Benzeneacetic acid, α-methyl-3-phenoxy-, calcium s alt (2:1)-(±)-, dihydrate

Transcription

1 FENOPROFEN CALCIUM- fenprfen calcium tablet, film cated Xspire Pharma, LLC Cardivas cular Thrmbtic Events Nnsteridal anti-inflammatry drugs (NSAIDs) cause an increased risk f serius cardivascular thrmbtic events, including mycardial infarctin and strke, which can be fatal. This risk may ccur early in treatment and may increase with duratin f use (see WARNINGS and PRECAUTIONS). Fenprfen calcium tablets are cntraindicated in the setting f crnary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS). Gastrintestinal Risk NSAIDs cause an increased risk f serius gastrintestinal adverse events including bleeding, ulceratin and perfratin f stmach r intestines, which can be fatal. These events can ccur at any time during use and withut warning symptms. Elderly patients are at greater risk fr serius gastrintestinal events (see WARNINGS). DESCRIPTION Fenprfen calcium is a nnsteridal, anti-inflammatry, antiarthritic drug. Chemically, fenprfen calcium is an arylacetic acid derivative. The structural frmula is as fllws: Benzeneacetic acid, α-methyl-3-phenxy-, calcium s alt (2:1)-(±)-, dihydrate Fenprfen calcium, USP is a white crystalline pwder, sluble in alchl (95%) t the extent f apprximately 15 mg/ml at 25 C, slightly sluble in water and insluble in benzene. The pka f fenprfen calcium is 4.5 at 25 C. Film-cated fenprfen calcium tablets fr ral administratin are available cntaining fenprfen calcium as the dihydrate equivalent t 600 mg f fenprfen and the fllwing inactive ingredients: cllidal silicn dixide, crscarmellse sdium, hyprmellse, magnesium stearate, micrcrystalline cellulse, plyethylene glycl, plysrbate 80, pregelatinized starch, sdium lauryl sulfate, titanium dixide and FD&C Yellw N. 6 Aluminum Lake. CLINICAL PHARMACOLOGY Fenprfen calcium is a nnsteridal, anti-inflammatry, antiarthritic drug that als pssesses analgesic and antipyretic activities. Its exact mde f actin is unknwn, but it is thught that prstaglandin

2 synthetase inhibitin is invlved. Results in humans demnstrate that fenprfen has bth anti-inflammatry and analgesic actins. The emergence and degree f erythemic respnse were measured in adult male vlunteers expsed t ultravilet irradiatin. The effects f fenprfen, aspirin and indmethacin were each cmpared with thse f a placeb. All three drugs demnstrated antierythemic activity. In all patients with rheumatid arthritis, the anti-inflammatry actin f fenprfen has been evidenced by relief f pain, increase in grip strength and reductins in jint swelling, duratin f mrning stiffness and disease activity (as assessed by bth the investigatr and the patient). The anti-inflammatry actin f fenprfen has als been evidenced by increased mbility (i.e., a decrease in the number f jints having limited mtin). The use f fenprfen in cmbinatin with gld salts r crticsterids has been studied in patients with rheumatid arthritis. The studies, hwever, were inadequate in demnstrating whether further imprvement is btained by adding fenprfen t maintenance therapy with gld salts r sterids. Whether r nt fenprfen used in cnjunctin with partially effective dses f a crticsterid has a sterid-sparing effect is unknwn. In patients with stearthritis, the anti-inflammatry and analgesic effects f fenprfen have been demnstrated by reductin in tenderness as a respnse t pressure and reductins in night pain, stiffness, swelling and verall disease activity (as assessed by bth the patient and the investigatr). These effects have als been demnstrated by relief f pain with mtin and at rest and increased range f mtin in invlved jints. In patients with rheumatid arthritis and stearthritis, clinical studies have shwn fenprfen t be cmparable t aspirin in cntrlling the afrementined measures f disease activity, but mild gastrintestinal reactins (nausea, dyspepsia) and tinnitus ccurred less frequently in patients treated with fenprfen than in aspirin-treated patients. It is nt knwn whether fenprfen calcium causes less peptic ulceratin than des aspirin. In patients with pain, the analgesic actin f fenprfen has prduced a reductin in pain intensity, an increase in pain relief, imprvement in ttal analgesia scres and a sustained analgesic effect. Under fasting cnditins, fenprfen is rapidly absrbed and peak plasma levels f 50 mcg/ml are achieved within 2 hurs after ral administratin f 600 mg dses. Gd dse prprtinality was bserved between 200 mg and 600 mg dses in fasting male vlunteers. The plasma half-life is apprximately 3 hurs. Abut 90% f a single ral dse is eliminated within 24 hurs as fenprfen glucurnide and 4 -hydrxy-fenprfen glucurnide, the majr urinary metablites f fenprfen. Fenprfen is highly bund (99%) t albumin. The cncmitant administratin f antacid (cntaining bth aluminum and magnesium hydrxide) des nt interfere with absrptin f fenprfen. There is less suppressin f cllagen-induced platelet aggregatin with single dses f fenprfen calcium than there is with aspirin. INDICATIONS AND USAGE Carefully cnsider the ptential benefits and risks f fenprfen calcium tablets, USP and ther treatment ptins befre deciding t use fenprfen calcium tablets. Use the lwest effective dse fr the shrtest duratin cnsistent with individual patient treatment gals (see WARNINGS). Fenprfen calcium tablets are indicated: Fr relief f mild t mderate pain in adults. Fr relief f the signs and symptms f rheumatid arthritis. Fr relief f the signs and symptms f stearthritis.

3 CONTRAINDICATIONS Fenprfen calcium tablets are cntraindicated in patients wh have shwn hypersensitivity t fenprfen calcium. Fenprfen shuld nt be given t patients wh have experienced asthma, urticaria r allergic-type reactins after taking aspirin r ther NSAIDs. Severe, rarely fatal, anaphylactic-like reactins t NSAIDs have been reprted in such patients (see WARNINGS: Anaphylactid Reactins, and PRECAUTIONS: Preexisting Asthma). Fenprfen is cntraindicated in the setting f crnary artery bypass graft (CABG) surgery (see WARNINGS). Fenprfen is cntraindicated in patients with a histry f significantly impaired renal functin (see WARNINGS: Advanced Renal Disease). WARNINGS Cardivascular Effects Cardivascular Thrmbtic Events Clinical trials f several COX-2 selective and nnselective NSAIDs f up t 3 years duratin have shwn an increased risk f serius cardivascular (CV) thrmbtic events, including mycardial infarctin (MI) and strke, which can be fatal. Based n available data, it is unclear that the risk fr CV thrmbtic events is similar fr all NSAIDs. The relative increase in serius CV thrmbtic events ver baseline cnferred by NSAID use appears t be similar in thse with and withut knwn CV disease r risk factrs fr CV disease. Hwever, patients with knwn CV disease r risk factrs had a higher abslute incidence f excess serius CV thrmbtic events, due t their increased baseline rate. Sme bservatinal studies fund that this increased risk f serius CV thrmbtic events began as early as the first weeks f treatment. The increase in CV thrmbtic risk has been bserved mst cnsistently at higher dses. T minimize the ptential risk fr an adverse CV event in NSAID-treated patients, use the lwest effective dse fr the shrtest duratin pssible. Physicians and patients shuld remain alert fr the develpment f such events, thrughut the entire treatment curse, even in the absence f previus CV symptms. Patients shuld be infrmed abut the signs and/r symptms f serius CV events and the steps t take if they ccur. There is n cnsistent evidence that cncurrent use f aspirin mitigates the increased risk f serius CV thrmbtic events assciated with NSAID use. The cncurrent use f aspirin and an NSAID, such as fenprfen calcium, increases the risk f serius gastrintestinal (GI) events (see GI WARNINGS). Status Pst Crnary Artery Bypass Graft (CABG) Surgery Tw large, cntrlled clinical trials f a COX-2 selective NSAID fr the treatment f pain in the first 10 t 14 days fllwing CABG surgery fund an increased incidence f mycardial infarctin and strke. NSAIDs are cntraindicated in the setting f CABG (see CONTRAINDICATIONS). Pst-MI Patients Observatinal studies cnducted in the Danish Natinal Registry have demnstrated that patients treated with NSAIDs in the pst-mi perid were at increased risk f reinfarctin, CV-related death, and allcause mrtality beginning in the first week f treatment. In this same chrt, the incidence f death in the first year pst MI was 20 per 100 persn years in NSAID-treated patients cmpared t 12 per 100 persn years in nn-nsaid expsed patients. Althugh the abslute rate f death declined smewhat after the first year pst-mi, the increased relative risk f death in NSAID users persisted ver at least

4 the next 4 years f fllw-up. Avid the use f fenprfen calcium tablets in patients with a recent MI unless the benefits are expected t utweigh the risk f recurrent CV thrmbtic events. If fenprfen calcium tablets are used in patients with a recent MI, mnitr patients fr signs f cardiac ischemia. Hypertensin NSAIDs, including fenprfen, can lead t nset f new hypertensin r wrsening f preexisting hypertensin, either f which may cntribute t the increased incidence f CV events. Patients taking thiazides r lp diuretics may have impaired respnse t these therapies when taking NSAIDs. NSAIDs, including fenprfen, shuld be used with cautin in patients with hypertensin. Bld pressure (BP) shuld be mnitred clsely during the initiatin f NSAID treatment and thrughut the curse f therapy. Heart Failure and Edema The Cxib and traditinal NSAID Trialists Cllabratin meta-analysis f randmized cntrlled trials demnstrated an apprximately 2-fld increase in hspitalizatins fr heart failure in COX-2 selectivetreated patients and nnselective NSAID-treated patients cmpared t placeb-treated patients. In a Danish Natinal Registry study f patients with heart failure, NSAID use increased the risk f MI, hspitalizatin fr heart failure, and death. Additinally, fluid retentin and edema have been bserved in sme patients treated with NSAIDs. Use f fenprfen calcium may blunt the CV effects f several therapeutic agents used t treat these medical cnditins [e.g., diuretics, ACE inhibitrs, r angitensin receptr blckers (ARBs)] (see Drug Interactins). Avid the use f fenprfen calcium tablets in patients with severe heart failure unless the benefits are expected t utweigh the risk f wrsening heart failure. If fenprfen calcium tablets are used in patients with severe heart failure, mnitr patients fr signs f wrsening heart failure. Gas trintes tinal Effects Risk f Ulceratin, Bleeding and Perfratin NSAIDs, including fenprfen, can cause serius gastrintestinal (GI) adverse events including inflammatin, bleeding, ulceratin and perfratin f the stmach, small intestine r large intestine, which can be fatal. These serius adverse events can ccur at any time, with r withut warning symptms, in patients treated with NSAIDs. Only ne in five patients, wh develp a serius upper GI adverse event n NSAID therapy, is symptmatic. Upper GI ulcers, grss bleeding r perfratin caused by NSAIDs ccur in apprximately 1% f patients treated fr 3 t 6 mnths, and in abut 2% t 4% f patients treated fr ne year. These trends cntinue with lnger duratin f use, increasing the likelihd f develping a serius GI event at sme time during the curse f therapy. Hwever, even shrt-term therapy is nt withut risk. NSAIDs shuld be prescribed with extreme cautin in thse with a prir histry f ulcer disease r gastrintestinal bleeding. Patients with a prir histry f peptic ulcer disease and/r gastrintestinal bleeding wh use NSAIDs have a greater than 10-fld increased risk fr develping a GI bleed cmpared t patients with neither f these risk factrs. Other factrs that increase the risk fr GI bleeding in patients treated with NSAIDs include cncmitant use f ral crticsterids r anticagulants, lnger duratin f NSAID therapy, smking, use f alchl, lder age and pr general health status. Mst spntaneus reprts f fatal GI events are in elderly r debilitated patients and therefre, special care shuld be taken in treating this ppulatin. T minimize the ptential risk fr an adverse GI event in patients treated with a NSAID, the lwest effective dse shuld be used fr the shrtest pssible duratin. Patients and physicians shuld remain alert fr signs and symptms f GI ulceratin and bleeding during NSAID therapy and prmptly initiate

5 additinal evaluatin and treatment if a serius GI adverse event is suspected. This shuld include discntinuatin f the NSAID until a serius GI adverse event is ruled ut. Fr high risk patients, alternate therapies that d nt invlve NSAIDs shuld be cnsidered. Renal Effects Lng-term administratin f NSAIDs has resulted in renal papillary necrsis and ther renal injury. Renal txicity has als been seen in patients in whm renal prstaglandins have a cmpensatry rle in the maintenance f renal perfusin. In these patients, administratin f a nnsteridal anti-inflammatry drug may cause a dse-dependent reductin in prstaglandin frmatin and, secndarily, in renal bld flw, which may precipitate vert renal decmpsitin. Patients at greatest risk f this reactin are thse with impaired renal functin, heart failure, liver dysfunctin, thse taking diuretics and ACE inhibitrs and the elderly. Discntinuatin f NSAID therapy is usually fllwed by recvery t the pretreatment state. Advanced Renal Disease N infrmatin is available frm cntrlled clinical studies regarding the use f fenprfen in patients with advanced renal disease. Therefre, treatment with fenprfen is nt recmmended in patients with advanced renal disease (see CONTRAINDICATIONS). Anaphylactid Reactins As with ther NSAIDs, anaphylactid reactins may ccur in patients withut knwn prir expsure t fenprfen. Fenprfen shuld nt be given t patients with the aspirin triad. This symptm cmplex typically ccurs in asthmatic patients wh experience rhinitis with r withut nasal plyps, r wh exhibit severe, ptentially fatal brnchspasm after taking aspirin r ther NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help shuld be sught in cases where an anaphylactid reactin ccurs. Skin Reactins NSAIDs, including fenprfen, can cause serius skin adverse events such as exfliative dermatitis, Stevens-Jhnsn Syndrme (SJS) and txic epidermal necrlysis (TEN), which can be fatal. These serius events may ccur withut warning. Patients shuld be infrmed abut the signs and symptms f serius skin manifestatins and use f the drug shuld be discntinued at the first appearance f skin rash r any ther sign f hypersensitivity. Pregnancy Starting at 30 weeks gestatin, fenprfen and ther NSAIDs shuld be avided by pregnant wmen as premature clsure f the ductus arterisus in the fetus may ccur. Ocular Studies t date have nt shwn changes in the eyes attributable t the administratin f fenprfen. Hwever, adverse cular effects have been bserved with ther anti-inflammatry drugs. Eye examinatins, therefre, shuld be perfrmed if visual disturbances ccur in patients taking fenprfen. Central Nervus Sys tem Cautin shuld be exercised by patients whse activities require alertness if they experience CNS side effects while taking fenprfen. Hearing Since the safety f fenprfen has nt been established in patients with impaired hearing, these patients shuld have peridic tests f auditry functin during prlnged therapy with fenprfen.

6 PRECAUTIONS General Fenprfen cannt be expected t substitute fr crticsterids r t treat crticsterid insufficiency. Abrupt discntinuatin f crticsterids may lead t disease exacerbatin. Patients n prlnged crticsterid therapy shuld have their therapy tapered slwly if a decisin is made t discntinue crticsterids. The pharmaclgical activity f fenprfen in reducing inflammatin may diminish the utility f these diagnstic signs in detecting cmplicatins f presumed nninfectius, painful cnditins. Hepatic Effects Brderline elevatins f ne r mre liver tests may ccur in up t 15% f patients taking NSAIDs including fenprfen. These labratry abnrmalities may prgress, may remain unchanged r may be transient with cntinuing therapy. Ntable elevatins f ALT r AST (apprximately three r mre times the upper limit f nrmal) have been reprted in apprximately 1% f patients in clinical trials with NSAIDs. In additin, rare cases f severe hepatic reactins, including jaundice and fatal fulminant hepatitis, liver necrsis and hepatic failure, sme f them with fatal utcmes have been reprted. A patient with symptms and/r signs suggesting liver dysfunctin, r in whm an abnrmal liver test has ccurred, shuld be evaluated fr evidence f the develpment f a mre severe hepatic reactin while n therapy with fenprfen. If clinical signs and symptms cnsistent with liver disease develp, r if systemic manifestatins ccur (e.g., esinphilia, rash, etc.), fenprfen shuld be discntinued. Hematlgical Effects Anemia is smetimes seen in patients receiving NSAIDs, including fenprfen. This may be due t fluid retentin, ccult r grss GI bld lss r an incmpletely described effect upn erythrpiesis. Patients n lng-term treatment with NSAIDs, including fenprfen, shuld have their hemglbin r hematcrit checked if they exhibit any signs r symptms f anemia. NSAIDs inhibit platelet aggregatin and have been shwn t prlng bleeding time in sme patients. Unlike aspirin, their effect n platelet functin is quantitatively less, f shrter duratin, and reversible. Patients receiving fenprfen wh may be adversely affected by alteratins in platelet functin, such as thse with cagulatin disrders r patients receiving anticagulants, shuld be carefully mnitred. Preexis ting As thma Patients with asthma may have aspirin-sensitive asthma. The use f aspirin in patients with aspirinsensitive asthma has been assciated with severe brnchspasm which can be fatal. Since crssreactivity, including brnchspasm, between aspirin and ther nnsteridal anti-inflammatry drugs has been reprted in such aspirin-sensitive patients, fenprfen shuld nt be administered t patients with this frm f aspirin sensitivity and shuld be used with cautin in patients with preexisting asthma. Infrmatin fr Patients Patients s huld be infrmed f the fllwing infrmatin befre initiating therapy with an NSAID and peridically during the curs e f nging therapy. Patients s huld als be encuraged t read the NSAID Medicatin Guide that accmpanies each pres criptin dis pens ed Cardivas cular Thrmbtic Events: Advise patients t be alert fr the symptms f cardivascular thrmbtic events, including chest pain, shrtness f breath, weakness, r slurring f speech, and t reprt any f these symptms t their healthcare prvider immediately (see WARNINGS). Fenprfen, like ther NSAIDs, can cause GI discmfrt and, rarely, serius GI side effects, such as ulcers and bleeding, which may result in hspitalizatin and even death. Althugh serius

7 GI tract ulceratins and bleeding can ccur withut warning symptms, patients shuld be alert fr the signs and symptms f ulceratins and bleeding, and shuld ask fr medical advice when bserving any indicative sign r symptms including epigastric pain, dyspepsia, melena and hematemesis. Patients shuld be apprised f the imprtance f this fllw-up (see WARNINGS: Gastrintestinal Effects: Risk f Ulceratin, Bleeding, and Perfratin). Fenprfen, like ther NSAIDs, can cause serius skin side effects such as exfliative dermatitis, SJS and TEN, which may result in hspitalizatin and even death. Althugh serius skin reactins may ccur withut warning, patients shuld be alert fr the signs and symptms f skin rash and blisters, fever r ther signs f hypersensitivity such as itching, and shuld ask fr medical advice when bserving any indicative signs r symptms. Patients shuld be advised t stp the drug immediately if they develp any type f rash and cntact their physicians as sn as pssible. Heart Failure and Edema:Advise patients t be alert fr the symptms f cngestive heart failure including shrtness f breath, unexplained weight gain, r edema and t cntact their healthcare prvider if such symptms ccur (see WARNINGS). Patients shuld be infrmed f the warning signs and symptms f hepattxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and "flu- like" symptms). If these ccur, patients shuld be instructed t stp therapy and seek immediate medical therapy. Patients shuld be infrmed f the signs f an anaphylactid reactin (e.g. difficulty breathing, swelling f the face r thrat). If these ccur, patients shuld be instructed t seek immediate emergency help (see WARNINGS). Starting at 30 weeks gestatin, fenprfen and ther NSAIDs shuld be avided by pregnant wmen as premature clsure f the ductus arterisus in the fetus may ccur. Labratry Tests Because serius GI tract ulceratins and bleeding can ccur withut warning symptms, physicians shuld mnitr fr signs r symptms f GI bleeding. Patients n lng-term treatment with NSAIDs, shuld have their CBC and a chemistry prfile checked peridically. If clinical signs and symptms cnsistent with liver r renal disease develp, systemic manifestatins ccur (e.g., esinphilia, rash, etc.) r if abnrmal liver tests persist r wrsen, fenprfen shuld be discntinued. Drug Interactins ACE Inhibitrs Reprts suggest that NSAIDs may diminish the antihypertensive effect f ACE inhibitrs. This interactin shuld be given cnsideratin in patients taking NSAIDs cncmitantly with ACE inhibitrs. Aspirin The cadministratin f aspirin decreases the bilgic half-life f fenprfen because f an increase in metablic clearance that results in a greater amunt f hydrxylated fenprfen in the urine. Althugh the mechanism f interactin between fenprfen and aspirin is nt ttally knwn, enzyme inductin and displacement f fenprfen frm plasma albumin binding sites are pssibilities. As with ther NSAIDs, cncmitant administratin f fenprfen calcium and aspirin is nt generally recmmended because f the ptential f increased adverse effects. Diuretics Clinical studies, as well as pst-marketing bservatins, have shwn that fenprfen can reduce the natriuretic effect f fursemide and thiazides in sme patients. This respnse has been attributed t inhibitin f renal prstaglandin synthesis. During cncmitant therapy with NSAIDs, the patient shuld be bserved clsely fr signs f renal failure (see WARNINGS: Renal Effects), as well as t assure diuretic efficacy.

8 Lithium NSAIDs have prduced an elevatin f plasma lithium levels and a reductin in renal lithium clearance. The mean minimum lithium cncentratin increased 15% and the renal clearance was decreased by apprximately 20%. These effects have been attributed t inhibitin f renal prstaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered cncurrently, subjects shuld be bserved carefully fr signs f lithium txicity. Methtrexate NSAIDs have been reprted t cmpetitively inhibit methtrexate accumulatin in rabbit kidney slices. This may indicate that they culd enhance the txicity f methtrexate. Cautin shuld be used when NSAIDs are administered cncmitantly with methtrexate. Warfarin The effects f warfarin and NSAIDs n GI bleeding are synergistic, such that users f bth drugs tgether have a risk f serius GI bleeding higher than users f either drug alne. Phenbarbital Chrnic administratin f phenbarbital, a knwn enzyme inducer, may be assciated with a decrease in the plasma half-life f fenprfen. When phenbarbital is added t r withdrawn frm treatment, dsage adjustment f fenprfen may be required. Plas ma Prtein Binding In vitr studies have shwn that fenprfen, because f its affinity fr albumin, may displace frm their binding sites ther drugs that are als albumin bund, and this may lead t drug interactins. Theretically, fenprfen culd likewise be displaced. Patients receiving hydantins, sulfnamides r sulfnylureas shuld be bserved fr increased activity f these drugs and, therefre, signs f txicity frm these drugs. Drug/Labratry Tes t Interactins Amerlex-M kit assay values f ttal and free triidthyrnine in patients receiving fenprfen have been reprted as falsely elevated n the basis f a chemical crss-reactin that directly interferes with the assay. Thyrid-stimulating hrmne, ttal thyrxine and thyrtrpin-releasing hrmne respnse are nt affected. Carcingenes is, Mutagenes is and Impairment f Fertility Lng-term studies in animals have nt been cnducted t evaluate the carcingenic ptential f fenprfen. Studies have nt been cnducted t determine the effect f fenprfen n mutagenicity r fertility. Pregnancy Teratgenic Effects. Pregnancy Categry C Prir t 30 Weeks Gestatin; Categry D starting at 30 Weeks Gestatin Starting at 30 weeks gestatin, fenprfen and ther NSAIDs shuld be avided by pregnant wmen as premature clsure f the ductus arterisus in the fetus may ccur. Fenprfen can cause fetal harm when administered t a pregnant wman starting at 30 weeks gestatin. If this drug is used during this time perid in pregnancy, the patient shuld be apprised f the ptential hazard t a fetus. There are n adequate and well cntrlled studies in pregnant wmen. Prir t 30 weeks gestatin, fenprfen shuld be used during pregnancy nly if the ptential benefit justifies the ptential risk t the fetus. Reprductive studies cnducted in rats and rabbits have nt demnstrated evidence f develpmental

9 abnrmalities when given daily ral dses f 50 r 100 mg/kg fenprfen calcium, respectively (0.15 and 0.6 times the maximum human daily dse f 3200 mg based n bdy surface area cmparisns). Hwever, animal reprductin studies are nt always predictive f human respnse. Nnteratgenic Effects Because f the knwn effects f nnsteridal anti-inflammatry drugs n the fetal cardivascular system (clsure f ductus arterisus), use during pregnancy (particularly late pregnancy) shuld be avided. Labr and Delivery The effects f fenprfen n labr and delivery in pregnant wmen are unknwn. In rat studies, maternal expsure t NSAIDs, as with ther drugs knwn t inhibit prstaglandin synthesis, increased the incidence f dystcia, delayed parturitin and decreased pup survival. Nurs ing Mthers It is nt knwn whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because f the ptential fr serius adverse reactins in nursing infants frm fenprfen, a decisin shuld be made whether t discntinue nursing r t discntinue the drug, taking int accunt the imprtance f the drug t the mther. Pediatric Us e Safety and effectiveness in pediatric patients belw the age f 18 have nt been established. Geriatric Us e As with any NSAIDs, cautin shuld be exercised in treating the elderly (65 years and lder). ADVERSE REACTIONS During clinical studies fr rheumatid arthritis, stearthritis r mild t mderate pain and studies f pharmackinetics, cmplaints were cmpiled frm a checklist f ptential adverse reactins, and the fllwing data emerged. These encmpass bservatins in 6,786 patients, including 188 bserved fr at least 52 weeks. Fr cmparisn, data are als presented frm cmplaints received frm the 266 patients wh received placeb in these same trials. During shrt-term studies fr analgesia, the incidence f adverse reactins was markedly lwer than that seen in lnger-term studies. Advers e Drug Reactins Reprted in 1% f Patients During Clinical Trials Diges tive Sys tem: During clinical trials with fenprfen calcium, the mst cmmn adverse reactins were gastrintestinal in nature and ccurred in 20.8% f patients receiving fenprfen as cmpared t 16.9% f patients receiving placeb. In descending rder f frequency, these reactins included dyspepsia (10.3% fenprfen vs. 2.3% placeb), nausea (7.7% vs. 7.1%), cnstipatin (7% vs. 1.5%), vmiting (2.6% vs. 1.9%), abdminal pain (2% vs. 1.1%) and diarrhea (1.8% vs. 4.1%). The drug was discntinued because f adverse gastrintestinal reactins in less than 2% f patients during premarketing studies. Nervus Sys tem: The mst frequent adverse neurlgic reactins were headache (8.7% vs. 7.5%) and smnlence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremr (2.2% vs. 0.4%) and cnfusin (1.4% vs. nne) were nted less frequently. Fenprfen was discntinued in less than 0.5% f patients because f these side effects during premarketing studies. Skin and Appendages: Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%) and rash (3.7% vs. 0.4%) were reprted. Fenprfen was discntinued in abut 1% f patients because f an adverse effect related t the skin during premarketing studies.

10 Special Sens es: Tinnitus (4.5% vs. 0.4%), blurred visin (2.2% vs. nne) and decreased hearing (1.6% vs. nne) were reprted. Fenprfen was discntinued in less than 0.5% f patients because f adverse effects related t the special senses during premarketing studies. Cardivas cular: Palpitatins (2.5% vs. 0.4%). Fenprfen was discntinued in abut 0.5% f patients because f adverse cardivascular reactins during premarketing studies. Mis cellaneus: Nervusness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5% vs. 0.4%), dyspnea (2.8% vs. nne), fatigue (1.7% vs. 1.5%), upper respiratry infectin (1.5% vs. 5.6%) and naspharyngitis (1.2% vs. nne). Advers e Drug Reactins Reprted in < 1% f Patients During Clinical Trials Diges tive Sys tem: Gastritis, peptic ulcer with/withut perfratin, gastrintestinal hemrrhage, anrexia, flatulence, dry muth and bld in the stl. Increases in alkaline phsphatase, LDH, SGOT, jaundice and chlestatic hepatitis, aphthus ulceratins f the buccal mucsa, metallic taste and pancreatitis (see PRECAUTIONS). Cardivas cular: Atrial fibrillatin, pulmnary edema, electrcardigraphic changes and supraventricular tachycardia. Geniturinary Tract: Renal failure, dysuria, cystitis, hematuria, liguria, aztemia, anuria, interstitial nephritis, nephrsis and papillary necrsis (see WARNINGS). Hypers ens itivity: Angiedema (angineurtic edema). Hematlgic: Purpura, bruising, hemrrhage, thrmbcytpenia, hemlytic anemia, aplastic anemia, agranulcytsis and pancytpenia. Nervus Sys tem: Depressin, disrientatin, seizures and trigeminal neuralgia. Special Sens es: Burning tngue, diplpia and ptic neuritis. Skin and Appendages: Exfliative dermatitis, txic epidermal necrlysis, Stevens-Jhnsn Syndrme and alpecia. Miscellaneus: Anaphylaxis, urticaria, malaise, insmnia, tachycardia, persnality change, lymphadenpathy, mastdynia and fever. OVERDOSAGE Signs and Symptms Symptms f verdse appear within several hurs and generally invlve the gastrintestinal and central nervus systems. They include dyspepsia, nausea, vmiting, abdminal pain, dizziness, headache, ataxia, tinnitus, tremr, drwsiness and cnfusin. Hyperpyrexia, tachycardia, hyptensin and acute renal failure may ccur rarely fllwing verdse. Respiratry depressin and metablic acidsis have als been reprted fllwing verdse with certain NSAIDs. Treatment T btain up-t-date infrmatin abut the treatment f verdse, a gd resurce is yur certified Reginal Pisn Cntrl Center. Telephne numbers f certified pisn cntrl centers are listed in the Physicians' Desk Reference (PDR). In managing verdsage, cnsider the pssibility f multiple drug verdses, interactin amng drugs and unusual drug kinetics in yur patient. Prtect the patient's airway and supprt ventilatin and perfusin. Meticulusly mnitr and maintain, within acceptable limits, the patient's vital signs, bld gases, serum electrlytes, etc. Absrptin f drugs frm the gastrintestinal tract may be decreased by giving activated charcal, which, in many cases, is mre effective than lavage; cnsider charcal instead f r in additin t gastric emptying. Repeated dses f charcal ver time may hasten eliminatin f sme drugs that have been absrbed.

11 Repeated dses f charcal ver time may hasten eliminatin f sme drugs that have been absrbed. Safeguard the patient's airway when emplying gastric emptying r charcal. Alkalinizatin f the urine, frced diuresis, peritneal dialysis, hemdialysis and charcal hemperfusin d nt enhance systemic drug eliminatin. DOSAGE AND ADMINISTRATION Carefully cnsider the ptential benefits and risks f fenprfen calcium tablets and ther treatment ptins befre deciding t use fenprfen calcium tablets. Use the lwest effective dse fr the shrtest duratin cnsistent with individual patient treatment gals (see WARNINGS). After bserving the respnse t initial therapy with fenprfen calcium tablets, the dse and frequency shuld be adjusted t suit an individual patient's needs. Analgesia Fr the treatment f mild t mderate pain, the recmmended dsage is 200 mg given rally every 4 t 6 hurs, as needed. Rheumatid Arthritis and Ostearthritis Fr the relief f signs and symptms f rheumatid arthritis r stearthritis the recmmended dse is 400 mg t 600 mg given rally, 3 r 4 times a day. The dse shuld be tailred t the needs f the patient and may be increased r decreased depending n the severity f the symptms. Dsage adjustments may be made after initiatin f drug therapy r during exacerbatins f the disease. Ttal daily dsage shuld nt exceed 3200 mg. Fenprfen calcium tablets may be administered with meals r with milk. Althugh the ttal amunt absrbed is nt affected, peak bld levels are delayed and diminished. Patients with rheumatid arthritis generally seem t require larger dses f fenprfen calcium tablets than d thse with stearthritis. The smallest dse that yields acceptable cntrl shuld be emplyed. Althugh imprvement may be seen in a few days in many patients, an additinal 2 t 3 weeks may be required t gauge the full benefits f therapy. HOW SUPPLIED Fenprfen Calcium Tablets, USP are available cntaining fenprfen calcium, USP equivalent t 600 mg fenprfen. The 600 mg tablet is an range film-cated, capsule-shaped tablet debssed with "600" n ne side f the tablet and scred n the ther side. They are available as fllws: NDC bttles f 100 tablets Stre at 20 t 25 C (68 t 77 F). [See USP Cntrlled Rm Temperature.] Prtect frm light. Dispense in a tight, light-resistant cntainer as defined in the USP using a child-resistant clsure. PHARMACIST: Dispense a Medicatin Guide with each prescriptin. Medicatin Guide fr Nnsteridal Anti-inflammatry Drugs (NSAIDs) What is the ms t imprtant infrmatin I s huld knw abut medicines called Nns teridal Antiinflammatry Drugs (NSAIDs)?

12 NSAIDs can cause serius side effects, including: Increased risk f a heart attack r strke that can lead t death. This risk may happen early in treatment and may increase: with increasing dses f NSAIDs with lnger use f NSAIDs D nt take NSAIDs right befre r after a heart s urgery called a crnary artery bypas s graft (CABG)." Avid taking NSAIDs after a recent heart attack, unles s yur healthcare prvider tells yu t. Yu may have an increas ed ris k f anther heart attack if yu take NSAIDs after a recent heart attack. Increased risk f bleeding, ulcers, and tears (perfratin) f the esphagus (tube leading frm the muth t the stmach), stmach and intestines: anytime during use withut warning symptms that may cause death The ris k f getting an ulcer r bleeding increas es with: past histry f stmach ulcers, r stmach r intestinal bleeding with use f NSAIDs taking medicines called crticsterids, anticagulants, SSRIs, r SNRIs increasing dses f NSAIDs lnger use f NSAIDs smking drinking alchl lder age pr health advanced liver disease bleeding prblems NSAIDs shuld nly be used: exactly as prescribed at the lwest dse pssible fr yur treatment fr the shrtest time needed What are NSAIDs? NSAIDs are used t treat pain and redness, swelling, and heat (inflammatin) frm medical cnditins such as different types f arthritis, menstrual cramps, and ther types f shrt-term pain. Wh shuld nt take NSAIDs? D nt take NSAIDs: if yu have had an asthma attack, hives, r ther allergic reactin with aspirin r any ther NSAIDs. right befre r after heart bypass surgery. Befre taking NSAIDs, tell yur healthcare prvider abut all f yur medical cnditins, including if yu:

13 have liver r kidney prblems have high bld pressure have asthma are pregnant r plan t becme pregnant. Talk t yur healthcare prvider if yu are cnsidering taking NSAIDs during pregnancy. Yu s huld nt take NSAIDs after 29 weeks f pregnancy. are breastfeeding r plan t breast feed. Tell yur healthcare prvider abut all f the medicines yu take, including pres criptin r verthe-cunter medicines, vitamins r herbal s upplements. NSAIDs and sme ther medicines can interact with each ther and cause serius side effects. D nt s tart taking any new medicine withut talking t yur healthcare prvider firs t. What are the pssible side effects f NSAIDs? NSAIDs can cause serius side effects, including: See What is the ms t imprtant infrmatin I s huld knw abut medicines called Nns teridal Anti-inflammatry Drugs (NSAIDs)? new r wrse high bld pressure heart failure liver prblems including liver failure kidney prblems including kidney failure lw red bld cells (anemia) life-threatening skin reactins life threatening allergic reactins Other side effects f NSAIDs include: stmach pain, cnstipatin, diarrhea, gas, heartburn, nausea, vmiting, and dizziness. Get emergency help right away if yu get any f the fllwing s ymptms: shrtness f breath r truble breathing chest pain weakness in ne part r side f yur bdy slurred speech swelling f the face r thrat Stp taking yur NSAID and call yur healthcare prvider right away if yu get any f the fllwing s ymptms: nausea mre tired r weaker than usual diarrhea itching yur skin r eyes lk yellw indigestin r stmach pain flu-like symptms vmit bld there is bld in yur bwel mvement r it is black and sticky like tar unusual weight gain skin rash r blisters with fever swelling f the arms, legs, hands and feet If yu take t much f yur NSAID, call yur healthcare prvider r get medical help right away. These are nt all the pssible side effects f NSAIDs. Fr mre infrmatin, ask yur healthcare prvider r pharmacist abut NSAIDs. Call yur dctr fr medical advice abut s ide effects. Yu may reprt s ide effects t FDA at FDA-1088.

14 800-FDA Other infrmatin abut NSAIDs Aspirin is an NSAID but it des nt increase the chance f a heart attack. Aspirin can cause bleeding in the brain, stmach, and intestines. Aspirin can als cause ulcers in the stmach and intestines. Sme NSAIDs are sld in lwer dses withut a prescriptin (ver-the-cunter). Talk t yur healthcare prvider befre using ver-the-cunter NSAIDs fr mre than 10 days. General infrmatin abut the safe and effective use f NSAIDs Medicines are smetimes prescribed fr purpses ther than thse listed in a Medicatin Guide. D nt use NSAIDs fr a cnditin fr which it was nt prescribed. D nt give NSAIDs t ther peple, even if they have the same symptms that yu have. It may harm them. If yu wuld like mre infrmatin abut NSAIDs, talk with yur healthcare prvider. Yu can ask yur pharmacist r healthcare prvider fr infrmatin abut NSAIDs that is written fr health prfessinals. Manufactured fr: Xspire Pharma, LLC, Ridgeland, MS, U.S.A. Fr mre infrmatin, call Xspire Pharma, LLC at This Medicatin Guide has been apprved by the U.S. Fd and Drug Administratin. Xspire Pharma, LLC. Ridgeland, MS U.S.A. REVISED JANUARY 2018 PRINCIPAL DISPLAY PANEL 600 mg NDC Fenprfen Calcium Tablets, USP 600 mg* PHARMACIST: Dispense the accmpanying Medicatin Guide t each patient.. Rx nly 100 Tablets *Each film-cated tablet cntains fenprfen calcium, USP equivalent t 600 mg f fenprfen. Dispense in a tight, light-resistant cntainer as defined in the USP using a child-resistant clsure. Keep cntainer tightly clsed. Keep this and all medicatin ut f the reach f children. Stre at 20 t 25 C (68 t 77 F). [See USP Cntrlled Rm Temperature.] Prtect frm light.

15 Usual Adult Dsage: See accmpanying prescribing infrmatin. Xspire Pharma, LLC Ridgeland, MS U.S.A. Xspirerx.cm

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