(RoChe)
`EC-NAPROSYN~ (naproxen delayed-release tablets)
`NAPROSYN~ (naproxen tablets)
`ANAPROX~/ANAPROX~ DS (naproxen sodium tablets)
`NAPROSYN~ (naproxen suspension)
`
`Rx only
`
`Cardiovascular Risk
`. NSAIDs may cause an increased risk of serious cardiovascular thrombotic
`events, myocardial infarction, and stroke, which can be fataL. This risk
`may increase with duration of use. Patients with cardiovascular disease or
`risk factors for cardiovascular disease may be at greater risk (see
`WARNINGS).
`. Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
`DS or NAPROSYN Suspension is contraindicated for the treatment of
`G)
`
`peri-operative pain in the setting of coronary artery bypass graft (CAB
`
`surgery (see WARNINGS).
`Gastrointestinal Risk
`. NSAIDs cause an increased risk of serious gastrointestinal adverse events
`including bleeding, ulceration, and perforation of the stomach or
`intestines, which can be fataL. These events can occur at any time during
`use and without warning symptoms. Elderly patients are at greater risk for
`serious gastrointestinal events (see WARNINGS).
`DESCRIPTION
`Naproxen is a proprionic acid derivative related to the arylacetic acid group of
`nonsteroidal anti-inflammatory drugs.
`
`The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-a-
`methyl-2-naphthaleneacetic acid and (S)-6-methoxy-a-methyl-2-
`naphthaJeneacetic acid, sodium salt, respectively. Naproxen and naproxen
`sodium have the following stiyctures, respectively:
`
`CH;¡
`
`wi 230.26
`
`napro,.n ,odium (R.-COONa) C14H "NaO, mol wl 252.23
`;Oo R..." napro'en (R..COOH) C14HI.o, mol
`CH:iÜ
`
`Naproxen has a molecular weight of 230.26 and a molecular formula of
`C14H1403. Naproxen sodium has a molecular weight of 252.23 and a
`molecular formula of CI4H13Na03.
`
`Naproxen is an odorless, white to off-white crystallne substance. It is lipid-
`soluble, practically insoluble in water at low pH and freely soluble in water at
`high pH. The octanol/water partition coeffcient of naproxen at pH 7.4 is 1.6
`
`1
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 1
`
`

`

`EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYNW (naproxen suspension)
`
`to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely
`soluble in water at neutral pH.
`
`NAPROSYN (naproxen tablets) is available as yellow tablets containing 250
`mg of naproxen, pink tablets containing 375 mg of naproxen and yellow
`tablets containing 500 mg of naproxen for oral administration. The inactive
`ingredients are croscarmellose sodium, iron oxides, povidone and magnesium .
`stearate.
`
`EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-
`coated :white tablets containing 375 mg of naproxen and 500 mg of naproxen
`for oral administration. The inactive ingredients are croscarmellose sodium,
`povidone and magnesium stearate. The enteric coating dispersion contains
`methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and
`purified water. The dissolution of this enteric-coated naproxen tablet is pH
`dependent with rapid dissolution above pH 6. There is no dissolution below
`pH4.
`
`ANAPROX (naproxen sodium tablets) is available as blue tablets containing
`275 mg ofnaproxen sodium and ANAPROX DS (naproxen sodium tablets) is
`available as dark blue tablets containing 550 mg of naproxen sodium for oral
`administration. The inactive ingredients are magnesium stearate,
`microcrystalline cellulose, povidone and talc. The coating suspension for the
`ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910,
`Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The
`coating suspension for the ANAPROX DS 550 mg tablet may contain
`hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene
`glycol 8000 or Opadry YS-1-4216.
`
`opaque oral suspension containing 125 mg/5 mL of naproxen in a
`
`NAPROSYN (naproxen suspension) is available as a light orange-colored
`vehicle
`containing, sucrose, magnesium aluminum silcate, sorbitol solution and
`sodium chloride (30 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C
`Yellow No.6, imitation pineapple flavor, imitation orange flavor and purified
`water. The pH ofthe suspension ranges from 2.2 to 3.7.
`
`CLINICAL PHARMACOLOGY
`Pharmacodynamics
`Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic
`and antipyretic properties. The sodium salt of naproxen has been developed as
`a more rapidly absorbed formulation of naproxen for use as an analgesic. The
`mechanism of action of the naproxen anion, like that of other NSAIDs, is not
`completely understood but may be related to prostaglandin synthetase
`inhibition.
`
`2
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 2
`
`

`

`EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYN(j (naproxen suspension)
`
`Pharmacokinetics
`Naproxen and naproxen sodium are rapidly and completely absorbed from the
`gastrointestinal tract with an in vivo bioavailability of 95%. The different
`dosage forms of NAPROSYN are bioequivalent in terms of extent of
`absorption (AUC) and peak concentration (Cmax); however, the products do
`differ in their pattern of absorption. These differences between naproxen
`products are related to both the chemical form of naproxen used and its
`formulation. Even with the observed differences in pattern of absorption, the
`elimination half-life of naproxen is unchanged across products ranging from
`12 to 17 hours. Steady-state levels ofnaproxen are reached in 4 to 5 days, and
`the degree of naproxen accumulation is consistent with this half-life. This
`suggests that the differences in pattern of release play only a negligible role in
`the attainment of steady-state plasma levels.
`
`Absorption
`
`Immediate Release
`After administration of NAPROSYN tablets, peak plasma levels are attained
`in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels
`are attained in 1 to 2 hours. The difference in rates between the two products
`is due to the increased aqueous solubility of the sodium salt of naproxen used
`in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN
`Suspension arc attained in 1 to 4 hours.
`
`Delayed Release
`EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier
`to disintegration in the acidic environment of the stomach and to lose integrity
`in the more neutral environment of the small intestine. The enteric polymer
`coating selected for EC-NAPROSYN dissolves above pH 6. When EC-
`NAPROSYN was given to fasted subjects, peak plasma levels were attained
`about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo
`labeled EC-NAPROSYN tablets demonstrated that
`EC-NAPROSYN dissolves primarily in the small intestine rather than in the
`stomach, so the absorption of the drug is delayed until the stomach is emptied.
`
`study in man using radio
`
`When EC-NAPROSYN and NAPROSYN were given to fasted subjects
`(n=24) in a crossover study following 1 week of dosing, differences in time to
`peak plasma levels (T max) were observed, but there were no differences in total
`absorption as measured by Cmax and AUC:
`
`3
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 3
`
`

`

`EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYN (naproxen suspension)
`
`Cmax (f.g/mL)
`
`Tmax (hours)
`AUCo-12 hr (f.g'hr/mL)
`
`EC-NAPROSYN*
`500 mg bid
`94.9 (18%)
`4 (39%)
`845 (20%)
`
`NAPROSYN*
`500 mg bid
`97.4 (13%)
`1.9 (61 %)
`767 (15%)
`
`*Mean value (coefficient of
`
`variation)
`
`Antacid Effects
`When EC-NAPROSYN was given as a single dose with antacid (54 mEq
`buffering capacity), the peak plasma levels of naproxen were unchanged, but
`the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with
`antacid 5 hours), although not significantly.
`
`Food Effects
`When EC-NAPROSYN was given as a single dose with food, peak plasma
`levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours).
`Residence time in the small intestine until disintegration was independent of
`food intake. The presence of food prolonged the time the tablets remained in
`the stomach, time to first detectable serum naproxen levels, and time to
`maximal naproxen levels (T max), but did not affect peak naproxen levels
`(Cmax).
`
`Distribution
`Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels
`naproxen is greater than 99% albumin-bound. At doses of naproxen greater
`than 500 mg/day there is less than proportional increase in plasma levels due
`to an increase in clearance caused by saturation of plasma protein binding at
`higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and
`1500 mg daily doses of naproxen, respectively). The naproxen anion has been
`found in the milk of lactating women at a concentration equivalent to
`approximately 1% of maximum naproxen concentration in plasma (see
`PRECAUTIONS: Nursing Mothers).
`
`Metabolism
`Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen,
`and both parent and metabolites do not induce metabolizing enzymes. Both
`naproxen and 6-0-desmethyl naproxen are further metabolized to their
`glucuronide conjugated metabolites.
`
`respective acyl
`
`Excretion
`The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the
`naproxen from any dose is excreted in the urine, primarily as naproxen (":1 %),
`6-0-desmethyl naproxen (":1 %) or their conjugates (66% to 92%). The plasma
`
`4
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 4
`
`

`

`EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen
`tablets), ANAPRO~/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYNW (naproxen suspension)
`
`half-life of the naproxen anion in humans ranges from 12 to 17 hours. The
`corresponding half-lives of both naproxen's metabolites and conjugates are
`shorter than 12 hours, and their rates of excretion have been found to coincide
`closely with the rate of naproxen disappearance from the plasma. Small
`amounts, 3% or less of the administered dose, are excreted in the feces. In
`patients with renal failure metabolites may accumulate (see WARNINGS:
`Renal Effects).
`
`Special Populations
`
`Pediatric Patients
`In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels
`following a 5 mg/kg single dose ofnaproxen 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
`pediatric and adult patients. Pharmacokinetic studies of naproxen were not
`pcrformed in pediatric patients younger than 5 years of age. Pharmacokinetic
`parameters appear to be similar following administration of naproxen
`suspension or tablets in pediatric patients. EC-NAPROSYN has not been
`studied in subjects under the age of 18.
`
`Geriatric Patients
`Studies indicate that although total plasma concentration of nàproxen is
`unchanged, the unbound plasma fraction of naproxen is increased in the
`elderly, although the unbound fraction is ..1% of the total naproxen
`concentration. Unbound trough naproxen concentrations in elderly subjects
`have been reported to range from 0.12% to 0.19% of total naproxen
`concentration, compared with 0.05% to 0.075% in younger subjects. The
`clinical significance of this finding is unclear, although it is possible that the
`increase in free naproxen concentration could be associated with an increase
`in the rate of adverse events per a given dosage in some elderly patients.
`
`Race
`Pharmacokinetic differences due to race have not been studied.
`
`Hepatic Insufficiency
`Naproxen pharmacokinetics has not been determined in subjects with hepatic
`insuffciency.
`
`Renal
`
`Insufficiency
`Naproxen pharmacokinetics has not been determined in subjects with renal
`insuffciency. Given that naproxen, its metabolites and conjugates are
`primarily excreted by the kidney, the potential exists for naproxen metabolites
`
`5
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 5
`
`

`

`EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYN(j (naproxen suspension)
`
`to accumulate in the presence of renal insufficiency. Elimination of naproxen
`is decreased in patients with severe renal impairment. Naproxen-containing
`products are not recommended for use in patients with moderate to severe and
`severe renal impairment (creatinine clearance ..30 mL/min) (see
`WARNINGS: Renal Effects).
`
`CLINICAL STUDIES
`
`General
`
`Information
`Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis,
`juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute
`gout. Improvement in patients treated for rheumatoid arthritis was
`demonstrated by a reduction in joint swellng, a reduction in duration of
`morning stiffness, a reduction in disease activity as assessed by both the
`investigator and patient, and by increased mobility as demonstrated by a
`reduction in walking time. Generally, response to naproxen has not been
`found to be dependent on age, sex, severity or duration of rheumatoid arthritis.
`
`In patients with osteoarthritis, the therapeutic action of naproxen has been
`shown by a reduction in joint pain or tenderness, an increase in range of
`motion in knee 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 a clinical trial comparing standard formulations of naproxen 375 mg bid
`(750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group
`terminated prematurely because of adverse events. Nineteen patients in the
`1500 mg group terminated prematurely because of adverse events. Most of
`these adverse events were gastrointestinal events.
`
`In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and
`juvenile arthritis, naproxen has been shown to be comparable to aspirin and
`indomethacin in controlling the aforementioned measures of disease activity,
`but the frequency and severity of the milder gastrointestinal adverse effects
`(nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus,
`dizziness, lightheadcdness) were less in naproxen-treated patients than in
`those treated with aspirin or indomethacin.
`
`In patients with ankylosing spondylitis, naproxen has been shown to decrease
`night pain, morning stiffness and pain at rest. In double-blind studics the drug
`was shown to be as effective as aspirin, but with fewer side effects.
`
`In patients with acute gout, a favorable response to naproxen was shown by
`significant clearing of inflammatory changes (eg, decrease in swellng, heat)
`within 24 to 48 hours, as well as by relief of pain and tenderness.
`
`6
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 6
`
`

`

`EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYN(j (naproxen suspension)
`
`Naproxen has been studied in patients with mild to moderate pain secondary
`to postoperative, orthopedic, postpartum episiotomy and uterine contraction
`pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in
`patients taking naproxen and within 30 minutes in patients taking naproxen
`sodium. Analgesic effect was shown by such measures as reduction of pain
`intensity scores, increase in pain relief scores, decrease in numbers of patients
`requiring additional analgesic medication, and delay in time to remedication.
`The analgesic effect has been found to last for up to 12 hours.
`
`Naproxen 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 corticosteroids, it did not appear to cause greater
`improvement over that seen with corticosteroids alone. Whether naproxcn has
`a "steroid-sparing" effect has not been adequately studied. When added to the
`regimen of patients receiving gold salts, naproxen did result in greater
`improvement. Its use in combination with salicylates is not recommended
`because there is evidence that aspirin increases the rate of excretion of
`naproxen and data are inadequate to demonstrate that naproxen and aspirin
`produce greater improvement over that achieved with aspirin alonc. In
`addition, as with other NSAIDs, the combination may result in higher
`frequency of adverse events than demonstrated for either product alone.
`
`In 51Cr blood loss and gastroscopy studies with normal volunteers, daily
`administration of 1000 mg of naproxen as 1000 mg of NAPROSYN
`(naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been
`demonstrated to cause statistically significantly less gastric bleeding and
`erosion than 3250 mg of aspirin.
`
`Three 6-week, double-blind, multicenter studies with EC-NAPROSYN
`(naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid,
`n=279) were conducted comparing EC-NAPROSYN with NAPROSYN,
`including 355 rheumatoid arthritis and osteoarthritis patients who had a recent
`history of NSAID-related GI symptoms. These studies indicated that EC-
`NAPROSYN and NAPROSYN showed no significant differences in effcacy
`or safety and had similar prevalence of minor GI complaints. Individual
`patients, however, may find one formulation preferable to the other.
`
`Five hundred and fifty-three patients received EC-NAPROSYN during long-
`term open-label trials (mean length of treatment was 159 days). The rates for
`clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been
`historically reported for long-term NSAID use.
`
`Geriatric Patients
`The hepatic and renal tolerability of long-term naproxen administration was
`studied in two double-blind clinical trials involving 586 patients. Of the
`
`7
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 7
`
`

`

`EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYN(j (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYN (naproxen suspension)
`
`patients studied, 98 patients were age 65 and older and 10 of the 98 patients
`were age 75 and older. Naproxen was administered at doses of 375 mg twice
`daily or 750 mg twice daily for up to 6 months. Transient abnormalities of
`laboratory tests assessing hepatic and renal function were noted in some
`patients, although there were no differences noted in the occurrence of
`abnormal values among different age groups.
`
`INDICATIONS AND USAGE
`Carcfully consider the potential benefits and risks of NAPROSYN, EC-
`NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and
`other treatment options before deciding to use NAPROSYN, EC-
`NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use
`the lowest effective dose for the shortest duration consistent with individual
`patient treatment goals (see WARNINGS).
`
`Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
`NAPROSYN Suspension is indicated:
`
`. For the relief of
`
`the signs and symptoms of
`
`rheumatoid arthritis
`
`. For the relief ofthe signs and symptoms of osteoarthritis
`
`. For the relief of
`
`the signs and symptoms of ankylosing spondylitis
`
`. For the relief of
`
`the signs and symptoms of
`
`juvenile arthritis
`
`Naproxen as NAPROSYN Suspension is recommended for juvenile
`rheumatoid arthritis in order to obtain the maximum dosage flexibility based
`on the patient's weight.
`
`Naproxen as NAPROSYN~ ANAPROX, ANAPROX DS and NAPROSYN
`Suspension is also indicated:
`
`. For relief of
`
`the signs and symptoms of
`
`. For relief of
`
`the signs and symptoms of
`
`tendonitis
`
`bursitis
`
`. For relief of the signs and symptoms of acute gout
`
`. For the management of
`
`pain
`
`. For the management of primary dysmenorrhea
`
`EC-NAPROSYN is not recommended for initial treatment of acute pain
`because the absorption of naproxen is delayed compared to absorption from
`other naproxen-containing products (see CLINICAL PHARMACOLOGY
`and DOSAGE AND ADMINISTRATION).
`
`8
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 8
`
`

`

`EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYN (naproxen suspension)
`
`CONTRAINDICA TIONS
`NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
`NAPROSYN Suspension are contraindicated in patients with known
`hypersensitivity to naproxen and naproxen sodium.
`NAPROSYN, EC-NAPROSYN,' ANAPROX, ANAPROX DS and
`NAPROSYN Suspension should not be given to patients who have
`experienced asthma, urticaria, or allergic-type reactions after taking aspirin or
`other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs
`have been reported in such patients (see WARNINGS: Anaphylactoid
`Reactions and PRECAUTIONS: Preexisting Asthma).
`NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
`NAPROSYN Suspension are contraindicated for the treatment of peri-
`G) surgery
`
`operative pain in the setting of coronary artery bypass graft (CAB
`
`(see WARNINGS).
`
`WARNINGS
`
`CARDIOVASCULAR EFFECTS
`Cardiovascular Thrombotic Events
`Clinical trials of several COX-2 selective and nonselective NSAIDs of up to
`three years duration have shown an increased risk of serious cardiovascular
`(CV) thrombotic events, myocardial infarction, and stroke, which can be fataL.
`All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.
`Patients with known CV disease or risk factors for CV disease may be at
`greater risk. To minimize the potential risk for an adverse CV event in patients
`treated with an NSAID, the lowest effective dose should be used for the
`shortest duration possible. Physicians and patients should remain alert for the
`development of such events, even in the absence of previous CV symptoms.
`Patients should be informed about the signs and/or symptoms of serious CV
`they occur.
`
`events and the steps to take if
`
`There is no consistent evidence that concurrent use of aspirin mitigatcs the
`increased risk of serious CV thrombotic events associated with NSAID use.
`The concurrent use of aspirin and an NSAID does increase the risk of serious
`GI events (see Gastrointestinal Effects - Risk of Ulceration, Bleeding, and
`Perforation).
`
`Two large, controlled, clinical trials of a COX-2 selective NSAID for the
`treatment of pain in the first 10-14 days following CABG surgery found an
`increased incidence of myocardial infarction and stroke. (see
`CONTRAINDICA TIONS).
`
`9
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 9
`
`

`

`EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYN(j (naproxen suspension)
`
`Hypertension
`NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
`ANAPROX DS and NAPROSYN Suspension, can lead to onset of new
`hypertension or worsening of pre-existing hypertension, either of which may
`contribute to the increased incidence of CV events. Patients taking thiazid~s or
`loop diuretics may have impaired response to these therapies when taking
`NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
`ANAPROX DS and NAPROSYN Suspension, should be used with caution in
`patients with hypertension. Blood pressure (BP) should be monitored closely
`during the initiation of NSAID treatment and throughout the course of
`therapy.
`
`Congestive Heart Failure and Edema
`Fluid retention, edema, and peripheral edema have been observed in some
`patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX,
`ANAPROX DS and NAPROSYN Suspension should be used with caution in
`patients with fluid retention, hypertension, or hear failure. Since each
`ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium
`(about 1 mEq per each 250 mg of naproxen), and each teaspoonful of
`NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of
`naproxen) of sodium, this should be considered in patients whose overall
`intakc of sodium must be severely restricted.
`
`Gastrointestinal Effects - Risk of Ulceration, Bleeding, and
`Perforation
`NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
`ANAPROX DS and NAPROSYN Suspension, can cause seflOUS
`gastrointestinal (GI) adverse events including inflammation, bleeding,
`ulceration, and perforation of the stomach, small intestine, or large intestine,
`which can be fataL.
`
`These serious adverse events can occur at any time, with or without warning
`symptoms, in patients treated with NSAIDs. Only one in five patients, who
`develop a serious upper GI adverse event on NSAID therapy, is symptomatic.
`Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs OCCU! in
`approximately 1 % of patients treated for 3-6 months, and in about 2-4% of
`patients treated for one year. These trends continue with longer duration of
`use, increasing the likelihood of developing a serious GI event at some time
`therapy. However, even short-term therapy is not without
`risk. The utility of periodic laboratory monitoring has not been demonstrated,
`nor has it been adequately assessed. Only 1 in 5 patients who develop a
`serious upper GI adverse event on NSAID therapy is symptomatic.
`
`during the course of
`
`10
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 10
`
`

`

`EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYNW (naproxen suspension)
`
`NSAIDs should be prescribed with extreme caution in those with a prior
`history of ulcer disease or gastrointestinal bleeding. Patients with a prior
`history of peptic ulcer disease and/or gastrointestinal bleeding who use
`NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
`compared to patients with neither of these risk factors. Other factors that
`increase the risk for GI bleeding in patients treated with NSAIDs include
`concomitant use of oral corticosteroids or anticoagulants, longer duration of
`NSAID therapy, smoking, use of alcohol, older age, and poor general health
`status. Most spontaneous reports of fatal GI events are in elderly or debilitated
`patients and therefore, special care should be taken in treating this population.
`To minimize the potential risk for an adverse GI event in patients treated with
`an NSAID, the lowest effective dose should be used for the shortest possible
`duration. Patients and physicians should remain alert for signs and symptoms
`of GI ulceration and bleeding during NSAID therapy and promptly initiate
`additional evaluation and treatment if a serious GI adverse event is suspected.
`This should include discontinuation of the NSAID until a serious GI adverse
`event is ruled out. For high risk patients, alternate therapies that do not
`involve NSAIDs should be considered.
`
`Epidemiological studies, both of the case-control and cohort design, have
`demonstrated an association between use of psychotropic drugs that interfere
`with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
`In two studies, concurrent use of an NSAID or aspirin potcntiated the risk of
`bleeding (see PRECAUTIONS - Drug Interactions). Although these studies
`focused on upper gastrointestinal bleeding, there is reason to belicve that
`bleeding at other sites may be similarly potentiated.
`
`NSAIDs should be given with care to patients with a history of inflammatory
`bowel disease (ulcerative colitis, Crohn's disease) as their condition may be
`exacerbated.
`
`Renal Effects
`
`Long-term administration of NSAIDs has resulted in renal papilary necrosis
`and other renal injury. Renal toxicity has also been seen in patients in whom
`renal prostaglandins have a compensatory role in the maintenance of renal
`perfusion. In these patients, administration of a nonsteroidal
`anti-inflammatory drug may cause a dose-dependent reduction in
`prostaglandin formation and, secondarily, in renal blood flow, which may
`precipitate overt renal decompensation. Patients at greatest risk of this
`reaction are those with impaired renal function, hypovolemia, heart failure,
`liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors,
`and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug
`therapy is usually followcd by recovery to the pretreatment state (see
`WARNINGS: Advanced Renal Disease).
`
`11
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 11
`
`

`

`EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYNW (naproxen suspension)
`
`Advanced Renal Disease
`No information is available from controlled clinical studies regarding the use
`of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
`NAPROSYN Suspension in patients with advanced renal disease. Therefore,
`treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS
`and NAPROSYN Suspension is not recommended in these patients with
`advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX,
`ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close
`monitoring of the patient's renal function is advisable.
`
`Anaphylactoid Reactions
`As with other NSAIDs, anaphylactoid reactions may occur in patients without
`known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX,
`ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC-
`NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
`should not be given to patients with the aspirin triad. This symptom complex
`typically occurs in asthmatic patients who experience rhinitis with or without
`nasal polyps, or who exhibit severe, potentially fatal bronchospasm after
`taking aspirin or other NSAIDs (see CONTRAINDICATIONS and
`PRECAUTIONS: Preexisting Asthma). Emergency help should be sought
`in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like
`anaphylaxis, may have a fatal outcome.
`
`Skin Reactions
`NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
`ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse
`events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and
`toxic epidermal necrolysis (TEN), which can be fataL. These serious events
`may occur without warning. Patients should be inforied about the signs and
`symptoms of serious skin manifestations and use of the drug should be
`discontinued at the first appearance of skin rash or any other sign of
`hypersensitivity.
`
`Pregnancy
`In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
`ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided
`because it may cause premature closure of the ductus areriosus.
`
`PRECAUTIONS
`General
`Naproxen-containing products such as NAPROSYN, EC-NAPROSYN,
`ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE~, and
`
`12
`
`MYLAN PHARMS. INC. EXHIBIT 1009 PAGE 12
`
`

`

`EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN (naproxen
`tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
`NAPROSYN (naproxen suspension)
`
`other naproxen products should not
`
`be used concomitantly since they all
`circulate in the plasma as the naproxen anion.
`NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
`NAPROSYN Suspcnsion cannot be expected to substitute for corticosteroids
`or to treat corticosteroid insufficiency. Abrupt discontinuation of
`corticosteroids may lead to disease exacerbation. Patients on prolonged
`corticosteroid therapy should have their therapy tapered slowly if a decision is
`made to discontinue corticosteroids and the patient should be observed closely
`for any evidence of adverse effects, including adrenal insufficiency and
`exacerbation of symptoms of arthritis.
`
`Patients with initial hemoglobin values of 109 or less who are to receive long-
`term therapy should have hemoglobin values determined periodically.
`The pharmacological activity of NAPROSYN, EC-NAPROSYN,
`ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever
`and inflammation may diminish the utility of these diagnostic signs in
`detecting complications of presumed noninfectious, noninflammatory 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.
`
`Hepatic Effects
`Borderline elevations of one or more liver tests may occur in up to 15% of
`patients taking NSAIDs including NAPROSYN, EC-NAPROSYN,
`ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic
`abnormalities may be the result of hypersensitivity rather than direct toxicity.
`These laboratory abnormalities may progress, may remain essentially
`unchanged, or may be transient with continued therapy. The SGPT (AL T) test
`is probably the most sensitive indicator of liver dysfunction. Notable
`elevations of AL T or AST (approximately three or more times the upper limit
`of normal) have been reported in approximately 1 % of patients in clinical
`trials with NSAIDs. In addition, rare cases of severe hepatic reactions,
`including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic
`failure, some of them with fatal outcomes have been reported.
`
`A patient with .symptoms and/or signs suggesting liver dysfunction, or in
`whom an abnormal liver test has occurred, should be evaluated for evidence
`of the