0001
`
`PSG2015
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`
`
`
`
`NAPRELAN®
`[nd' pré-lénl
`(naproxen sodium)
`CONTROLLED RELEASE TABLETS
`Equivalent to 375 mg and 500 mg naproxen
`
`'
`
`1%
`
`DESCRIPTION
`Naprelan contains naproxen sodium, a member of the my
`lacotic acid group of nonsteroidal anti-inflammatory drugs
`(NSAIDs).
`Naprelan uses the proprietary IPDASTM (Intestinal Protec-
`tive Drug Absorption System) technology. It is a rapidly dis—
`integrating tablet system combining an immediate release
`component and a sustained release component of micropar~
`tlcles that are widely dispersed, allowing absorption of the
`active ingredient throughout the gastrointestinal (GI) tract,
`maintaining blood levels over 24 hours.
`The chemical name for naproxen sodium is 2—naphthalene-
`acetic acid, 6-methoxy-dvmethybsodium salt, (S)- with the
`following structural formula:
`
`GilaCHCOONa
`
`CHQO ,
`
`Naproxen sodium
`
`Molecular Weight:
`252.24
`
`Molecular Formula:
`C1,,l‘l13N2103
`Naproxen sodium is an odorless crystalline powder, white to
`creamy in color. It is soluble in methanol and water.
`Naprelan contains 412.5 mg or 550 mg of naproxen sodium,
`equivalent to 375 mg and 500 mg of naproxen and 37.5 mg
`and 50 mg sodium respectively Each Naprclan tablet also
`contains the following inactive ingredients: ammonia meth-
`acrylate copolymer Type A, ammonio niethacrylate copoly-
`iner Type B, citric acid, crospovidone, magnesium stearate,
`methucrylic acid copolymer Type A. microcrystalline cellu-
`lose, povidone, and talc. The tablet coating contains hydrox—
`ypropyl methylcellulosc, polyethylene glycol, and titanium
`dioxide.
`CLINICAL PHARMACOLOGY
`Naproxen is
`o nonsteroidal antidnflammatory drug
`(NSAID). with analgesic and antipyretic properties. As with
`other NSAIDs, its mode of action is not fully understood;
`however, its ability to inhibit prostaglandin synthesis may
`be involved in the anti-inflammatory elfect.
`PHARMACOKINETICS
`Although naproxen itself is well absorbed, the sodium salt
`form is more rapidly absorbed resulting in higher peak.
`plasma levels for a given dose. Approximately 30% of the
`total naproxen sodium dose in Naprelan is present in the
`dosage form as an immediate release component. The re—
`maining neproxen sodium is coated as microparticles to pro-
`vide sustained release properties. Alter oral administration,
`plasma levels of naproxen are detected within 80 minutes of
`dosing, with peak plasma levels occurring approximately 5
`hours after dosing. The observed terminal elimination half—
`lifc of naproxon from both immediate release naproxen so-
`dium and Noprelan is approximately 15 hours. Steady state
`levels of naproxen are achieved in 3 days and the degree of
`naproxcn accumulation in the blood is consistent with this.
`[See figure at top of next columnl
`
`c". Time (hours)
`
`uu
`
`Pharmacokinetic Parameters at Steady State Day 5 (Mean
`of 24 Subjects)
`
`Para»
`meter
`(units)
`
`naproxen 500 mg
`Q12h/5 days
`(1000 mg)
`
`Naprelan 2 x 500 mg
`tablets (1000 mg) ‘
`Q24h/5 days
`
`AUC 0-24
`(mchhl
`mL)
`
`Mean SD Range
`
`Mean
`
`SD Range
`
`1446
`
`168
`
`1167—-
`1858
`
`1448 145
`
`1173—
`1774
`
`94
`
`13
`
`74—127
`
`95
`
`13
`
`71—117
`
`Cnlllx
`(mog/mL)
`Cuv
`49—74
`6
`60
`49—77
`7
`60
`(mcidmL)
`C’min
`23—48
`7
`33
`13-51
`9
`36
`(meg/mil)
`Tnmx
`(hrs)
`3
`1
`l4
`5
`2
`2—10
`
`
`Absorption
`Naproxen itself is rapidly and completely absorbed from the
`GI tract with an in, viva bioavailability of 95%. Based on the
`pharmacokinotic profile, the absorption phase of Naprelan
`occurs in the first 4—6 hours after administration, This co-
`incides with disintegration of the tablet in the stomach, the
`transit of the sustained release microparticlos through the
`small intestine and into the proximal large intestine.An in
`viva imaging study hasheen performed in healthy volun.
`teers which confirms rapid disintegration of the tablet ma-
`trix and dispersion of the microparticles.
`The absorption rate fromthe sustained release particulate
`component ofNaprelan is slower than that for conventional
`naproxen sodium tablets. It is this prolongation of drug ab-
`sorption processes which maintains plasma levels and al~
`lows for once daily dosing.
`Food Effects
`No significant food effects were observed when twenty<four
`subjects were given a single dose of Naprelzm 500 mg either
`after an overnight fast or 30 minutes after ameal. In com—
`mon with conventional naproxeu and naproxen sodium for
`mulations, food causes a slight decrease in the rate of
`naproxen absorption following Naprelan administration.
`Distribution
`Naproxen has a volume of distribution of 0.16 L/kg. At ther»
`apeutic levels naproxen is greater than 99% albumin-
`bound. At doses of naproxen greater than 500 mg/day there
`is a less than proportional increase in plasma levels due to
`an increase in clearance caused by saturation of plasma pro-
`tein binding at higher doses. However the concentration of
`unbound naproxen continues to increase proportionally to
`dose. Naprelan exhibits similar dose proportional character—
`istics.
`llrIez’abolism
`_
`.
`_
`Naproxen is extensively metabolized to 6-0-desmethyl
`naproxen and both parent and metabolites do not induce
`metabolizing enzymes.
`Elimination
`The elimination half—lifeof Naprelan and conventional
`naproxen is approximately 15 hours. Steady state condi-
`tions are attained after 2—3 doses of Naprelan. Most of the
`drug is excreted in the urine, primarily as unchanged
`naproxen (less than 1%). 6v0-desmethyl naproxen (less than
`1%) and their glucuronide or other conjugates (66—92%), A
`small amount (<5%) of the drug is excreted in the feces. The
`rate of excretion has been found to coincide closely with the
`rate of clearance from the plasma. In patients with renal
`failure metabolites may accumulate.
`Special Populations
`Pediatric Use
`No pediatric studies have been performed with Naprelan,
`thus safety of Naprolnn in pediatric populations has not
`been established.
`Renal Insufficiency
`anroxen pharmacokinetics have not been determined in
`subjects with renal insufficiency. Given that naproxen is me—
`
`0002
`
`PHUUUUI lNl—UHlVlAl IUN VVYl: I H-AYtHSl LAUUHA‘l UHlt5/333b
`Cartridge Units and Sterile Cartridge~Needle Units, in
`boxes of 10 TUBEX in TAMP-R-TELQD tamper—resistant
`packages as follows:
`.
`NDC 0008-0235-50, 2 mL size Blunt Pointe"
`NDC 0008-0235-01, 2 mL size (22 gauge x 1-1/4 inch needle).
`Mepergau (mepen'dine HCl and promethazine HCl) Injec-
`tion is also available in vials as follows:
`NDC 00080234, 10 mL vial.
`L
`Do not use if solution is discolored or contains a precipi-
`tate.
`Protect from light
`Use carton to protect contents from light
`Store at room temperature, approximately 25° c (77" F)
`Manufactured by:
`Wyeth Laboratories Inc.
`A Wyeth«Ayerst Company
`Philadelphia, PA 19101
`
`tabolized and conjugates are primarily adoretedby the kid-
`pays, the potential exists for naproxen metabolites to accu-
`mulate in the presence of renal insufficiency.
`.
`CLINICAL STUDIES
`_
`,
`RHEUMATOID ARTHRITIS
`The use of Naprelan for the managementof the signs and
`symptoms of rheumatoid arthritis was assessed in a 12
`week double-blind, randomized, placebo and active—con—
`trolled study in 348 patients. Two Na’prelan 500 mg tablets
`(1000 mg) once daily and naproxen 500 mg tablets twice
`daily (1000 mg) were more effective than placebo. Clinical
`effectiveness was demonstrated at one week and continued
`for the duration of the study.
`OSTEOARTHRITIS
`The use of Naprelan for the management of the signs and
`symptoms of osteoarthritis of the knee was assessed in a 12
`week double—blind, placebo and activecontrolled study in
`347 patients. Two Naprelan 500 mg tablets (1000 mg) once
`daily and naproxen 500 mg tablets twice daily (1000 mg)
`were more eifective than placebo. Clinical effectiveness was
`demonstrated at one week and continued for the duration of
`the study.
`‘
`'
`ANALGESIA
`The onset of the analgesic effect of Naprelan was seen
`within 30 minutes in a pharmacckinetic/pharmacodynamic
`study of patients with pain following oral surgery. In con-
`trolled clinical trials, naproxen has been used in combina-
`tiou with gold, D~penicillamine, methotrexate and corticos-
`teroids. Its use in combination with salicylate‘is not recom~
`mended because there is evidence that aspirin increases the
`rate of excretion of naproxen and data are inadequate to
`demonstrate that naproxen and aspirin produce greater im-
`provement over that achieved with aspirin alone. In addi-
`tion, as with other NSAIDs the combination may result in
`higher frequency of adverse events than'demonstrated for
`either product alone.
`,
`SPECIAL STUDIES
`In a double—blind randomized, parallel g'rpup study, 19 sub
`jects received either two Naprelan 500 mg tablets (1000 mg)
`once daily or naproxenBOO mg tablets (1000 mg) twice daily
`for 7 days. Mucosal biopsy scores and endoscope scores were
`lower in the subjects who received Naprelau. In another
`double—blind, randomized, crossover study, 23 subjects re
`ceived two Naprelan 500 mg tablets (1000 mg) once daily,
`naproxen 500 mg tablets (1000 mg) twice daily, and aspirin
`650 mg four times daily (2600 mg) for 7 days each. There
`were significantly fewer duodenal erosions seen with
`Naprelan than with either noproxen or aspirin. There were
`significantly fewer gastric erosions with both Naprelan and
`naproxen than with aspirin.
`The clinical significance of these findings is unknown.
`INDIVIDUALIZATION OF DOSAGE
`RHEUMATOID ARTHRITIS, OSTEOARTHRITIS, AND
`ANKYLOSING SPONDYLITIS
`Naprelan‘like other NSAIDs shows considerable variation
`in response. The recommended starting dose of Naprelan in
`adults is two Naprelan 375 mg tablets (750 mg) once daily,
`or two Naprelan 500 mg tablets (1000 mg) once daily. Pa—
`tients already taking naproxen 250 mg, 375 mg or 500 mg
`twice daily (morning and evening) may’ have their total
`daily dose replaced with Naprelan as a single daily dose,
`During long-term administration, the dose of Naprelan may
`be adjusted up or down depending on the clinical response
`of the patient.
`In patients who tolerate lower doses of Naprelan well, the
`dose may be increased to three Naprelan 500 mg tablets
`( 1500 mg) once daily for limited periods when a higher level
`of anti—inflammatory/analgesic activity is required. When
`treating patients, especially at the higher dose levels, the
`physician should observe sufficient increased clinical benefit
`to offset the potential increased risk: (See CLINICAL
`PHARMACOLOGY). The lowest effective dose should be
`sought and used in every patient.
`.
`Symptomatic improvement
`in arthritis usually begins
`within one week; however, treatment for, two weeks may be
`required to achieve a therapeutic benefit. A lower dose
`should be considered in patients with renal or hepatic inr
`pairment or in elderly patients (see PRECAUTIONS).
`Studies indicate that although total plasma concentration of
`naproxen is unchanged, the unbound plasma fraction of
`naproxon is increased in the elderly. Caution inadvised
`when high doses are required and some adjustmentof dos-
`age may be required in elderly patients. As with other drugs
`used in the elderly it is prudent to use the lowest effective
`dose.
`.
`w
`ANALGESIA, DYSMENORRHEA, BURSITIS, AND TENv
`DINITIS
`r:
`,
`The recommended starting dose is twoNaprelan 500 mg
`tablets (1000 mg) once daily. For patients requiring greater
`analgesic benefit, three Naprelan 500 mg tablets (1500 mg)
`may be used for a limited period. Thereafter, the total daily
`dose should not exceed two Naprelan 500 mg tablets (1000
`mg).
`
`‘ C
`
`ontinued on next page
`Consul! 1 99 S FDR“ supplements and future editions for revisions
`
`
`
`Plasma Naproxen Concentrations
`Mean of 24 Subjects (+l—ZSD)
`(Steady State. Day 5)
`a». naproxon 500 mg own
`~9— Nanrolan 1000 my own
`no naproxcn 4 l-2SD
`— ~ Naprelan ¢/»2SD
`
`(meg/ML)
`I25
`100
`\nb
`0
`
`0002
`
`

`

`3336/WYETH—AYERST LABORATORIES
`
`Naprelan—Cont.
`
`,.
`ACUTE GOU’I‘
`The recommended (lose on the first day is two or three
`Nuprelan 500 mg tablets (1000—1500 mg) once daily, fol-
`lowed by two Naprelnn 500 mg tablets (1000 mg) once‘daily,
`until the attack has subsided.
`INDICATIONS AND USAGE
`Naprelan is indicated for the treatment of rheumatoid a1“
`thritis, osteoarthritis, ankylosing spondylitis, tendinitis,
`bursitis, and acute gout. It is also indicated in :the relief of
`mild to moderate pain and the treatment of primarydys-
`menorrhea.
`CONTRAINDICATIONS
`All naproxen products are contraindicated in patients who
`have had allergic reactions to prescription as well as to over-
`the-counter products containing naproxen. Anaphylactoid
`reactions may occur in patients without previous known ex-
`posure or hypersensitivity to aspirin, \naproxen, or other
`NSAIDs, or in individuals with a history of angiocdema, ur~
`ticaiia, bronchospastic reactivity (cg, asthma), and nasal
`polyps. Anaphylactoid reactions, like anaphylaxis, may
`have a fatal outcome. Therefore, careful questioning ofpa~
`tients for such things as asthma, nasal polyps, urticaria,
`and hypotension associated with NSAIDS before starting
`therapy is important. In addition, if such symptoms occur
`during therapy, treatment with Naprelau should be discon—
`tinucd.
`WARNINGS
`RISK OF GI ULCERATION, BLEEDING AND PERFORA
`TION WITH NSAID THERAPY
`Serious GI toxicity, such as bleeding, ulceration, and perfo~
`ration, can occur at any time, with or without warning
`symptoms, in patients treated chronically with NSAID ther-
`apy. Although minor upper GI problems, such as dyspepsia,
`are common, usually developing early in therapy, physi-
`cians should remain alert for ulcerations and bleeding in
`patients treated chronically with NSAIDs even in the ab-
`sence of previous GI tract symptoms; In patients observed
`in clinical trials with naproxen of several months to two
`years duration, symptomatic upper GI ulcers, gross bleed»
`mg or perforation appear to occur in approximately 1% of
`patients treated for 3—6 months, and in about 241% of pa-
`tients treated for one year. Physicians should inform pa—
`tients about the signs and/or symptoms of Serious GI toxic—
`ity and what steps to take if they occur.
`‘
`Studies to date with all naproxen products have not identi—
`lied any subset of patients not at risk of developing peptic
`ulceration and bleeding or any differences between different
`naproxen products in their propensity to cause peptic ulcer-
`ation and bleeding. Except for a prior history of serious GI
`events and other risk factors known to be associated with
`peptic ulcer disease, such as alcoholism, smoking etc, no
`risk factors (e.g., age, sex) have been associated with in—
`creased risk. Elderly or debilitatedpatients seem to tolerate
`ulceration or bleeding less well than other individuals and
`most spontaneous reports of fatal GI events are in this pop—
`ulation. Studies to date are inconclusive concerning the rel-
`ative. risk of various NSAIDs in causing such reactions.
`High doses of any NSAID probably carry a greater risk of
`these reactions, although controlled clinical trials showing
`this do not exist in most cases. In considering the use of rel-
`atively large doses (within the recommended dosage range),
`sufficient benefit should be anticipated to offset the poten-
`tial increased risk of GI toxicity.
`PRECAUTIONS
`GENERAL
`NAPRELAN SHOULD NOT BE USED CONCOMlTANTL
`WITH OTHER NAPROXEN PRODUCTS SINCE THEY ALL
`CIRCULATE IN THE PLASMA AS THE NAPHOXEN ANION.
`The antipyretic and anti~inflammatory activities of the drug
`may reduce fever and inflammation, thus diminishing their
`utility as diagnostic signs.
`Because of adverse eye findings in animal studies with
`drugs of this class, it is recommended that ophthalmic stud—
`ies be carried out if any change or disturbance in vision oc—
`curs.
`Renal Effects
`long term administration of
`As with other NSAIDs,
`naproxen to animals has resulted in renal papillary necrosis
`and other abnormal renal pathology. In humans, there have
`been reports of acute interstitial nephritis, hemotufia, pro—
`teinuria, and occasionally nephrotic syndrome associated
`with noproxen-containing products and other NSAIDs‘since
`they have been mzu‘ketcd.
`A second form of renal toxicity has been seen in patients
`taking naproxen as well as other NSAIDs. In patients with
`prerenal conditions with reduction in renal blood flow or
`blood volume,- renal prostuglandins have a supportive role
`in the maintenance of renal perfusion. Administration of a
`NSAID may cause a dose-dependent reduction in prostu~
`glandin formation and may precipitate overt renal dccom»
`pensntion. Patients at greatest risk of this reaction are
`Information will be superseded by SUpplements and subsequent editions
`
`1
`
`
`
`those with impaired renal function, heart failure, livcr dys-
`function, diuretic uSe, and theelderly. Discontinuation of
`NSAID therapy is typically followed by recovery to the pre~
`treatment state.
`Naproxen and its metabolites are eliminated primarily by
`the kidneys, therefore the drug should be used with great
`caution in patients with significantly impaired renal func-
`tion and the monitoring of serum creatinine and/or creati~
`nine clearance is advised in these patients. Caution should
`be used if the drug is given to patientswit‘h creatinine clear—
`ance of less‘than 20 mL/minute because accumulation of
`naproxen has been seen in such patients.
`kimono Efibcts
`As with other NSAIDs, borderline elevations of one or more
`liver tests may occur in up to 15% of patients. These abnor’
`malities may progress, may remain essentially unchanged,
`or may resolve with continued therapy. The ALT (SGI’T) is
`probably the most sensitive indicator of liver dysfunction.
`Meaningful (3 times the upper limit of normal) elevations of
`ALT (SGP’I‘) or AST (SGOT) occurred in controlled clinical
`trials in less than 1% of patients. ’A patient with symptoms
`and/or signs suggesting liver dysfunction, or in whom an ab»
`normal liver test has occurred, should be evaluated for evi.
`deuce of the development of more severe hepatic reaction
`while on therapy with naproxen. Severe hepatic reactions,
`including jaundice and cases offntal hepatitis have been re-
`ported with naproxcn as with other NSAIDs. Although such
`reactions are rare, if abnormal liver tests persist or worsen,
`if clinical signs and symptoms consistent with liver disease
`develop, or if systemic manifestations occur (e.g. eosinophi-
`lie, rash, fever, etc.), naproxen should be discontinued.
`Chronic alcoholic liver disease and probably other diseases
`with decreased or abnormal plasma proteins (albumin) re-
`duce the total plasma concentration of naproxen, but the
`plasma concentration of unbound naproxen is increased.
`incision is advised when high doses are required and some
`adjustment of dosage may be required in these patients. It
`is prudent to use the lowest effective dose,
`Fluid Retention, and Edema
`Peripheral edema has been observed in some patients re-
`ceiving‘naproxen. Naprelan (naproxen sodium) tablets con-
`tain 37.5 mg or 50 mg of sodium (1.5 1111301 or 2.0 niEq re,
`spectively). This should be considered in patients whose
`overall intake of sodium must be severely restricted. For
`these reasons, Naprelan should be used‘with caution in pa-
`ticnts with fluid retention, hypertension or heart failure.
`INFORMATION FOR PATIENTS
`Naprelan, like other drugs of its class, is not free of side
`effects. This formulation of naproxen can cause discomfort
`and, rarely, there are more serious side effects, such as GI
`bleeding, which may result in hospitalization and even fatal
`outcomes. NSAIDs are often essential agents in the man»
`agement of arthritis and have a major role in the treatment
`of pain but they also may be commonly employed for condi-
`tions which are less serious. Physicians may Wish to discuss
`with their patients the potential iisks (see WARNINGS,
`PRECAUTIONS, and ADVERSE REACTIONS) and
`likely benefits of Naprelan treatment. Caution should be ex‘
`ercised by patients whose activities require alertness if they
`experience drowsiness, dizm‘ness, vertigo or depression durs
`ing therapy with naproxen.
`LABORATORY TESTS
`Because serious GI tract ulceration and bleeding can occur
`without warning symptoms, physicians should follow pa-
`tients chronically treated with Naprclan for the signs and
`symptoms of ulceration and bleeding, and should inform
`them of the importance of this follow-up and what they
`should do if certain signs and symptoms do appear. Patients
`with initial hemoglobin values of 10 grams or less who are
`to receive long—term therapy should have hemoglobin values
`determined periodically. (See WARNINGS—JIISK OF GI
`ULCERATION, BLEEDING AND PERFORATION WITH
`NSAID THERAPY).
`DRUG INTERACTIONS
`The use of NSAIDs in patients who are receiving ACE in—
`hibitors may potentiatc renal disease states (See PRECAU-
`TIONSMchol Efli’ctsl. In vitro studies have shown that
`naproxen union, because of its affinity for protein, may dis,
`place from their binding site other drugs which are also a1—
`bumin-bound (see CLINICAL PHARMACOLOGY«—
`PHARMACOKINE’I‘ICS).
`Theoretically, the nuproxcn anion itself could likewise be
`displaced. Shorttcrm controlled studies failed to show that
`taking the drug significantly affects prothrombin times
`when administered to individuals on coumarin-type antico—
`agulants. Caution is advised nonetheless, since interactions
`have been seen with other nonsteroidal agents of this class.
`Similarly, patients receiving the drug and a hydantoin, sul-
`fonnmide or sulfonylurea should be observed for signs of
`toxicity to these drugs.
`Concomitant administration of nnproxen and aspirin is not
`recommended because naproxen is displaced from its bind-
`ing sites during the concomitant administration of aspirin,
`resulting in lower plasma concentrations and peak plasma
`levels.
`‘
`
`
`
`PHYSICIANS’ DESK REFERENCE®
`
`_
`
`The nutriuretic effect offiirosemidehas been reported to be
`inhibited by some ’drugslof this class. Inhibition of renal
`lithium clearance leading to increases in plésma lithium
`concentrations has also been reported; anfoxen and other
`NSAIDs can reduce the antihypertensive effect of proprzmg
`0101 and other beta—blockers.
`,
`p
`,
`,
`Probenecid given concurrently increases haproxen anion
`plasma levels and extends its plasma half~life significantly.
`Caution should be used ifnaproxen is administeied concom-
`itantly with hiethotrexate. Naproxen, naxiroXen sodium’and
`other NSAIDS have been reported to reduce the tubular se-
`cretion of methotrcxatc in an animal model, poeSibly in-
`creasing the toxicity of methotrexute.
`"
`’
`'
`DRUG/LABORATORY TEST INTERACTIONS
`Naproxen may decrease platelet aggregation and prolong
`bleeding time. This effect should be kept in mind when
`bleeding times are determined. The administration of
`naproxen may result in increased urinary values’for l7-
`ketogenic steroids because of an interaction between the
`drug and/or its metabolites with m—dinitrobenzene used in
`this assay. Although l7—hydr0xy—corticosteroid measure—
`ments (Porter-Silber test) do not appear to be artifactually
`altered, it is suggested that therapy with naproxcn'be tern;
`poraiily discontinued 72 hours before adrenal function tests
`are performed if the Porter—Silber test is to be used.
`_
`,
`Naproxen may interfere with some urinary assaysof 5,—hy-
`droxyindoleacetic acid (5HIAA).
`’
`l
`i
`I
`’
`I
`CARCINOGENESIS
`'
`A two year study was performed in rats to evaluate the car—
`cinogenic potential of naproxen at doses of 8 mg/kg/day, .16
`mg/kg/day, and 24 mg/kg/day (50 rug/int“), 100 mg/mz, and
`150 mg/ml). The maximum dose used was 0.28 times the
`systemic exposure to humans at the recommended dose. No
`evidence of tumorigenicity was found.
`’
`PREGNANCY '
`'
`,
`Teralogenic Effects: Pregnancy Category B,
`Reproduction studies have been peribrmed in rats at 20 mg/
`kg/day (125 mg/mz/day 0.23 times the human ”systemicex—
`posure) rabbits at 20 mg/kg/day (220 mg/mZ/day, 0.27 times
`the human systemic exposure) and mice at 170 ing/kg/day
`(510 mg/niglday, 0.28 times the human systemic exposure)
`with no evidence of impaired fertility or harm to the fetus
`due to the drug. There are no adequate and well—controlled
`studies in pregnant women. Because animal reproduction
`studies are not always predictive of human response,
`Naprelan should be used during pregnancy only if the po-
`tential benefits justify the potential risks to the fetus.
`Nontcmtogenic Effects
`There is some evidence to suggest that when inhibitors of
`prostaglandin synthesis are used to delay preterm labor
`there is an increased risk of neonatal complications such as
`necrotizing enterocolitis, patent duotus orteriosus, and in‘
`trncranial hemorrhage. Naproxen treatment given in the
`lute pregnancy to delay parturition has been associated
`with persistent pulmonary hypertension, renal dysfunction,
`and abnormal prostaglandin E levels in preterm infants.
`Because of the known effect of drugs of this class on the hu-
`man fetal cardiovascular system (closure of ductus arterio—
`sus), use duringlthird trimester should be avoided.
`NURSING MOTHERS
`,
`_
`,
`The naproxcn anion has been found in the milk of lactating
`women at alconcentration of approximately 1% ofthat fdund
`in the plasma. Because of the possible sdvers‘eefi'ects'of
`prostaglandin—inhibit‘ing drugs on neonates, use in nursing
`mothers should be avoided.
`PEDIATRIC USE *
`No pediatric studies have been performed with Naprelan,
`thus safety of Naprelan in pediatric populations has not
`been established.
`‘
`ADVERSE REACTIONS
`As with all drugs in this class, the frequency and severity of
`adverse events depends on several factors: the dose of'the
`drug and duration of treatment; the age, the sex, physical
`condition of the patient; any concurrent medical diagnoses
`or individual risk factors.
`'
`.
`The following adverse reactions are divided into three parts
`based on frequency and whether or not the possibility exists
`of a causal relationship between drug usage and these ad-
`verse events. In these reactions listed as “Probable Causal
`Relationship” there is at least one case for each adverse re-
`action where there is evidence to suggest that there is a cauv
`sal relationship between drug usage and the reported event.
`The adverse reactions reported were based on the results
`from two double-blind controlled clinical trials of three
`months duration with an additionalrnine month open-label
`extension. A total of 542 patients received Naprelan either
`in the double-blind period or in the nine month open—label
`extension. Of these 542 patients, 232 received Naprelan,
`167 were initially treated with Naprosyn and 143 were ini--
`tially treated with placebo. Adverse reactions reported by
`patients who received Naprelan are shown by body system.
`Those adverse reactions observed with naproxen but not re
`ported in controlled trials with Naprelan are italicized;
`The most frequent adverse events from the double-blind
`and open—label clinical trials were headache (15%), followed
`
`0003
`
`0003
`
`

`

`Central Nervous System: Aseptic meningitis, cognitive dys'
`function.
`Dermatologic—Epidcrmal necrolysis, uryllzema multiforme,
`Shavens-Johnson syndrome,
`Gnstrointestinal-—~~Non~pcptic G1 ulceration, ulcerativc slo-
`nmtitis.
`Cardiovascular—~Vasculitis.
`OVERDOSAGE
`Significant naproxen overdosage may be characterized by
`drowsiness, heartburn, indigestion, nausea, or vomiting.
`Because naproxcn sodium may be rapidly absorbed, high
`and early blood levels should be anticipated.A few patients
`have experienced seizures, but it is not clear whether or not
`these were drug—related. It is not known what dose of the
`drug would be life threatening The oral LDBO of the drug is
`. 500 rug/kg in rats, 1200 rug/kg in mice, 4000 mg/kg in ham—
`sters and greater than 1000 rug/kg in dogs.
`Should a patient ingest a large number of tablets, acciden~
`tally or purposelhlly, the stomach may be emptied and usual
`supportive measures employed. In animals 0.5 g/kg of acti»
`vated charcoal was effective in reducing plasma levels of
`naproxen. Hemodialysis does not decrease the plasma con-
`centration ofnaproxen because of the high degree of its pro«
`toin binding.
`DOSAGE AND ADMINISTRATION
`RHEUMATOID ARTHRITIS, OSTEOARTI—IRITIS, AND
`ANKYLOSING SPONDYLI’I‘IS
`The usual daily (lose of Naprelan is two Naprelan 375 mg
`tablets (750 mg) once daily, or two Naprelan 500 mg tablets
`(1000 mg) once a day. Both larger and smaller doses maybe
`required in individual patients (see Individualization of
`Dosage). Regardless of indication, the dosage should be in»
`dividualized to achieve effective. dose and minimize adverse
`events, however the maximum daily dose is three Naprelan
`500 mg once daily.
`MANAGEMENT OF PAIN, PRIMARY DYSMENORRHEA,
`AND ACUTE TENDINITIS AND BURSI’I‘IS
`The recommended starting dose is two Naprelan 500 mg
`tablets (1000 mg) once daily. For patients requiring greater
`analgesic benefit, three Naprelan 500 mg tablets (1500 mg)
`may be used for a limited period. Thereafter, the total daily
`dose should not exceed two Naprelan 500 mg tablets (1000‘
`mg).
`ACUTE GOUT
`The recommended dose on the first day is two to three
`Naprelan 500 mg tablets (10004500 mg) once daily, fol~
`lowed by two Naprclan 500 mg tablets (1000 mg) once daily,
`until the attack has subsided.
`‘
`,
`HOW SUPPLIED
`Naprelan® (naproxen sodium) Controlled Release Tablets
`are available as follows:
`Naprelan 875: white, capsule—shaped tablet with “W” on one
`side and “901” on the reverse; in bottles of 100; NDC 0008~
`0901—03. Each tablet contains 412.5 mg naproxen sodium
`equivalent to 375 mg naproxen.
`Naprelan 500: white, capsule-shaped tablet with “W" on one
`side and “902” on the reverse; in bottles of '75; NDC 0008—
`0902-02. Each tablet contains 550 mg naproxen sodium
`equivalent to 500 mg naproxen.
`Caution: Federal law prohibits dispensing without prescrip-
`tion.
`‘
`,
`US Patent Pending.
`Store at controlled room temperature, 20°~25° C l68°~77°
`F).
`‘
`Dispense in a well-closed container.
`Manufactured for
`Wyeth Laboratories Inc,
`A Wyeth-Ayerst Company
`Philadelphia, PA 19101
`by
`élan pharma ltd.
`Athlone, Ireland
`Shown in Product Identification Guide, page 344
`
`PRODUCT INFORMATION
`
`by dyspepsia (14%), and flu syndrome (10%). The incidence
`of other adverse events occurring in 3%-—9% of the patients
`are marked with an asterisk.
`Those reactions occurringin less than 3‘2? of the patients are
`unmarked.
`INCIDENCE GREATER THAN 1%: (PROBABLE CAUSAL
`RELATIONSHIP)
`Body as a Wholewl’ain (backl‘h, pain”: infectioni‘, fever, iu~
`jury (accident), asthenia, pain chest, headache (15ft), flu
`syndrome (10%).
`Gastrointest‘ al—«Nausea’l’, (liarrhea‘i, constipationi“, ab-
`
`dominal pai
`', flatulence, gastritis. vomiting, (lysphagia,
`dyspepsia (140’). heartburn‘fi stomalitls.
`Hematolog‘ichnc-mia, ecchymosis
`
`Respiratory~Pharyngitis3“, rhinitis , sinusitis”, bronchitis,
`cough increased,
`Renal—wUrinary tract infection‘”, cystitis.
`Dermatologichkin rash‘“, slain eruptions”; ccchylnoscs‘“,
`purpura.
`Metabolic and Nutrition~l30ripheral edema. hyperglyce-
`mic.
`Central Nervous Systcin-wDizziness, parosthesia, insom~
`
`nia, drowsiness‘fi lightlzcadcdncss.
`Cai‘diovasculm «Allyperlension, edema”: (lyspnca’l’, palpitw
`lions.
`MusculoskeletalmCi-amps (leg), myalgia, arthrolgia, joint
`disorder> tendon disorder.
`Special SeiiSGSwTinnitus""2 hearing disturbances. visual
`disturbances.
`General~7 ‘lz-irsl.
`INCIDENCE LESS ’[‘HAN 1% (PROBABLE CAUSAL RE—
`LATIONSHIP)
`Body as a WholeMAbscoss, monilia, neck rigid, pain neck,
`abdomen enlarged, carcinoma, cellulitis, edema general, LE
`syndrome, malaise, mucous membrane disorder, allergic re—
`action, pain pelvic.
`_
`GastrointestinalwAnorexia, cholecystitis, cholelithiasis,
`cructation, GI hemorrhage, rectal hemorrhage, stomat’itis
`aphthous, stomatitis ulcer, ulcer mouth, ulcer stomach,
`periodontal abscess, cardiospasm, colitis, osophagitis, gas—
`troenteritis, GI disorder, rectal disorder, tooth disorder, hep—
`atosplenomegaly, liver function abnormality, melena, ulcer
`esophagus, hemalemesis, jaundice, pancreatitis, necrosis.
`KenalMDysmcnorrhea, (lysuria, kidney function abnormal-
`ity, nocturia, prostate disorder, pyelonephritis, carcinoma
`breast, urinary incontinence, kidney calculus, kidney fail—
`ure, menorrhagia, metrorrhagia, neoplasm breast, nephro—
`sclerosis, hematuria, pain kidney, pyuria, urine abnormal,
`urinary frequency, urinary retention, uterine spasm, vagini»
`tis, glomerulor nephritis, Inrpcrkalcmia, interstitial nephri—
`lis, nep/zrolic syndrome, renal disease, renal failure, renal
`papillary necrosis.
`Hematologicheukopenia, bleeding time increased, eosino~
`philia, abnormal RBC, abnormal WBC, thrombocytopenia,
`agranulocytosis, granulocytopcnia.
`,
`Central Nervous System—Depression, anxiety, hypertonia,
`nervousness, neuralgia, neuritis, vertigo, amnesia, confu-
`sion, eta-ordination, abnormal diplopia, emotional lability,
`hematoma subdural, paralysis, dream. abnormalities,
`in»
`ability to concentrate, muscle weakness.
`Dermatologic: Angiodcrmatitis, herpes simplex, dry Skin,
`sweating, ulcer skin, acne, alopecia, dermatitis Contact, ec-
`zema,