Hydrocodone bitartrate and ibuprofen tablet, film coated
Spl unclassified section
H y d r o c o d o n e B i t a rtr a t e a n d I b u p r o f e n T a b l et s
7.5 m g/200 m g
C - II
Warning: addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; cytochrome p450 3a4 interaction; risks from concomitant use with benzodiazepines or other cns depressants; and serious cardiovascular and gastrointestinal events
Addiction, Abuse, and Misuse
Hydrocodone bitartrate and ibuprofen tablet 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 hydrocodone bitartrate and ibuprofen tablets , and monitor all patients regularly for the development of these behaviors and conditions (see WARNINGS: Addiction, Abuse, and Misuse ).
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of hydrocodone bitartrate and ibuprofen tablets . Monitor for respiratory depression, especially during initiation of hydrocodone bitartrate and ibuprofen tablets or following a dose increase (see WARNINGS: Life-Threatening Respiratory Depression ).
Accidental ingestion of even one dose of hydrocodone bitartrate and ibuprofen tablets , especially by children, can result in a fatal overdose of hydrocodone (see WARNINGS: Life-Threatening Respiratory Depression ).
Neonatal Opioid Withdrawal Syndrome
Prolonged use of hydrocodone bitartrate and ibuprofen tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see WARNINGS: Neonatal Opioid Withdrawal Syndrome ).
Cytochrome P450 3A4 Interaction
The concomitant use of hydrocodone bitartrate and ibuprofen tablets with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients taking hydrocodone bitartrate and ibuprofen tablets and any CYP3A4 inhibitor or upon discontinuation of a CYP3A4 inducer for signs and symptoms of respiratory depression and sedation (see WARNINGS: Risks of Concomitant Use or Discontinuation of CytochromeP450 3A4 Inhibitors and Inducers , PRECAUTIONS: Drug Interactions ).
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: Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants , PRECAUTIONS: Drug Interactions ).
Reserve concomitant prescribing of
hydrocodone bitartrate and ibuprofen tablets
and benzodiazepines or other CNS
depressants for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
- Follow patients for signs and symptoms of respiratory depression and sedation.
Cardiovascular Thrombotic Events
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use
WARNINGS: Cardiovascular Thrombotic Events
- Hydrocodone bitartrate and ibuprofen tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS , WARNINGS: Cardiovascular Thrombotic Events ).
Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
D es cri p t ion
Each hydrocodone bitartrate and ibuprofen tablet contains:
Hydrocodone Bitartrate, USP 7.5 mg
Ibuprofen, USP 200 mg
Hydrocodone bitartrate and ibuprofenis supplied in a fixed combination tablet form for oral administration. Hydrocodone bitartrate and ibuprofencombines the opioid agonist, hydrocodone bitartrate, with the nonsteroidal anti-inflammatory (NSAID) agent, ibuprofen.
Hydrocodone bitartrate is a semisynthetic opioid agonist. Its chemical name is: 4,5 -epoxy-3 methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). Its chemical formula is: C 18H 21NO 3C 4H 6O 62H 2O, and the molecular weight is 494.50. Its structural formula is:
Ibuprofen is anonsteroidal anti-inflammatoryagent [non-selectiveCOX inhibitor]with analgesic and antipyreticproperties.Its chemical nameis: ()-2-( p-isobutylphenyl)propionic acid.Its chemical formulais: C 13H 18O 2, and themolecularweight is: 206.29.Its structural formulais:
Inactiveingredients in hydrocodone bitartrate and ibuprofentablets include: colloidal silicon dioxide, croscarmellose sodium, hypromellose 2910 3cP, hypromellose 2910 6cP, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polyethylene glycol 8000, polydextrose, pregelatinized starch, titanium dioxide and triacetin.
Mechanism of action
H y d r o c odone C ompon e n t
Hydrocodone is a full opioid agonist with relative selectivity for the mu-opioid receptor, althoughitcaninteractwithother opioidreceptorsathigher doses.Theprincipaltherapeutic actionofhydrocodoneisanalgesia.Likeallfullopioidagonists,thereisnoceilingeffectfor analgesiawithhydrocodone. Clinically,dosageistitratedtoprovideadequate analgesiaandmay belimited byadversereactions, includingrespiratoryand CNSdepression.
Theprecisemechanism ofthe analgesic action is unknown. However, specificCNSopioid receptors for endogenouscompounds with opioid-like activityhavebeen identified throughout thebrain and spinal cordand arethought to playarolein the analgesic effects ofthis drug.
I bu p r o fe n C ompon e nt
Ibuprofen has analgesic,anti-inflammatory, and antipyreticproperties.
Themechanism ofaction, likethat ofotherNSAIDs, is not completelyunderstood, but involves inhibition ofcyclooxygenase (COX-1and COX-2).
Ibuprofen is apotent inhibitorofprostaglandin synthesis in vitro.Ibuprofen concentrations reached duringtherapyhaveproduced in vivo effects. Prostaglandins sensitize afferent nerves and potentiatetheaction ofbradykinin in inducing pain in animal models. Prostaglandins are mediators ofinflammation. Becauseibuprofen is an inhibitorofprostaglandin synthesis, its modeof action maybedueto adecreaseofprostaglandins in peripheral tissues.
E ffec ts on the C e n t ra l N e r vous S y st e m
Hydrocodoneproducesrespiratorydepression bydirect action on brain stem respiratorycenters. The respiratorydepression involves a reduction inthe responsiveness ofthebrain stem respiratorycenters to both increases in carbon dioxidetension and electrical stimulation.
Hydrocodonecauses miosis, even in total darkness. Pinpoint pupils areasign ofopioid overdose but arenot pathognomonic (e.g., pontinelesions ofhemorrhagicorischemicorigins mayproducesimilar findings). Marked mydriasis ratherthan miosis maybeseen dueto hypoxiain overdosesituations.
E ffec ts on the G a st r oint e stin a l T rac t a nd Oth e r S mooth Mus c le
Hydrocodonecausesa reduction in motilityassociated with an increasein smooth muscletonein the antrum ofthestomach and duodenum. Digestion of food in thesmall intestineis delayed and propulsive contractions aredecreased. Propulsiveperistalticwaves in the colon aredecreased, whiletonemaybeincreased to thepoint ofspasm, resultingin constipation.Otheropioid-induced effects mayincludea reduction in biliaryand pancreaticsecretions, spasm ofsphincterofOddi, and transient elevations in serum amylase.
E ffec ts on the Ca r diov a s c ul ar S y s t em
Hydrocodoneproduces peripheral vasodilation, which mayresult in orthostatichypotension or syncope. Manifestations ofhistamine release and/orperipheral vasodilation mayincludepruritus, flushing, red eyes, sweating, and/ororthostatichypotension.
E ffec ts on the End o cr ine S y st em
Opioids inhibit thesecretion of adrenocorticotropichormone (ACTH), cortisol, and luteinizing hormone(LH)in humans ( s e e ADVERSE REACTIONS:Postmarketing Experience ). Theyalso stimulateprolactin, growth hormone (GH)secretion, and pancreaticsecretion ofinsulin and glucagon.
Chronicuseofopioids mayinfluencethehypothalamic-pituitary-gonadal axis,leadingto androgen deficiencythatmaymanifest as low libido, impotence, erectiledysfunction, amenorrhea, orinfertility. The causal roleofopioids in the clinical syndromeofhypogonadism is unknown becausethevarious medical, physical, lifestyle, and psychological stressors that may influencegonadal hormonelevels havenot been adequatelycontrolledforin studies conductedto date ( s e e ADVERSE REACTIONS:Postmarketing Experience ).
E ffec ts on the I mmu n e S y s t e m
Opioids havebeen shown to haveavarietyofeffects on components oftheimmunesystem in both in vitro and animal models. The clinical significanceofthesefindingsis unknown. Overall, the effects ofopioids appearto bemodestlyimmunosuppressive.
C on ce nt ra tion - E f f i ca c y R e l a tionships
Theminimum effective analgesic concentration will varywidelyamongpatients, especially amongpatients who havebeen previouslytreatedwith potent agonist opioids. Theminimum effective analgesic concentration ofhydrocodonefor anyindividual patientmayincreaseover timedueto an increasein pain, thedevelopmentofanew pain syndrome,and/orthe development of analgesictolerance ( s e e DOSAGEAND ADMINISTRATION ).
C on ce nt ra tion - Adv e r se R eac tion R e l a tionships
Thereis arelationship between increasinghydrocodoneplasma concentration and increasing frequencyofdose-relatedopioid adversereactionssuch as nausea, vomiting, CNSeffects, and respiratorydepression.Inopioid-tolerant patients, thesituation maybealtered bythe development oftoleranceto opioid-related adversereactions ( s e e DOSAGEAND ADMINISTRATION ).
Abso r ption
Afteroral dosingwith thehydrocodone bitartrate and ibuprofentablet, apeak hydrocodoneplasmalevel of27 ng/mL is achieved at 1.7 hours, and apeak ibuprofen plasmalevel of30 mcg/mL is achieved at 1.8 hours. The effect of foodon the absorption of either component from thehydrocodone bitartrate and ibuprofentablet has not been established.
Dist r ibution
Ibuprofen is highlyprotein-bound (99%)likemost othernon-steroidal anti-inflammatoryagents. Although the extent ofprotein bindingofhydrocodonein human plasmahas not been definitely determined, structural similarities to related opioid analgesics suggest thathydrocodoneis not extensivelyprotein bound. As most agents in the5-ringmorphinangroupofsemi-synthetic opioids bind plasmaprotein to asimilardegree (range19%[hydromorphone]to 45% [oxycodone]), hydrocodoneis expected to fall within this range.
Elimin a tion
Hydrocodoneexhibits acomplexpattern ofmetabolism, including O-demethylation, N- demethylation, and 6-keto reduction to the corresponding6--and 6--hydroxymetabolites. Hydromorphone, apotent opioid, is formed from the O-demethylation ofhydrocodoneand contributes to thetotal analgesic effect ofhydrocodone. The O- and N - demethylation processes aremediated byseparate P-450 isoenzymes: CYP2D6 and CYP3A4, respectively.
Ibuprofen is present in this product as aracemate,and following absorption it undergoes interconversion in theplasma from theR-isomerto theS-isomer. Both the R- and S-isomers are metabolized to two primarymetabolites: (+)-2-4'-(2hydroxy-2-methyl-propyl)phenyl propionic acid and (+)-2-4'-(2carboxypropyl)phenyl propionic acid, both ofwhichcirculatein theplasma at low levels relativeto theparent.
E xc r e tion
Hydrocodoneand its metabolites areeliminated primarilyin thekidneys, with amean plasma half-lifeof4.5 hours.Ibuprofen is excreted in theurine, 50%to 60% as metabolites and approximately15% as unchanged drug and conjugate. Theplasmahalf-lifeis 2.2 hours.
S p ec i f ic P opul a tions
No significant pharmacokineticdifferences basedon ageorgenderhavebeen demonstrated. The pharmacokinetics ofhydrocodone and ibuprofen from hydrocodone bitartrate and ibuprofentablets has not been evaluated in children.
R e nal I mpairm e nt
The effect ofrenal insufficiencyon thepharmacokinetics ofthehydrocodone bitartrate and ibuprofen tabletsdosage form has not been determined.
D r u g I nt e r ac tion S tudi e s
When NSAIDswere administered with aspirin, theprotein bindingofNSAIDs werereduced, although theclearanceoffreeNSAID was not altered. Theclinical significanceofthis interaction is not known ( s e e PRECAUTIONS:Drug Interactions ).
In single-dosestudies ofpost-surgical pain (abdominal, gynecological, orthopedic), 940 patients werestudiedat doses ofoneortwo tablets. Hydrocodone bitartrate and ibuprofen tabletsproducedgreater efficacythan placebo andeach ofits individual components given at thesamedose. No advantagewas demonstrated forthetwo-tablet dose.
Indications and usage
Hydrocodone bitartrate and ibuprofentablets areindicated fortheshort-term management of acutepain severe enough to require an opioid analgesicand forwhich alternativetreatments areinadequate.
Limitations of use
Carefullyconsiderthepotential benefits and risksofhydrocodone bitartrate and ibuprofen tabletsand othertreatment options beforedecidingto usehydrocodone bitartrate and ibuprofen tablets. Usethelowest effectivedosage fortheshortest duration consistent with individual patient treatmentgoals ( s e e WARNINGS:Cardiovascular Thrombotic Events , Gastrointestinal Bleeding, Ulceration, and Perforation ). Do not usehydrocodone bitartrate and ibuprofen tabletsfor thetreatment ofconditions such as osteoarthritisor rheumatoid arthritis.
Becauseofthe risks ofaddiction, abuse, and misusewith opioids, even at recommended doses ( s e e WARNINGS:Addiction, Abuse, and Misuse ),reservehydrocodone bitartrate and ibuprofen tabletsforusein patients for whom alternativetreatment options (e.g., non-opioid analgesics):
- Havenot been tolerated,or arenotexpected to betolerated,
- Havenot providedadequate analgesia, orarenot expected to provide adequate analgesia
Hydrocodone bitartrate and ibuprofen tabletsarecontraindicated in patients with:
- Significant respiratorydepression
- Acuteorseverebronchial asthmain an unmonitored settingorin theabsenceof resuscitative equipment
WARNINGS:Life-Threatening RespiratoryDepression in Patients with ChronicPulmonaryDiseaseor in Elderly, Cachectic, or Debilitated Patients
- Known orsuspectedgastrointestinal obstruction, includingparalyticileus
WARNINGS:Risks of Usein Patients with Gastrointestinal Conditions
- Known hypersensitivity(e.g.,anaphylactic reactions, serious skin reactions)to hydrocodone, ibuprofen,or anycomponents ofthedrugproduct
Serious Skin Reactions
).Patients known to behypersensitiveto otheropioids mayexhibit cross-sensitivityto hydrocodone.
- Historyofasthma, urticaria, orotherallergic-typereactions aftertaking aspirin orother NSAIDs. Severe, sometimes fatal, anaphylacticreactions to NSAIDs havebeen reported in such patients
Exacerbation of Asthma Related to Aspirin Sensitivity
- In thesettingofcoronaryarterybypass graft(CABG)surgery ( s e e WARNINGS: Cardiovascular ThromboticEvents ).
Addi c tion, abus e , a nd m isuse
Hydrocodone bitartrate and ibuprofen tablet contains hydrocodone,aScheduleIIcontrolled substance.As an opioid-containingproduct, hydrocodone bitartrate and ibuprofen tabletsexposes users to the risks of addiction, abuse, and misuse ( s e e DRUG ABUSE ANDDEPENDENCE ).
Although the risk ofaddiction in anyindividual is unknown, it can occurin patients appropriatelyprescribedhydrocodone bitartrate and ibuprofen tablets. Addiction can occur at recommended dosages and if thedrugis misused orabused.
Assess each patients risk foropioid addiction, abuse, ormisusepriorto prescribing hydrocodone bitartrate and ibuprofen tablets, and monitor all patients receivinghydrocodone bitartrate and ibuprofen tablets forthedevelopment ofthese behaviors andconditions. Risks areincreased in patients with apersonal orfamilyhistoryof substance abuse (includingdrugor alcohol abuseor addiction)ormental illness (e.g., major depression). Thepotential forthese risks should not, however, prevent thepropermanagement of pain in any given patient.Patients at increasedrisk maybeprescribed opioid-containingproducts such as hydrocodone bitartrate and ibuprofen tablets,but usein such patients necessitates intensivecounselingabout therisks and properuseofhydrocodone bitartrate and ibuprofen tablets alongwith intensivemonitoringforsignsof addiction, abuse, and misuse.
Opioids aresought bydrugabusers and peoplewith addiction disorders, and aresubject to criminal diversion. Considerthese risks when prescribingordispensing hydrocodone bitartrate and ibuprofen tablets. Strategies to reducetheserisks includeprescribing thedrugin thesmallest appropriatequantity and advisingthepatienton theproperdisposal ofunused drug ( s e e PRECAUTIONS: Information for Patients ). Contact local stateprofessional licensingboard orstate controlled substances authorityforinformationon how to prevent and detect abuseordiversion ofthis product.
Life-threatening respiratory depression
Serious, life-threatening,or fatal respiratorydepression has been reportedwith theuseof opioids, even when usedas recommended. Respiratorydepression, ifnot immediately recognized and treated,maylead to respiratoryarrest and death. Management of respiratory depression mayinclude closeobservation, supportivemeasures,and useofopioid antagonists, dependingon thepatients clinical status ( s e e OVERDOSAGE ). Carbon dioxide (CO 2) retention from opioid-induced respiratorydepression can exacerbatethesedating effects ofopioids.
Whileserious, life-threatening, orfatal respiratorydepression can occur atanytimeduringthe useofhydrocodone bitartrate and ibuprofen tablets, the risk is greatest duringtheinitiation oftherapyorfollowingadosage increase. Monitorpatients closelyforrespiratorydepression, especiallywithin the first24 to 72 hours ofinitiating therapywith and followingdosageincreases ofhydrocodone bitartrate and ibuprofen tablets.
To reducethe risk ofrespiratorydepression, properdosing and titration ofhydrocodone bitartrate and ibuprofen tablets are essential ( s e e DOSAGEAND ADMINISTRATION ). Overestimatingthehydrocodone bitartrate and ibuprofen tablets dosage when convertingpatients from anotheropioid product can result in a fataloverdosewith the first dose.
Accidental ingestion ofeven onedoseofhydrocodone bitartrate and ibuprofen tablets,especiallybychildren, canresult in respiratorydepression and death dueto an overdoseofhydrocodone bitartrate and ibuprofen tablets.
Neonatal opioid withdrawal syndrome
Prolonged useofhydrocodone bitartrate and ibuprofen tablets duringpregnancycan result in withdrawal in theneonate. Neonatal opioid withdrawal syndrome, unlikeopioid withdrawal syndromein adults, maybe life-threateningifnot recognized and treated, andrequires management accordingto protocols developed byneonatologyexperts. Observenewborns forsigns ofneonatalopioid withdrawal syndromeand manageaccordingly.Advisepregnant women usingopioids foraprolongedperiod ofthe risk ofneonatal opioid withdrawal syndrome and ensurethat appropriatetreatment will be available ( s e e PRECAUTIONS:Pregnancy , Information for Patients ).
Risks of concomitant use or discontinuation of cytochrome p450 3a4 inhibitors and inducers
Concomitant useofhydrocodone bitartrate and ibuprofen tablets with aCYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungalagents (e.g.,ketoconazole), and proteaseinhibitors (e.g., ritonavir), mayincreaseplasma concentrations of hydrocodoneand prolongopioid adverse reactions, which maycausepotentiallyfatal respiratorydepression ( s e e WARNINGS:Life- Threatening RespiratoryDepression ), particularlywhen an inhibitoris added afterastabledose ofhydrocodone bitartrate and ibuprofen tabletsis achieved. Similarly, discontinuation ofaCYP3A4 inducer, suchas rifampin, carbamazepine,and phenytoin, in hydrocodone bitartrate and ibuprofen tablets-treatedpatients mayincrease hydrocodoneplasmaconcentrations and prolongopioid adversereactions.When using hydrocodone bitartrate and ibuprofen tabletswith CYP3A4 inhibitors ordiscontinuingCYP3A4 inducers in hydrocodone bitartrate and ibuprofen tabletstreated patients, monitorpatients closelyat frequent intervals and considerdosage reduction of hydrocodone bitartrate and ibuprofen tablets until stabledrug effects areachieved ( s e e DOSAGE AND ADMINISTRATION , PRECAUTIONS:Drug Interactions ).
Concomitant useofhydrocodone bitartrate and ibuprofen tablets with CYP3A4 inducers ordiscontinuation ofaCYP3A4 inhibitor could decreasehydrocodoneplasmaconcentrations, decreaseopioid efficacyor, possibly, lead to awithdrawal syndromein apatient who had developed physical dependenceto hydrocodone. When usinghydrocodone bitartrate and ibuprofen tablets with CYP3A4 inducers ordiscontinuingCYP3A4 inhibitors, monitorpatients closelyat frequent intervals and considerincreasingtheopioid dosageifneeded to maintain adequateanalgesiaorifsymptoms ofopioidwithdrawal occur ( s ee DOSAGE AND ADMINISTRATION , PRECAUTIONS:Drug Interactions ).
Risks from concomitant use with benzodiazepines or other cns depressants
Profound sedation, respiratorydepression, coma, and death mayresult from the concomitant use ofhydrocodone bitartrate and ibuprofen tablets with benzodiazepines orotherCNSdepressants (e.g., non-benzodiazepine sedatives/hypnotics,anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, otheropioids, alcohol). Becauseofthese risks, reserveconcomitant prescribing ofthesedrugs foruseinpatients forwhom alternativetreatment options areinadequate.
Observational studies havedemonstrated thatconcomitant useofopioid analgesics and benzodiazepines increases the risk ofdrug-relatedmortalitycompared to useofopioid analgesics alone. Becauseofsimilarpharmacological properties, it is reasonableto expect similar risk with the concomitant useofotherCNSdepressant drugs with opioid analgesics ( s e e PRECAUTIONS: Drug Interactions ).
Ifthedecision is madeto prescribeabenzodiazepineorotherCNSdepressant concomitantly with an opioid analgesic,prescribethelowest effectivedosages and minimum durations of concomitant use.In patients alreadyreceivinganopioid analgesic, prescribealowerinitial dose ofthebenzodiazepineorotherCNSdepressant than indicated in the absenceof an opioid, and titratebased on clinicalresponse.Ifan opioid analgesicis initiated in apatient alreadytaking a benzodiazepineorotherCNSdepressant, prescribealowerinitial doseoftheopioid analgesic, and titratebased onclinical response.Follow patients closelyforsigns andsymptoms of respiratorydepression and sedation.
Adviseboth patients andcaregivers about therisks of respiratorydepression and sedation when hydrocodone bitartrate and ibuprofen tabletsare usedwith benzodiazepines orotherCNSdepressants (includingalcohol and illicit drugs). Advisepatients not to driveoroperateheavymachineryuntil the effects of concomitant useofthebenzodiazepineorotherCNSdepressant havebeendetermined. Screen patients for risk ofsubstanceusedisorders, includingopioid abuseand misuse, and warn them of the risk foroverdose anddeath associated with theuseof additional CNSdepressants including alcohol and illicit drugs ( s e e PRECAUTIONS:Drug Interactions , Information for Patients ).
Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients
Theuseofhydrocodone bitartrate and ibuprofen tablets in patients with acuteorseverebronchial asthmain an unmonitored settingorin the absenceof resuscitativeequipment is contraindicated.
Pati e nts w ith C hro n ic Pulmonary Dis e as e : Hydrocodone bitartrate and ibuprofen tablets-treated patients with significant chronicobstructivepulmonarydiseaseor corpulmonale, and thosewith asubstantiallydecreased respiratoryreserve, hypoxia, hypercapnia, orpre-existingrespiratorydepression are at increased risk ofdecreased respiratorydriveincludingapnea, even at recommended dosages of hydrocodone bitartrate and ibuprofen tablets ( s e e WARNINGS:Life-Threatening RespiratoryDepression ).
Eld e rl y , C a c h ec ti c , or D e bilitat e d Pati e nts: Life-threateningrespiratorydepression is more likelyto occurin elderly,cachectic, ordebilitated patients becausetheymayhave altered pharmacokinetics or altered clearance compared toyounger, healthierpatients ( s e e WARNINGS: Life-Threatening RespiratoryDepression ).
Monitorsuch patients closely, particularlywhen initiatingand titrating hydrocodone bitartrate and ibuprofen tabletsand whenhydrocodone bitartrate and ibuprofen tabletsaregivenconcomitantlywith otherdrugs that depress respiration ( s e e WARNINGS:Life-Threatening RespiratoryDepression ). Alternatively, considertheuseofnon-opioid analgesics in thesepatients.
Cases of adrenal insufficiencyhavebeenreportedwith opioid use, moreoften following greater than onemonth ofuse. Presentation of adrenal insufficiencymayincludenon-specificsymptoms and signs includingnausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.If adrenal insufficiencyis suspected, confirm thediagnosis with diagnostictestingas soon as possible.If adrenal insufficiencyis diagnosed, treat with physiologic replacement doses of corticosteroids. Weanthepatient offoftheopioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Otheropioids maybetried as some cases reported useofadifferent opioid without recurrenceof adrenalinsufficiency. Theinformation availabledoes not identifyanyparticularopioids as beingmorelikelyto be associated with adrenal insufficiency.
Hydrocodone bitartrate and ibuprofen tablets maycauseseverehypotension includingorthostatichypotension and syncopein ambulatorypatients. Thereis increased risk in patients whose abilityto maintain blood pressure has alreadybeencompromised byareduced blood volumeor concurrent administration of certain CNSdepressant drugs(e.g., phenothiazines orgeneral anesthetics) ( s e e PRECAUTIONS:Drug Interactions ). Monitorthesepatients forsigns ofhypotensionafterinitiatingortitratingthe dosageofhydrocodone bitartrate and ibuprofen tablets.In patients with circulatoryshock, hydrocodone bitartrate and ibuprofen tablets maycause vasodilation that can further reducecardiacoutput and blood pressure.Avoid theuseof hydrocodone bitartrate and ibuprofen tablets in patients with circulatoryshock.
Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness
In patients who maybesusceptibleto theintracranial effects ofCO 2retention (e.g., thosewith evidenceofincreased intracranial pressureorbrain tumors), hydrocodone bitartrate and ibuprofen tablets mayreduce respiratorydrive, and theresultant CO 2retention can furtherincreaseintracranial pressure. Monitorsuch patients forsigns ofsedation and respiratorydepression, particularlywhen initiatingtherapywith hydrocodone bitartrate and ibuprofen tablets.
Opioids mayalso obscurethe clinical coursein apatient with ahead injury. Avoid theuseofhydrocodone bitartrate and ibuprofen tablets in patients with impaired consciousness or coma.
Risks of use in patients with gastrointestinal conditions
Hydrocodone bitartrate and ibuprofen tabletsare contraindicated in patients with known orsuspectedgastrointestinal obstruction, includingparalyticileus.
Thehydrocodonein hydrocodone bitartrate and ibuprofen tablets maycausespasm ofthesphincterof Oddi. Opioids may causeincreases in serumamylase. Monitorpatients with biliarytract disease, including acute pancreatitis, forworseningsymptoms.
Increased risk of seizures in patients with seizure disorders
Thehydrocodonein hydrocodone bitartrate and ibuprofen tablets mayincreasethe frequencyofseizures in patients with seizuredisorders, and mayincreasethe risk ofseizures occurringin other clinical settings associated with seizures.Monitorpatients with ahistoryofseizuredisorders forworsened seizure control duringhydrocodone bitartrate and ibuprofen tablets therapy.
Avoid theuseofmixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol)or partial agonist (e.g., buprenorphine)analgesics inpatients who arereceivingafull opioid agonist analgesic, includinghydrocodone bitartrate and ibuprofen tablets.In thesepatients, mixed agonist/antagonist and partial agonist analgesics mayreducetheanalgesiceffect and/orprecipitatewithdrawal symptoms ( s ee PRECAUTIONS:Drug Interactions ).
When discontinuinghydrocodone bitartrate and ibuprofen tabletsin aphysically-dependent patient, graduallytaperthedosage ( s e e DOSAGE AND ADMINISTRATION ). Do not abruptlydiscontinuehydrocodone bitartrate and ibuprofen tabletsin thesepatients ( s e e DRUG ABUSE AND DEPENDENCE ).
Risks of driving and operating machinery
Hydrocodone bitartrate and ibuprofen tabletsmayimpairthemental orphysical abilities needed to perform potentially hazardous activities suchas driving a caroroperatingmachinery. Warn patients not to driveor operatedangerous machineryunless theyaretolerant to the effects ofhydrocodone bitartrate and ibuprofen tabletsand know how theywill react to themedication ( s e e PRECAUTIONS: Information for Patients ).
Cardiovascular thrombotic events
Clinical trials ofseveralCOX-2 selectiveand nonselectiveNSAIDs ofup to threeyears duration haveshown an increasedrisk ofserious cardiovascular (CV)thrombotic events, including myocardial infarction (MI), and stroke,which canbe fatal.Based onavailabledata, it is unclear that the risk forCV thrombotic events is similar for all NSAIDs. Therelativeincreasein serious CV thrombotic events overbaselineconferred byNSAID use appears to besimilarin thosewith and without known CV diseaseor risk factorsforCV disease. However, patients with known CV diseaseor risk factors had ahigher absoluteincidenceofexcess serious CV thrombotic events, dueto theirincreased baseline rate. Someobservational studies found that this increasedrisk of serious CV thrombotic events began asearlyas the first weeks oftreatment. Theincreasein CV thrombotic risk has beenobserved most consistentlyat higherdoses.
To minimizethepotential risk for an adverseCVevent in NSAID-treatedpatients, usethelowest effectivedose fortheshortest duration possible. Physiciansand patients should remain alert for thedevelopment ofsuchevents, throughout the entiretreatment course, even in the absenceof previous CV symptoms.Patients should beinformed about thesymptomsofserious CV events and thesteps to takeiftheyoccur.
Thereis no consistent evidencethatconcurrent useof aspirin mitigates theincreased risk of serious CV thrombotic events associated with NSAID use. The concurrentuseof aspirin andan NSAID, such as ibuprofen, increases the risk ofserious gastrointestinal (GI) events ( s e e WARNINGS:Gastrointestinal Bleeding, Ulceration, and Perforation ).
Status Post C oronary Ar t e ry B y pass Graft ( C AB G ) Sur g e ry
Two large,controlled clinical trials ofaCOX-2 selectiveNSAIDforthetreatment ofpain in the first 10-14 days followingCABG surgeryfound an increased incidenceofmyocardial infarction and stroke. NSAIDsarecontraindicated in thesettingofCABG ( s e e CONTRAINDICATIONS ).
Post -M I Pati e nts
Observational studies conducted in theDanish National Registryhavedemonstrated that patients treated with NSAIDs in thepost-MIperiod were at increasedrisk of reinfarction, CV-related death, and all-causemortalitybeginningin the first week oftreatment.In this same cohort, the incidenceofdeath in thefirstyearpost-MIwas 20per100 personyears inNSAID-treated patients compared to 12per100 personyears in non-NSAID exposed patients. Although theabsolute rateofdeath declined somewhat afterthefirstyearpost-MI, theincreased relative risk ofdeath in NSAID userspersisted overat least thenext fouryears of follow-up.
Avoid theuseofhydrocodone bitartrate and ibuprofen tabletsin patients witha recent MIunless thebenefits areexpected to outweigh therisk of recurrent CV thrombotic events.Ifhydrocodone bitartrate and ibuprofen tabletsareused in patients with a recent MI, monitorpatients forsigns ofcardiacischemia.
Gastrointestinal bleeding, ulceration, and perforation
NSAIDs, includingibuprofen, causeseriousgastrointestinal (GI) adverse events including inflammation, bleeding,ulceration, and perforation ofthe esophagus, stomach, small intestine, or largeintestine, whichcanbe fatal. Theseseriousadverse events can occurat anytime, with or without warningsymptoms, in patients treated with hydrocodone bitartrate and ibuprofen tablets. Onlyonein fivepatients who develop aserious upperGI adverse event onNSAID therapyis symptomatic. UpperGI ulcers,gross bleeding, orperforation caused byNSAIDs occurred in approximately1%of patients treated for3-6 months, and in about 2%-4%ofpatients treated foroneyear.However, even short-term NSAID therapyis not without risk.
Risk Fa c tors for GI Bl e e ding, Ul ce ration, and P e rforation
Patients with apriorhistoryofpepticulcerdisease and/orgastrointestinalbleeding who used NSAIDs had agreaterthan 10-fold increasedrisk fordevelopingaGIbleed compared to patients without these risk factors. Other factors that increasethe risk forGIbleedingin patients treated with NSAIDs includelongerduration ofNSAID therapy; concomitant useoforalcorticosteroids, aspirin, anticoagulants, orselectiveserotonin reuptakeinhibitors (SSRIs); smoking; useof alcohol;olderage; and poorgeneral health status. Most postmarketing reports of fatal GI events occurred in elderlyordebilitated patients. Additionally, patients with advanced liverdisease and/or coagulopathyare at increasedrisk forGIbleeding.
Strat e gi e s to M inimize the GI Ris k s in N SA I D - t r e a t e d pati e nts:
- Usethelowest effectivedosage fortheshortest possibleduration.
- Avoid administration ofmorethan oneNSAIDatatime.
- Avoid usein patients at higherrisk unless benefits are expected to outweightheincreased risk ofbleeding. Forhighrisk patients, as well as thosewith activeGIbleeding, consider alternatetherapies otherthan NSAIDs.
- Remain alert forsigns and symptoms ofGIulceration and bleedingduring NSAIDtherapy.
- Ifaserious GIadverse event is suspected, promptlyinitiate evaluation andtreatment, and discontinuehydrocodone bitartrate and ibuprofen tablets until aserious GIadverse event is ruled out.
- In thesettingofconcomitant useoflow-doseaspirin for cardiacprophylaxis, monitor patients more closelyforevidenceofGIbleeding ( s e e PRECAUTIONS:Drug Interactions ).
Elevations ofALT orAST (threeormoretimes theupperlimit ofnormal [ULN])havebeen reported in approximately1%ofNSAID-treatedpatients in clinical trials with NSAIDS.Inaddition, rare, sometimesfatal, cases ofseverehepaticinjury, includingfulminant hepatitis, liver necrosis, and hepaticfailurehavebeenreported.
Elevations ofALT orAST (less than threetimesULN)mayoccurin up to15%ofpatients takingNSAIDs including ibuprofen.
Inform patients ofthewarningsigns and symptoms ofhepatotoxicity(e.g.,nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upperquadrant tenderness, andflulikesymptoms). Ifclinical signs and symptoms consistent with liverdiseasedevelop, orifsystemicmanifestations occur(e.g., eosinophilia, rash, etc.), discontinuehydrocodone bitartrate and ibuprofen tablets immediately, and perform aclinical evaluation ofthepatient.
NSAID-containingproducts, includinghydrocodone bitartrate and ibuprofen tablets, can lead to new onset orworseningof pre-existinghypertension, eitherofwhich maycontributeto theincreased incidenceofCV events. Patients taking angiotensin converting enzyme(ACE)inhibitors, thiazidediuretics, or loop diuretics mayhaveimpaired responseto thesetherapieswhen taking NSAIDs ( s e e PRECAUTIONS:Drug Interactions ).
Monitorblood pressure(BP)duringtheinitiation ofNSAID treatment andthroughout the course oftherapy.
Heart failure and edema
TheCoxib and Traditional NSAID TrialistsCollaboration meta-analysisof randomized controlled trials demonstrated anapproximatelytwo-fold increasein hospitalizations forheart failurein COX-2 selective-treated patients and nonselectiveNSAID-treated patients compared to placebo-treated patients. InaDanish National Registrystudyofpatients with heart failure, NSAID useincreased therisk ofMI, hospitalization forheart failure,and death.
Additionally, fluid retention and edemahavebeenobserved in somepatients treated with NSAIDs. Useofhydrocodone bitartrate and ibuprofen tablets mayblunt theCV effects ofseveral therapeuticagents used to treat thesemedical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptorblockers [ARBs]) ( s e e PRECAUTIONS:Drug Interactions ).
Avoid theuseofhydrocodone bitartrate and ibuprofen tablets in patients withsevereheartfailureunless thebenefits are expected to outweigh therisk ofworseningheart failure.Ifhydrocodone bitartrate and ibuprofen tabletsare used in patients with severeheart failure,monitorpatients forsigns ofworseningheart failure.
Renal toxicity and hyperkalemia
R e nal T o x i c ity
Long-term administration ofNSAIDs has resulted in renal papillarynecrosis and other renal injury.
Renal toxicityhasalso been seen in patients in whom renal prostaglandinshaveacompensatory rolein themaintenanceof renal perfusion.In thesepatients, administration of an NSAID may causeadose-dependent reduction in prostaglandinformation and, secondarily, in renal blood flow, which mayprecipitateovert renal decompensation. Patients at greatest risk ofthis reaction arethosewith impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, thosetaking diuretics and ACE inhibitors or angiotensin receptorblockers (ARBs),and the elderly. Discontinuation ofNSAID therapywas usuallyfollowed byrecoveryto the pretreatment state.
No information is available from controlled clinical studies regardingtheuseofhydrocodone bitartrate and ibuprofen tablets in patients with advancedrenal disease. Therenaleffects ofhydrocodone bitartrate and ibuprofen tablets mayhasten the progression ofrenal dysfunction in patients with pre-existingrenal disease.
Correct volumestatus in dehydrated orhypovolemicpatients priorto initiatinghydrocodone bitartrate and ibuprofen tablets. Monitor renal function inpatients with renal orhepaticimpairment, heartfailure, dehydration, or hypovolemiaduringuseofhydrocodone bitartrate and ibuprofen tablets ( s e e PRECAUTIONS:Drug Interactions ). Avoid the useofhydrocodone bitartrate and ibuprofen tablets in patients with advancedrenal diseaseunless thebenefits areexpected to outweigh therisk ofworseningrenal function.Ifhydrocodone bitartrate and ibuprofen tabletsare used inpatients with advanced renal disease,monitorpatients forsigns ofworseningrenal function.
H y p e r k al e mia
Increases in serum potassium concentration, includinghyperkalemia, havebeen reported with useofNSAIDs,even in somepatients without renal impairment.In patients with normal renal function, those effects havebeenattributed to ahyporeninemic-hypoaldosteronism state.
Ibuprofen has beenassociated with anaphylacticreactions in patients with and without known hypersensitivityto ibuprofen and in patients withaspirin-sensitive asthma ( s e e CONTRAINDICATIONS , WARNINGS:Exacerbation of Asthma Related to AspirinSensitivity ).
Seek emergencyhelp ifan anaphylacticreaction occurs.
Exacerbation of asthma related to aspirin sensitivity
A subpopulation ofpatients with asthmamayhave aspirin-sensitive asthmawhich mayinclude chronic rhinosinusitis complicated bynasal polyps; severe, potentiallyfatal bronchospasm; and/orintoleranceto aspirin and otherNSAIDs.Becausecross-reactivitybetweenaspirin and otherNSAIDs has been reported in such aspirin-sensitivepatients, hydrocodone bitartrate and ibuprofen tabletsare contraindicated in patients with this form of aspirin sensitivity ( s e e CONTRAINDICATIONS ). When hydrocodone bitartrate and ibuprofen tabletsare used in patients with pre-existingasthma (without known aspirin sensitivity), monitorpatients for changes in thesigns and symptoms of asthma.
Serious skin reactions
NSAIDs, includingibuprofen, cancauseserious skin adverseevents such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), whichcan be fatal. Theseseriousevents mayoccurwithout warning.Inform patients about thesigns and symptoms ofserious skinreactions, and to discontinuetheuseofhydrocodone bitartrate and ibuprofen tabletsat the first appearanceofskin rash or anyothersign ofhypersensitivity. Hydrocodone bitartrate and ibuprofen tabletsare contraindicated in patients with previous serious skin reactions to NSAIDs ( s e e CONTRAINDICATIONS ).
Premature closure of fetal ductus arteriosus
Ibuprofen maycausepremature closureofthefetal ductus arteriosus. Avoid useofNSAID- containingproducts, includinghydrocodone bitartrate and ibuprofen tablets, inpregnant women starting at 30 weeks of gestation (third trimester) ( s e e PRECAUTIONS: Pregnancy ).
Anemiahas occurred in NSAID-treated patients.This maybedueto occult orgross blood loss, fluid retention, or an incompletelydescribedeffecton erythropoiesis.Ifapatient treated with hydrocodone bitartrate and ibuprofen tabletshaveanysigns orsymptoms of anemia, monitorhemoglobin orhematocrit.
NSAID-containingproducts, includinghydrocodone bitartrate and ibuprofen tablets, mayincreasethe risk ofbleedingevents. Co-morbid conditions such as coagulation disorders, concomitant useofwarfarin, other anticoagulants, antiplatelet agents (e.g.,aspirin), serotonin reuptakeinhibitors (SSRIs), and serotonin norepinephrinereuptakeinhibitors (SNRIs)mayincreasethis risk. Monitorthese patients forsigns ofbleeding ( s e e PRECAUTIONS:Drug Interactions ).
Asepticmeningitis with fever andcomahas beenobserved on rareoccasions in patients on ibuprofen therapyas found in hydrocodone bitartrate and ibuprofen tablets. Although it is probablymorelikelyto occurin patients with systemiclupus erythematosus and related connectivetissuediseases, it has been reported in patients whodo not have an underlyingchronicdisease.Ifsigns orsymptoms of meningitis develop in apatient on hydrocodone bitartrate and ibuprofen tablets, thepossibilityofits beingrelated to ibuprofen should be considered.
Masking of inflammation and fever
Thepharmacological activityofhydrocodone bitartrate and ibuprofen tablets inreducinginflammation,and possiblyfever, maydiminish theutilityofdiagnosticsigns in detectinginfections.
Blurred ordiminished vision, scotomata, and changes in colorvision havebeen reported with oral ibuprofen.Discontinueibuprofen ifapatientdevelops such complaints, and referthepatient for an ophthalmologic examination that includes central visual fields andcolorvision testing.
Information for patients
Advisethepatient to read the FDA-approved patient labeling (Medication Guide)thataccompanies each prescription dispensed. Patients, families, ortheircaregivers should be informed ofthe followinginformation beforeinitiatingtherapywith hydrocodone bitartrate and ibuprofen tablets and periodicallyduringthecourseofongoingtherapy.
1. Addi c tion, Abus e , a nd M isuse
Inform patients that theuseofhydrocodone bitartrate and ibuprofen tablets, even when taken as recommended, canresult in addiction, abuse, andmisuse, which can lead to overdose and death ( s e e WARNINGS: Addiction, Abuse, and Misuse ).Instruct patients not to sharehydrocodone bitartrate and ibuprofen tabletswith others and to takesteps to protect hydrocodone bitartrate and ibuprofen tabletsfrom theft ormisuse.
2. L i f e- Th r ea t e ni n g R e spi r a to r y D e p re ssion
Inform patients oftherisk oflife-threateningrespiratorydepression, includinginformation that the risk is greatest when starting hydrocodone bitartrate and ibuprofen tablets orwhen thedosageis increased,andthat it can occurevenat recommended dosages ( s e e WARNINGS:Life-Threatening RespiratoryDepression ).Advisepatients how to recognize respiratorydepression and to seek medicalattention ifbreathingdifficulties develop.
3. A cc id e nt al I n g e stion
Inform patients that accidental ingestion, especiallybychildren, mayresult in respiratory depression ordeath ( s e e WARNINGS:Life-Threatening RespiratoryDepression ).Instruct patients to takesteps to storehydrocodone bitartrate and ibuprofen tabletssecurelyand to disposeofunused hydrocodone bitartrate and ibuprofen tabletsappropriatelyas described below.
4. I nt e r a c tions with B e n z odi a z e pin e s a nd Oth er C NS D e p re s s a nts
Inform patients andcaregivers that potentiallyfatal additive effects mayoccurif hydrocodone bitartrate and ibuprofen tablet is usedwith benzodiazepines orotherCNSdepressants, includingalcohol, and not to usethese concomitantlyunless supervised byahealthcareprovider ( s e e WARNINGS:Risks fromConcomitant Usewith Benzodiazepines or OtherCNS Depressants , PRECAUTIONS:Drug Interactions ).
5. S er otonin S y nd r ome
Inform patients that opioids could causea rarebutpotentiallylife-threateningcondition resultingfrom concomitant administration ofserotonergicdrugs. Warn patients ofthe symptoms ofserotonin syndromeand to seek medical attention rightawayifsymptoms develop.Instruct patientsto inform theirhealthcareproviders iftheyaretaking, orplan to takeserotonergicmedications ( s e e PRECAUTIONS:Drug Interactions ).
6. MA O I I nt e r ac tion
Inform patients to avoid takinghydrocodone bitartrate and ibuprofen tablets whileusinganydrugs that inhibit monoamineoxidase. Patients should not start MAOIswhiletakinghydrocodone bitartrate and ibuprofen tablets ( s e e PRECAUTIONS:Drug Interactions ).
7. Ad re n al I ns u ff i c i e n c y
Inform patients that opioids could causeadrenal insufficiency,apotentiallylife-threatening condition. Adrenal insufficiencymaypresent withnon-specificsymptoms and signs suchas nausea, vomiting,anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medicalattention iftheyexperienceaconstellation ofthesesymptoms ( s e e WARNINGS:Adrenal Insufficiency ).
8. I mpo r t a nt Administ ra tion I nst r u c tions
Instruct patients how to properlytakehydrocodone bitartrate and ibuprofen tablets. Fortheshort-term (generallyless than10 days)management ofacutepain, therecommended doseofhydrocodone bitartrate and ibuprofen tablets is onetablet every4 to 6 hours,as necessary.Inform patients that thedosageshould notexceed 5 tablets in a24-hourperiod ( s e e DOSAGE AND ADMINISTRATION ).
9. H y pot e nsion
Inform patients that hydrocodone bitartrate and ibuprofen tablets maycauseorthostatichypotension andsyncope.Instruct patients how to recognizesymptoms oflow bloodpressureand how to reducethe risk of serious consequences should hypotension occur (e.g., sit orliedown, carefullyrisefrom a sittingorlyingposition) ( s e e WARNINGS:SevereHypotension ).
10. An a p h y l a x is
Inform patients that anaphylaxis has been reportedwith ingredientscontained in hydrocodone bitartrate and ibuprofen tablets. Advisepatients how to recognizesuch areaction and when to seek medical attention ( s e e CONTRAINDICATIONS , WARNINGS:AnaphylacticReactions ).
11. P re g n a n c y
N e onatal Opioid W ithdra w al S y ndrome
Inform femalepatients ofreproductivepotential that prolonged useofhydrocodone bitartrate and ibuprofen tablets during pregnancycanresult in neonatal opioid withdrawal syndrome, which maybelife-threatening ifnot recognized and treated ( s e e BoxedWarning , WARNINGS:Neonatal OpioidWithdrawal Syndrome , PRECAUTIONS:Pregnancy ).
Embr y o - F e tal T o x i c ity
Inform femalepatients ofreproductivepotential that hydrocodone bitartrate and ibuprofen tabletscan cause fetal harm and to inform theprescriberofaknown orsuspected pregnancy.Inform pregnant women to avoid useofhydrocodone bitartrate and ibuprofen tabletsand otherNSAIDs starting at 30 weeksgestation becauseofthe risk ofpremature closing ofthe fetal ductus arteriosus ( s e e WARNINGS:PrematureClosure of Fetal Ductus Arteriosis , PRECAUTIONS:Pregnancy ).
12. L a c t a tion
Advisenursingmothers to monitorinfants forincreased sleepiness (morethan usual), breathingdifficulties, orlimpness.Instruct nursing mothers to seek immediatemedical careif theynoticethesesigns ( s e e PRECAUTIONS:Nursing Mothers ).
13. I n fer tili t y
Inform patients that chronicuseofopioids maycause reduced fertility.It isnot known whetherthese effects onfertilityarereversible. Advise femalepatients ofreproductive potential who desirepregnancythat NSAIDs, includinghydrocodone bitartrate and ibuprofen tablets, maybe associated with a reversibledelayinovulation ( s e e PRECAUTIONS:Carcinogenicity, Mutagenicity, Impairment of Fertility ).
14. D r iving or Op e r a ting H e a v y M ac hin e r y
Inform patients that hydrocodone bitartrate and ibuprofen tablets mayimpairthe abilityto perform potentiallyhazardous activities such as driving a caroroperatingheavymachinery. Advisepatients not to perform such tasks until theyknow how theywill react to themedication ( s e e WARNINGS:Risks of Driving and Operating Machinery ).
15. C onstip a tion
Advisepatients ofthepotential forsevere constipation, includingmanagement instructions and when to seek medical attention ( s e e ADVERSE REACTIONS:ClinicalTrials Experience ).
16. C ar diov a s c ul a r T h r omb o tic Ev e nts
Advisepatients to be alert forthesymptoms ofcardiovascularthromboticevents, including chest pain, shortness ofbreath, weakness, orslurringofspeech,and to report anyofthese symptoms to theirhealthcareproviderimmediately ( s e e WARNINGS:Cardiovascular ThromboticEvents ).
17. G a st r oint e stin a l B l e e ding, Ul cera tion, a nd Pe rf o r a t ion
Advisepatients to report symptoms ofulcerations and bleeding, includingepigastricpain, dyspepsia, melena,and hematemesis to theirhealthcareprovider.In thesettingof concomitant useoflow-dose aspirin forcardiacprophylaxis, inform patients oftheincreased risk for and thesigns andsymptoms ofGIbleeding ( s e e WARNINGS:Gastrointestinal Bleeding, Ulceration, and Perforation ).
18. H e p a toto x i c i t y
Inform patients ofthewarningsigns and symptoms ofhepatotoxicity(e.g.,nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upperquadrant tenderness, and"flu-like" symptoms).Iftheseoccur, instruct patients to stop hydrocodone bitartrate and ibuprofen tabletsand seek immediate medical therapy ( s e e WARNINGS:Hepatotoxicity ).
19. H ear t Fa ilu r e a nd Ed e ma
Advisepatients to be alert forthesymptoms of congestiveheart failureincludingshortness of breath, unexplained weight gain, oredemaand to contact theirhealthcareproviderifsuch symptoms occur ( s e e WARNINGS:Heart Failureand Edema ).
20. S er ious S kin R eac tions
Advisepatients to stop hydrocodone bitartrate and ibuprofen tablets immediatelyiftheydevelop anytypeof rashand to contact theirhealthcareprovider as soon as possible ( s e e WARNINGS:Serious Skin Reactions ).
21. Avoid C on c omit a nt use of N S A I Ds
Inform patients that theconcomitant useofhydrocodone bitartrate and ibuprofen tablets with otherNSAIDs orsalicylates (e.g., diflunisal, salsalate)is not recommended dueto theincreased risk ofgastrointestinal toxicity, and littleorno increasein efficacy ( s e e WARNINGS:Gastrointestinal Bleeding, Ulceration, and Perforation , PRECAUTIONS:Drug Interactions ). Alert patients that NSAIDs maybepresentin overthe countermedications fortreatment ofcolds, fever,or insomnia.
22. Use of N S A I DS a nd L o w - Dose Aspi r in
Inform patients not to uselow-dose aspirinconcomitantlywith hydrocodone bitartrate and ibuprofen tablets until theytalk to theirhealthcareprovider ( s e e PRECAUTIONS:Drug Interactions ).
23. Ophth a lmolo g i ca l E ff e c ts
Instruct patients to reportanysigns ofblurred vision orothereyesymptoms ( s ee PRECAUTIONS:Ophthalmological Effects ).
24. Dispos a l of Unus e d Hydrocodone Bitartrate and Ibuprofen Tablets
Advisepatients to flush theunused tablets down thetoilet when hydrocodone bitartrate and ibuprofen tablets are no longer needed ortocontact theDrugEnforcement Agency(DEA)to find thelocation of an authorized collector (1-800-882-9539).
Becauseserious GIbleeding, hepatotoxicity, and renal injurycan occurwithout warning symptoms orsigns,considermonitoringpatients with aCBCand a chemistryprofileperiodically ( s e e WARNINGS:Gastrointestinal Bleeding, Ulceration, and Perforation , Renal Toxicityand Hyperkalemia , Hepatotoxicity ).
I nhibito r s of C Y P 3A4 a n d C Y P 2D6
The concomitant useofhydrocodone bitartrate and ibuprofen tabletsand CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungalagents (e.g.ketoconazole), proteaseinhibitors (e.g., ritonavir), can increasetheplasma concentration ofhydrocodone,resulting in increased or prolonged opioid effects.These effects could bemorepronounced with concomitant useof hydrocodone bitartrate and ibuprofen tabletsand CYP2D6 and CYP3A4 inhibitors, particularlywhen aninhibitoris added afterastabledoseofhydrocodone bitartrate and ibuprofen tablets is achieved ( s e e WARNINGS:Risksof Concomitant Useor Discontinuation of CytochromeP450 3A4 Inhibitors and Inducers ).
AfterstoppingaCYP3A4 inhibitor, as the effects oftheinhibitordecline, thehydrocodone plasma concentration will decrease ( s e e CLINICALPHARMACOLOGY:Pharmacokinetics ), resultingin decreased opioid efficacyorawithdrawal syndromein patientswho had developed physical dependencetohydrocodone bitartrate and ibuprofen tablets.
Ifconcomitant useis necessary, considerdosagereduction ofhydrocodone bitartrate and ibuprofen tablets until stabledrug effects are achieved. Monitorpatients for respiratorydepression and sedation at frequent intervals.IfaCYP3A4 inhibitoris discontinued,consideradosageincreaseofhydrocodone bitartrate and ibuprofen tablets until stabledrugeffects are achieved. Monitor forsigns ofopioid withdrawal.
C Y P 3A4 I ndu c er s
The concomitant useofhydrocodone bitartrate and ibuprofen tabletsand CYP3A4 inducers, suchas rifampin, carbamazepine, and phenytoin, can decreasetheplasma concentration ofhydrocodone ( s ee CLINICALPHARMACOLOGY:Pharmacokinetics ), resultingin decreasedefficacyoronset ofa withdrawal syndromeinpatients who havedeveloped physical dependenceto hydrocodone ( s ee WARNINGS:Withdrawal ).
AfterstoppingaCYP3A4 inducer, as theeffects oftheinducerdecline, thehydrocodoneplasma concentration will increase ( s e e CLINICALPHARMACOLOGY:Pharmacokinetics ), whichcould increaseorprolong both thetherapeuticeffects and adversereactions,and maycause serious respiratorydepression.
Ifconcomitant useis necessary, consideradosageincreaseofhydrocodone bitartrate and ibuprofen tablets until stabledrug effects are achieved. Monitor forsigns ofopioidwithdrawal.IfaCYP3A4 induceris discontinued, considerhydrocodone bitartrate and ibuprofen tablets dosagereduction and monitor forsigns ofrespiratory depression.
B e n z odi a z e pin e s a nd Ot h e r C e nt ra l N er vous S y s t e m ( C N S ) D e p re ss a nts
Dueto additivepharmacologiceffect, the concomitant useofbenzodiazepines orotherCNS depressants suchas benzodiazepines and othersedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, generalanesthetics, antipsychotics, and otheropioids, includingalcohol, increasethe risk ofhypotension, respiratorydepression, profound sedation,coma, and death.
Reserve concomitant prescribingofthesedrugsforusein patients forwhom alternative treatment options areinadequate.Limit dosages and durations to theminimum required. Follow patients closelyforsignsof respiratorydepression and sedation ( s e e WARNINGS:Life- Threatening RespiratoryDepression ).
S er oton e r g ic D r u g s
The concomitant useofopioids with otherdrugs that affect theserotonergicneurotransmitter system, suchas selectiveserotonin reuptakeinhibitors (SSRIs), serotonin and norepinephrine reuptakeinhibitors (SNRIs), tricyclicantidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs thateffect theserotonin neurotransmittersystem (e.g., mirtazapine, trazodone, tramadol), and monoamineoxidase (MAO)inhibitors (thoseintended to treat psychiatric disorders and also others,such as linezolid and intravenous methyleneblue), has resulted in serotonin syndrome ( s e e PRECAUTIONS: Information for Patients ).
Ifconcomitant useis warranted, carefullyobservethepatient, particularlyduringtreatment initiation and dose adjustment. Discontinuehydrocodone bitartrate and ibuprofen tablets ifserotonin syndromeis suspected.
Mono a mine O x id a se I nh i bito r s ( MA O I s)
MAOIinteractions with opioids maymanifest asserotonin syndromeoropioid toxicity(e.g., respiratorydepression, coma).
Ifurgent useof an opioidis necessarywith MAOIs such as phenelzine, tranylcypromine, linezolid, usetest doses and frequent titration ofsmall doses to treat painwhile closely monitoringblood pressure and signs and symptoms ofCNSand respiratorydepression.
Theuseofhydrocodone bitartrate and ibuprofen tabletsisnot recommendedforpatientstakingMAOIs orwithin14days of stoppingsuchtreatment.
Mi x e d A g onist/Ant a g on i st a nd P ar ti a l A g onist O p ioid An a l g e si c s
Agonist/antagonist analgesics such as pentazocine, nalbuphine, butorphanol and buprenorphine mayreducethe analgesiceffect ofhydrocodone bitartrate and ibuprofen tabletsand/orprecipitatewithdrawal symptoms in thesepatients.
Avoid concomitant useofthesedrugs. Mus c le R e l a x a nts
Hydrocodone,as well asotheropioid analgesics,mayenhancetheneuromuscularblocking action ofskeletal musclerelaxants and produceanincreased degreeofrespiratorydepression.
Monitorpatients forsigns of respiratorydepression that maybegreaterthan otherwise expected and decreasethedosageofhydrocodone bitartrate and ibuprofen tabletsand/orthemuscle relaxant as necessary.
Anti c holin er g i cs
The concomitant useofanticholinergicdrugs mayincrease risk ofurinaryretention and/or severeconstipation, which maylead to paralyticileus.
Monitorpatients forsigns ofurinaryretentionorreduced gastricmotilitywhen hydrocodone bitartrate and ibuprofen tablets is used concomitantlywith anticholinergicdrugs.
D r u g s Th a t I nt e rf e r e W ith H e most a sis
Ibuprofenand anticoagulants such as warfarin haveasynergisticeffect onbleeding. The concomitant useofibuprofen and anticoagulantshave an increased risk ofserious bleeding compared to theuseof eitherdrugalone.
Serotonin releasebyplatelets playsan important rolein hemostasis. Case-control and cohort epidemiological studies showed that concomitantuseofdrugs that interferewith serotonin reuptakeand an NSAIDmaypotentiatethe risk ofbleedingmorethan an NSAIDalone.
Monitorpatients with concomitant useofhydrocodone bitartrate and ibuprofen tablets with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g.,aspirin), SSRIs,and SNRIs forsigns ofbleeding ( s e e WARNINGS: HematologicToxicity ).
Aspi r in
Controlled clinical studies showed that the concomitant useofNSAIDs and analgesicdoses of aspirin does not produceanygreatertherapeuticeffect than theuseofNSAIDs alone.In a clinical study, theconcomitant useof an NSAIDand aspirin wasassociated with asignificantly increased incidenceofGI adverse reactions as compared to useoftheNSAID alone ( s ee WARNINGS:Gastrointestinal Bleeding, Ulceration, and Perforation ).
Concomitant useofhydrocodone bitartrate and ibuprofen tabletsand analgesicdoses of aspirin is not generallyrecommended becauseoftheincreasedrisk ofbleeding ( s e e WARNINGS:HematologicToxicity ).
A C E - I nhibito r s, An g iot e nsin R ece ptor B l o c k er s, a nd B e t a- blo c k er s
NSAIDs maydiminish the antihypertensiveeffectof angiotensin converting enzyme (ACE)inhibitors, angiotensin receptorblockers (ARBs),orbeta-blockers (includingpropranolol).
During concomitant useofhydrocodone bitartrate and ibuprofen tabletsand ACE-inhibitors, ARBs, orbeta-blockers, monitor blood pressureto ensurethat thedesired blood pressureis obtained.
In patients who are elderly,volume-depleted (includingthoseon diuretictherapy), orhaverenal impairment, coadministration of an NSAID withACE inhibitors orARBs mayresult in deterioration ofrenal function, includingpossibleacuterenal failure. Monitor forsigns of worseningrenal function ( s e e WARNINGS:RenalToxicityand Hyperkalemia ). Theseeffects are usuallyreversible.
When thesedrugs are administered concomitantly, patients should be adequatelyhydrated. Assess renal function at thebeginningofthe concomitant treatment and periodicallythereafter.
Diu re ti c s
Clinical studies, as well as post-marketingobservations, showed that NSAIDs reduced the natriureticeffect ofloopdiuretics (e.g., furosemide) and thiazidediuretics in somepatients. This effect has been attributedto theNSAID inhibition of renal prostaglandin synthesis.
During concomitant useofhydrocodone bitartrate and ibuprofen tablets with diuretics, observepatients forsigns of worseningrenal function, in addition to assuringdiuretic efficacyincluding antihypertensive effects ( s e e WARNINGS:Renal Toxicityand Hyperkalemia ).
Di g o x in
The concomitant useofibuprofen with digoxin has been reported to increasetheserum concentration and prolongthehalf-lifeofdigoxin.
During concomitant useofhydrocodone bitartrate and ibuprofen tabletsand digoxin, monitorserum digoxin levels.
NSAIDs haveproducedelevations in plasmalithium concentration andreductions in renal lithium clearance. Themean minimum lithium concentration increased 15%, and therenal clearancedecreased byapproximately20%. This effect has been attributedto NSAID inhibition of renal prostaglandin synthesis.
During concomitant useofhydrocodone bitartrate and ibuprofen tabletsand lithium, monitorpatients forsigns oflithium toxicity.
M e thot re x a te
Concomitant useofNSAIDsand methotrexatemayincreasethe risk formethotrexatetoxicity(e.g., neutropenia, thrombocytopenia, renal dysfunction).
During concomitant useofhydrocodone bitartrate and ibuprofen tabletsand methotrexate, monitorpatients formethotrexate toxicity.
C y c lospo r ine
Concomitant useofhydrocodone bitartrate and ibuprofen tabletsand cyclosporinemayincreasecyclosporines nephrotoxicity.
During concomitant useofhydrocodone bitartrate and ibuprofen tabletsand cyclosporine, monitorpatients forsigns of worseningrenal function.
N S A I Ds a nd S a li c y l a t es
Concomitant useofibuprofen with otherNSAIDsorsalicylates (e.g., diflunisal, salsalate) increases the risk ofGItoxicity, with littleorno increasein efficacy ( s e e WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
The concomitant useofibuprofen with otherNSAIDs orsalicylates is not recommended. P e m e t re x ed
Concomitant useofhydrocodone bitartrate and ibuprofen tabletsand pemetrexed mayincreasetherisk ofpemetrexed associated myelosuppression, renal, and GItoxicity(seethepemetrexed prescribing information).
During concomitant useofhydrocodone bitartrate and ibuprofen tabletsand pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79mL/min, monitor formyelosuppression, renal and GItoxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin)should be avoided for aperiod oftwo days before, thedayof, and two daysfollowingadministration ofpemetrexed.
In theabsenceofdataregardingpotential interaction between pemetrexed and NSAIDs with longerhalf-lives (e.g., meloxicam, nabumetone),patients takingtheseNSAIDs should interrupt dosingforat least fivedaysbefore, thedayof,andtwo daysfollowingpemetrexed administration.
Carcinogenicity, mutagenicity, impairment of fertility
C arc in o g e n e sis
Long-term animal studies to evaluatethecarcinogenicpotential ofthe combination of hydrocodoneand ibuprofen, ibuprofenalone, orhydrocodone alonehavenot been conducted.
Mut a g e n e sis
Themutagenicpotentialofthe combination ofhydrocodone and ibuprofenorhydrocodonealone has not been investigated.
In published studies, ibuprofen was not mutagenicin thein vitro bacterialreversemutation assay(Ames assay). I mp a i r m e nt of F er tili t y
Animal studies evaluatingtheimpact ofthe combination ofhydrocodone and ibuprofen or hydrocodonealoneon fertilityhavenot been conducted.
Inapublished study, dietaryadministration ofibuprofen to maleand female rats 8-weeks priorto and duringmating at doselevels of20 mg/kg(0.2-times theMRHD of1000 mgibuprofen based on bodysurface areacomparison)did not impact maleor female fertilityorlittersize.
In otherstudies, adult micewere administered ibuprofen intraperitoneallyat adoseof5.6 mg/kg/day(0.03-times theMRHD based on bodysurface areacomparison)for35 or60 days in males and 35 days in females. Therewas noeffecton sperm motilityorviabilityin males but decreased ovulation was reported in females.
Based on themechanism of action, theuseofprostaglandin-mediated NSAIDs, including ibuprofen, maydelayorprevent ruptureofovarian follicles, which has been associated with reversibleinfertilityin somewomen. Small studies in women treated withNSAIDs havealso shown a reversibledelayin ovulation. Considerwithdrawal ofNSAID-containingproducts, includinghydrocodone bitartrate and ibuprofen tablets, in women who havedifficulties conceivingorwho areundergoing investigation ofinfertility.
Chronicuseofopioids maycausereduced fertilityin females and males ofreproductive potential.It is not knownwhetherthese effects onfertilityarereversible ( s e e ADVERSE REACTIONS:Postmarketing Experience ).
R isk S umm a r y
Useofdrugproducts containingNSAIDs, includinghydrocodone bitartrate and ibuprofen tablets, duringthethird trimesterof pregnancyincreases therisk ofprematureclosureofthe fetal ductus arteriosus. Avoid useof NSAIDs, including hydrocodone bitartrate and ibuprofen tablets, in pregnant women starting at 30 weeks gestation (third trimester). Prolonged useofopioid analgesics duringpregnancycancauseneonatal opioid withdrawal syndrome ( s e e WARNINGS:NeonatalOpioidWithdrawal Syndrome ). Thereareno availabledatawith hydrocodone bitartrate and ibuprofen tablets in pregnant women to inform adrug-associated risk formajorbirth defects andmiscarriage.Datafrom observational studies regardingpotentialembryofetal risks ofNSAID usein women in thefirst orsecond trimesters ofpregnancyare inconclusive.
Inanimal reproduction studies, an increasein thepercentageoflitters and fetuses with anymajor abnormalityand an increasein thenumberoflitters and fetuseswith oneormorenonossified metacarpals was observed when the combinationofhydrocodoneand ibuprofen wasadministered orallyto pregnant rabbits duringorganogenesis at 1.8 times themaximum daily dose. Thereareno animal reproductiveand developmental toxicologystudies with hydrocodone alone.
In publishedanimal reproduction studies testingibuprofen alone, therewereno clear developmental effectsat doses up to 1.2 times themaximum recommended human dose (MRHD)in the rabbit and 1.8 times in theMRHD rat when dosed throughout gestation.In contrast, an increasein membranous ventricularseptal defects was reportedin rats treated onGestation Days 9&10 with 3 times theMRHD. Based on animal data, prostaglandins havebeen shown to have an important rolein endometrial vascularpermeability, blastocyst implantation, and decidualization.In animal studies, administration ofprostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss ( s e e Data). Based on animal data, advisepregnant women ofthepotential riskto a fetus.
The estimated background risk ofmajorbirth defects and miscarriage fortheindicated population is unknown. Allpregnancieshaveabackgroundrisk ofbirthdefect,loss, orother adverseoutcomes.In theU.S. general population,the estimated background risk ofmajorbirth defectsand miscarriagein clinicallyrecognized pregnancies is 2% to 4% and 15% to 20%, respectively.
C lini ca l C onsid era tions
F e tal/n e onatal ad ve rse r e a c tions
Prolonged useofopioid analgesics duringpregnancyformedical ornonmedical purposescan result in physical dependencein theneonate and neonatal opioid withdrawal syndromeshortly afterbirth.
Neonatal opioid withdrawal syndromepresents as irritability, hyperactivityandabnormal sleep pattern, high-pitchedcry,tremor, vomiting, diarrhea, and failuretogain weight. Theonset, duration, and severityofneonatal opioid withdrawal syndromevarybased on thespecificopioid used, duration ofuse, timingandamount oflast maternal use,and rateof elimination ofthedrug bythenewborn. Observenewborns forsymptomsofneonatal opioid withdrawal syndromeand manageaccordingly ( s e e WARNINGS:Neonatal OpioidWithdrawal Syndrome ).
L abor and D e li ve ry
Opioids cross theplacenta and mayproducerespiratorydepression and psycho-physiologic effects in neonates. An opioid antagonist, such asnaloxone, must be available for reversal of opioid-induced respiratorydepression in theneonate. Monitorneonates exposed to opioid analgesics duringlaborforsigns ofexcess sedation and respiratorydepression.
Thereareno studies on the effects ofhydrocodone bitartrate and ibuprofen tablets duringlaborordelivery.In animal studies, NSAIDs, includingibuprofen, inhibit prostaglandin synthesis, causedelayed parturition, and increasetheincidenceofstillbirth.
Hydrocodone bitartrate and ibuprofen tabletsare not recommended forusein women during and immediatelypriorto labor, when useofshorter-actinganalgesics orother analgesictechniquesaremore appropriate. Opioid analgesics, includinghydrocodone bitartrate and ibuprofen tablets, can prolonglaborthrough actions that temporarilyreduce thestrength, duration, and frequencyofuterine contractions. However, this effect is not consistent and maybeoffset byan increasedrateof cervical dilatation, which tends to shorten labor. Monitorneonatesexposed to opioid analgesics duringlabor forsigns of excess sedation and respiratorydepression.
D a ta
Pregnant rabbits weretreated with 10, 33, or95 mg/kgof1:27 ratio ofhydrocodone:ibuprofen (thehigh doseis 1.8 times themaximum dailydoseofboth compounds based on surfacearea) from Gestation Day5 to18. Thedoseof95 mg/kgofthecombination, which also produced maternal toxicity(44%decreasein bodyweightgain compared tocontrol),resulted in anincreasein thepercentageoflitters and fetuses with anymajorabnormalityand an increasein the numberoflitters and fetuses with oneormorenonossified metacarpals (aminor abnormality).
Pregnant rats weretreated with 50, 100, or166 mg/kgofa1:27 ratio ofhydrocodone:ibuprofen (thehigh doseis 1.6 times themaximum dailydoseofboth compounds based on bodysurface area) from Gestation Day5 to 15. No reproductivetoxicitywas noted despitethepresenceof maternal toxicityin the100 and 166 mg/kg groups(21% and 60%decreasein bodyweightgain compared to control).
Inapublished study,female rabbitsgiven 7.5, 20,or60 mg/kgibuprofen (0.15, 0.39, or1.2 times themaximum recommended human dailydoseof1000 mgofibuprofen based on body surface area)from Gestation Days 1 to 29, nocleartreatment-relatedadversedevelopmental effects werenoted. Thisdosewas associated withsignificant maternal toxicity(stomach ulcers, gastriclesions).In thesamepublication, femalerats were administered 7.5,20, 60, 180 mg/kg ibuprofen (0.07, 0.2, 0.6,1.8 times themaximum dailydose)did not result in clearadverse developmental effects. Maternal toxicity(gastrointestinal lesions)was noted at 20 mg/kgand above.
Inapublished study,ratswereorallydosed with 300 mg/kgibuprofen(3 times themaximum human dailydoseof1000 mgbased on bodysurfacearea)duringGestation Days 9 and 10 (critical timepoints forheart development in rats).Ibuprofen treatment resulted in an increasein theincidenceofmembranous ventricularseptal defects. This dosewas associated withsignificant maternal toxicityincluding gastrointestinal toxicity(1 out of20animals).In thesame study/publication rabbitsweredosed on GestationDay9, 10 and 11 with 500 mg/kg(9.7 times themaximum human dailydose),and onlyoneincidenceeach ofamembranous ventricular septal defect andgastroschisis was noted in the rabbit fetuses. This dosewas also associatedwith maternal toxicity.
R isk S umm a r y
Hydrocodoneis present in human milk. A published lactation studyreportsvariable concentrations ofhydrocodone and hydromorphone (an activemetabolite)in breast milk withadministration ofimmediate-releasehydrocodoneto nursingmothers in theearlypost-partum period. This lactation studydid not assess breastfed infants forpotential adversedrug reactions.
Limited published literature reports that, followingoral administration, ibuprofen is present in human milk at relativeinfant doses of0.06%to 0.6%ofthematernal weight-adjusted dailydose.
Lactation studies havenot been conducted with hydrocodone bitartrate and ibuprofen tablets, and no information is available on the effects ofthedrug on thebreastfed infant orthe effects ofthedrugon milk production.
Thedevelopmentaland health benefits ofbreastfeedingshould beconsidered alongwith the mothers clinical need forhydrocodone bitartrate and ibuprofen tabletsand anypotential adverseeffects on thebreastfed infant from hydrocodone bitartrate and ibuprofen tablets or from theunderlyingmaternal condition.
C lini ca l C onsid era tions
Monitorinfants exposed to hydrocodone bitartrate and ibuprofen through breast milk for excess sedation and respiratorydepression.Withdrawal symptoms can occurin breastfed infants when maternal administration ofhydrocodoneis stopped, orwhen breastfeedingis stopped.
Thesafetyand effectiveness ofhydrocodone bitartrate and ibuprofen tablets inpediatricpatients below theageof16 havenot been established.
Incontrolled clinical trials therewas no differencein tolerabilitybetween patients less than65years of age and thosegreater than or equal to 65,apartfrom an increased tendencyofthe elderlyto develop constipation. However, elderlypatients are atgreater risk for NSAID-associated seriouscardiovascular, gastrointestinal, andrenal adversereactions as well as possibleincreasedrisk of respiratory depression with opioids. Ingeneral, usecaution when selectingadosage for an elderlypatient, usuallystartingat thelow end ofthedosingrange, reflectingthegreaterfrequencyofdecreased hepatic, renal, orcardiacfunction and of concomitant diseaseorotherdrug therapy ( s e e WARNINGS:Cardiovascular ThromboticEvents , Gastrointestinal Bleeding, Ulceration, and Perforation , Renal Toxicityand Hyperkalemia ).
Respiratorydepression is the chief risk for elderlypatients treated with opioids, and has occurred afterlargeinitial doses were administered to patients who werenot opioid-tolerant orwhen opioids were coadministered with otheragents that depress respiration. Titratethedosageof hydrocodone bitartrate and ibuprofen tablets slowlyin geriatricpatients and monitor closelyforsigns of central nervous system andrespiratorydepression ( s e e WARNINGS:Life-Threatening RespiratoryDepression in Patients with ChronicPulmonaryDiseaseor in Elderly, Cachectic, or Debilitated Patients ).
Both hydrocodone and ibuprofen areknown to besubstantiallyexcreted bythekidney,and the risk of adverse reactionsto this drugmaybegreaterin patients with impaired renalfunction. Becauseelderlypatientsaremorelikelyto havedecreased renal function, careshould betaken in doseselection, and it maybeuseful to monitor renal function.
Patients with hepaticimpairment mayhavehigher hydrocodoneplasmaconcentrations than thosewith normal function.In patients with severehepaticimpairment, usealow initial dose. Monitorthesepatients closelyfor adverseeventssuch as respiratorydepression, sedation, and hypotension.
Patients with renal impairment mayhavehigherhydrocodoneplasmaconcentrations than those with normal function. Usealow initial dosein patients with renal impairment and monitor closelyfor adverseevents such as respiratorydepression, sedation, and hypotension.
The following adverse reactions aredescribed below and elsewherein thelabelingincludingtheWARNINGSsection.
- Addiction, Abuse, and Misuse
- Neonatal Opioid Withdrawal Syndrome
- Interactions with CytochromeP450 3A4InhibitorsandInducers
- Interactions with Benzodiazepines orOtherCNSDepressants
- Gastrointestinal Bleeding, Ulceration, and Perforation
- HeartFailureand Edema
- Renal Toxicityand Hyperkalemia
- Exacerbation ofAsthma Related to Aspirin Sensitivity
- Serious Skin Reactions
- PrematureClosureofFetal Ductus Arteriosus
Clinical trials experience
Becauseclinical trials are conducted underwidelyvarying conditions, adversereaction rates observed in the clinical trials ofadrugcannot bedirectlycompared to ratesin the clinical trials of anotherdrug and maynot reflect therates observed in practice.
Hydrocodone bitartrate and ibuprofen tabletswereadministered to approximately300 pain patients in asafetystudythat employed dosages andaduration oftreatment sufficient to encompass therecommended usage ( s e e DOSAGE AND ADMINISTRATION ). Adverse event ratesgenerallyincreased with increasingdailydose. The event rates reported below arefrom approximately150 patients who werein agroup that received onetablet ofhydrocodone bitartrate and ibuprofen tablets anaverageofthreeto fourtimes daily. Theoverall incidence rates of adverseexperiences in thetrials werefairlysimilar forthis patient groupand thosewho received the comparison treatment, acetaminophen 600 mgwith codeine60 mg.
The followinglists adverse events that occurred with an incidenceof1%orgreaterin clinical trials ofhydrocodone bitartrate and ibuprofen tablets,without regard to thecausal relationship ofthe events to thedrug. To distinguish differentratesofoccurrencein clinicalstudies, the adverseevents arelisted as follows:
name of ad ve rse e v e nt = l e ss than 3%
ad ve rse e ve nts mar k e d w ith an ast e risk * = 3% to 9%
ad ve rse e ve nt rat e s o v e r 9% are in par e nth e s e s.
B o d y a s a W hole
Abdominal pain*; Asthenia*; Fever; Flu syndrome; Headache(27%);Infection*; Pain. C ar diov a s c ul ar
C e nt ral N er vous S y st em
Anxiety*; Confusion; Dizziness (14%); Hypertonia;Insomnia*; Nervousness*; Paresthesia; Somnolence (22%); Thinkingabnormalities.
Di g e stive
Anorexia; Constipation (22%); Diarrhea*; Drymouth*; Dyspepsia(12%);Flatulence*; Gastritis; Melena; Mouth ulcers; Nausea (21%); Thirst; Vomiting*.
M e t a bolic a nd Nut r ition a l Diso r d er s
R e spi ra to r y
Dyspnea; Hiccups; Pharyngitis; Rhinitis. S kin a nd App e nd a g e s
S p ec i al S e ns esTinnitus.
U r o g e nit al
I n c id e n c e l e ss th a n 1%
Body as a W hole
C ardio v as c ular
Arrhythmia; Hypotension; Tachycardia.
C e ntral N e r v ous S y st em
Agitation; Abnormal dreams; Decreased libido; Depression; Euphoria; Mood changes; Neuralgia; Slurred speech; Tremor, Vertigo.
Dig e sti v e
Chalkystool; "Clenching teeth"; Dysphagia; Esophageal spasm; Esophagitis; Gastroenteritis; Glossitis; Liverenzymeelevation.
Me tabolic and N utrition a lWeight decrease.
M us c ulos ke l e talArthralgia; Myalgia.
R e spiratory
Asthma; Bronchitis; Hoarseness;Increased cough;Pulmonarycongestion; Pneumonia; Shallow breathing; Sinusitis.
S k in and App e ndag e sRash; Urticaria.
Sp ec ial S e ns e s
Altered vision; Bad taste; Dryeyes.
Urog e nital
Cystitis; Glycosuria;Impotence; Urinaryincontinence; Urinaryretention.
The following adverse reactions havebeen identified duringpost approvaluseofhydrocodone. Becausethese reactions are reported voluntarilyfrom apopulation ofuncertain size, it is not always possibleto reliablyestimatetheir frequencyorestablish a causal relationship to drug exposure.
S er otonin s y nd r om e :Cases ofserotonin syndrome, apotentiallylife-threateningcondition, have been reported duringconcomitant useofopioids with serotonergicdrugs.
Ad re n a l insu ff i c i e n c y :Cases of adrenal insufficiencyhavebeen reportedwith opioid use, more often following greaterthan onemonth ofuse.
An a p h y l a x is:Anaphylaxis has been reported withingredients contained inhydrocodone bitartrate and ibuprofen tablets.
And r o g e n d e f i c i e n c y :Cases of androgen deficiencyhaveoccurred with chronicuseofopioids ( s e e CLINICALPHARMACOLOGY:Pharmacodynamics ).
Drug a b u s e and d e p e nd e nce
Hydrocodone bitartrate and ibuprofen tabletscontain hydrocodone,aScheduleIIcontrolled substance.
Hydrocodone bitartrate and ibuprofen tabletcontains hydrocodone,asubstancewith ahigh potential for abusesimilarto otheropioids includingfentanyl, hydromorphone,methadone, morphine, oxycodone, oxymorphone, and tapentadol. Hydrocodone bitartrate and ibuprofen tabletscanbe abused and is subject to misuse, addiction, and criminal diversion ( s e e WARNINGS:Addiction, Abuse, and Misuse ).
All patients treated withopioids require careful monitoringforsigns ofabuse and addiction, becauseuseofopioid analgesicproducts carries the risk of addiction evenunder appropriate medical use.
Prescription drugabuseis theintentional non-therapeuticuseofaprescription drug,even once, forits rewardingpsychological orphysiological effects.
Drugaddiction is a clusterofbehavioral, cognitive, and physiological phenomenathat develop afterrepeated substanceuse and includes: astrongdesireto takethedrug,difficulties in controllingits use, persistingin its usedespiteharmful consequences, ahigherpriority given to drugusethan to otheractivities and obligations, increased tolerance,and sometimes aphysical withdrawal.
Drugseekingbehavioris verycommon with substanceusedisorders. Drug-seekingtactics include emergencycalls orvisits nearthe end ofofficehours,refusal to undergo appropriate examination, testingor referral, repeatedlossofprescriptions, tampering with prescriptions, and reluctanceto providepriormedical records orcontact information forothertreating healthcareprovider(s).Doctorshopping (visitingmultipleprescribers toobtain additional prescriptions)is commonamongdrugabusers andpeoplesufferingfrom untreated addiction.
Preoccupation with achievingadequatepain reliefcan beappropriatebehaviorin apatient with poorpain control.
Abuse and addiction areseparate and distinct from physical dependenceand tolerance. Healthcareproviders should be awarethat addiction maynot beaccompanied byconcurrent toleranceand symptoms ofphysical dependencein all addicts.In addition, abuseofopioids can occurin the absenceoftrue addiction.
Hydrocodone bitartrate and ibuprofen tablets, likeotheropioids, can bediverted fornon-medical useinto illicit channels of distribution. Careful record-keepingofprescribing information, includingquantity, frequency, and renewal requests, asrequired bystateand federal law, is stronglyadvised.
Proper assessment ofthepatient, properprescribingpractices, periodicre-evaluation oftherapy, and properdispensing and storage are appropriatemeasures that help to limit abuseofopioid drugs.
R isks S p ec i f ic to Abuse of Hydrocodone Bitartrate and Ibuprofen Tablets
Abuseofhydrocodone bitartrate and ibuprofen tabletsposes a risk ofoverdoseand death. Therisk is increasedwith concurrent abuseofhydrocodone bitartrate and ibuprofen tablets with alcoholand othercentral nervous system depressants ( s e e WARNINGS:Risks from Concomitant Usewith Benzodiazepines or Other CNS Depressants ).
Parenteral drugabuseiscommonlyassociated with transmission ofinfectious diseases such as hepatitis and HIV.
Both tolerance and physical dependence can develop during chronicopioidtherapy. Toleranceis theneed forincreasingdoses ofopioids to maintain adefined effect such as analgesia (in the absenceofdiseaseprogression orother external factors). Tolerancemayoccurto both thedesired and undesired effects ofdrugs, and maydevelop at different ratesfordifferent effects.
Physical dependenceresults in withdrawal symptoms after abrupt discontinuation orasignificant dosage reduction ofadrug. Withdrawal also maybeprecipitated through the administration of drugs with opioid antagonist activity(e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), orpartialagonists (e.g., buprenorphine). Physical dependencemaynot occurto a clinicallysignificant degreeuntil afterseveral days to weeks ofcontinued opioid usage.
Hydrocodone bitartrate and ibuprofen tablets should not be abruptlydiscontinued in aphysically-dependent patient ( s ee DOSAGE AND ADMINISTRATION:Discontinuation of hydrocodone bitartrate and ibuprofen tablets ).Ifhydrocodone bitartrate and ibuprofen tabletsare abruptlydiscontinued inaphysically-dependent patient, awithdrawal syndromemayoccur. Someor all ofthe followingcan characterizethis syndrome:restlessness, lacrimation,rhinorrhea,yawning, perspiration, chills, myalgia,and mydriasis. Othersigns and symptoms also maydevelop, includingirritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, orincreased blood pressure,respiratoryrate, or heart rate.
Infants born to mothers physicallydependent on opioids will also bephysicallydependent and mayexhibit respiratorydifficulties and withdrawal signs ( s e e PRECAUTIONS:Pregnancy ).
Following an acuteoverdosage, toxicitymayresult from hydrocodoneand/oribuprofen.
H y d r o c odone C ompon e n t
Acuteoverdosewith opioids can bemanifested byrespiratorydepression,somnolence progressingto stupororcoma, skeletal muscle flaccidity, cold andclammyskin, constricted pupils, and, in some cases, pulmonaryedema, bradycardia, hypotension, partial or complete airwayobstruction, atypical snoring, and death. Marked mydriasis ratherthan miosis maybe seen with hypoxiain overdosesituations.
I bu p r o fe n C ompon e nt
Symptoms followingacuteNSAID overdosages havebeen typicallylimited to lethargy, drowsiness, nausea, vomiting, and epigastricpain,which havebeengenerallyreversiblewith supportive care. Gastrointestinal bleedinghas occurred ( s e e WARNINGS:Gastrointestinal Bleeding, Ulceration, and Perforation ). Hypertension, acute renal failure, respiratorydepression, and comahaveoccurred,but wererare ( s e e WARNINGS:Hypertension , Renal Toxicityand Hyperkalemia ).
Treatment of overdose
Incaseofoverdose, priorities arethere-establishment ofapatent and protected airwayand institution of assisted orcontrolled ventilation, ifneeded. Employothersupportivemeasures (includingoxygenand vasopressors)in themanagement of circulatoryshock and pulmonary edema as indicated. Cardiac arrest orarrhythmiaswill require advanced life-support techniques.
Theopioid antagonists, naloxoneornalmefene,arespecificantidotes to respiratorydepression resultingfrom opioid overdose. For clinicallysignificant respiratoryorcirculatorydepression secondaryto hydrocodoneoverdose,administer anopioid antagonist. Opioid antagonists should not be administered in the absenceofclinicallysignificant respiratoryor circulatorydepression secondaryto hydrocodoneoverdose.
Becausetheduration ofopioid reversal is expectedto beless than theduration of action of hydrocodone,carefullymonitorthepatient untilspontaneous respiration is reliablyre-established.Iftheresponseto an opioid antagonist is suboptimal oronlybriefin nature, administer additional antagonist as directed bytheproducts prescribinginformation.
Inan individual physicallydependent on opioids, administration ofthe recommended usual dosageoftheantagonist will precipitate an acutewithdrawal syndrome. Theseverityofthe withdrawal symptoms experienced will depend onthedegreeofphysical dependence and the doseofthe antagonist administered.Ifadecision is madeto treat serious respiratorydepression in thephysicallydependent patient, administration ofthe antagonist should bebegun with care and bytitration with smallerthan usual doses ofthe antagonist.
Managepatients with symptomatic and supportive care followingan NSAIDoverdosage. Thereareno specificantidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams perkgofbodyweight in pediatricpatients) and/orosmotic catharticin symptomaticpatients seen within fourhours ofingestion orin patients with alargeoverdose(5 to 10 times the recommended dosage).Forceddiuresis, alkalinization ofurine, hemodialysis, orhemoperfusion maynot beusefuldueto high protein binding.
For additional information about overdosagetreatment contact apoison control center(1-800-222-1222).
Dosage and administration
Carefullyconsiderthepotential benefits and risksofhydrocodone bitartrate and ibuprofen tabletsand othertreatment options beforedecidingto usehydrocodone bitartrate and ibuprofen tablets. Usethelowest effectivedosage fortheshortest duration consistent with individual patient treatmentgoals ( s e e WARNINGS:Cardiovascular Thrombotic Events , Gastrointestinal Bleeding, Ulceration, and Perforation ).
Initiatethedosingregimen foreach patient individually, takinginto account thepatient's severity ofpain, patient response,prior analgesictreatmentexperience, andrisk factors for addiction, abuse, and misuse ( s e e WARNINGS:Addiction, Abuse, and Misuse ).
Monitorpatients closelyfor respiratorydepression, especiallywithin the first 24 to 72 hours of initiatingtherapyandfollowingdosageincreaseswith hydrocodone bitartrate and ibuprofen tabletsandadjust thedosage accordingly ( s e e WARNINGS:Life-Threatening RespiratoryDepression ).
Afterobservingthe responseto initial therapywith hydrocodone bitartrate and ibuprofen tablets, thedose and frequency should be adjusted to suit an individual patient's needs.
Fortheshort-term (generallyless than 10 days)management ofacutepain,the recommended doseofhydrocodone bitartrate and ibuprofen tablets is onetablet every4 to 6 hours, as necessary. Dosageshould not exceed5 tablets in a24-hourperiod.It should bekept inmind that toleranceto hydrocodonecan develop with continued use and that theincidenceofuntoward effects is dose related.
Thelowest effectivedoseorthelongest dosinginterval should besought for each patient ( s e e W AR N I N G S ), especiallyin the elderly. Afterobservingtheinitial responseto therapywith hydrocodone bitartrate and ibuprofen tablets, thedoseand frequencyofdosing should be adjusted to suit theindividual patient's need, without exceedingthetotal dailydose recommended.
Titration and maintenance of therapy
Individuallytitratehydrocodone bitartrate and ibuprofen tablets to adosethat provides adequate analgesia and minimizes adversereactions. Continuallyreevaluatepatientsreceivinghydrocodone bitartrate and ibuprofen tablets to assess the maintenanceofpain control and the relativeincidenceof adversereactions, as well as monitoringforthedevelopment of addiction, abuse, ormisuse ( s e e WARNINGS:Addiction,Abuse, and Misuse ).Frequent communication is important amongtheprescriber, othermembers ofthehealthcareteam, thepatient, and thecaregiver/familyduringperiodsof changinganalgesic requirements, includinginitial titration.
Ifthelevel ofpain increases afterdosagestabilization, attempt to identifythesourceofincreased pain beforeincreasingthehydrocodone bitartrate and ibuprofen tablets dosage.Ifunacceptableopioid-related adverse reactions areobserved, consider reducingthedosage. Adjust thedosagetoobtain an appropriate balancebetween management ofpain and opioid-related adversereactions.
Discontinuation of hydrocodone bitartrate and ibuprofen tablets
When apatient who hasbeen takinghydrocodone bitartrate and ibuprofen tabletsregularlyand maybephysicallydependent no longerrequires therapywith hydrocodone bitartrate and ibuprofen tablets, taperthedosegradually, by25%to 50%every2 to 4 days, whilemonitoringcarefullyforsigns and symptoms ofwithdrawal.Ifthepatient develops thesesigns orsymptoms, raisethedoseto theprevious level and tapermoreslowly, eitherbyincreasingtheinterval between decreases, decreasingthe amountof changein dose, or both. Do not abruptlydiscontinuehydrocodone bitartrate and ibuprofen tabletsin aphysicallydependentpatient ( s ee WARNINGS:Addiction,Abuse, and Misuse , DRUG ABUSE AND DEPENDENCE ).
Hydrocodone bitartrate and ibuprofen tablets are availableas:
White, film-coated roundconvextablets, debossedwith " 524"on oneside and plain on theotherside.
Bottles of15, 20, 30 and 60 tablets
Store at 20to 25C(68to 77F)[SeeUSP Controlled Room Temperature].
Dispensein atight, light-resistant container.
Spl medguide section
H y d r o c odon e B i t a r t r a t e (hye droe koe done bye tar trate) a n d I bup r of en ( eye" bue proe' fen ) T a b le t s ) , C I I
Hydrocodone bitartrate and ibuprofen
hydrocodone bitartrate and ibuprofen
A v o id t aki n g N S A I DS a ft er a r e c e n t h eart a tt ack, un less y ou r h e al th c a r e p r o v i d er t el l s y o u to . Y o u m ay h a v e an i n cr eased r i s k o f a noth er h e a r t a tt ack if y o u t a k e N S A I Ds a ft er a r ece n t h ea r t a tt a ck.
|past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs||taking medicines called corticosteroids, anticoagulants, SSRIs, or SNRIs|
|increasing doses of NSAIDS||older age|
|longer use of NSAIDS||poor health|
|smoking||advanced liver disease|
|drinking alcohol||bleeding problems|
hydrocodone bitartrate and ibuprofen
|Be fo r e t a ki n g hydrocodone bitartrate and ibuprofen tablets, t ell y ou r h eal th c a r e p r o v i d er if y o u h a v e a h is t o r y of :|
hydrocodone bitartrate and ibuprofen
hydrocodone bitartrate and ibuprofen
hydrocodone bitartrate and ibuprofen
|G et e m e r g e n c y m e d i c al h elp if y o u h a v e:|
|S to p hydrocodone bitartrate and ibuprofen tablets a n d c all y ou r h eal th c a r e p r o v i d er r i gh t a w ay if y o u h a v e a n y o f th e fo ll o w i n g s y mptom s:|
|diarrhea||thereis bloodinyourbowelmovementoritis black andstickyliketar|
|your skin or eyes look yellow||skin rash or blisters with fever|
|indigestion or stomach pain||swelling of the arms and legs, hands and feet|
|These are not all the possible side effects of hydrocodone bitartrate and ibuprofen tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.|
Actavis Laboratories FL, Inc.
Fort Lauderdale, FL 33314 USA
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
Th i s Me d i c a t i o n G u i d e h a s b e e n a p pro v e d b y t h e U. S . Fo o d a n d D ru g A dm i n i s t r a t i o n .
Revised: January 2017
Ingredients and appearance - Product information
Hydrocodone bitartrate and ibuprofen tablet, film coated- Hydrocodone bitartrate and ibuprofen
|Product Type||HUMAN PRESCRIPTION DRUG LABEL||Item Code (Source)||NDC: 43063-349|
|Route of Administration||Oral|
|Hydrocodone bitartrate ( UNII: NO70W886KK)( Hydrocodone - UNII: 6YKS4Y3WQ7 )||7.5 mgin 1|
|Ibuprofen ( UNII: WK2XYI10QM)( Ibuprofen - UNII: WK2XYI10QM )||200 mgin 1|
|Silicon dioxide||( UNII: ETJ7Z6XBU4)|
|Croscarmellose sodium||( UNII: M28OL1HH48)|
|Hypromellose 2910 (3 mpa.s)||( UNII: 0VUT3PMY82)|
|Hypromellose 2910 (6 mpa.s)||( UNII: 0WZ8WG20P6)|
|Lactose monohydrate||( UNII: EWQ57Q8I5X)|
|Magnesium stearate||( UNII: 70097M6I30)|
|Microcrystalline cellulose||( UNII: OP1R32D61U)|
|Polyethylene glycol 400||( UNII: B697894SGQ)|
|Polyethylene glycol 8000||( UNII: Q662QK8M3B)|
|Polydextrose||( UNII: VH2XOU12IE)|
|Starch, corn||( UNII: O8232NY3SJ)|
|Titanium dioxide||( UNII: 15FIX9V2JP)|
|Triacetin||( UNII: XHX3C3X673)|
|#||Item Code||Package Description||Marketing Start Date|
|1||NDC: 43063-349-15||15 in 1 BOTTLE, PLASTIC||2017/01/27|
|2||NDC: 43063-349-20||20 in 1 BOTTLE, PLASTIC||2017/03/01|
|3||NDC: 43063-349-30||30 in 1 BOTTLE, PLASTIC||2017/02/09|
|4||NDC: 43063-349-60||60 in 1 BOTTLE, PLASTIC||2012/03/09|
|Marketing Category||Application Number or Monograph Citation||Territorial Authority||Marketing Start Date|
Labeler - PD-Rx Pharmaceuticals, Inc.( 156893695)
|PD-Rx Pharmaceuticals, Inc.||156893695||repack( 43063-349)|
Principal display panel
7.5 mg/200 mg