0001
`
`PSG2012
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`:onsult 1994 Supplements for revisions
`
`Physicians' Desk Reference®
`
`'ace areas, prolonged use. the addition of occlusive dressings.
`and dosage form.
`l'herefore. patients receiving a large dose ofa potent topical
`ateroid applied to a large surface area or under an occlusive
`[racing should be evaluated periodically for evidence of
`EIPA axis suppression by using the urinary free cortisol and
`tCTl-l stimulation tests. If HPA axis suppression is noted,
`in attempt should be made to withdraw the drug. to reduce
`:he frequency of application, or to substitute a less potent
`itemid.
`Recovery of EPA axis function is generally prompt and com—
`plete upon discontinuation of the drug. Infrequently. signs
`and symptoms of steroid withdrawal may occur. requiring
`iupplernental systemic corticosteroids.
`Children may absorb proportionally larger amounts of topi-
`:al corticosteroids and thus be more susceptible to systemic
`:oxieity. (See PRECAUTIONS—Pediatric Use).
`Not for ophthalmic use. Severe irritation is possible if
`fluocinonide solution contacts the eye. If that should occur,
`immediate flushing of the eye with a large volume of water is
`recommended.
`topical corticosteroids should be
`If irritation develops,
`discontinued and appropriate therapy instituted.
`As with any topical corticosteroid product. prolonged use
`may produce atrophy of the skin and subcutaneous tissues.
`When used on intertriginous or flexor areas, or on the face.
`this may occur even with short-term use.
`In the presence of dermatological infections, the use of an
`appropriate antifungel or antibacterial agent should be in-
`stituted. Ifa favorable response does not occur promptly, the
`corticosteroid should be discontinued until the infection has
`been adequately controlled.
`As with all antibiotics, prolonged use of NEDSYNALAR
`may result in over-growth of oonsusceptible organisms. If
`11.
`:ilpeerinfoction occurs, appropriate measures should be
`SYNALAR-HP cream should not be used for prolonged pe-
`rioda and the quantity per day should not exceed 2 g. of for-
`mulated material.
`Information for the Patient: Patients using topical cortioo
`steroids should receive the following information and in-
`structions:
`1. This medication is to be used as directed by the physician.
`It is for external use only. Avoid contact with the eyes If
`there is contact with the eyes and severe irritation occurs.
`immediately flush with a large volume of water.
`2. Patients should be advised not to use this medication for
`any disorder other than for which it was prescribed.
`3. The treated skin area should notbe bandaged or otherwise
`covered or wrapped as to be occlusive unless directed by
`the physician.
`4. Patients should report any signs of local adverse reactions
`especially under occlusive dressing.
`5. Parents of pediatric patients should be advised not to use
`tight-fitting diapers or plastic pants on a child being
`treated in the diaper area. as these garments may consti—
`tute occlusive dressings.
`Laboratory Tests: The following tests may be helpful in
`evaluating HPA axis suppression: Urinary free cortisol test
`and ACTH stimulation test.
`Carcinogenesis. Mutsgeneois. and Impairment of Fertility:
`Long-term animal studies have not been performed to evalu-
`ate the carcinogenic potential or the effect on fertility of
`topical corticosteroids.
`Studies to determine mutagenicity with predniaolone and
`hydrocortisone have revealed negative results.
`Pregnancy Category c: Corticosteroids are generally tera-
`togenic in laboratory animals when administered systemi-
`cally at relatively low dosage levels. The more potent cortico-
`steroids have been shown to be teratogenic after dermal ap
`plication in laboratory animals. There are no adequate and
`well-controlled studies in pregnant women on teratogenic
`efi'ects from topically applied corticosteroids. Therefore,
`topical corticosteroids should be used during pregnancy only
`if the potential benefit justifies the potential risk to the fe-
`tus. Drugs of this class should not be used extensively on
`pregnant patients, in large amounts. or for prolonged periods
`of time.
`It is not known whether topical adminiov
`Nursing Mothers:
`tration of corticosteroids could result in sufficient systemic
`absorption to produce detectable quantities in breast milk.
`Systemically administered corticosteroids are secreted into
`breast milk in quantifies not likely to have a deleterious ef-
`fect on the infant Nevertheless, caution should be exercised
`when topical corticosteroids are administered to a nursing
`WOM-
`Pediatric Use: SYNALAR—HP cream 02% should not be
`used on infants uptozyears ot'age.
`Pediatric patients may demonstrate greater ansceptibilityno
`topical corticosteroid-induced HPA axis suppression and
`Cushing‘s syndrome than mature patients because of a
`larger skin surface area to body weight ratio.
`Hypothalamio-pituitary-adrenal
`(HPA) axis suppression,
`Cuahing's syndrome, and intracranial turperteosion have
`been reported in children receiving topical corticosteroids.
`Manifestations of adrenal suppression in children include
`
`linear growth retardation, delayed weight gain, low plasma
`mrtisol levels, and absence of responseto ACTH stimulation.
`Manifestations ofintracranial hypertension include bulging
`fontanelles, headaches, and bilateral papilledema.
`_
`Administration of topical corticostemds to children should
`be limited to the least amount compatible with an effective
`therapeutic regimen. Chronic corticosteroid therapy may
`interfere with the growth and development of children.
`ADVERSE REACTIONS
`The following local adverse reactions are reported infre-
`quontly with topical corticosteroids, but may occur more
`frequently with the use of occlusive dressings. These reac-
`tions are listed in an approximate decreasing order of occur
`rence: burning, itching. irritation, dryness, folliculitis, hy-
`pertrichoaia, acneiform eruptions. hypopig-mentation. peri-
`oral dermatitis, allergic contact dermatitis, maceration of
`the skin. secondary infection, skin atrophy, etriae, miiiaria.
`The following reactions have been reported with the topical
`use of neomycin: ototoxicity and nephrotouricity.
`OVERDOSAGE
`Topically applied corticosteroids can be absorbed in suf-
`ficient amounts to produce systemic effects (See PRE-
`CAUTIONS).
`DOSAGE AND ADMINISTRATION
`Topical corticosteroids are generally appliedto the affected
`area as a thin film from two to four times daily depending on
`the severity of the condition. In hairy sites, the hair should
`be ported to allow direct contact with the lesion.
`_
`Occlusive dressings may be used for the management ofpso-
`rissis or recalcitrant conditions. Some plastic films may be
`flammable and due care should be exercised in their use.
`Similarly, caution should be employed when such films are
`used on children or left in their proximity, to avoid the possi-
`bility of accidental suffocation.
`If an infection develops, the use of occlusive dressings
`should be discontinued and appropriate antimicrobial then-
`any instituted.
`HOW SUPPLIED
`
`'
`-
`(104°59-
`LIDEX® (fluocinonide) gel 0.059e-15 g Tube (NBC 0033-
`250743), 30 g Tube (NBC 0033-2503161). 60 g Tube (NDC
`0033250747), and 120 g Tuba {NDC 0033250132). Store at
`controlled room temperature, 154033 (SQ—36'1“).
`IIDEX® (fluocluonide) ointment 00506—15 g Tube (NBC
`0033-2514-13). 30 g Tube (NIX) 0033251444). 60 g Tube
`(NBC 0033-2514413, and 120 g Tube (NBC 00332514~22l
`Store at room temperature. Avoid temperature above 30“C
`(861‘).
`top'cnl solution 0.05%—Plastic
`(fluocinonide)
`LIDEXG)
`squeeze bottles 20 on (NBC 0033251744) and 60 cc (NBC
`00313-251746). Store at room temperature. Avoid excessive
`heat, above 40'C (1041’).
`LIDEX-E® (fluocinonlde) cream 0.05%15 g Tube {NBC
`00333-251343). 30 g Tube {NDC 00343-251314). 60 g Tube
`(NDC 0033-25134”, and 120 g Tube (NBC 03332513221
`Store at room temperature. Avoid excessive heat, above 400
`(1041‘).
`NEO-SYNAIARG) cream—15 g Tube (NBC 00334250313},
`30 g Tube (NBC 00313—250514), 60 g Tube CN'DC 0033-2505-
`17). Store at room temperature. Avoid freeming and excessive
`heat, above 400 [104
`.
`SYNAGORTQ (hydrocortiaonei cream 196—15 g'I‘ubetNDC
`0033-1351913), 30 3‘ Tube (N'DC 0033251944}, and 60 g Tube
`(NBC 0033-2519-17). SYNACORTG) (hydrocartisonfl cream
`2593—430 gTube (N'DC 0033-2520141 Store at room temper-
`ature. Avoid excessive heat, above 4013 (104'Fl.
`SYNALAEC'D (fluocinolone acetonide) cream 002595—15 g
`Tube (NBC {1133-2501-13), 30 3' Tube (NBC 0033250144).
`60 g Tube (NBC 0033250147), and 425 g Jar (NBC 0033-
`2501-23). Store tubes at room temperature. Avoid frosting
`and exmssive heat. above 400 (1041'). Store jars at con-
`trolled room temperature, 15'—30’C (50—8910.
`SYNALARG) (fluocinolone acetonide) cream 0.01%—15 g
`Tube (NBC 0033—2502-13), 30 g Tube (N'DC 0033250214).
`SOgTubeflilDC0033-2502-17),andd25gdar(NDCm33-
`250%33). Store tubes at room temperature. Avoid frosting
`and excessive heat. above 4013 (104T). Store jars at con-
`trolled room temperature, 16'—30’C (ST-89F).
`SYNALARG) (fluocinolone acetonide) ointment 0.025%45
`g Tube (NBC 0033-2501143), 30 3' Tube (NBC 0033250444),
`60gTubefND00033-2504-11).end425gdarfND00033-
`2504-33). Store at room temperature. Avoid excessive heat,
`above 40C (1041’).
`solution
`topical
`acetonide)
`SYNALARCD (fluooinolone
`0.01%—m cc WWW-44) andfiflccmmm
`46). Store at room temperature. Avoid freezing.
`SYNALAR-HPGJ (fluocinolone acetonide) cream 0296—12 g
`Tube (NBC 0033—2503121 Share at room temperature. Avoid
`excessive heat, above 40°C (10410.
`
`0002
`
`2363
`
`SYNEMOLG) (fluocinolone acetonide) cream 002595—45 g
`Tube (NBC 0033-2509-13). 30 g Tube (NDC 0033-23314},
`60 g Tube (NDC 0033—25094?) Store at room temperature.
`Avoid excessive heat, above 401') (104“Fl.
`CAUTION: Federal law prohibits dispensing without a
`prescription.
`LlDEX ointment: U.S. Patent No. 4,017,615 Revised #91
`© 1990 Syntax Laboratories, Inc.
`
`
`naeaosvuo)
`[#5 bro—aw l
`{naproxenl
`Tablets and Suspension
`
`Products of Syntax Puerto Rico. Inc.
`
`B
`
`DESCRIPTION
`NAPROSYNGB (naproxen) tablets for oral administration
`each contain 250 mg, 3'35 mg or 500 mg of naproxen.
`NAPROSYN suspension for oral administration contains
`125m/5mLofnaproxen.NAPROSYN isamember of the
`arylacetic acid group of nonsteroidal anti-inflammatory
`drugs.
`'The chemical name for naproxen is 2-naphtbaleneacetic
`acid. 6-methoxy-cr—methyl-.{+).
`Naproxen is an odorless, white to off-white crystalline sub
`stance. It is lipid soluble, practically insoluble in water atlow
`pH and freely soluble in water at high pH.
`Each tablet contains nsproxan, the active ingredient, with
`the following inactive ingredients: Croacarmelloae sodium,
`iron oxides, magnesium atearate and povidone.
`NAPROSYN suspension for oral administration contains
`125 mgfli ml. of naproxen, the active ingredient, in a vehicle
`of FDt'rC Yellow #6, fumaric acid, imitation orange flavor,
`imitation pineapple flavor, magnesium aluminum silicate,
`methylparaben, purified water, sodium chloride, sorbitol
`solution and sucrose.
`CIJNICAL'PEAEMACOLOGY
`NAPROSYN (naproxenlia a nonateroidal anti-inflammatory
`drug with analgesic and anfipy-retic properties Naproxen
`sodium, the sodium salt of naproxen. has been developed as
`an analgesic because it is more rapidly absorbed. The na-
`pronen anion inhibits prostaglandin synthesis but beyond
`this its mode of action is unknown.
`Naproxen is rapidly and completely absorbed from tbe'gas-
`uninteatinal tract Alter administration of naproxen, peak
`levels of naproxen anion are attained in 2 to 4 hours,
`with steady-state conditions normally achieved after 4-5
`doses. The mean biological half-life of the anion in humans is
`approximately 13 hours. and at therapeutic levels it is
`greater than 99% albumin bound. At doses of naprox-
`greaterthan 300mg1daythereisalackofdoseproportional-
`ity due to an increase in clearance caused by saturation of
`proteins at higher doses. Approximately 95% of the dose is
`excreted in the urine, primarily as naproxen, 6-0-deamethyl
`naproxen or their conjugates. The rate of excretion has been
`found to coincide closely with the rate ofdrug disappearance
`from the plasma. The drug dose not induce metabolizing
`enzymes.
`Inchildien0f5to16yearsofagewitlrartbritiaplssmana-
`proxen levels following a 5 mgfkg single dose of suspension
`were found to be similar to those found in normal adults fol-
`lowing s 500 mg dose. The terminal half-life appears to be
`similar in children and adults. Pharmacolrinetic studies of
`naproxen were not performed in children ofleas than 5 years
`of age.
`'
`The drug was studied in patients with rheumatoid arthritis.
`osteoarthritis,
`juvenile arthritis, anlryloaing spondylitis,
`tendinitis and bursitis, and acute gout. It is not a corticoste-
`roid. lmprovementin patients treawd for rheumatoid arthri-
`tis has been demonstrated by a reduction in joint swelling, a
`reduction in pain, a reduction in duration of morning stiff-
`nesaamductionindisesseactivityaaassassedbyhoththe
`investigator and patient, and by into-eased mobility as dem-
`onstrated by a reduction in walking lime.
`'
`in patients with osteoarthritis. the therapeutic action of the
`drug has been shown by a reduction in joint pain or tender-
`ness, an increase in range of motion in lmee joints, increased
`mobility as demonstrated by a reduction in walking time.
`and improvement in capacity to perform activities of daily
`living impaired by the disease.
`In clinical studies in patients with rheumatoid arthritis,
`osteoarthritis. and juvenile arthritis, the drug has been
`shown to be comparable to aspirin and indomethacin in con-
`trolling the aforementioned measures ofdisease activity. but
`the frequency and severity of the milder gastrointestinal
`adverse effects (nausea. dyspepsia, heartburn) and nervous
`system adverse effects (tinnitus, diminm lightheadedneas)
`were less than in both the aspirin— and indomethacin-trealed
`Continued on next page
`
`0002
`
`

`

`2364
`
`Syntax—Cont.
`
`patients. It is not known whether the drug causes less peptic
`uluarat‘ion than aspirin.
`In patients with ankylosing spondylitis, the drug has been
`shown to decrease night pain, morning stiffness and pain at
`rest. In doublebljnd studies the drug was shown to be as ef-
`fective as aspirin, but with fewer side ed‘ects.
`In patients with acute gout, a favorable response to the drug
`was shown by significant clearing of inflammatory changes
`.(e.g., decrease in swelling. heat) within 24-48 hours. as well
`as by relief of pain and tenderness.
`The drug may be used safely in combination with gold salts
`and/or corticosteroids; however. in controlled clinical trials,
`when added to the regimen of patients receiving corticoste-
`roids it did not appear a: cause greater improvement over
`that seen with corticosteroids alone. Whether the drug could
`be used in conjunction with partially effective doses of corti-
`costeroid for a “steroid-sparing" effect has not been ade
`quately studied. When added to the regimen of patients re-
`ceiving gold salts the drug did result in greamr improve
`ment. Its use in combination with salicylates is not recom-
`mended because data are inadequate to demonstrate that
`the drug produces greater improvement over that achieved
`with aspirin alone. Further, there is someevidence that aspi-
`rin increases the rate of excretion of the drug.
`Generally. improvement due to the drug has not been found
`to be dependent on age, sex, severity or duration of disease.
`In clinical trials in patienm with osteoarthritis and rheuma—
`told arthritis comparing treatments of 1'50 mg per day with
`1,500 mg per day, there were trends toward increased effi-
`cacy with the higher dose and a more clearcut increase in
`adverse reactions. particularly gastrointestinal reactions
`severe enough to cause the patient to leave the trial, which
`approximately doubled.
`The drug was studied in patients with mild to moderate pain,
`and pain relief was obtained within 1 hour. It is not a nar-
`cotic and is not a CNS~ecting drug. Controlled doubleblind
`studies have demonstrated the analgesic properties of the
`drug in, for example, post-operative, postpartum, orthopedic
`and uterine contraction pain and dysmenorrhea. In dysmen-
`orrheic patients, the drug reduces the level of prostaglandina
`in the uterus. which correlates with a reduction in the fre
`quency and severity of uterine contractions. Analgesic ac-
`tion has been shown by such measures as a reduction ofpain
`intensity scores. increase in pain relief scores, decrease in
`numbers of patients requiring additional analgesic medicam
`tion, and delay in time for required remedication. The anal-
`gesic effect has been found to last for up to 7 hours.
`In 51Cr blood loss and gastroscopy studies with normal volun-
`teers, daily administration of 1000 mg of the drug has been
`demonstrated to cause statistically significantly less gastric
`bleeding and erosion than 3250 mg of aspirin.
`INDICATIONS AND USAGE '
`NAPROSY‘N (naproxenl is indicated for the treatment of
`rheumatoid arthritis. osteoarthritis, juvenile arthritis, an-
`kylosing spondylitis, tendinitis and bursitis, and acute gout.
`It is also indicated in the relief of mild to moderate pain and
`for the treatment of primary dysmenorrhea.
`CONTRAINDICATIONS
`tients who have had aller-
`The drug is contraindicated in
`gic reactions to NAPROSYNCgaIEnapi-oxen), ANAPROX®
`(naproxen sodium) or ANAPROX® DS (naproxen sodium).
`It is also contraindicated in patients in whom aspirin or
`other nonsteroidal anti—inflammatorylanalgesic drugs in-
`duce the syndrome of asthma. rhinitis, and nasal polyps.
`Both types of reactions have the potential of being fatal. An-
`aphylactoid reactions to NAPROSYN, ANAPROX, or
`ANAPROX DS, whether of the true allergictype Or the pher-
`macologic idiosyncratic (cg. aspirin syndrome) type, usually
`but not always occur in patients with a known history ofsucb
`reactions. Therefore, careful questioning of patients for such
`things as asthma, nasal polyps. urticaria, and hypotension
`associated with nonsteroidal anti-inflammatory drugs before
`starting therapy is important. In addition, if such symptoms
`occur during therapy, treatment should be discontinued.
`WARNINGS
`Risk of GI Ulceration, Bleeding and Porforation with NSAID
`Therapy:
`Serious gastrointestinal toxicity such as bleeding, ulcer-
`ation, and perforation, can occur at any time, with Or with
`out warning symptoms, in patients treated chronically with
`NSAID therapy. Although minor upper gastrointestinal
`problems, such as dyspepsia, are common, usually develop-
`ing early in therapy, physicians should remain alert for ul-
`ceration and bleeding in patients treated cbmnically with
`NSAIDs even in the absence of previous GI tract symptoms.
`In patients observed in clinical trials of several months to
`two years duration, symptomatic upper GI ulcers, gross
`bleeding or perforation appear to occur in approximately 1%
`of patients treated for 3—6 months, and in about 24% of pa—
`tients treated for one year. Physicians should inform pa-
`
`Physicians’ Desk Reference®
`tienn about the signs and:ror symptoms of serious GI toxicity
`and what steps to take if they occur.
`Studies to date have not identified any subset of patients not
`at risk of developing peptic ulceration and bleeding. Except
`for a prior history of serious GI events and other risk factors
`known to be emaciated with peptic ulcer disease, such as
`alcoholism. smoking, etc, no risk factors (e.g.. age, sex) have
`been associated with increased risk. Elderly or debilitated
`patients seem to tolerate ulceration or bleeding less well
`than other individuals and most spontaneous reports of fatal
`GI events are in this population. Studies to date are inconclu-
`sive concerning the relative risk of various NSAIDs in caus-
`ing such reactions. High doses of any NSAID probably carry
`a greater riskofthese reactions, although controlled clinical
`trials showing this do not exist in most cases. In considering
`the use of relatively large doses (within the recommended
`dosage range), sufficient benefit should be anticipated to
`offset the potential increased risk of GI toxicity.
`PRECAUTIONS
`General:
`NAPHOSYN (NAPROXENI SHOULD NOT BE USED CON-
`CUMITANTL‘I’ WITH THE RELATED DRUG fiNAPHOXOR
`ANAPROXDS [NRPROXEN SODIUM] SINCE THEY BOTH
`CIRCULATE IN PLASMA AS THE NAFROXEN ANION.
`Renal Effects: As with other nonsteroidal anti-inflamma-
`tory drugs, long-term administration of naproxen to animals
`has resulted in renal papillary necrosis and other abnormal
`renal pathology. In humans, there have been reports ofacute
`interstitial nephritis with hematuria, preteinuria, and occa-
`sionally nephrotic syndrome.
`A second form of renal toxicity has been seen in patients
`with prerenal conditions leading to the reduction in renal
`blood flow or blood volume, where the renal prostaglandins
`haven supportive role in the maintenance ofrenal parfiiaion.
`in these patients. administration of a nonsteroidal anti-in-
`flammatory drug may cause a dose-dependent reduction in
`prostaglandin formation and may precipitate overt renal
`decom
`tion. Patients at greatest risk ofthis reaction are
`those with impaired renal function. heart failure, liver dya-
`functiou. those taking diuretics, and the elderly. Discon-
`tinuation of nonsteroidal anti—inflammatory therapy is typi-
`cally followed by recovery to the pretreatment state.
`NAPROSYN and its metabolites are eliminated primarily
`by the kidneys. therefore the drug should be used with great
`motion in patients with significantly impaired renal func-
`tion and the monitoring of serum creatinine andfor creati-
`nine clearance is advised in these patients. Caution shouldbe
`used ifthe drugis given topatients with creatinine clearance
`of less than 20 leminute because accumulation of ne-
`proxen metabolites has been seen in such patients
`Chronic alcoholic liver disease and probably other forms of
`cirrhosis reduce the total plasma concentration ofnaproxen,
`but the plasma concentration of unbound napmen is in-
`creased. Caution is advised when high doses are required and
`some adjustment of dosage may be required in these pa~
`tients. It is prudent to use the lowest effective dose.
`Studies indicate that although total plasma concentration of
`naproxen is unchanged, the unbound plasma fraction of ne-
`proxen is increased in the elderly. Caution is advised when
`high doses are required and some adjustment of dosage may
`be required in elderly patients. As with other drugs used in
`the elderly, it. is prudent to use the lowest effective does.
`As with other nonsteroidal antidnflammatory drugs, border—
`line elevations of one or more liver tests may occur in up to
`15% of patients. These abnormalities may progress, may
`remain essentially unchanged, or may be transient with
`continued therapy. The SGPT (ALT) test is probably the
`most sensitive indicator of liver dysfunction. Meaningful (3
`times the upper limit of normal) elevations of SGPI' or SCOT
`(AST) occurred in controlled clinical trials in less than 1% of
`patients. A patient with symptoms andz'or signs suggesting
`liver dysfunction, or in whom an abnormal liver test has
`occurred, should be evaluated for evidence of the develop-
`ment of more severe hepatic reaction while on therapy with
`this drug. Severe hepatic reactions. including jaundice and
`cases of fatal hepatitis, have been reported with this drug as
`with other nonateroidal anti-inflammatory drugs. Although
`such reactions are rare. if abnormal liver tests persist or
`worsen. ifclinical signs and emphasis oumistent with liver
`disease develop, or if systemic manifestations occur (eg. eo-
`einophilia, rash, etc), this drug should be discontinued.
`Ifsteroid dosage is reduced or eliminated during them)?!" the
`steroid dosage should be reduced slowly and the patients
`must be observed closely for any evidence of adverse effects,
`including adrenal insufficiency and exacerbation of symp-
`toms of arthritis.
`Patients with initial hemoglobin values of 10 grams or less
`who are to receive long-term-tberapy should have hemoglo
`bin values determined periodically.
`Peripheral edema has been observed in some patients. For
`this reason, the drug should be used with caution in patients
`with fluid retention, hypertension or heart failure.
`Naprosyn suspension contains 8 mgme of sodium. This
`should be considered in patients whose overall intake of so-
`dium must be restricted.
`
`0003
`
`Consult 1994 Supplements for revisions
`
`The antipyretic and anti-inflammatory activities of the drug
`may reduce fever and inflammation, thus diminishing their
`utility as diagnostic signs in detecting complications of pre-
`sumed non-infectious, non-inflammatory painful conditions.
`Because of adverse eye findings in animal studies with drugs.
`of this class. it is recommended that ophthalmic studies be
`carried out if any change or disturbance in vision occurs.
`Information for Patients:
`Naproxen, like other drugs of its class, is not free of side ef-
`fects. The side effects of these drugs can cause discomfort
`and, rarely, there are more serious side effecm, such as gas-
`trointestinal bleeding. which may result in hospitalization
`and even fatal outcomes.
`NSAIDs Gdanstemidal Anti—Inflammatory Drugs] are often
`essential agents in the management of arthritis and have a
`major role in the treatment of pain, but they also may be
`commonly employed for conditions which are less serious.
`Physicians may wish to discuss with theirpatients the poten-
`tial risks (see Warnings, Precautions, and Adverse Reactions
`sections) and likely benefits of NSAID treatment, particu-
`larly when the drugs are used for less serious conditions
`where treatment without NSAJIIS may represent an swept
`able alternative to both the patient and physician.
`Caution should be exercised by patients whose activiti-
`require alertness if they experience drowsiness. dizziness.
`vertigo or depression during therapy with the drug.
`Laboratory Tests:
`Because serious GI tract ulceration and bleeding can occur
`withoutwarningsymptoms, physicians should follow chroni-
`cally treated patients for the signs and symptoms of ulcer-
`ation and bleeding-and should inform them of the impon
`tance of this follow—up (see Risk of GI Ulcerations, Bleeding
`and Perforation with NSAJI) Therapy).
`Drug Interactions:
`In tin-a studies have shown that naproxen anion, because of
`its affinity for protein, may displace from their binding sites
`other drugs which are also albumin-bound. Theoretically.
`the naproxen anion itself could likewise be displaced. Short
`term controlled studies failed to show that taking the drug
`significantly affects protbrombin times when administered
`to individuals on ceumalin—type anticoagulants. Caution is
`advised nonetheless, since interactions have been seen with
`other nonsteroidal agents of this class. Similarly, patients
`receiving the drug and a hydantoin. sulfonamids or sulfonyl-
`urea should be observed for signs of toxicity to these drugs.
`The nah-luretic effect of furoeemide has been reported to be
`inhibited by some drugs of this class. Inhibition of renal lith-
`ium clearancsleading to increases in plasma lithium concen-
`trations has also been reported.
`This and other nonsteroidal enti‘inilammatory drugs can
`reduce the antihypertensive effect of propranolol and other
`beta-blockers.
`Probenecid given concurrently increases naproxen anion
`plasma levels and extends its plasma half-life significantly.
`Caution should be used if this drug is administered concomi-
`tantly with methotrexate. Nspromen and other nonsteroidal
`anti—inflammatory drugs have been repurted to reduce the
`tubular secretion ofmethotrexate in an animal model, possi-
`bly enhancing the toxicity of that drug.
`Drugflnboratory Test interactions:
`The drug may decrease platelet aggregation and prolong
`bleeding time. This effect should be keptin mind when blood—
`ing times are determined.
`The administration oftbe drug may result inincreased uri-
`nary valuas for 17-kstogenic steroids because of an interac~
`tion between the drug and/or its metabolites with mdiuitro-
`benzene used in this assay. Although l7-bydroxy-corticoste-
`roid measurements (Porter-Silber test) do not appear to be
`artifactually altered. it is
`that therapy with the
`drug be temperarily discontinued 72 hours before adrenal
`function tests are performed.
`The drug may biterfere with some urinary assays of
`Shydroxy indoleacetic acid (SI-ISLAM.
`Carcinogenesis:
`A twoyear shidy was performed in rats to evaluate the carci—
`nogenic potential of the drug. No evidence of carcinogenicity
`was found.
`Pregnancy:
`Teratogenic Effects: Pregnancy Category B. Reproduction
`studies have been performed in rats, rabbits and mice at
`doses up to six times the human dose and have revealed no
`evidence of impaired fertility or harm to the fetus due to the
`drug. There are, however. no adequate and well-controlled
`studies in pregnant women. Because animal reproduction
`studies are not always predictive of human response. the
`drug should not be used during pregnancy unlo- clearly
`needed. Because of the known effect of drugs of this class on
`the human fetal cardiovascular system [closure of ductus
`arterlnsus), use during late pregnancy should be avoided.
`Non-teratogenic Effects: As with other drugs known to
`inhibit proslaglandin synth-is, an increased incidence of
`dystocia and delayed parturition occurred in rats.
`Nursing Mothers:
`The naproxen anion has been found in the milk of lactating
`women at a concentration of approximately 1% of that found
`in the plasma. Because of the possible adverse effects of pros-
`
`0003
`
`

`

`Sonsult 1994 Supplements for revisions
`
`aglandin-inhibiting drugs on neonates. use in nursing moth-
`ers should be avoided.
`)ediatric Use:
`iafety and effectiveness in children below the age of 2 years
`lave not been established. Pediatric dosing recommenda-
`.ions for juvenile arthritis are based on wellcontrolled stud-
`es [see Dosage and Administration). There are no adequate
`:ffectiveness or dose-response data for other pediatric condi-
`.ions, but the experience in juvenile arthritis and other use
`experience have established that single doses of 2.5-5 mgr“ kg.
`vith total daily dose not exceeding 15 mgfkgi’day. are safe in
`:hildren over 2 years of age.
`XDVERSE REACTIONS
`the following adverse reactions are divided into 3 parts
`iased on frequency and likelihood of causal relationship to
`taproxen.
`Incidence greater than 1%
`'robable Causal Relationship:
`\dverse reactions reported in controlled clinical trials in 960
`:atients treated for rheumatoid arthritis or osteoarthritis
`ire listed below. In general, these reactions were reported 2
`o 10 times more frequently than they were in studies in the
`N52 patients treated far mild to moderate pain or for dysmen-
`irrhea.
`a clinical study found gastrointestinal reactions to be more
`'requent and more severe in rheumatoid arthritis patients
`.aking 1,500 mg naproxen daily compared to those taking
`’50 mg daily {see Clinical Pharmacology}.
`n controlled clinical trials with about 80 children and in
`yell—monitored open studies with about 400 children with
`-uvcnile arthritis. the incidences of rash and prolonged
`flooding times were increased, the incidences of gastrointes-
`Joel and central nervous system reactions were about the
`ammo. and the incidences of other reactions were lower in
`:hildren than in adults.
`Eastroimestinal: The most frequent complaints reported
`‘elated to the gastrointestinal tract. They were: constipa-
`.ion", heartburn'. abdominal pain". nausea', dyspepsia.
`liarrhea. stomatitis.
`Gentral Nervous System: Headache‘. dininess'. drowsi-
`iess‘. lightheadedness, vertigo.
`‘Jermatologic:
`Itching lpruritusl'. skin eruptions“, ecchy-
`noses‘, sweating, purpura.
`‘ipecial Senses: Tinnitus'. hearing disturbances. visual
`listurbances.
`Zardiovascular: Edema‘, dyspnea‘, palpitations.
`Senora}: Thirst.
`Incidence less than 1%
`3mbable Causal Relationship:
`[‘he following adverse reactions were reported less fre-
`luently than 1% during controlled clinical
`trials and
`.hrough voluntary reports since marketing. The probability
`if a causal relationship exists between the drug,r and these
`1dverse reactiOns:
`function tests. colitis.
`liver
`Eastrointestinal: Abnormal
`gastrointestinal bleeding andlor perforation, hematcmesis.
`luundice. melena. peptic ulceration with bleeding andfor
`rerforation. vomiting.
`ienal: Glomerular nephritis. hematuria. hyperkalemia.
`nterstitial nephritis. nephrotic syndrome, renal disease.
`-enal failure. renal papillary necrosis.
`Hematologic: Agranulocytosis. eosinophilia. granulocyto—
`nenia. leukopenia. thrombocytopenia.
`Central Nervous System: Depression. dream abnormali—
`;ies. inability to concentrate,
`insomnia. malaise, myalgia
`and muscle weakness.
`Dermatologic: Alopecia. photosensitive dermatitis. skin
`rashes.
`Special Senses: Hearing impairment.
`Cardiovascular: Congestive heart failure.
`Respiratory: Eosinophilic pneumon