the usual precautions and serial blood pressure monitoring. In severe cases of intoxication, peritoneal dialysis, hemodialysis, or exchange transfusion may be lifesaving. Hypoprothrombinemia should be treated with vitamin K, intravenously. Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration. Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Typically, a dose of 0.4 to 2 mg is given parenterally and may be repeated if an adequate response is not achieved. Since the duration of action of codeine may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression.

SPL MEDGUIDE SECTION.


Medic a tion Guide FIORINAL with CODEINE ( FYORE-in-ALL ) (Butalbital, Aspirin, Caffeine, and Codeine Phosphate) capsules , CIII FIORINAL with CODEINE is: A strong prescription painmedicine thatcontains anopioid (narcotic) that is indicated for the relief of the symptom complex of tension (or muscle contraction) headache, when other pain treatments such as non-opioid pain medicines donottreat your painwellenough or you cannottoleratethem. An opioid pain medicine that can put you at risk for overdoseand 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. Importa n t information a b out FIORINAL with CODEINE: Get eme r ge n c y help right a w ay if y ou take too m u ch FIORINAL with CODEINE (o v erdose). When you first start taking FIORINAL with CODEINE, when your dose is changed, or if you take too much (overdose),serious or life-threateningbreathing problems that can lead to death may occur. Taking FIORINAL with CODEINE with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your FIORINAL with CODEINE. They could die from taking it. Store FIORINALwith CODEINEaway from children and in a safe place to prevent stealing or abuse. Selling or giving away FIORINAL with CODEINE is against the law. Important Information Guiding Use in Pediatric Patients: Do not give FIORINAL with CODEINE to a child younger than 12 years of age. Do not give FIORINAL with CODEINE to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids . Avoid giving FIORINAL with CODEINE to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems. Do not give FIORINAL with CODEINE to a child or teenager with a viral illness. Reye syndrome, a life-threatening condition, can happen when aspirin (an ingredient in FIORINAL with CODEINE ) is used in children and teenagers who have certain viral illnesses. Do not ta k e FIORINAL with CODEINE if y ou h a v e: severe asthma, trouble breathing, or other lung problems. a bowelblockage or have narrowing of the stomach or intestines. known allergy to nonsteroidal anti-inflammatory drug products (NSAIDs) a rare disorder in which your blood doesnt clot normally (hemophilia) Before taking FIORINAL with CODEINE, tell your healthcare provider if you have a history of: headinjury, seizures liver, kidney, thyroid problems problems urinating pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, or mental health problems. have been told by your healthcare provider that you are a rapid metabolizer of certain medicines Tell y our healthca r e pr ov ider if y ou are: pregnant or planning to become pregnant. FIORINAL with CODEINE may harm your unborn baby. Prolonged use of FIORINAL with CODEINE during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding.Not recommended; may harm your baby. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking FIORINAL with CODEINE with certain other medicines can cause serious side effects that could lead to death. When taking FIORINAL with CODEINE: Do not change your dose. Take FIORINAL with CODEINE exactly as prescribed by your healthcare provider.Use the lowest dose possible for the shortest time needed. Take your prescribed dose of 1 or 2 capsules every 4 hours. Total daily dosage should not exceed 6 capsules. Do not takemore 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 FIORINAL with CODEINE regularly, do not stop taking FIORINAL with CODEINE withouttalking to your healthcare provider. After you stop taking FIORINAL with CODEINE, dispose the unused FIORINAL with CODEINE in accordance with the local state guidelines and/or regulations. While taking FIORINAL with CODEINE DO NO T : Drive or operate heavy machinery, until you know how FIORINAL with CODEINE affects you. FIORINAL with CODEINE can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-countermedicines that contain alcohol. Using productscontaining alcoholduring treatment with FIORINAL with CODEINE may cause you to overdose and die. The possible side effects of FIORINAL with CODEINE: constipation, nausea, sleepiness, vomiting, tiredness, headache,dizziness, abdominal pain. Call your healthcare provider if you have anyof these symptoms and they are severe. Get eme r ge n c y medical help if y ou ha v e: trouble breathing, shortness of breath, fast heartbeat,chest pain,swellingof your face, tongue, or throat, extreme drowsiness, light-headedness whenchanging positions, feeling faint, agitation, highbody temperature, troublewalking,stiff muscles, or mental changes such as confusion. If you are a nursing mother taking FIORINAL with CODEINE and your breastfeeding baby has increased sleepiness, confusion, difficulty breathing, shallow breathing, limpness, or difficulty breastfeeding. These are not all the possible side effects of FIORINAL with CODEINE. Callyour doctor for medical advice about side effects. Youmay report side effects to FDA at 1-800-FDA-1088. For m ore inform a tion go to dail y med.nlm.nih.gov Distributed by: Allergan USA, Inc. Irvine, CA 926112, www.FIORINALwithCODEINE.com or call1-800-678-1605 2017 Allergan. All rights reserved. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 08/2017

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.7) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. (5.9) Severe Hypotensi on: Monitor during dose initiation and titration. Avoiduse of FIORINAL with CODEINE in patients with circulatory shock.(5.10) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of FIORINAL with CODEINE in patients with impairedconsciousness or coma. (5.11) 5. 1 Addiction, Abuse, and Misuse FIORINAL with CODEINE contains codeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance. As FIORINAL with CODEINE contains butalbital and codeine, it exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed FIORINAL with CODEINE. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patients risk for addiction, abuse, or misuse prior to prescribing FIORINAL with CODEINE, and monitor all patients receiving FIORINAL with CODEINE 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 FIORINAL with CODEINE, but use in such patients necessitates intensive counseling about the risks and proper use of FIORINAL with CODEINE along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids and barbiturates are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.Consider these risks when prescribing or dispensing FIORINAL with CODEINE. 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 Patient Counseling Information ( 17 )]. 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. 5. 2 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 ( 10 )]. 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 FIORINAL with CODEINE, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of FIORINAL with CODEINE. To reduce the risk of respiratory depression, proper dosing and titration of FIORINAL with CODEINE are essential [see Dosage and Administration ( 2.1 )]. Overestimating the FIORINAL with CODEINE dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of FIORINAL with CODEINE, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratorydepression, coma, and death mayresult from the concomitant useofFIORINALwith CODEINE with benzodiazepines orotherCNSdepressants (e.g., non-benzodiazepine sedatives/hypnotics,anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics,other opioids, alcohol). Becauseofthese risks, reserveconcomitant prescribingofthesedrugs forusein patients for whom alternativetreatment options areinadequate. Observational studies havedemonstrated thatconcomitant useofopioid analgesics and benzodiazepines increasesthe risk ofdrug-relatedmortalitycompared to useofopioid analgesics alone.Becauseofsimilar pharmacological properties, it is reasonableto expect similar risk with theconcomitant useofotherCNS depressant drugswith opioid analgesics [s e e Drug I nt e ra c tions ( 7 )]. Ifthedecision is madeto prescribeabenzodiazepineorotherCNSdepressant concomitantlywith anopioid analgesic, prescribethelowest effectivedosages and minimum durations ofconcomitant use.In patients already receivinganopioid analgesic,prescribealower initial doseofthebenzodiazepineorotherCNSdepressant than indicated in the absenceof an opioid, and titratebased on clinical response.If an opioid analgesicis initiated in apatient alreadytakingabenzodiazepineorotherCNSdepressant, prescribealowerinitial doseoftheopioid analgesic, and titratebased on clinical response. Follow patients closelyforsigns and symptoms ofrespiratory depression and sedation. Adviseboth patients andcaregivers about therisks of respiratorydepression and sedation whenFIORINAL with CODEINE is usedwith benzodiazepines orotherCNSdepressants (includingalcohol and illicit drugs). Advisepatients not to driveoroperateheavymachineryuntil theeffects ofconcomitant useofthe benzodiazepineorotherCNSdepressant havebeen determined. Screen patients for risk ofsubstanceuse disorders, includingopioid abuse and misuse, andwarn them oftherisk foroverdose and death associated with theuseof additional CNSdepressants including alcohol and illicit drugs [s e e Drug I nt e r a c tions ( 7 ) and Pati e nt C ouns e ling I nformation ( 17 )]. 5. 4 Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon postmarketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post- operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death: FIORINALwith CODEINE is contraindicatedforall childrenyoungerthan 12years ofage[s e e C ontraindi c ations ( 4 )] . FIORINAL with CODEINE is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )]. Avoid theuseofFIORINALwith CODEINE in adolescents 12 to 18yearsofagewho haveother risk factors thatmayincreasetheirsensitivityto therespiratorydepressant effects of codeineunless the benefits outweigh the risks. Risk factors includeconditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. As with adults, when prescribing FIORINAL withCODEINE for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and thesigns of morphine overdose [see Use in Specific Populations ( 8.4 ), Overdosage ( 10 )]. N ursing M oth e rs A t least one d ea th w as re po r t e d in a nu r sing i n fa nt who w as e x pos e d to hi g h l e v e ls o f mo r phine in b rea st milk b eca use t h emoth e r w as an ult r a -ra p i d m e t a boli z er of c od e in e . B r e a st f e e ding is not r ec o mm e nd e d du r ing t rea tm e nt withF I O R I NA L with C OD E I NE [s e e Use in S p ec ific Populations ( 8.2 )] . C Y P2D6 G e n e tic Variabilit y : Ultra - rapid m e taboliz e r Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). [see Overdosage ( 10 )] . Therefore, individuals who are ultra-rapid met abolizers should not use FIORINAL with CODEINE . 5.5 Neonatal Opioid Withdrawal Syndrome Prolonged useofFIORINALwith CODEINE duringpregnancycanresultin withdrawal in theneonate. Neonatal opioid withdrawal syndrome, unlikeopioid withdrawal syndromein adults, maybelife-threateningif not recognized and treated, and requires management accordingto protocols developed byneonatologyexperts. Observenewborns forsigns ofneonatal opioid withdrawal syndromeandmanageaccordingly. Advise pregnant women usingopioids foraprolonged period ofthe risk ofneonatal opioid withdrawal syndrome and ensurethat appropriatetreatment will be available[s e e Use in Sp e c ific Po p ulations ( 8.1 , 8.2 ) , Pati e nt C ouns e ling I nformatio n ]. 5. 6 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with FIORINAL with CODEINE requires careful consideration of the effects on codeine and the active metabolite, morphine. Cytochrome P450 3A4 Interaction The concomitant use of FIORINAL with CODEINE with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. The concomitant use of FIORINAL with CODEINE with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Follow patients receiving FIORINAL with CODEINE and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when FIORINAL with CODEINE is used in conjunction with inhibitors and inducers of CYP3A4. If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of FIORINAL with CODEINE until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the FIORINAL with CODEINE dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. [ Drug Interactions ( 7 )]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of FIORINAL with CODEINE with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. Follow patients receiving FIORINAL with CODEINE and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when FIORINAL with CODEINE are used in conjunction with inhibitors of CYP2D6. If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the FIORINAL with CODEINE dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the FIORINAL with CODEINE dosage and follow the patient for signs and symptoms of respiratory depression or sedation. [see Drug Interactions ( 7 )]. 5. 7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of FIORINAL with CODEINE 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: FIORINAL with CODEINE-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 FIORINAL with CODEINE [see Warnings and Precautions ( 5.7 )]. 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 and Precautions ( 5.7 )]. Monitor such patients closely, particularly when initiating and titrating FIORINAL with CODEINE and when FIORINAL with CODEINE is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 )]. Alternatively, consider the use of non-opioid analgesics in these patients. 5. 8 Interaction with Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeines active metabolite, including respiratory depression, coma, and confusion. FIORINAL with CODEINE should not be used in patients taking MAOIs or within 14 days of stopping such treatment. 5. 9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one 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. 5. 10 Severe Hypotension FIORINAL with CODEINE 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 Drug Interactions ( 7 )]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of FIORINAL with CODEINE. In patients with circulatory shock, FIORINAL with CODEINE may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of FIORINAL with CODEINE in patients with circulatory shock. 5. 11 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), FIORINAL with CODEINE 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 FIORINAL with CODEINE. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of FIORINAL with CODEINE in patients with impaired consciousness or coma. 5. 12 Risks of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease FIORINAL with CODEINE is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The codeine in FIORINAL with CODEINE 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. Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. The aspirin in FIORINAL with CODEINE can cause GI side effects including stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. 5. 13 Increased Risk of Seizures in Patients with Seizure Disorders The codeine in FIORINAL with CODEINE 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 FIORINAL with CODEINE therapy. 5. 14 Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including FIORINAL with CODEINE. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. When discontinuing FIORINAL with CODEINE in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration ( 2.3 )]. Do not abruptly discontinue FIORINAL with CODEINE in these patients [see Drug Abuse and Dependence ( 9.2 , 9.3 )]. 5. 15 Risks of Driving and Operating Machinery FIORINAL with CODEINE 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 FIORINAL with CODEINE and know how they will react to the medication. 5.1 6 Coagulation Abnormalities and Bleeding Risks Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (i.e. hemophilia) or acquired (i.e. liver disease or vitamin K deficiency) bleeding disorders. Aspirin is contraindicated in patients with hemophilia. Aspirin administered pre-operatively may prolong the bleeding time. Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. 5.1 7 Reyes Syndrome Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses. 5.1 8 Allergy Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products (NSAIDs) and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). 5. 19 Drug/Laboratory Test Interactions Aspirin: Aspirin may interfere with the following laboratory determinations in blood: serum amylase,fasting blood glucose, cholesterol, protein, serum glutamic-oxalacetic transaminase (SGOT), uric acid,prothrombin time and bleeding time. Aspirin may interfere with the following laboratory determinationsin urine: glucose, 5-hydroxy-indoleacetic acid, Gerhardt ketone, vanillylmandelic acid (VMA), uricacid, diacetic acid, and spectrophotometric detection of barbiturates. Codeine: Codeine may increase serum amylase levels.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Table 1 includes clinically significantdrug interactions with FIORINAL with CODEINE. Table 1: Clinically Significant Drug Interactions with FIORINAL with CODEINE Inhibitors of CYP3A4 Clinical Impact: The concomitant use of FIORINAL with CODEINE with CYP3A4 inhibitors may result in an increase in codeine plasma concentrationswith subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of FIORINAL with CODEINE is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [ see Clinical Pharmacology ( 12.3 ) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. Intervention: If concomitant use with CYP3A4 inhibitor is necessary, consider dosage reduction of FIORINAL with CODEINE until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the FIORINAL with CODEINE dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of FIORINAL with CODEINE and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology ( 12.3 )], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see Warnings and Precautions ( 5.14 )]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the codeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology( 12.3 )], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the FIORINAL with CODEINE dosage as needed. If a CYP3A4 inducer is discontinued, considerFIORINAL with CODEINEdosage reduction, and monitor for signs of respiratory depression and sedation at frequent intervals. Examples Rifampin, carbamazepine, phenytoin Inhibitors of CYP2D6 Clinical Impact: Codeine in FIORINAL with CODEINE is metabolized by CYP2D6 to form morphine. The concomitant use of FIORINAL with CODEINE and CYP2D6 inhibitors can increase the plasma concentration of codeine, butcan decrease the plasma concentrations of active metabolitemorphine which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of FIORINAL with CODEINE is achieved [see Clinical Pharmacology ( 12.3 )]. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of FIORINAL with CODEINE and monitor patients closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the FIORINAL with CODEINE as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the FIORINAL with CODEINE and monitor the patient for signs and symptoms of respiratory depression or sedation. Examples paroxetine, fluoxetine, bupropion, quinidine Benzodiazepines and other Central Nervous System (CNS) Depressants Clinic a l Im p act: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Inter v entio n : Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.3 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinic a l Im p act: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmittersystemhasresultedinserotoninsyndrome. Inter v entio n : If concomitant use is warranted, carefully observe the patient, particularlyduring treatment initiation and dose adjustment. Discontinue FIORINAL with CODEINE if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors(SSRIs), serotonin andnorepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine,trazodone, tramadol), monoamine oxidase (MAO) inhibitors(those intended to treat psychiatric disordersand also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinic a l Im p act: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.8 )]. Inter v entio n : Do not use FIORINAL with CODEINE in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and P a rti a l Agonist Opioid A n algesics Clinic a l Im p act: May reduce the analgesic effect ofFIORINAL with CODEINE and/or precipitate withdrawalsymptoms. Inter v entio n : Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine, Muscle Relaxants Clinic a l Im p act: Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Inter v entio n : Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of FIORINAL with CODEINE and/or the muscle relaxant as necessary. Diuretics Clinic a l Im p act: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretichormone. Inter v entio n : Monitorpatientsforsignsofdiminisheddiuresisand/oreffectsonbloodpressure andincreasethedosageofthediureticasneeded. The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Anticholinergic Drugs Clinic a l Im p act: The concomitant use of anticholinergicdrugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Inter v entio n : Monitorpatients forsignsofurinaryretentionorreducedgastricmotilitywhenFIORINAL with CODEINE is used conco m ita n tly with a n ti c holin e rgic d rugs. Anticoagulants Clinic a l Im p act: Aspirin may enhance the effects of anticoagulants. Concurrent use may increase the risk of bleeding. Aspirin can also displace warfarin from protein binding sides, leading to prolongation of both the prothrombin time and the bleeding time. Inter v entio n : Monitor patients for signs of bleeding. Examples: Warfarin, heparin, enoxaparin, clopidogrel, prasugrel, rivaroxaban, apixaban Uricosuric Agents Clinic a l Im p act: Aspirin inhibits the uricosuric effects of uricosuric agents. Inter v entio n : Avoid concomitant use. Examples: Probenecid Carbonic Anhydrase Inhibitors Clinical Impact: Concurrent use with aspirin can lead to high serum concentrations of the carbonic anhydrase inhibitor and cause toxicity due to competition at the renal tubule for secretion. Intervention: Consider reducing the dose of the carbonic anhydrase inhibitor and monitor patient for any adverse effects from the carbonic anhydrase inhibitor. Examples: Acetazolamide, methazolamide Methotrexate Clinic a l Im p act: Aspirin may enhance the toxicity of methotrexate by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Inter v entio n : Use caution if using concomitantly, especially in elderly patients or patients with renal impairment. Monitor patients for methotrexate toxicity. Nephrotoxic Agents Clinical Impact: Concomitant use with aspirin may lead to additive nephrotoxicity due to the inhibition of renal prostaglandins by aspirin. Also, the plasma concentration of aspirin is increased by conditions that reduce the glomerular filtration rate or tubular secretion. Intervention: Use FIORINAL with CODEINE with caution if used concomitantly with nephrotoxic agents. Closely monitor the renal function of patients Examples: Aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, cyclosporine, foscarnet, or parenteral vancomycin Angiotensin Converting Enzyme (ACE) Inhibitors Clinical Impact: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Intervention: Use caution if using concomitantly. Monitor the blood pressure and renal function of patients. Examples: Ramipril, captopril Beta Blockers Clinical Impact: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Intervention: Use caution if using concomitantly. Monitor the blood pressure and renal function of patients Examples: Metoprolol, propranolol Hypoglycemic Agents Clinical Impact: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Intervention: Patients should be advised to consult a physician if any signs or symptoms of hypoglycemia occur. Examples: Insulin, glimepiride, glipizide Anticonvulsants Clinical Impact: Aspirin can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Intervention: Use caution if using concomitantly. Examples: Phenytoin, valproic acid Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Clinic a l Im p act: Concurrent use with aspirin may increase the risk of bleeding or lead to decreased renal function. Aspirin may enhance serious side effects and toxicity of ketorolac by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Inter v entio n : Avoid concomitant use. Examples: Ketorolac, ibuprofen, naproxen, diclofenac Corticosteroid s Clinic a l Im p act: Inpatientsreceivingconcomitantcorticosteroidsandchronicuseofaspirin,withdrawalofcorticosteroidsmayresultinsalicylismbecausecorticosteroidsenhancerenal clearanceofsalicylatesandtheirwithdrawalisfollowedbyreturntonormalratesofrenalclearance. Inter v entio n : Avoid concomitant use Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue FIORINAL with CODEINE if serotonin syndrome is suspected. (7) Mixed Agonist/Antagonist a nd Partial Agonist Opioid Analgesics: Avoid use withFIORINAL with CODEINE because they may reduce analgesic effect of FIORINAL with CODEINE or precipitate withdrawal symptoms. (7)

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-termstudies in animals to evaluate the carcinogenic potential of the combination of butalbital, aspirin, caffeine, and codeine or butalbital alone have not been conducted. Administration of aspirin for 68 weeks at 0.5 percent in the feed of rats was not carcinogenic. Two-year carcinogenicity studies with codeine sulfate have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of codeine sulfate (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) for two years. Similarly there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of codeine sulfate (approximately 10 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) for two years. In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 4 and 7 times, respectively, the maximum human daily dose on a mg/m2 basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg (equivalent to the MHDD on a mg/m2 basis). Mutagenesis There are no genetic toxicology data for butalbital. Codeine sulfate was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay. Aspirin is not mutagenic in the Ames Salmonella assay; however, aspirin did induce chromosome aberrations in cultured human fibroblasts Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay.Caffeine was negative in the in vitro bacterial reverse mutation assay (Ames test). Impairment of Fertility No adequate studies have been conducted in animals to characterize the impact of the combinations of butalbital, aspirin, caffeine, and codeine on fertility. There are also no data on butalbital alone or codeine alone. Aspirin inhibits ovulation in rats. Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcutaneously (2 times the MHDD on a mg/m2 basis) for 4 days prior to mating with untreated females, caused decreased male reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Pregnancy:May cause fetal harm(8.1) Lactation: Breastfeeding not recommended. (8.2) 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. [see Warnings and Precautions ( 5.5 )].Use of aspirin, including FIORINAL with CODEINE, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including FIORINAL with CODEINE, in pregnant women starting at 30 weeks of gestation (third trimester). Available data with FIORINAL with CODEINE n pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies have not been conducted with the combination of butalbital, acetaminophen, caffeine, and codeine phosphate capsules or with butalbital alone. In animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 2.8 times maximum recommended human dose (MRHD) of 180 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 4 to 6 times the MRHD, and cranial malformations/ cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as aspirin, resulted in increased pre- and post-implantation loss. The 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. AlthoughFIORINAL withCODEINEwasnotimplicatedinthebirthdefect,afemale infantwasbornwithlissencephaly, pachygyriaandheterotopicgraymatter. Theinfant wasborn8weeks prematurely toawomanwhohadtaken anaverageof90FIORINALwithCODEINEeachmonth fromthefirstfewdaysofpregnancy. Thechilds developmentwasmildly delayedandfromoneyearofageshehadpartial simple motorseizures. Withdrawalseizureswerereportedinatwo-day-oldmaleinfantwhosemother had takenabutalbital-containingdrugduringthelast2monthsofpregnancy.Butalbital was foundintheinfantsserum. Theinfantwasgivenphenobarbital5mg/kg,whichwastaperedwithoutfurther seizureorotherwithdrawalsymptoms. Studies ofaspirinuse inpregnantwomen havenotshownthat aspirinincreasestherisk ofabnormalitieswhenadministeredduringthefirst trimesterofpregnancy.In controlledstudies involving41,337 pregnantwomenandtheiroffspring,therewasnoevidencethataspirin takenduring pregnancycaused stillbirth,neonataldeathor reducedbirthweight.Incontrolledstudies of50,282 pregnantwomenandtheiroffspring,aspirin administrationinmoderateandheavydosesduring the firstfourlunar monthsofpregnancyshowednoteratogeniceffect. Therapeuticdosesofaspirin inpregnantwomenclosetotermmaycausebleedinginmother,fetus,orneonate.Duringthe last6monthsofpregnancy,regularuseof aspirininhighdosesmayprolong pregnancyanddelivery. 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 and Precautions ( 5.5 )]. Labor or Delivery There are no studies on the effects of FIORINAL with CODEINE during labor or delivery. In animal studies, NSAIDS, including aspirin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Opioids such as codeine 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. FIORINAL with CODEINE is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including FIORINAL with CODEINE, 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. Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported. Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. Use during pregnancy, especially in the third trimester, should be avoided. Data Animal Data Animal reproduction studies have not been conducted with the combination of butalbital, aspirin, caffeine, and codeine phosphate capsules or with butalbital alone. Codeine In a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 14 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral; approximately 4 to 16 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis), reportedly produced cranioschisis in all of the fetuses examined. In studies in rats, doses at the 120 mg/kg level (oral; approximately 6 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 2.8 times the recommended daily dose of 180 mg/day for adults on a mg/mg2 basis) administered between Gestation Day 7 and 12 reportedly resulted in delayed ossification in the offspring. No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) of codeine during organogenesis. Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 1.6 times the maximum recommended human dose of 180 mg/day on a body surface area comparison. Caffeine In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained release pellets at 50 mg/kg (less than the maximum recommended daily dose on a mg/m2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. 8. 2 Lactation Risk Summary C od e ine a nd its ac tive m e t a bolit e , mo r phin e , a r e p re s e nt in hum a n milk. Th er e a r e publish e d studi e s a nd ca s e s th at h a ve re p o r t ed e x ce s s ive s e d a tion, re spi r a to r y d e p re ssion, a nd d ea th in in fa nts e x pos e d toc od e ine via b r ea st milk. W om e n who ar e ult ra - r a pid m e t a boli z er s of c od e i ne ac hi e v e h i g h er th an e x p ec t eds er um l e v e ls of mo r phin e , pot e nti a l l y l ea di n g to h i g h e r l e v e ls of mo r phi n e in b rea st milk th a t ca n be d a ng er ousin th e ir b rea st f ed in fa nts. Inwomen withnormal codeinemetabolism(normalCYP2D6activity),theamount ofcodeinesecretedinto humanmilkislowand dose-dependent.Thereis no information on the effects ofthe codeineon milk production. Becauseofthepotential forserious adverse reactions, includingexcess sedation, respiratorydepression, and death in abreastfed infant, advisepatients that breastfeedingis not recommended duringtreatment with FIORINAL with CODEINE (seeW arnin g s and Pr ec autions, 5.6 ). The aspirin and caffeine in FIORINAL with CODEINE are also excreted in breast milk in small amounts. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Furthermore, nursing women are advised against aspirin use because of the possible development of Reye's Syndrome in their babies. Barbiturates and caffeine are also excreted in breast milk in small amounts. Because of potential for serious adverse reactions in nursing infants from Butalbital, aspirin, caffeine, and codeine phosphate capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Clinical Considerations Ifinfants are exposedto FIORINALwith CODEINE through breast milk, theyshould bemonitoredfor excess sedation and respiratorydepression. Withdrawal symptoms can occurin breastfed infants when maternal administrationof an opioid analgesicisstopped, orwhen breast-feedingis stopped. 8.3 Females and Males of Reproductive Potential 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 ( 6.2 ) , Clinical Pharmacology ( 12.2 )], Nonclincical Pharmacology ( 13.1 ) ]. Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including aspirin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including aspirin, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8. 4 Pediatric Use Preparations containing aspirin should be kept out of the reach of children. Reye's Syndrome is a rare condition that affects the brain and liver and is most often observed in children given aspirin during a viral illness. Safety andeffectivenessinpediatricpatientshavenot beenestablished. Thesafetyand effectiveness ofFIORINALwithCODEINE in pediatricpatients havenot been established. Life-threatening respiratory depression and death have occurred in children who received codeine [see Warnings and Precautions ( 5.4 )]. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine.Because of the risk of life-threatening respiratory depression and death: FIORINAL with CODEINE is contraindicated for all children younger than 12 years of age [see Contraindications ( 4 )] . FIORINAL with CODEINE is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )] . Avoid the use of FIORINAL with CODEINE in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression[see Warnings and Precautions ( 5.4 )]. 8. 5 Geriatric Use Clinical studies ofFIORINAL withCODEINEdidnotinclude sufficientnumbersofsubjects aged65andovertodeterminewhether theyrespond differentlyfromyounger subjects.Other reportedclinicalexperiencehasnotidentifieddifferencesin responsesbetweentheelderlyandyoungerpatients.In general,doseselectionforan elderly patient should becautious,usuallystartingatthe lowendofthe dosing range,reflectingthe greater frequencyofdecreasedhepatic,renal,orcardiacfunction, andof concomitantdiseaseor other drugtherapy. Butalbital is known to be substantially excreted by the kidney, and the risk of toxic 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. Elderly patients (aged 65 years or older) may have increased sensitivity to FIORINAL with CODEINE. 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 FIORINAL with CODEINEslowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [ see Warnings and Pre cautions ( 5.7 )]. Components of this product areknown 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. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions.If the anticipated benefit for the elderly patient outweighs these potential risks,dose selection should start at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions ]. 8.6 Hepatic Impairment No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of aspirin, codeine and butalbital in this patient population are unknown. Start these patients cautiously with lower doses of FIORINAL with CODEINE or with longer dosing intervals and titrate slowly while carefully monitoring for side effects.In patients with severe hepatic disease, monitor effects of therapy with serial liver function tests. 8.7 Renal Impairment FIORINAL with CODEINE contains aspirin, which should be avoided in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute). Codeinepharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients cautiously with lower doses of FIORINAL with CODEINE or with longer dosing intervals and titrate slowly while carefully monitoring for side effects.In patients with renal disease, monitor effects of therapy with serial renal function tests.

RECENT MAJOR CHANGES SECTION.


Boxed Warning 08/2017 Indication and Usage (1) 12/2016 Dosage and Administration (2) 12/2016 Contraindications (4) 08/2017 Warnings and Precautions (5) 08/2017

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling( MedicationGuide ). Addiction, Abuse, and Misuse Informpatients that the use of FIORINAL with CODEINE, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1 ) ] . Instruct patients not to share FIORINAL with CODEINE with others and to take steps to protect FIORINAL with CODEINE from theft or misuse. Life-Threatening Res p iratory Depression Informpatients of the risk of life-threatening respiratory depression, including informationthattheriskis greatest when starting FIORINAL with CODEINE or when the dosage isincreased, and that it can occur evenat recommended dosages[see Warnings and Precautions ( 5.2 ) ]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingest ion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death.Instruct patients to take steps to store FIORINAL with CODEINE securely and to properly dispose of unused FIORINAL with CODEINE in accordance with the local state guidelines and/or regulations. Risks from Concomitant Use with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if FIORINAL with CODEINE is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )]. Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children Advise caregivers that FIORINAL with CODEINE is contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12-18 years of age receiving FIORINAL with CODEINE to monitor for signs of respiratory depression [see Warnings and Precautions ( 5.4 )] . Serotonin S yndro m e Informpatients that opioids could cause a rare butpotentially 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 informtheir healthcare providersif they are taking, or plan to take serotonergicmedications.[see Drug Interactions ( 7 ) ]. MAOI Interaction Inform patients not to take FIORINAL with CODEINE while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking FIORINAL with CODEINE [see Drug Interactions ( 7 )]. Adrenal In s ufficiency Informpatientsthat 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 aconstellation ofthese symptoms[s e e Warnings and Precautions ( 5.9 ) ]. I m portant Ad m i nistration Instructions Instruct patients how to properly take FIORINAL with CODEINE. [ s ee Dosage and Administration ( 2.2 ) ].Patientsshould takethe drugonlyfor aslongasitisprescribed,inthe amountsprescribed,andnomorefrequentlythan prescribed. Hypotension Informpatients that FIORINAL with CODEINE may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of seriousconsequencesshould hypotension occur (e.g., sit or lie down, carefully rise froma sitting or lying position) [see Warnings and Precautions ( 5.10 ) ]. Anaphylaxis Informpatients that anaphylaxis has been reportedwith ingredients contained in FIORINAL with CODEINE. Advise patients howto recognize such a reaction and when to seek medical attention[see Contraindications ( 4 ) , Adverse Reactions ( 6 ) ] . Aspirin Allergy PatientsshouldbeinformedthatFIORINALwithCODEINEcontainsaspirinandshouldnotbetaken bypatientswithanaspirin or NSAIDs allergy[see Warnings and Precautions ( 5.18 )]. Pregnancy Neonatal Opioid Withdrawal Syndrome Informfemale patients of reproductive potential that prolonged use of FIORINAL with CODEINE during pregnancy can result in neonatal opioid withdrawalsyndrome,whichmaybelife-threatening if notrecognized and treated[see Warnings and Precautions ( 5.5 ) , Use in Specific Populations ( 8.1 ) ] . Embryo-Fetal Toxicity Informfemale patients of reproductive potential that FIORINAL with CODEINE can (or may) cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy[see Use in Specific Populations ( 8.1 ) ] . Lactation Advise wom e n th a t b r e a s t fee di n g is not rec omm e n d e d du r i n g t rea tm e nt wi t h F I O R I NA L withC OD E I NE[see Use in Specific Populations ( 8.2 ) ]. Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. Risk of Bleeding Inform patients about the signs and symptoms of bleeding. Tell patients to notify their physician if they are prescribed any drug which may increase risk of bleeding. Counsel patients who consume three or more alcoholic drinks daily about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin [see Warnings and Precautions ( 5.16 )]. Driving or Operating H eavy Machinery Informpatients that FIORINAL with CODEINE may impair the ability to performpotentially hazardous activities such as driving a caror operatingheavy machinery. Advise patients not to perform such tasksuntil they know how they will react to the medication [see Warnings and Precautions ( 5.15 ) ]. Constipation Advise patients of the potential forsevere constipation, including management instructions and when to seek medical attention [see A dverse Reactions ( 6 ) ]. Disposal of Unused FIORINAL with CODEINE Advise patients to properly dispose of unused FIORINAL with CODEINE 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 the local state guidelines and/or regulations. Distributed By: Allergan USA, Inc. Irvine, CA 92612 2017 Allergan. All rights reserved.

CLINICAL STUDIES SECTION.


14 CLINICAL TRIALS Evidence supporting the efficacy of FIORINAL with CODEINE is derived from 2 multi-clinic trials that compared patients with tension headache randomly assigned to 4 parallel treatments: FIORINAL with CODEINE, codeine, Fiorinal (butalbital, aspirin, and caffeine capsules, USP), and placebo. Response was assessed over the course of the first 4 hours of each of 2 distinct headaches, separated by at least 24 hours FIORINAL with CODEINE proved statistically significantly superior to each of its components (Fiorinal, codeine) and to placebo on measures of pain relief. Evidence supporting the efficacy and safety of FIORINAL with CODEINE in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because codeine and butalbital are habit-forming and potentially abusable.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Butalbital, a barbiturate, is a GABAA receptor agonist and may inhibit excitatory AMPA receptors. Aspirin is a nonsteroidal anti-inflammatory drug and a non-selective irreversible inhibitor of cyclooxygenases. Caffeine is a methylxanthine and CNS stimulant. The exact mechanism with respect to the indication is not clear; however, the effects of caffeine may be due to antagonism of adenosine receptors. Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown. 12.2 Pharmacodynamics Effects on the Central Nervous System Butalbital, a barbiturate, is a central nervous system (CNS) depressant that can produce sedation, respiratory depression, and euphoria. The potential impact of butalbital on painful stimuli is not clear and in some individuals barbiturates may increase reaction to painful stimuli. Codeine produces respiratory depression by directaction on brain stemrespiratory centers. The respiratory depression involves a reduction in the responsiveness of thebrain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Codeine causes miosis, even in total darkness. Pinpoint pupils are a sign ofopioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic orischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia inoverdose situations. Aspirin works by inhibiting the bodys production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever, however, other mechanisms may be involved. Effects on the Gastrointestinal Tract and Other Smooth Muscle Codeine causes areduction inmotility associated withan increase in smooth muscle tone inthe 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, spasmof sphincter of Oddi, and transient elevations in serumamylase. Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood, but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing. Effects on the Cardiovascular System Butalbital may decrease blood pressure and heart rate when administered at sedative and hypnotic doses. Codeine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histaminerelease and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating. and/or orthostatic hypotension. Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclooxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor, thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. Effects on the Endocrine System Opioids inhibit the secretion ofadrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans[ see Adverse Reactions ( 6.2 ) ]. They also stimulate prolactin, growth hormone (GH) secretion, andpancreaticsecretionof 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 ( 6.2 )]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune systemin in vitro and animal models. The clinical significance of these findings is unknown. Overall,the effects of opioids appear to be modestly immunosuppressive. ConcentrationEfficacy 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 codeine 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 ( 2.1 , 2.2 ) ]. ConcentrationAdverse Reaction Relationships There is a relationship between increasing codeine 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 oftolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.2 , 2.3 ) ]. 12.3 Pharmacokinetics Bioavailability: ThebioavailabilityofthecomponentsofthefixedcombinationofFIORINAL withCODEINEisidenticaltotheirbioavailabilitywhenFiorinal(Butalbital,Aspirin,andCaffeineCapsules,)andcodeineareadministeredseparatelyin equivalentmolar doses. Thebehaviorofthe individualcomponentsisdescribedbelow Aspirin Absorption Thesystemicavailabilityofaspirin afteranoraldoseishighly dependentonthe dosage form,the presenceoffood,the gastric emptyingtime,gastric pH,antacids, bufferingagents,andparticlesize.Thesefactors affectnot necessarilythe extentofabsorptionoftotalsalicylatesbut morethe stabilityofaspirin priortoabsorption. Distribution During theabsorptionprocess and afterabsorption,aspirinismainlyhydrolyzedtosalicylicacidand distributedtoallbodytissuesand fluids,includingfetaltissues, breast milk,andthe centralnervoussystem(CNS).Highestconcentrationsare found inplasma,liver,renalcortex,heart, andlung.Inplasma,about 50%-80%ofthe salicylicacidanditsmetabolitesare looselybound toplasmaproteins. Elimination Metabolism The biotransformation of aspirin occurs primarily in the hepatocytes. The major metabolites are salicyluric acid (75%), the phenolic and acyl glucuronides of salicylate (15%), and gentisic and gentisuric acid (1%). The bioavailability of the aspirin component of FIORINAL with CODEINE is equivalent to that of a solution except for a slower rate of absorption. A peak concentration of 8.8 mcg/mL was obtained at 40 minutes after a 650 mg dose. Excretion The clearance of total salicylates is subject to saturable kinetics; however, first-order elimination kinetics are still a good approximation for doses up to 650 mg. The plasma half-life for aspirin is about 12 minutes and for salicylic acid and/or total salicylates is about 3 hours. The elimination of therapeutic doses is through the kidneys either as salicylic acid or other biotransformation products. The renal clearance is greatly augmented by an alkaline urine as is produced by concurrent administration of sodium bicarbonate or potassium citrate. Codeine Absorption Codeine is readily absorbed from the gastrointestinal tract.The bioavailability of the codeine component of FIORINAL with CODEINE is equivalent to that of a solution. Peak concentrations of 198 ng/mL were obtained at 1 hour after a 60 mg dose. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. Distribution Itisrapidlydistributedfromtheintravascularspacesto thevariousbodytissues,withpreferentialuptakeby parenchymatousorganssuchas theliver, spleen,andkidney.Codeinecrossestheblood-brainbarrier,andisfoundinfetaltissueandbreastmilk.Theplasma concentrationdoesnot correlatewithbrainconcentrationorreliefofpain,however,codeineisnot boundtoplasmaproteinsanddoesnot accumulateinbodytissues. Elimination Metabolism About 70-80% of administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6glucuronide (C6G) and via O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucurodination of codeine to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of codeine to morphine and P450 3A4 is the major enzyme mediating conversion of codeine to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are known to have analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties. Excretion The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide-conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces. Butalbital Absorption Butalbital is well absorbed from the gastrointestinal tract. The bioavailability of the butalbital component of FIORINAL with CODEINE is equivalent to that of a solution except for a decrease in the rate of absorption. A peak concentration of 2,020 ng/mL is obtained at about 1.5 hours after a 100 mg dose. Distribution Butalbitalisexpectedto distributeto mostof thetissuesin thebody. Barbiturates,in general,mayappearinbreast milkandreadily crossthe placentalbarrier.Theyare bound toplasmaandtissueproteinstoavaryingdegree andbindingincreasesdirectlyasafunctionoflipid solubility. The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20 mcg/mL. This falls within the range of plasma protein binding (20% to 45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells. Elimination Elimination of butalbital is primarily via the kidney (59% to 88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products included parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% was conjugated. Caffeine Absorption Likemostxanthines,caffeineisrapidlyabsorbed. Thebioavailability ofthecaffeine componentforFIORINAL withCODEINEisequivalenttothatofasolution exceptforaslightly longertimetopeak.Apeakconcentrationof1,660 ng/mLwasobtainedinlessthananhourfor an80mgdose.anddistributedinallbodytissues andfluids, includingthe CNS,fetaltissues,andbreastmilk. Distribution Caffeine isdistributedinallbodytissues andfluids, includingthe CNS,fetaltissues,andbreastmilk. Elimination Caffeineisclearedrapidlythrough metabolismand excretionintheurine. Metabolism Caffeine is mainly metabolized by CYP1A2. Other enzymes, including CYP2E1, CYP3A4, CYP2C8 and CYP2C9 may play a minor role in its metabolism. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methylxanthine and 1-methyluric acid. Excretion Of the 70%ofthe dosethathasbeenrecoveredinthe urine, only3%wasunchangeddrug.The plasmahalf-lifeisabout3hours.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS FIORINAL with CODEINE is contraindicatedfor : All children younger than 12 years of age [see Warnings and Precautions (5.4)] Postoperative management in children younger than 18 years of age followingtonsillectomy and/or adenoidectomy[see Warnings and Precautions (5.4)] . FIORINAL with CODEINE is also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.7 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.7 )] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.8 )/Drug Interactions ( 7 )]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 )] Hypersensitivity or intolerance to aspirin, caffeine, butalbital, or codeine. Hemophilia [see Warnings and Precautions ( 5.16 )] Reyes Syndrome [see Warnings and Precautions ( 5.17 )] Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions ( 5.18 )] Syndrome of asthma, rhinitis, and nasal polyps [see Warnings and Precautions ( 5.18 )] Children younger than12years of age (4) Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (4) Significant respiratory depression (4) Acute or severe bronchial asthma (4) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (4) Known or suspected gastrointestinal obstruction, including paralytic ileus (4) Hypersensitivity to aspirin, caffeine, butalbital, or codeine(4) Hemophilia (4) Reyes Syndrome (4) Known allergy to NSAIDs(4) Syndrome of asthma, rhinitis, and nasal polyps (4)