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

`

`Syntex—Cont.
`
`
`
`ANAPROX®
`[an 'a-prox ]
`ANAPROX® DS
`(naproxen sodium)
`Tablets
`
`Revised 11/92
`
`B
`
`B
`
`2350
`Physicians’ Desk Reference®
`Consult 1994 Supplements for revisions
`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. Therole,if any, of oxymeth-
`anabolics.
`olone is unclear because malignant transformation has been
`Because iron deficiency anemia has been observed in some
`seen 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.
`Larynx: Deepening of the voice in women.
`Oxymetholone has been shown to decrease 17-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 prepubertal 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 de-
`PRECAUTIONS,Pediatric Use), muscle cramps.
`creased 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-
`Drug/Laboratory Test Interferences: Therapy with andro-
`lytes (sodium, chloride, potassium, phosphate, calcium).
`genic anabolic steroids may decrease levels of thyroxine-
`Metabolic/Endocrine: Decreased glucose tolerance (see
`binding globulin resulting in decreased total T, serum levels
`PRECAUTIONS), increased serum levels of low-density lipo-
`and increased resin uptake of T; and Ty. Free thyroid hor-
`proteins and decreased levels of high-density lipoproteins
`mone levels remain unchanged and thereis no clinical evi-
`(see PRECAUTIONS, Laboratory tests), increased creatine
`and creatinine excretion, increased serum levels of creati-
`dence of thyroid dysfunction. Altered tests usually persist for
`2-3 weeks after stopping anabolic therapy.
`nine phosphokinase (CPK). Reversible changes in liver func-
`Anabolic steroids may cause an increase in prothrombin
`tion tests also eccur including increased bromsulphalein
`time.
`(BSP) retention and increases in serum bilirubin, glutamic
`Anabolic steroids have been shown to alter fasting blood
`oxaloacetic transaminase (SGOT), and alkaline phosphatase.
`sugar and glucose tolerancetests.
`DRUG ABUSE AND DEPENDENCE
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`Controlled Substance:
`Animal data: Testosterone has been tested by subcutaneous
`ANADROL-50is considered to be a controlled substance and
`injection and implantation in mice and rats. The implant
`is listed in Schedule III.
`induced cervical-uterine tumors in mice, which metastasized
`OVERDOSAGE
`in some cases. There is suggestive evidence that injection of
`testosterone into somestrains 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 mg/kg body weight per day, The usual effective dose is 1-
`Humandata: There are rare reports of hepatocellular carci-
`2 mg/kg/day 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 maintenancedose is usually
`tatic carcinoma although conclusive evidence to support this
`necessary in patients with congenital aplastic anemia.
`concept is lacking.
`HOW SUPPLIED
`This compound has not been tested for mutagenicpotential.
`However, as noted above, carcinogenic effects have been
`ANADROL-50 (oxymetholone) is supplied in bottles of 100
`attributed to treatment with androgenic hormones. The po-
`white scored tablets imprinted with “2902” and “SYNTEX”
`(NDC 0033-2902-42).
`tential carcinogeniceffects likely occur through a hormonal
`mechanism rather than by a direct chemical interaction
`CAUTION: Federal law prohibits dispensing without pre-
`mechanism.
`scription.
`02-2902-42-08
`Impairment of fertility was not tested directly in animal
`species. However, as noted below under ADVERSE REAC-
`© 1991 Syntex Laboratories, Inc.
`TIONS,oligospermia in males and amenorrhea in females
`Shown in Product Identification Section, page 332
`are potential adverse effects of treatment with ANADROL®
`tablets. Therefore, impairmentof 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 anabolics, women who take oxymeth-
`olone 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-monthintervals in order to avoid the risk of compromising
`the adult height.
`ADVERSE REACTIONS
`Hepatic:
`Cholestatic jaundice with, rarely, hepatic necrosis and
`death. Hepatocellular neoplasms andpeliosis hepatis have
`been reported in association with long-term androgenic ana-
`bolic steroid therapy (see WARNINGS).
`Genitourinary System:
`In Men:
`Prepubertal: Phallic enlargement and increased frequency
`of erections.
`Inhibition of testicular function, testicular
`Postpubertal:
`atrophy and oligospermia,
`impotence, chronic priapism,
`epididymitis, bladder irritability, and decrease in seminal
`volume.
`In Women:
`Clitoral enlargement, menstrual irregularities.
`In both sexes:
`Increased or decreased libido.
`CNS: Excitation, insomnia.
`Gastrointestinal: Nausea, vomiting, diarrhea.
`Hematologic: Bleeding in patients on concomitant antico-
`agulant therapy, iron-deficiency anemia.
`
`they have been associated with liver failure. They are
`often not recognized until life-threateningliver failure
`or intra-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 androgen-dependent, 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 maybe silent until
`life-threatening intra-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-
`tein and sometimes increased low density lipoprotein.
`The changes may be very marked and could havea seri-
`ous impact on the risk of atherosclerosis and coronary
`artery disease.
`
`Cholestatic hepatitis and jaundice oceur with 17-alpha-al-
`kylated androgens atrelatively low doses. Clinical jaundice
`may be painless, with or without pruritus. It may also be
`associated with acute hepatic enlargement and right upper-
`quadrantpain, which has been mistaken for acute (surgical)
`obstruction ofthe bile duct. Drug-induced 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 tests 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 patients with pre-existing cardiac,
`renal or hepatic disease. Concomitant administration with
`adrenal steroids or ACTH mayaddto the edema. This is gen-
`erally controllable with appropriate diuretic and/ordigitalis
`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 enhanceathletic
`ability.
`PRECAUTIONS
`General:
`Women shouldbe observed for signs ofvirilization (deepen-
`ing of the voice, hirsutism, acne, and clitoromegaly), To pre-
`ventirreversible change, drug therapy must be discontinued
`when mild virilism is first detected. Such virilization is usual
`following androgenic anabolic stercid use at high doses,
`Somevirilizing changes in womenareirreversible even after
`promptdiscontinuance of therapy and are not, prevented by
`concomitant use of estrogens. 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
`II, V, VIL, and X, and an increase in prothrombin time.
`information for the patient:
`The physician should instruct patients to report any of the
`following side effects of androgens.
`:
`Adult or Adolescent Males: Too frequentor 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).
`Because of the hepatotoxicity associated with the use of 17-
`alpha-alkylated androgens,
`liver function tests should be
`obtained periodically.
`.
`Periodic (every 6 months) x-ray examinations of bone age
`should be made during treatment of prepubertal patients to
`determine the rate of bone maturation and the effects of an-
`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 normalon dis-
`continuation of treatment. Increased low-density lipopro-
`teins and decreased high-density lipoproteins are con-
`sidered cardiovascular risk factors. Serum lipids and high-
`density lipoprotein cholesterol
`should be determined
`periodically.
`
`Products of Syntex 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) film-
`coated tablets for oral administration each contain 550 mg of
`naproxen sodium, which is equivalent to 500 mg naproxen
`with 50 mg (about 2 mEq) sodium. Naproxen scdium is a
`member of the arylacetic acid group of nonsteroidal anti-
`inflammatory drugs.
`The chemical name of naproxen sodium is 2-naphthalenea-
`cetic acid, 6-methoxy-a-methyl-, sodium salt, (—)-.
`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 methylcellulose
`2910, Opaspray
`K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215.
`Each ANAPROX DS 550 mg tablet contains naproxen so-
`dium, the active ingredient, with magnesium stearate, mi-
`crocrystalline cellulose, povidone, and talc. The coating sus-
`pension may contain hydroxypropyl methylcellulose 2910,
`Opaspray K-1-4227, polyethylene glycol 8000 or Opadry YS-
`1-4216.
`j
`CLINICAL PHARMACOLOGY
`The sodium salt of naproxen has been developed as an anal-
`gesic because it is more rapidly absorbed. Naproxenis a non-
`steroidal anti-inflammatory drug with analgesic and antipy-
`retic properties. Naproxen anion inhibits prostaglandin syn-
`thesis but beyond this its mode ofaction is unknown.
`
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`

`Consult 1994 Supplementsfor revisions
`
`Naproxen 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 steady-state conditions normally achieved
`after 4-5 doses. The mean biological half-life of the anion in
`humans is approximately 13 hours,andat therapeutic levels
`it is greater than 99% albumin bound. Approximately 95%
`of the dose is excreted in the urine, primarily as naproxen,
`6-0-desmethyl naproxen 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 notin-
`duce metabolizing enzymes.
`In children of 5 to 16 years of age with arthritis, plasma na-
`proxenlevels following a 5 mg/kg single dose of naproxen
`suspension (see Dosage and Administration) were foundto be
`similar to those found in normal adults following a 500 mg
`dose. The terminal half-life appears to be similarin children
`and adults. Pharmacokinetic studies of naproxen were not
`performed in children of less than 5 years of age.
`The drug wasstudied in patients with mild to moderate pain,
`and pain relief was obtained within 1 hour.It is not a nar-
`cotie and is not a CNS-acting drug. Controlled double-blind
`studies have demonstrated the analgesic properties of the
`drug in, for example, post-operative, post-partum, orthopedic
`and uterine contraction pain and dysmenorrhea.In dysmen-
`orrheic patients, the drug reducesthe levelof 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 remedication. The anal-
`gesic effect has been found to 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. Improvementin 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-
`ness, an increase in range of motion in kneejoints, increased
`mobility as demonstrated by’a reduction in walking time,
`and improvementin 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 adverseeffects (tinnitus, dizziness, lightheadedness)
`wereless than in both the aspirin- and indomethacin-treated
`patients. It is not known whetherthe drug causes less peptic
`ulceration than aspirin.
`In patients with ankylosing spondylitis, the'drug has been
`shownto decrease night pain, morningstiffness and pain at
`rest. In double-blind 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 shownbysignificantclearing of inflammatory changes
`(eg., decrease in swelling, heat) within 2448 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 ofpatients 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 thataspi-
`rin increases the rate of excretion of the drug.
`Generally, improvement due to the drug has not been found
`to be dependent onage, sex, severity or duration ofdisease.
`In clinicaltrials in patients with osteoarthritis and rheuma-
`toid arthritis comparing treatments of 825 mg per day with
`1,650 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.
`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 4,250 mg of aspirin,
`
`Physicians’ Desk Reference®
`INDICATIONS AND USAGE
`Naproxen sodiumis indicated in therelief of mild to moder-
`ate pain andfor the treatment of primary dysmenorrhea.
`It is also indicated for the treatment of rheumatoidarthritis,
`osteoarthritis,
`juvenile arthritis, ankylosing spondylitis,
`tendinitis and bursitis, and acute gout.
`CONTRAINDICATIONS
`‘The drug is contraindicated in patients who have had aller-
`gic
`reactions
`to ANAPROX® (naproxen
`sodium),
`ANAPROX® DS or to NAPROSYN® (naproxen).It is also
`contraindicated in patients in whom aspirin or other nonste-
`roidal anti-inflammatory/analgesic drugs induce the syn-
`drome of asthma, rhinitis, and nasal polyps. Both types of
`reactions have the potential of being fatal. Anaphylactoid
`reactions to ANAPROX, ANAPROX DS or NAPROSYN,
`whetherof the true allergic type or the pharmacologic idio-
`syneratic (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 therapyis important.In addition,if such symptoms
`occur during therapy, treatment should be discontinued.
`WARNINGS
`Risk of Gl Ulceration, Bleeding and Perforation 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 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
`bleedingor perforation appearto occur in approximately 1%
`ofpatients treated for 3-6 months, andin about 24% of pa-
`tients treated for one year. Physicians should inform pa-
`tients about the signs and/or symptomsof serious GI toxicity
`and what steps to take if they occur.
`Studies to date have notidentified any subsetof patients not
`atrisk of developing peptic ulceration and bleeding. Except
`for a prior history of serious GI events and otherrisk factors
`known to be associated with peptic ulcer disease, such as
`alcoholism, smoking,ete., 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 offatal
`Gl events are in this population. Studies to date are inconclu-
`sive concerning therelative risk of various NSAIDsin caus-
`ing such reactions. High doses ofany NSAID probably carry
`agreaterrisk ofthese reactions, although controlled clinical
`trials showing this do not exist in most cases. In considering
`the use ofrelatively 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 DS (NA-
`PROXEN SODIUM) SHOULD NOT BE USED CONCOMI-
`TANTLY WITH THE RELATED DRUG NAPROSYN (NA-
`PROXEN) SINCE THEY BOTH CIRCULATE IN PLASMA AS
`THE NAPROXEN ANION.
`so
`Renal Effects: As with other nonsteroidal anti-inflammatory
`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 ofrenal toxicity has been seen in patients
`with prerenal conditions leading to a reduction in renal
`blood flow or blood volume, wherethe renal prostaglandins
`have asupportiverole in the maintenance ofrenal perfusion.
`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
`decompensation.Patients atgreatestrisk ofthis reaction are
`those with impaired renalfunction, heart failure,liver dys-
`function, those taking diuretics, and the elderly. Discon-
`tinuation of nonsteroidal anti-inflammatorytherapy is typi-
`cally followed by recovery to the pretreatmentstate.
`Naproxen sodium andits 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 and/or
`creatinine clearance is advised in these patients. Caution
`should be used if the drugis given to patients with creatinine
`clearanceof less than 20 mL/minute 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 naproxen,
`but the plasma concentration of unbound naproxen is in-
`
`2351
`
`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 lowesteffective dose.
`Studies indicate that although total plasma concentration of
`naproxen is unchanged, the unbound plasmafraction of na-
`proxen is increased in the elderly. Caution is advised when
`high doses are required and some adjustment of dosage may
`be requiredin elderly patients. As with other drugs used in
`the elderly, it is prudent to 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
`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 SGPT or SGOT
`(AST)occurred in controlled clinicaltrials in less than 1% of
`patients. A patient with symptoms and/orsigns suggesting
`liver dysfunction, or in whom an abnormalliver 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 symptomsconsistent with liver
`disease develop, or if systemic manifestations occur (e.g.,
`eosinophilia, rash, etc.), this drug should be discontinued.
`If steroid dosageis reduced or eliminated during therapy,the
`steroid dosage should be reduced slowly and the patients
`must be observed closely for any evidence of adverseeffects,
`including adrenal insufficiency and exacerbation of symp-
`tomsof arthritis.
`Patients with initial hemoglobin values of 10 gramsorless
`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 mEq)of sodium,this should be consid-
`ered in patients 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 ofits class,is not free of
`side effects, The side effects of these drugs can cause discom-
`fort and, rarely, there are more serious sideeffects, such as
`gastrointestinal bleeding, which may result in hospitaliza-
`tion and even fatal outcomes.
`NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) are often
`essential agents in the managementofarthritis 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 drowsiness, dizziness,
`vertigo or depression during therapy with the drug.
`Laboratory Tests:
`Because serious GI tract ulceration and bleeding can occur
`without warning symptoms, physiciansshould follow chroni-
`cally treated patients for the signs and symptoms of ulcer-
`ation and bleeding and should inform them of the impor-
`tance ofthis follow-up (see Risk of GI Ulcerations, Bleeding
`and Perforation with NSAID Therapy).
`;
`Drug Interactions:
`In vitro studies have shown that naproxen anion, because of
`its affinity for protein, may displace from their bindingsites
`other drugs which are also albumin-bound, Theoretically,
`the naproxen anionitself 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 sulfony!-
`urea should be observed forsigns of toxicity to these drugs.
`The natriuretic effect of furosemide has been reported to be
`inhibited by some drugsofthis class. Inhibition of renallith-
`ium clearance leading to increases in plasmalithium concen-
`trations has also been reported.
`
`Continued on next page
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`

`

`Refer to entry under TRI-NORINYL® tablets (norethin-
`drone and ethinyl estradiol).
`Shown in Product Identification Section, page 332
`
`2352
`Physicians’ Desk Reference®
`Consult 1994 Supplementsfor revisions
`
` within this period, a trial for an additional two weeks should
`
`Special Senses: Tinnitus*, hearing disturbances, visual
`be.considered.
`Syntex—Cont.
`disturbances.
`:
`For Acute Gout:
`Cardiovascular; Edema*, dyspnea’, palpitations.
`The recommended starting dose is 825 mg, followed by
`General: Thirst.
`This and other nonsteroidal anti-inflammatory drugs can
`275 mg every eight hours until the attack has subsided.
`"Incidence of reported reaction between 3% and 9%. Those
`reduce the antihypertensiveeffect 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.
`Probenecid given concurrently increases naproxen anion
`ke given in two divided doses. The 275 mg ANAPROXtablet
`Incidence less than 1%
`plasma levels and extends its plasmahalf-life significantly.
`is not well suited to this dosage so use of the related drug
`Probable Causal Relationship:
`Caution should be used if this drug is administered con-
`NAPROSYN® (naproxen)as the 250 mgscored tablet or the
`The following adverse reactions were reported less fre-
`comitantly with methotrexate. Naproxen and other nonste-
`125 mg/5 mL suspension is
`recommended for
`this
`indication.
`roidal anti-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
`possbily enhancing the toxicity of that drug.
`ANAPROX® (naproxen sodium) is available in filmcoated
`adverse reactions.
`Drug/Laboratory Test Interactions:
`tablets of 275 mg (light blue), in bottles of 100 tablets (NDC
`liver function tests, colitis,
`Gastrointestinal: Abnormal
`The drug may decrease platelet aggregation and prolong
`18393-274-42) (NSN 6505-01-155-5157) and 500 tablets (NDC
`gastrointestinal bleeding and/or perforation, hematemesis,
`bleeding time. This effect should be kept in mind when bleed-
`18398-274-62) (NSN 6505-01-130-6832)-or in cartons of 100
`jaundice, melena, peptic ulceration with bleeding and/or
`ing times are determined.
`individually blister packed tablets (NDC 18393-274-53).
`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 17-ketogenic steroids because of an interac-
`coated tablets of 550 mg (dark blue), in bottles of 100 tablets
`(NDC 18393-276-42) (NSN 6505-01-305-8174) and 500 tablets
`interstitial nephritis, nephrotic syndrome, renal disease,
`tion between the drug and/orits metabolites with m-dinitro-
`(NDC 18393-276-62) or in cartons of 100 individually blister
`renalfailure, renal papillary necrosis.
`benzene used in this assay. Although 17-hydroxy-corticoste-
`roid measurements (Porter-Silber test) do not appear to be
`Hematologic: Agranulocytosis, eosinophilia, granulocyto-
`packed tablets (NDC 18393-276-53). Store at room tempera-
`ture in well-closed containers.
`penia, 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; 3,998,966 and others.
`and muscle weakness.
`The drug may interfere with some urinary assays of
`02-0276-42-04
`Revised 9/90
`5-hydroxy indoleacetic acid (5HIAA).
`Dermatologic: Alopecia, photosensitive dermatitis, skin
`rashes.
`©1990 Syntex Puerto Rico, Inc.
`Carcinogenesis:
`Shown in Product Identification Section, page 332
`A two-year study was