0001
`
`PSG2013
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`Syntax—Cont.
`
`
`
`ANAPROX®
`[on 'd-pmx]
`ANAPHOX® D5
`{naproxen sodium!
`Tablets
`
`Revised 11/92
`
`lad
`
`‘1“
`
`2350
`Consult 1994 Supplements for revisions
`Physicians' Desk References;
`Leukemia has been observed in patients with aplastic ane-
`Hemoglobin and hematocrit should be checked periodically
`for polycythemia in patients who are receiving high doses of
`mia treated with oxymetholone. The role, if any. ofoxymeth-
`anabolits.
`clone is unclear because malignant transformation has been
`Because iron deficiency anemia has been observed in some
`won in blood dyscrasias and leukemia has been reported in
`patients treated with oxymetholone, periodic determination
`patients with aplastic anemia who have not been treated
`of the serum iron and iron binding capacity is recommended.
`with oxymetholone.
`If iron deficiency is detected, it should be appropriately
`Breast: Gynecomastia.
`treated with supplementary iron.
`tarynx: Deepening of the voice in women.
`Oxymetholone has been shown to decrease l7—ketosteroid
`Hair.- Hirsutism and male-pattern baldness in women,
`excretion.
`male-pattern of hair loss in postpubertal males.
`Drug interaction:
`Skin: Acne (especially in women and prepuhertal boys).
`Anabolic steroids may increase sensitivity to anticoagulants;
`Skeletal.- Premature closure of epiphyses in children {see
`therefore dosage of an anticoagulant may have to be dc-
`PRECAUTIONS, Pediatric Use}. muscle cramps.
`crcased in order to maintain the prothrombin time at the
`Body as a whole: Chills.
`desired therapeutic level.
`Fluid and Electrolytes: Edema, retention of serum electro-
`DrugfLaboratory Test Interferences: Therapy with andro—
`lytes (sodium, chloride, potassium. phosphate, calcium}.
`genic anabolic steroids mayr decrease levels of thyroxine—
`Metabolic/Endocrine: Decreased glucose tolerance (see
`binding globulin resulting in decreased total T4 serum levels
`PRECAUTIONS), increased serum levels oflow-density lipcr
`and increased resin uptake of Ta and Tr Free thyroid hor-
`proteins and decreased levels of high-density lipoproteins
`mone levels remain unchanged and there is no clinical evi-
`(See PRECAUTIONS, Laboratory tests}. increased creatine
`and creatinino excretion. increased serum levels of creati-
`dence of thyroid dysfunction. Altered tests usually persist for
`2-3 weeks 81hr stopping anabolic therapy.
`nine phospholiinase (CPK). Reversible changes in liver func-
`Anabolic steroids may cause an increase in prothrombin
`tion tests also occur including increased bromsulphalein
`time.
`(ESP) retention and increases in serum bilirubin, glutamic
`Anabolic steroids have been shown to alter fasting blood
`occaloacetic transaminase {SCOT}, and alkaline phosphatase.
`sugar and glucose tolerance tests.
`DRUG ABUSE AND DEPENDENCE
`Carcinogenesis. Motsgenesls, impairment of Fertility:
`Controlled Substance:
`Animal data: Testosterone has been tested by subcutaneous
`ANADROLSO is considered to be a controlled substance and
`injection and implantation in mice and rats. The implant
`is listed in Schedule III.
`induced cervioaLuterine tumors in mice, which metastasized
`OVERDOSAGE
`in some cases. There is suggestive evidence that injection of
`testosterone into some strains of female mice increases their
`There have been no reports of acute overdosage with
`anabolics.
`susceptibility to hepatoma. Testosterone is also known to
`increase the number of tumors and decrease the degree of
`DOSAGE AND ADMINISTRATION
`differentiation of chemically induced carcinomas ofthe liver
`The recommended daily dose in children and adults is 1-
`in rats.
`5 mgfkg body weight per day. The usual effective dose is 1~
`Human data: There are rare reports of hepatocellular carci-
`2 mgfkgfday but higher doses may be required and the dose
`noma in patients receiving long-term therapy with andro-
`should be individualized. Response is not often immediate
`gens in high doses. Withdrawal of the drugs did not lead to
`and a minimum trial of three to six months should be given.
`regression of the tumors in all cases.
`Following remission, some patients may be maintained with—
`Geriatric patients treated with androgens may be at an in-
`out the drug; others may be maintained on an established
`creased risk of developing prostatic hypertrophy and pros—
`lower daily dosage. A continued maintenance dose is usually
`tatic carcinoma although conducive evidence to support this
`necessary in patients with congenital aplostic anemia.
`concept is lacking.
`HOW SUPPLIED
`This compound has not been tested for mutagenic potential.
`However, as noted above, carcinogenic effects have been
`ANADROLoD (oxymetholone) is supplied in bottles of 100
`attributed to treatment with androgenic hormones. The po-
`white scored tablets imprinted with "2902" and "SYNTEX"
`{NDC 0033-2902421
`tential carcinogenic effects likely occur through a hormonal
`mechanism rather than by a direct chemical interaction
`CAUTEDN: Federal law prohibits dispensing without pre—
`mechanism.
`scription.
`023902—4205
`Impairment of fertility was not tested directly in animal
`species. However, as noted below under ADVERSE REAC—
`6:) 1991 Syntex Laboratories, Inc.
`TIONS, oligospermia in males and amenorrhea in females
`Shown in. Product Identification Section, page 332
`are potential adverse effects of trmtment with ANADROLC'B
`tablets. Therefore. impairment of fertility is a possible out-
`come of treatment with ANADROL.
`Pregnancy:
`Pregnancy category X. See CONTRAINDICATIONS.
`Nursing Mothers.-
`It is not known whether anabolics are excreted in human
`milk. Because of the potential for serious adverse reactions
`in nursed infants from anabolica, women who take oxymeth-
`clone should not nurse.
`Pediatric Use:
`Anabolic!androgenic steroids should be used very cautiously
`in children and only by specialists who are aware of their
`effects on bone maturation.
`Anabolic agents may accelerate epiphyseal maturation more
`rapidly than linear growth in children, and the effect may
`continue for 6 months after the drug has been stopped.
`Therefore. therapy should be monitored by x—ray studies at
`6-month intervals in order to avoid the risk ofcompromising
`the adult height.
`ADVERSE REACTIONS
`Haparic:
`Cholevtatic jaundice with, rarely, hepatic necrosis and
`death. Hepatocellular neoplasms and peliosis hepatic have
`been reported in association with long-term androgenic una-
`holic steroid therapy [see WARNINGS).
`Genitourinary System:
`In Men:
`Prepubertal: Phallic enlargement and increased frequency
`of erections.
`Inhibition of testicular function, testicular
`Poatpuberta]:
`atrophy and oligoepermia,
`impoteme, chronic priapism,
`epididymitis. bladder irritability, and decrease in seminal
`volume.
`In Women:
`Climral enlargement, menstrual irregularities.
`In both sexes:
`Increased or decreased libido.
`Gills: Excitation, insomnia.
`.
`Gastrointestinal: Nausea, vomiting, diarrhea.
`Hematologic: Bleeding in patients on concomitant antrw
`agulant therapy, irondcficiency anemia.
`
`they have been associated with liver failure, They are
`often not recognized until life-threatening liver failure
`or intro-abdominal hemorrhage develops. Withdrawal
`of drug usually results in complete disappearance of
`lesions.
`Liver cell tumors are also reported. Most often these
`tumors are benign and androgendependent. but fatal
`malignant tumors have been reported. Withdrawal of
`drug often results in regression or cessation of progres-
`sion of the tumor. However, hepatic tumors associated
`with androgens or anabolic steroids are much more vas-
`cular than other hepatic tumors and may be silent until
`lifethreatening intro-abdominal hemorrhage develops.
`Blood lipid changes that are known to be associated
`with increased risk of atherosclerosis are seen in pa-
`tients treated with androgens and anabolic steroids.
`These changes include decreased high density lipopro—
`tcin and sometimes increased low density lipoprotein.
`The changes may be very marked and could have a seri-
`ous impact on the risk of atherosclerosis and coronary
`artery disease.
`
`Cholestatic hepatitis and jaundice occur with l'l-alpha-al-
`kylated androgens at relatively low doses. Clinical jaundice
`may be painless. with or without pruritus. It may also be
`associated with acute hepatic enlargement and right upper-
`quadrant pain, which has been mistaken for acute (surgical)
`obstruction of the bile duct. Drug-indu ced jaundice is usually
`reversible when the medication is discontinued. Continued
`therapy has been associated with hepatic coma and death.
`Because of the hepatotoxicity associated with oxymetholone
`administration, periodic liver function team are recom-
`mended.
`In patients with breast cancer, anabolic steroid therapy may
`cause hypercalcemia by stimulating osteolysis. In this case.
`the drug should be discontinued.
`Edema with or without congestive heart failure may be a
`serious complication in patienm with pro-existing cardiac.
`renal or hepatic disease. Concomitant administration with
`adrenal steroids or ACTH may add to the edema. This is gen-
`erally controllable with appropriate diuretic and for digitalis
`therapy.
`Geriatric male patients treated with androgenic anabolic
`steroids may be at an increased risk for the development of
`prostate hypertrophy and prostatic carcinoma.
`Anabolic steroids have not been shown to enhance athletic
`ability.
`PRECAUTIONS
`General:
`Women should be observed for signs of virilization (deepen-
`ing of the voice, hirsutism, acne. and clitoromegalrl To pre—
`vcnt irreversible change, drug therapy must be discontinued
`when mild virilism is firstdetected. Such virilization is usual
`following androgenic anabolic steroid use at high doses.
`Some virilizing changes in women are irreversible even after
`prompt discontinuance of therapy and are not prevented by
`concomitant use of estrogena. Menstrual irregularities. in-
`cluding amenorrhea, may also occur.
`The insulin or oral hypoglycemic dosage may need adjust-
`ment in diabetic patients who receive anabolic steroids.
`Anabolic steroids may cause suppression of clotting factors
`If, V, VII, and X, and an increase in prothrombin time.
`information for the patient:
`The physician should instruct patients to report any of the
`following side elfccls of androgens.
`,
`Adultor Adolescent Males: Too frequent or persistent erec-
`tions of the penis, appearance or aggravation of acne.
`Women: Hoarseness. acne, changes in menstrual periods.
`or more hair on the face.
`All Patients: Any nausea, vomiting, changes in skin color or
`ankle swelling.
`laboratory Tests:
`Women with disseminated breast carcinoma should have
`frequent determination of urine and serum calcium levels
`during the course of androgenic anabolic steroid therapy (see
`WARNINGS).
`Bccause of the hepatotoxicity associated with the use of 17-
`alpha-alkylated androgens.
`liver function tests should be
`obtained periodically.
`_
`Periodic [every 6 months) xvray examinations of bone age
`should be made during treatment of prepubertol patients to
`determine the rate of bone maturation and the effects ofan-
`drogenic anabolic steroid therapy on the epiphyseal centers.
`Anabolic steroids have been reported to lower the level of
`high-density lipoproteins and raise the level of low-density
`lipoproteins. These changes usually revert to normal on dis
`continuation of treatment. Increased lowdensity Lipopro
`teins and decreased high-density lipoproteins are con—
`sidered cardiovascular risk factors, Serum lipids and high-
`density lipoprotein cholesmrol
`should be determined
`periodically,
`
`Products of Syntax Puerto Rico. inc.
`DESCRIPTION
`ANAPROX® {naproxen sodium) filmcoated tablets for oral
`administration each contain 275 mg of naproxen sodium,
`which is equivalent to 250 mg naproxen with 25 mg (about 1
`mEq) sodium. ANAPROX® DS (naproxen sodium) lilm-
`coated tablets for oral administration each contain 550 mg of
`naproxen sodium, which is equivalent to 500 mg naproxzen
`with 50 mg (about 2 mqu sodium. Naproxen sodium is a
`member of the myluoetic acid group of nonsteroidai anti—
`inflammatory drugs.
`The chemical name of naproxen sodium is 2-naphthalenea-
`cetic acid, 6-mothoxy-a-methyl-, sodium salt, (—l—.
`Naproxen sodium is a white to creamy white, crystalline
`solid, freely soluble in water.
`Each ANAPROX 275 mg tablet contains naproxen sodium,
`the active ingredient, with lactose, magnesium stearate, and
`microcrystalline cellulose. The coating suspension may con-
`tain
`hydroxypropyl methylcellulosc
`2910, Opaspray
`K—l—lZlDA, polyethylene glycol 8900 or Opadry ifs-14215.
`Each ANAPROX D3 550 mg tablet contains naproxen so-
`dium, the active ingredient, with magnesium stearate. mi—
`crocrystalline cellulose, pov'idons, and talc. The coating sus-
`pension may contain bydroxypropyl methylcelluiose 2910,
`Opospray iii-14227, polyethylene glycol 8000 or Opadry Y3
`142i6.
`'
`CLINICAL PHARMACOLOGY
`The sodium salt of naproxen has been developed as an anal-
`gesic because it is more rapidly absorbed. Naproxen is a non—
`steroidal anti—inflammatory drug with analgesic and antipy-
`retic properties. Naproxen anion inhibits prostaglandin syn-
`thesis but beyond this its mode of action is unknown.
`
`0002
`
`0002
`
`

`

`Consult 1994 Supplements for revisions
`
`Naprcxen sodium is rapidly and completely absorbed from
`the gastrointestinal tract. After administration of naproxen
`sodium. peak plasma levels of naproxen anion are attained
`at 1—2 hours with smady-state conditions normally achieved
`after H doses. The mean biological half—life of the anion in
`humans is approximamly 13 hours. and at therapeutic levels
`it is greater than 99% albumin bound. Approximately 95%
`of the dose is excreted in the urine. primarily as naproxen,
`6—O-desmethyl naproxcn or their conjugates. The rate of ex—
`cretion has been found to coincide closely with the rate of
`drug disappearance from the plasma. The drug does not in-
`duce metabolizing enzymes.
`In children of5 to 16 years of age with arthritis, plasma na-
`proxen levels following a 5 mgrIr kg single dose of naproxen
`suspension (see Dosage and Administration) were found to be
`similar to those found in normal adults following a 500 mg
`dose. The terminal half-life appears to be similar in children
`and adults. Phorrnacokinetic studies of naproxen were not
`performed in children of less than 5 years of age.
`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-acting drug. Controlled double-blind
`studios have demonstrated the analgesic properties of the
`drug in. for example, post—operative. postpartum, orthopedic
`and uterine contraction pain and dysmcnorrhea. In dysmen—
`orrheic patients, the drug reduces the level of prostaglandins
`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 reduction of pain
`intensity scores. increase in pain relief scores. decrease in
`numbers of patients requiring additional analgesic medica—
`tion. and delay in time for required remedioation. The anal-
`gesic effect has been found a: last for up to 7 hours.
`The drug was studied in patients with rheumatoid arthritis,
`osteoarthritis.
`juvenile arthritis, ankylosing spondylitis,
`tendinitis and bursitis, and acute gout. It is not a corticoste-
`roid. Improvement in patients treated for rheumatoid arthri~
`tis has been demonstrated by a reduction in joint swelling, a
`reduction in pain. a reduction in duration of morning stiff—
`ness. a reduction in disease activity as assessed by both the
`investigator and patient. and by increased mobility as dem-
`onstrated by a reduction in walking time.
`In patients with osteoarthritis, the therapeutic action of the
`drug has been shown by a reduction in joint pain or tender-
`bass. an increase in range of motion in knee joinm. 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 a: 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, dizziness, lightheadedness)
`were less than in both the aspirin- and indomethacin-treated
`patients. It is not known whether the drug muses lees peptic
`ulceration than aspirin
`In patients with ankylosing spondylitis, the'drug has been
`shown to decrease night pain. morning stiffness and pain at
`rest. In doubleblind studies the drug was shown to be as ef-
`fective as aspirin, but with fewer side effects.
`In patients with acute gout. a favorable response to the drug
`was shown by significant clearing of inflammatory changes
`(eg, 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
`andfor corticosteroids; however, in controlled clinical trials,
`when added to the regimen of patients receiving corticoste-
`roids it did not appear to cause greater improvement over
`that seen with corticosteroids alone. Whether the drug could
`be used in conjunction with partially effective doses ofcorti-
`costeroids 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 greater 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 some evidence 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 patients with osteoarthritis and rheuma-
`toid arthritis comparing treatments of 825 mg per day with
`LBSD mg per day, there were trends toward increased eff-
`cacy with the higher dose and a more clearcut increase in
`adverm reactions, particularly gastrointestinal reactions
`severe enough to cause the patient to leave the trial. which
`approximately doubled.
`In "‘Cr blood loss and gastroscopy studies with normal volun-
`teers, daily administration of 1,100 mg of naproxen sodium
`has been demonstrated to cause statistically significantly
`less gastric bleeding and erosiOn than 3,250 rug of aspirin.
`
`Physicians’ Desk References
`INDICATIONS AND USAGE
`Naproxen sodium is indicated in the relief of mild to moder—
`ate pain and for the treatment of primary dysmenorrhea.
`It is also indicamd for the treatment of rheumatoid arthritis,
`osteoarthritis.
`juvenile arthritis, anlrylosing spondylitis,
`tendinitis and bursitis. and acute gout.
`CONTRAINDICATIONS
`The drug is contraindicated in patients who have had aller—
`gic
`reactions
`to ANAPROXG)
`(naproxen
`sodium).
`ANAPROX® D5 or to NAPROSYNG) (naproxen). It is also
`contraindicated in patients in whom aspirin or other nonsta-
`roidal anti-inflammatoryfanalgesic drugs induce the syn-
`drome of asthma. rhinitis, and nasal polyps. Both types of
`reactions have the potential of being fatal. Anapbylactoid
`reactions to ANAPROX, ANAPROX DS or NAPROSYN,
`whether of the true allergic type or the pharmacologic idio—
`syncratic (e.g., aspirin syndrome) type. usually but not al-
`ways occur in patients with a known history of such reac-
`tions. 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, ifsuch symptoms
`occur during therapy, treatment should be discontinued.
`WARNINGS
`Risk of GI Ulcoration. Bleeding and Federation with "SAID
`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-
`cerationmnd bleeding in patients treated chronically 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 pas
`ticnts about the signs and Ior symptoms of serious GI toxicity
`and what steps to take if they occur.
`Studies to date have not identified any subset ofpafients 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 associated with peptic ulcer disease, such as
`alcoholism. smoking. em, 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 todate are inconclu-
`sive concerning the relative risk of various NSAIDs in cans
`ing 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 relatively large doses (within the recommended
`dosage range), sufficient benefit should be anticipated to
`offset the potential increased risk of GI toxicity.
`PRECAUTIONS
`General:
`ANAPROX [NAPROXEN SODIUM] or ANAPROX 05 {NA-
`PROXEN SODIUM) SHOULD NOT BE USED CONCDMI‘
`TANTL‘I’ WITH THE RELATED DRUG NAPROSYN [NA-
`PBOXEN) SINCE THEY BOTH CIRCULATE IN PLASMA AS
`THE NAPROXEN ANION.
`'
`'
`Renal Effects: As with other nonsteroidal anti‘inflam motory
`drugs, long-term administration of naproxen to animals has
`resulted in renal papillary necrosis and other abnormal re-
`nal pathology. In humans, there have been reports of acute
`interstitial nephritis with hematuria, proteinuria, and occa—
`sionally nephrotic syndrome.
`A second form of renal toxicity has been seen in patients
`with prerenal conditions leading to a reduction in renal
`blood flow or blood volume. where the renal prostaglandins
`have asupportive role in the maintenance of renal perfusion.
`In these patients. administration of a nonsteroidal anti—in-
`flammatory drug may cause a doscdependcnt reduction in
`prostaglandin formation and may precipitate overt renal
`decompensation. Patients at greatest risk of this reaction are
`those with impaired renal function, heart failure, liver dys
`function. those taking diuretics. and the elderly. Discou—
`tinuation of nonsteroidal anti-inflammatory therapy is typi-
`cally followed by recovery to the pretreatment state.
`Naproxen sodium and its metabolites are eliminated primar-
`ily by the kidneys, therefore the drug should be used with
`great caution in patients with significantly impaired renal
`function and the monitoring of serum creatinine andfor
`creatinine clearance is advised in these patients. Caution
`should be used ifthe drug is given to patients with creatlninc
`clearance of less than 20 mLfminute because accumulation
`of naproxen metabolites has been seen in such patients.
`Chronic alcoholic liver disease and probably other forms of
`cirrhosis reduce the total plasma concentration of naproroen,
`but the plasma concentration of unbound naproxen is in-
`
`0003
`
`235 1
`
`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 na-
`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 m use the lowest effective dose.
`As with other nonsteroidal anti-inflammatory 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
`centinued therapy. The SGP‘I‘ (ALT) test is probably the
`most sensitive indicator of liver dysfunction. Meaningful (3
`times the upper limit of normal) elevations of SGPT or SGOT
`(ASTJ occurred in controlled clinical trials in less than 1% of
`patients. A patient with symptoms andi’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 nonsteroidal anti—inflammatory drugs. 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 (cg.
`cosinophilia, rash. am}, this drug should be discontinued.
`Ifsteroid dosage is reduced or eliminated during therapy. 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 therapy should have hemoglo—
`bin values determined periodically.
`Peripheral edema has been observed in some patients. Since
`each naproxen sodium tablet contains approximately 25 mg
`or 50 mg (about 1 or 2 mqu of sodium. this should be consid—
`ered in patienm whose overall intake of sodium must be
`markedly restricted. For these reasons. the drug should be
`used with caution in patients with fluid retention. hyperten—
`sion or heart failure.
`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 sodium, like other drugs of its class, is not free of
`side effects. The side effects of these drugs can cause discom-
`fort and. rarely, there are more serious side effects. such as
`gastroinmtinal bleeding, which may result in hospitaliza—
`tion and even fatal outoomm.
`NSAl'Ds (Nonsteroidal 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 their patients 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 NSAIDs may represent an accept-
`able alternative to both the patient and physician.
`Caution should be exercised by patients whose activities
`require alertness if they experience drowsinu. dizziness.
`vertigo or depression during therapy with the drug.
`Laboratory Tests:
`Because serious GI tract ulceration and bleeding can occur
`without warning symptoms. physicians should follow chroni-
`cally treamd patients for the signs and symptoms of ulcer-
`ation and bleeding and should inform them of the impor-
`tance of this follow-up (see Risk of GI Ulcerations, Bleeding
`and Perforation with NSAID Therapy).
`_
`Drug interactions:
`In citro 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 prothrombin times when administered
`to individuals on coumarin-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. sulfonamide or sulfonyl-
`urea should be observed for signs of toxicity to these drugs.
`The natriuretic effect of furosemide has been reported to be
`inhibited by some drugs of this class. Inhibition of renal lith-
`ium clearance leading to increasm in plasma lithium concen-
`trations has also been reported.
`
`Continued on next page
`
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`2352
`Consult 1994 Supplements for revisions
`Physicians’ Desk Reference®
`Special Senses: Tinnitus', hearing disturbances, visual
` within this period. a trial for an additional two weeks should
`
`
`be considered.
`SyntexHCont.
`disturbances.
`I
`For Acute Gout:
`Cardiovascular: Edema‘, dyspnea'. palpitations.
`The recommended starting dose is 325 mg, followed by
`General: ' Thirst.
`This and other nonsteroidal anti-inflammatory drugs can
`275 mg every eight hours until the attack has subsided.
`'lncidence of reported reaction between 3% and 9%. These
`reduce the antihypertensive effect of propranolol and other
`For Juvenile Arthritis:
`beta-blockers.
`reactions occurring in less than 3% of the patients are un—
`The recommended total daily dose is approximately 10 mg!
`marked.
`Prohenecid given concurrently increases naproxen anion
`kg given in two divided doses. The 275 mg ANAPROX tablet
`lncidence less than 1%
`plasma levels and extends its plasma half-life significantly.
`is not well suited to this dosage so use of the related drug
`Probable Causal Relationship:
`Caution should he used if this drug is administered con-
`NAPROSYNGJ (naproxen') as the 250 mg scored tablet or the
`The following adverse reactions were reported less fre
`comitantly with methotrexate. Naproxen and other nonste
`125 mgf5 mL suspension is
`recommended for
`this
`indication.
`roidal an ti—inflammatory drugs have been reported to reduce
`quently than 1% during controlled clinical
`trials and
`the tubular secretion of methotrexate in an animal model,
`through voluntary reports since marketing. The probability
`HOW SUPPLIED
`of a causal relationship exists between the drug and these
`posshily enhancing the toxicity of that drug.
`ANAPROX® (naproxen sodium) is available in filmmated
`adverse reactions.
`DrugfLaboratory Test Interactions:
`tablets of 275 mg (light blue), in bottles of 100 tablets (NBC
`liver function tests, colitis,
`Gastrointestinal: Abnormal
`The drug may decrease platelet aggregation and prolong
`18393—234412) (NSN 6505-01-155-5157l and 500 tablets (NBC
`gastrointestinal bleeding andlor perforation, hemammesis,
`bleeding time. This effect should be kept in mind when bleed-
`18393-274-62) (NSN 650501—1306832l-or in cartons of IDEI
`jaundice. melena. peptic ulceration with bleeding andl'or
`ing times are determined.
`individually blister packed tablets (NBC 18393-27453).
`The administration of the drug may result in increased uri-
`perforation, vomiting.
`ANAPROX® DS (naproxen sodium] is available in film-
`Renal: Glomerular nephritis, hematuria, hyperkalemia,
`nary values for 1’l-ketogenic steroids because ofan interac-
`coated tablets of 550 mg (dark blue). in bottles of 100 tablets
`(NDC 13393-27642) (NSN 6505—0130531?“ and 500 tablets
`interstitial nephritis, nephrotic syndrome. renal disease,
`tion between the drug andfor its metabolites with mdinitro—
`(NDC 18393—23662) or in cartons of 100 individually blister
`renal failure, renal papillary necrosis.
`benzene used in this assay. Although I'l-hydroxy-corticoste-
`roid measurements lPortenSilber test) do not appear to be
`Hematologic: Agranulocytosis. cosinophilia, granulocytd
`packed tablets (NDC 18393-27653). Store at room tempera-
`ture in well—”closed containers.
`pcnia. leukopenia, thrombocytopenia.
`artifactually altered, it is suggested that therapy with the
`CAUTION: Federal law prohibits dispensing without pre-
`Central Nervous System: Depression, dream abnormali—
`drug be temporarily discontinued 72 hours before adrenal
`scription.
`ties,
`inability to concentrate,
`insomnia. malaise. myalgia
`function tests are performed.
`U.S. Patent Nos. 4,009,197; 3,993,966 and others.
`and muscle weakness.
`The drug may inmrferc with some urinary assays of
`020275-4204
`Refined WEB
`5-hydroxy indoleaoetic acid [SHIAAI
`Dermatologic: AIOpecia, photosensitive dermatitis. skin
`rashes.
`@1990 Syntax Puerto Rico. inc.
`Carcinogenesis:
`Shown: in Product Identification Section, page 332
`A two-year study was performed in rats to evaluate the