FLUMADINE- rimantadine hydrochloride tablet
FLUMADINE- rimantadine hydrochloride syrup
Flumadine® (rimantadine hydro chlo ride) is a synthetic antiviral drug available as a 10 0 mg film-co ated tablet and as a syrup fo r o ral administratio n. Each film-co ated tablet co ntains 10 0 mg o f rimantadine hydro chlo ride plus hydro xypro pyl methylcellulo se, mag nesium stearate, micro crystalline cellulo se, so dium starch g lyco late, FD&C Yello w No . 6 Lake and FD&C Yellow No . 6 . T he film coat co ntains hydro xypro pyl methylcellulo se and po lyethylene g lyco l. Each teaspo o nful (5 mL) o f the syrup co ntains 50 mg o f rimantadine hydro chlo ride in an aqueo us so lutio n co ntaining citric acid, parabens (methyl and pro pyl), saccharin so dium, so rbito l, D&C Red No . 33 and flavo rs.
Rimantadine hydro chlo ride is a white to o ff-white crystalline po wder which is freely soluble in water (50 mg /mL at 20 °C). Chemically, rimantadine hydro chlo ride is alpha-methyltricyclo -[184.108.40.206/3.7]decane-1-methanamine hydro chlo ride, with an empirical fo rmula o f C12H21N•HCI, a mo lecular weig ht o f 215.77 and the fo llo wing structural formula:
T he mechanism o f actio n o f rimantadine is no t fully understo o d. Rimantadine appears to exert its inhibito ry effect early in the viral replicative cycle, po ssibly inhibiting the unco ating o f the virus. Genetic studies sug g est that a virus pro tein specified by the virio n M2 g ene plays an impo rtant ro le in the susceptibility o f influenza A virus to inhibitio n by rimantadine.
Rimantadine is inhibito ry to the in vitro replicatio n o f influenza A virus iso lates fro m each o f the three antig enic subtypes, i.e., H1N1, H2N2 and H3N2, that have been iso lated fro m man. Rimantadine has little o r no activity ag ainst influenza B virus (Ref. 1,2). Rimantadine do es no t appear to interfere with the immuno g enicity o f inactivated influenza A vaccine.
A quantitative relatio nship between the in vitro susceptibility o f influenza A virus to rimantadine and clinical respo nse to therapy has no t been established.
Susceptibility test results, expressed as the co ncentratio n o f the drug required to inhibit virus replicatio n by 50 % o r mo re in a cell culture system, vary g reatly (fro m 4 ng /mL to 20 μg /mL) depending upo n the assay pro to co l used, size o f the virus ino culum, iso lates o f the influenza A virus strains tested, and the cell types used (Ref. 2).
Rimantadine-resistant strains o f influenza A virus have emerg ed amo ng freshly iso lated epidemic strains in clo sed setting s where rimantadine has been used. Resistant viruses have been sho wn to be transmissible and to cause typical influenza illness. (Ref. 3)
Altho ug h the pharmaco kinetic pro file o f Flumadine has been described, no pharmaco dynamic data establishing a co rrelatio n between plasma co ncentratio n and its antiviral effect are available.
T he tablet and syrup fo rmulatio ns o f Flumadine are equally abso rbed after o ral administratio n. T he mean ± SD peak plasma co ncentratio n after a sing le 10 0 mg do se o f Flumadine was 74 ± 22 ng /mL (rang e: 4 5 to 138 ng /mL). T he time to peak co ncentratio n was 6 ± 1 ho urs in healthy adults (ag e 20 to 4 4 years). T he sing le do se eliminatio n half-life in this po pulatio n was 25.4 ± 6 .3 ho urs (rang e: 13 to 6 5 ho urs).
T he sing le do se eliminatio n half-life in a g ro up o f healthy 71 to 79 year-o ld subjects was 32 ± 16 ho urs (rang e: 20 to 6 5 ho urs).
After the administratio n o f rimantadine 10 0 mg twice daily to healthy vo lunteers (ag e 18 to 70 years) fo r 10 days, area under the curve (AUC) values were appro ximately 30 % g reater than predicted fro m a sing le do se. Plasma tro ug h levels at steady state rang ed between 118 and 4 6 8 ng /mL. In these patients no ag e-related differences in pharmaco kinetics were detected. Ho wever, in a co mpariso n o f three g ro ups o f healthy o lder subjects (ag e 50 -6 0 , 6 1-70 and 71-79 years), the 71 to 79 year-o ld g ro up had averag e AUC values, peak co ncentratio ns and eliminatio n half-life values at steady state that were 20 to 30 % hig her than the o ther two g ro ups. Steady-state co ncentratio ns in elderly nursing ho me patients (ag e 6 8 to 10 2 years) were 2- to 4 -fo ld hig her than tho se seen in healthy yo ung and elderly adults.
T he pharmaco kinetic pro file o f rimantadine in children has no t been established. In a g ro up (n=10 ) o f children 4 to 8 years o ld who were g iven a sing le do se (6 .6 mg /kg ) o f Flumadine syrup, plasma co ncentratio ns o f rimantadine rang ed fro m 4 4 6 to 9 8 8 ng /mL at 5 to 6 ho urs and fro m 170 to 4 24 ng /mL at 24 ho urs. In so me children drug was detected in plasma 72 ho urs after the last do se.
Fo llo wing o ral administratio n, rimantadine is extensively metabo lized in the liver with less than 25% o f the do se excreted in the urine as unchang ed drug . T hree hydro xylated metabo lites have been fo und in plasma. T hese metabo lites, an additio nal co njug ated metabo lite and parent drug acco unt fo r 74 ± 10 % (n=4 ) o f a sing le 20 0 mg do se o f rimantadine excreted in urine o ver 72 ho urs.
In a g ro up (n=14 ) o f patients with chro nic liver disease, the majo rity o f who m were stabilized cirrho tics, the pharmaco kinetics o f rimantadine were no t appreciably altered fo llo wing a sing le 20 0 mg o ral do se co mpared to 6 healthy subjects who were sex, ag e and weig ht matched to 6 o f the patients with liver disease. After administratio n o f a sing le 20 0 mg do se to patients (n=10 ) with severe hepatic dysfunctio n, AUC was appro ximately 3-fo ld larg er, eliminatio n half-life was appro ximately 2-fo ld lo ng er and apparent clearance was abo ut 50 % lo wer when co mpared to histo ric data fro m healthy subjects.
Studies o f the effects o f renal insufficiency o n the pharmaco kinetics o f rimantadine have g iven inco nsistent results. Fo llo wing administratio n o f a sing le 20 0 mg o ral do se o f rimantadine to 8 patients with a creatinine clearance (CLcr) o f 31-50 mL/min and 6 patients with a CLcr o f 11-30 mL/min, the apparent clearance was 37% and 16 % lo wer, respectively, and plasma metabo lite co ncentratio ns were hig her when co mpared to weig ht-, ag e-, and sex-matched healthy subjects (n=9 , CLcr > 50 mL/min). After a sing le 20 0 mg o ral do se o f rimantadine was g iven to 8 hemo dialysis patients (CLcr 0 -10 mL/min), there was a 1.6 -fo ld increase in the eliminatio n half-life and a 4 0 % decrease in apparent clearance co mpared to ag e-matched healthy subjects. Hemo dialysis did no t co ntribute to the clearance o f rimantadine.
T he in vitro human plasma pro tein binding o f rimantadine is abo ut 4 0 % o ver typical plasma co ncentratio ns. Albumin is the majo r binding pro tein.
Flumadine is indicated fo r the pro phylaxis and treatment o f illness caused by vario us strains of influenza A virus in adults.
Flumadine is indicated fo r pro phylaxis ag ainst influenza A virus in children.
PROPHYLAXIS: In co ntro lled studies o f children o ver the ag e o f 1 year, healthy adults and elderly patients, Flumadine has been sho wn to be safe and effective in preventing sig ns and sympto ms o f infectio n caused by vario us strains o f influenza A virus. Early vaccinatio n o n an annual basis as reco mmended by the Centers for Disease Co ntro l's Immunizatio n Practices Adviso ry Co mmittee is the metho d o f cho ice in the pro phylaxis of influenza unless vaccinatio n is co ntraindicated, no t available o r no t feasible. Since Flumadine do es no t completely prevent the ho st immune respo nse to influenza A infectio n, individuals who take this drug may still develo p immune respo nses to natural disease o r vaccinatio n and may be pro tected when later expo sed to antig enically-related viruses. Fo llo wing vaccinatio n during an influenza o utbreak, Flumadine pro phylaxis sho uld be co nsidered fo r the 2 to 4 week time perio d required to develo p an antibo dy respo nse. Ho wever, the safety and effectiveness o f Flumadine pro phylaxis have no t been demo nstrated fo r lo ng er than 6 weeks.
TREATMENT: Flumadine therapy sho uld be co nsidered fo r adults who develo p an influenza-like illness during kno wn o r suspected influenza A infectio n in the co mmunity. When administered within 4 8 ho urs after o nset o f sig ns and sympto ms o f infectio n caused by influenza A virus strains, Flumadine has been sho wn to reduce the duratio n o f fever and systemic sympto ms.
Flumadine is co ntraindicated in patients with kno wn hypersensitivity to drug s o f the adamantane class, including rimantadine and amantadine.
An increased incidence o f seizures has been repo rted in patients with a histo ry o f epilepsy who received the related drug amantadine. In clinical trials o f Flumadine, the o ccurrence o f seizure-like activity was o bserved in a small number o f patients with a histo ry o f seizures who were no t receiving antico nvulsant medicatio n while taking Flumadine. If seizures develo p, Flumadine sho uld be disco ntinued.
T he safety and pharmaco kinetics o f rimantadine in renal and hepatic insufficiency have o nly been evaluated after sing le do se administratio n. In a sing le do se study o f patients with anuric renal failure, the apparent clearance o f rimantadine was appro ximately 4 0 % lo wer and the eliminatio n half-life was 1.6 - fo ld g reater than that in healthy ag e-matched co ntro ls. In a study o f 14 perso ns with chro nic liver disease (mo stly stabilized cirrho tics), no alteratio ns in the pharmaco kinetics were o bserved after the administratio n o f a sing le do se o f rimantadine. Ho wever, the apparent clearance o f rimantadine fo llo wing a sing le do se to 10 patients with severe liver dysfunctio n was 50 % lo wer than repo rted fo r healthy subjects. Because o f the po tential fo r accumulatio n o f rimantadine and its metabo lites in plasma, cautio n sho uld be exercised when patients with renal o r hepatic insufficiency are treated with rimantadine.
T ransmissio n o f rimantadine resistant virus sho uld be co nsidered when treating patients who se co ntacts are at hig h risk fo r influenza A illness. Influenza A virus strains resistant to rimantadine can emerg e during treatment and such resistant strains have been sho wn to be transmissible and to cause typical influenza illness (Ref. 3). Altho ug h the frequency, rapidity, and clinical sig nificance o f the emerg ence o f drug -resistant virus are no t yet established, several small studies have demo nstrated that 10 % to 30 % o f patients with initially sensitive virus, upo n treatment with rimantadine, shed rimantadine resistant virus. (Ref. 3, 4 , 5, 6 )
Clinical respo nse to rimantadine, altho ug h slo wer in tho se patients who subsequently shed resistant virus, was no t sig nificantly different fro m tho se who did no t shed resistant virus. (Ref. 3) No data are available in humans that address the activity o r effectiveness o f rimantadine therapy in subjects infected with resistant virus.
Cimetidine: T he effects o f chro nic cimetidine use o n the metabo lism o f rimantadine are no t kno wn. When a sing le 10 0 mg do se o f Flumadine was administered o ne ho ur after the initiatio n o f cimetidine (30 0 mg fo ur times a day), the apparent to tal rimantadine clearance o f this sing le do se in no rmal healthy adults was reduced by 18 % (co mpared to the apparent to tal rimantadine clearance in the same subjects in the absence o f cimetidine).
Acetamino phen: Flumadine, 10 0 mg , was g iven twice daily fo r 13 days to 12 healthy vo lunteers. On day 11, acetamino phen (6 50 mg fo ur times daily) was started and co ntinued fo r 8 days. T he pharmaco kinetics o f rimantadine were assessed o n days 11 and 13. Co administratio n with acetamino phen reduced the peak co ncentratio n and AUC values fo r rimantadine by appro ximately 11%.
Aspirin: Flumadine, 10 0 mg , was g iven twice daily fo r 13 days to 12 healthy vo lunteers. On day 11, aspirin (6 50 mg , fo ur times daily) was started and co ntinued fo r 8 days. T he pharmaco kinetics o f rimantadine were assessed o n days 11 and 13. Peak plasma co ncentratio ns and AUC o f rimantadine were reduced appro ximately 10 % in the presence o f aspirin.
Live Attenuated Influenza Vaccine (LAIV): T he co ncurrent use o f Flumadine with live attenuated influenza vaccine has no t been evaluated. Ho wever, because o f po tential interference between these pro ducts, the live attenuated intranasal influenza vaccine sho uld no t be administered until 4 8 ho urs after cessatio n o f Flumadine and Flumadine sho uld no t be administered until two weeks after the administratio n o f live attenuated intranasal influenza vaccine unless medically indicated. T he co ncern abo ut po tential interference arises principally fro m the po tential fo r antiviral drug s to inhibit replicatio n o f live vaccine virus.
Carcinogenesis: Carcino g enicity studies in animals have no t been perfo rmed.
Mutagenesis: No mutag enic effects were seen when rimantadine was evaluated in several standard assays fo r mutag enicity.
Impairment of Fertility: A repro ductio n study in male and female rats did no t sho w detectable impairment o f fertility at do sag es up to 6 0 mg /kg /day (3 times the maximum human do se based o n bo dy surface area co mpariso ns).
Teratogenic Effects: Preg nancy Categ o ry C. T here are no adequate and well-co ntro lled studies in preg nant wo men. Rimantadine is repo rted to cro ss the placenta in mice. Rimantadine has been sho wn to be embryo to xic in rats when g iven at a do se o f 20 0 mg /kg /day (11 times the reco mmended human do se based o n bo dy surface area co mpariso ns). At this do se the embryo to xic effect co nsisted o f increased fetal reso rptio n in rats; this do se also pro duced a variety o f maternal effects including ataxia, tremo rs, co nvulsio ns and sig nificantly reduced weig ht g ain. No embryo to xicity was o bserved when rabbits were g iven do ses up to 50 mg /kg /day (5 times the reco mmended human do se based o n bo dy surface area co mpariso ns). Ho wever, there was evidence o f a develo pmental abno rmality in the fo rm o f a chang e in the ratio o f fetuses with 12 o r 13 ribs. T his ratio is no rmally abo ut 50 :50 in a litter but was 8 0 :20 after rimantadine treatment.
Nonteratogenic Effects: Rimantadine was administered to preg nant rats in a peri- and po stnatal repro ductio n to xicity study at do ses o f 30 , 6 0 and 120 mg /kg /day (1.7, 3.4 and 6 .8 times the reco mmended human do se based o n bo dy surface area co mpariso ns). Maternal to xicity during g estatio n was no ted at the two hig her do ses o f rimantadine, and at the hig hest do se, 120 mg /kg /day, there was an increase in pup mo rtality during the first 2 to 4 days po stpartum. Decreased fertility o f the F1 g eneratio n was also no ted fo r the two hig her do ses.
Fo r these reaso ns, Flumadine sho uld be used during preg nancy o nly if the po tential benefit justifies the risk to the fetus.
Flumadine sho uld no t be administered to nursing mo thers because o f the adverse effects no ted in o ffspring o f rats treated with rimantadine during the nursing perio d. Rimantadine is co ncentrated in rat milk in a do se-related manner: 2 to 3 ho urs fo llo wing administratio n o f rimantadine, rat breast milk levels were appro ximately twice tho se o bserved in the serum.
In children, Flumadine is reco mmended fo r the pro phylaxis o f influenza A. T he safety and effectiveness o f Flumadine in the treatment o f sympto matic influenza infectio n in children have no t been established. Pro phylaxis studies with Flumadine have no t been perfo rmed in children belo w the ag e o f 1 year.
In 1,0 27 patients treated with Flumadine in co ntro lled clinical trials at the reco mmended do se o f 20 0 mg daily, the mo st frequently repo rted adverse events invo lved the g astro intestinal and nervo us systems.
Incidence >1%: Adverse events repo rted mo st frequently (1-3%) at the reco mmended do se in co ntro lled clinical trials are sho wn in the table belo w.
|Rimantadine||Co ntro l|
|(n=10 27)||(n=9 8 6 )|
|Inso mnia||2.1%||0 9 %|
|Nervo usness||1.3%||0 .6 %|
|Fatigue||1.0%||0 .9 %|
|Vomiting||1.7%||0 .6 %|
|Anorexia||1.6%||0 .8 %|
|Dry mouth||1.5%||0 .6 %|
|Abdo minal Pain||1.4%||0 .8 %|
|Body as a Whole|
|Asthenia||1.4 %||0 .5%|
Less frequent adverse events (0 .3 to 1%) at the reco mmended do se in co ntro lled clinical trials were:
Gastrointestinal System: diarrhea, dyspepsia; Nervous System: impairment o f co ncentratio n, ataxia, so mno lence, ag itatio n, depressio n; Skin and Appendages: rash; Hearing and Vestibular: tinnitus; Respiratory: dyspnea.
Additional adverse events (less than 0.3%) reported at recommended doses in controlled clinical trials were: Nervo us System: g ait abno rmality, eupho ria, hyperkinesia, tremo r, hallucinatio n, co nfusio n, co nvulsio ns; Respiratory: bro ncho spasm, co ug h; Cardiovascular: pallo r, palpitatio n, hypertensio n, cerebro vascular diso rder, cardiac failure, pedal edema, heart blo ck, tachycardia, synco pe; Reproduction: no n-puerperal lactatio n; Special Senses: taste lo ss/chang e, paro smia.
Rates o f adverse events, particularly tho se invo lving the g astro intestinal and nervo us systems, increased sig nificantly in co ntro lled studies using hig her than reco mmended do ses o f Flumadine. In mo st cases, sympto ms reso lved rapidly with disco ntinuatio n o f treatment. In additio n to the adverse events repo rted abo ve, the fo llo wing were also repo rted at hig her than reco mmended do ses: increased lacrimatio n, increased micturitio n frequency, fever, rig o rs, ag itatio n, co nstipatio n, diapho resis, dysphag ia, sto matitis, hypesthesia and eye pain.
Adverse Reactio ns in T rials o f Rimantadine and Amantadine: In a six-week pro phylaxis study o f 4 36 healthy adults comparing rimantadine with amantadine and placebo , the fo llo wing adverse reactio ns were repo rted with an incidence >1 %.
|20 0 mg /day||20 0 mg /day|
|(n=14 5)||(n=14 3)||(n=14 8 )|
|Inso mnia||3.4 %||0 .7%||7.0 %|
|Nervo usness||2.1%||0 .7%||2.8 %|
|Impaired Co ncentratio n||2.1%||1.4 %||2.1%|
|Dizziness||0 .7%||0 .0 %||2.1%|
|Depressio n||0 .7%||0 .7%||3.5%|
|T o tal % o f subjects with adverse reactio ns||6 .9 %||4 .1%||14 .7%|
|T o tal % o f subjects withdrawn due to adverse reactio ns||6 .9 %||3.4 %||14 .0 %|
GERIATRIC USE: Appro ximately 20 0 patients o ver the ag e o f 6 4 were evaluated fo r safety in co ntro lled clinical trials with Flumadine® (rimantadine hydro chlo ride). Geriatric subjects who received either 20 0 mg o r 4 0 0 mg o f rimantadine daily fo r 1 to 50 days experienced co nsiderably mo re central nervo us system and g astro intestinal adverse events than co mparable g eriatric subjects receiving placebo . Central nervo us system events including dizziness, headache, anxiety, asthenia, and fatig ue, o ccurred up to two times mo re o ften in subjects treated with rimantadine than in tho se treated with placebo . Gastro intestinal sympto ms, particularly nausea, vo miting , and abdo minal pain o ccurred at least twice as frequently in subjects receiving rimantadine than in tho se receiving placebo . T he g astro intestinal sympto ms appeared to be do se related. In patients o ver 6 4 , the reco mmended do se is 10 0 mg , daily (see Clinical Pharmacology and Dosage and Administration).
As with any o verdo se, suppo rtive therapy sho uld be administered as indicated. Overdo ses o f a related drug , amantadine, have been repo rted with adverse reactio ns co nsisting o f ag itatio n, hallucinatio ns, cardiac arrhythmia and death. T he administratio n o f intraveno us physo stig mine (a cho linerg ic ag ent) at do ses o f 1 to 2 mg in adults (Ref. 7) and 0 .5 mg in children (Ref. 8 ) repeated as needed as lo ng as the do se did no t exceed 2 mg /ho ur has been repo rted anecdo tally to be beneficial in patients with central nervo us system effects fro m o verdo ses o f amantadine.
FOR PROPHYLAXIS IN ADULTS AND CHILDREN: Adults: T he reco mmended adult do se o f Flumadine is 10 0 mg twice a day. In patients with severe hepatic dysfunctio n, renal failure (CrCI ≤10 mL/min.) and elderly nursing ho me patients, a do se reductio n to 10 0 mg daily is reco mmended. T here are currently no data available reg arding the safety o f rimantadine during multiple do sing in subjects with renal o r hepatic impairment. Because o f the po tential fo r accumulatio n o f rimantadine metabo lites during multiple do sing , patients with any deg ree o f renal insufficiency sho uld be mo nito red fo r adverse effects, with do sag e adjustments being made as necessary.
Children: In children less than 10 years o f ag e, Flumadine sho uld be administered o nce a day, at a do se o f 5 mg /kg but no t exceeding 150 mg . Fo r children 10 years o f ag e o r o lder, use the adult do se.
FOR TREATMENT IN ADULTS: T he reco mmended adult do se o f Flumadine is 10 0 mg twice a day. In patients with severe hepatic dysfunctio n, renal failure (CrCI ≤10 mL/min) and elderly nursing ho me patients, a do se reductio n to 10 0 mg daily is reco mmended. T here are currently no data available reg arding the safety o f rimantadine during multiple do sing in subjects with renal o r hepatic impairment. Because o f the po tential fo r accumulatio n o f rimantadine metabo lites during multiple do sing , patients with any deg ree o f renal insufficiency sho uld be mo nito red fo r adverse effects, with do sag e adjustments being made as necessary. Flumadine therapy sho uld be initiated as so o n as po ssible, preferably within 4 8 ho urs after o nset o f sig ns and sympto ms o f influenza A infectio n. T herapy sho uld be co ntinued fo r appro ximately seven days fro m the initial o nset o f sympto ms.
Flumadine® tablets (rimantadine hydro chlo ride tablets) are supplied as 10 0 mg tablets (o rang e, o val- shaped, film-co ated) in bo ttles o f 10 0 (NDC 0 4 56 -0 521-0 1). Imprint o n tablets: (Fro nt) FLUMADINE 10 0 ; (Back) FOREST .
Flumadine® syrup (rimantadine hydro chlo ride syrup) co ntaining 50 mg o f rimantadine hydro chlo ride per teaspo o nful (5 mL) (purplish-red, raspberry-flavo red) is supplied in bo ttles o f 8 o z (NDC 0 4 56 -0 527-0 8 ).
T ablets and syrup sho uld be sto red at 15° - 30 °C (59 ° - 8 6 °F).
Rx o nly
1. Belshe, R.B., Burk, B., Newman, F., Cerruti, R.L. and Sim, I.S. (19 8 9 ) J. Infect. Dis. 159 , 4 30 -4 35.
2. Sim, I.S., Cerruti, R.L. and Co nnell, E.V., (19 8 9 ) J. Resp. Dis. (Suppl.), S4 6 -S51.
3. Hayden, F.G., Belshe, R.B., Clo ver, R.D. et al (19 8 9 ) N.Eng l. J. Med. 321 (25), 16 9 6 -170 2.
4 . Hall, C.B., Do lin, R., Gala, C.L., et al (19 8 7) Pediatrics 8 0 , 275-28 2.
5. T ho mpso n, J., Fleet, W., Lawrence, E. et al (19 8 7) J. Med. Vir. 21, 24 9 -255.
6 . Belshe, R.B., Smith, M.H., Hall, C.B., et al (19 8 8 ) J. Viro l. 6 2, 150 8 -1512.
7. Casey, D.F. N. Eng l. J. Med. 19 78 :29 8 :516 .
8 . Berko witz, C.D. J. Pediatrics 19 79 :9 5:14 4 .
Rev. 9 /0 0
MG #9 0 4 0 (0 9 )
FOREST PHARMACEUT ICALS, INC. Subsidiary o f Fo rest Labo rato ries, Inc. St. Lo uis, MO 6 30 4 5
(rimantadine hydrochloride tablets)
rimantadine hydrochloride tablet
rimantadine hydrochloride syrup
|Labeler - Allergan, Inc. (144796497)|