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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER: 20-121/S009
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`FINAL PRINTED LABELING
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`PLAINTIFFS'
`~
`TRIAL EXHIBIT~
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`PTX0059 f
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`APOTEX_AZFL 0060185
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`PTX0059-00001
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`CIPLA LTD. EXHIBIT 2020 PAGE 1
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`For Intranasal Use Only.
`
`2 FLONASE®
`(fluticasone propionate)
`3
`4 Nasal Spray, 50 meg
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`11
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`PRODUCT INFORMATION
`
`SHAKE GENTLY
`BEFORE USE.
`
`DESCRIPTION: Fluticasone propionate, the active ingredient of FLONASE Nasal Spray, is a synthetic
`corticosteroid with the chemical name of S·fluoromethyl 6a,9a-difluoro-11 ~-hydroxy- 16a- methyl -3-oxo-•
`17a-propionyloxyandrosta·1 ,4-diene- 17~-carbothioate and the following chemical structure:
`
`COSCH,F
`.... OCOC,H,
`.... cH,
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`Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6. It is
`practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly
`soluble in methanol and 95% ethanol.
`FLONASE Nasal Spray 50 meg is an aqueous suspension of microfine fluticasone propionate for
`topical administration to the nasal mucosa by means of a metering, atomizing spray pump. FLONASE
`Nasal Spray also contains microcrystalline cellul_ose and carboxymethylcellulose sodium, dextrose,
`0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol, and has a pH
`between 5 and 7.
`It is necessary to prime the pump before first use or after a period of non-use (1 week or more).
`After initial priming (six actuations), each actuation delivers 50 meg of fluticasone propionate in 1 00 mg
`of formulation through the nasal adapter. Each bottle of FLONASE Nasal Spray provides 120 metered
`sprays. After 120 metered sprays, the amount of fluticasone propionate delivered per actuation may
`not be consistent and the unit should be discarded.
`
`CLINICAL PHARMACOLOGY: Fluticasone propionate is a synthetic, trifluorinated corticosteroid with
`anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor
`system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM
`concentrations/respectively. Fluticasone propionate was threefold to fivefold more· potent" than
`dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support
`its potent glucocorticoid activity.
`In preclinical studies, fluticasone propionate revealed progesterone-like activity similar to the natural
`hormone. However, the clinical significance of these findings in relation to the low plasma levels (see
`Pharmacokinetics) is not known.
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`APOTEX_AZFL 0060186
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`PTX0059-00002
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`CIPLA LTD. EXHIBIT 2020 PAGE 2
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`FLONASE® (fluticasone propionate) Nasal Spray, 50 meg
`
`The precise mechanism through which fluticasone propionate affects allergic rhinitis symptoms is
`not known . Corticosteroids have been shown to have a wide range of effects on multiple cell types
`(e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g.,
`histamine. eicosanoids, leukotrienes, and cytokines) involved in inflammation. In seven trials in adults,
`FLONASE Nasal Spray has decreased nasal mucosal eosinophils in 66% (35% for placebo) of
`patients and basophils in 39% (28% for placebo) of patients. The direct relationship of these findings to
`long-term symptom relief is not known.
`FLONASE Nasal Spray, like other corticosteroids, is an agent that does not have an immediate
`effect on allergic symptoms. A decrease in nasal symptoms has been noted in some patients 12 hours
`after initial treatment with FLONASE Nasal Spray. Maximum benefit may not be reached for several
`days. Similarly, when corticosteroids are discontinued, symptoms may not return for several days.
`Pharmacokinetics: Absorption: The activity of FLONASE Nasal Spray is due to the parent drug,
`fluticasone propionate. Indirect calculations indicate that fluticasone propionate delivered by the
`intranasal route has an absolute bioavailability averaging less than 2%. After intranasal treatment of
`patients with allergic rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above
`the level of detection (50 pg/ml) only when recommended doses were exceeded and then only in
`occasional samples at low plasma levels. Due to the low bioavailability by the intranasal route, the
`majority of the pharmacokinetic data was obtained via other routes of administration. Studies using
`oral dosing of radiolabeled drug have demonstra~ed that fluticasone propionate is highly extracted
`from plasma and absorption is low. Oral bioavailability is negligible, and the majority of the circulating
`radioactivity is due to an inactive metabolite.
`Distribution: Following intravenous administration, the initial disposition phase for fluticasone
`propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of
`distribution averaged 4.2 Llkg. The percentage ·ot fluticasone propionate bound to human plasma
`proteins averaged 91% with no obvious concentration relationship. Fluticasone propionate is weakly
`and reversibly bound to erythrocytes and freely equilibrates between erythrocytes and plasma.
`Fluticasone propionate is not significantly bound to human transcortin.
`Metabolism: The total blood clearance of fluticasone propionate is high (average, 1 093 mUmin),
`with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite
`detected in man is the 17P-carboxylic acid derivative of fluticasone propionate, which is formed
`through the cytochrome P450 3A4 pathway. This inactive metabolite had approximately 2000 times
`less affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and
`negligible pharmacological activity in animal studies. Other metabolites detected in vitro using
`cultured human hepatoma cells have not been detected in man.
`In a multipl~-dose drug interaction study, co(Jdministration of orally inhaled flutic::asone propionate
`(500 meg twice daily) and erythromycin (333 mg three times daily) did not affect fluticasone
`propionate pharmacokinetics.
`In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1 000 meg,
`5 times the maximum daily intranasal dose) and ketoconazole (200 mg once daily) resulted in
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`CIPLA LTD. EXHIBIT 2020 PAGE 3
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`FLONASe® (fluticasone propionate) Nasal Spray, 50 meg
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`increased fluticasone propionate concentrations, a reduction in plasma cortisol AUC, and no effect on
`urinary excretion of cortisol.
`Excretion: Following intravenous dosing, fluticasone propionate showed polyexponential kinet1cs
`and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled
`oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as
`parent drug and metabolites.
`Special Populations: Fluticasone propionate was not studied in any special populations. and no
`gender-specific pharmacokinetic data have been obtained.
`Pharmacodynamics: In a trial to evaluate the potential systemic and topical effects of FLONASE
`Nasal Spray on allergic rhinitis symptoms, the benefits of comparable drug blood levels produced by
`FLONASE Nasal Spray and oral fluticasone propionate were compared. The doses used were
`200 meg of FLONASE Nasal Spray, the nasal spray vehicle (plus oral placebo), and 5 and 10 mg of
`oral fluticasone propionate {plus nasal spray vehicle) per day for 14 days. Plasma levels were
`undetectable in the majority of patients after intranasal dosing, but present at low levels in the majority
`after oral dosing. FLONASE Nasal Spray was significantly more effective in reducing symptoms of
`allergic rhinitis than either the oral fluticasone propionate or the nasal vehicle. This trial demonstrated
`that the therapeutic effect of FLONASE Nasal Spray can be attributed to the topical effects of
`fluticasone propionate.
`In another trial, the potential systemic effects of FLONASE Nasal Spray on the
`hypothalamic-pituitary-adrenal (HPA) axis were also studied in allergic patients. FLONASE Nasal
`Spray given as 200 meg once daily or 400 meg ~ice daily was compared with placebo or oral
`prednisone 7.5 or 15 mg given in the morning. FLONASE Nasal Spray at either dose for 4 weeks did
`not affect the adrenal response to 6-hour cosyntropin stimulation, while both doses of oral prednisone
`significantly reduced the response to cosyntropirt
`Clinical Trials: A total o1 13 randomized, double-blind, parallel, multicenter, vehicle-controlled clinical
`trials were conducted in the United States in adults and pediatric patients (4 years of age and older)
`with seasonal or perennial allergic rhinitis. The trials included 2633 adults (1439 men and 1194
`women) with a mean age of 37 years (range, 18 to 79). A total of 440 adolescents (405 boys and 35
`girts), mean age of 14 (range, 12 to 17), and 500 children {325 boys and 175 girls), mean age of 9
`(range, 4 to 11) were also studied. The overall racial distribution was 89% white, 4% black, and 7%
`other. These trials evaluated the total nasal symptom scores (TNSS} that included rhinorrhea, nasal
`obstruction, sneezing, and nasal itching in known allergic patients who were treated for 2 to 24 weeks.
`Subjects treated with FLONASE Nasal Spray exhibited significantly greater decreases in TNSS than
`vehicle placebo-treated patients. Nasal mucosal basophils and eosinophils were also reduced at the
`end of treatmer;~_t in adult studies; however, the clinical significance of this decrease is not· known.
`There were no significant differences between fluticasone propionate regimens whether
`administered as a single daily dose of 200 meg (two 50-meg sprays in each nostril) or as 100 meg (one
`50-meg spray in each nostril) twice daily in six clinical trials. A clear dose response could not be
`identified in clinical trials. In one trial, 200 meg/day was slightly more effective than 50 meg/day during
`the first few days of treatment; thereafter, no difference was seen.
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`APOTEX_AZFL 0060188
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`PTX0059-00004
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`CIPLA LTD. EXHIBIT 2020 PAGE 4
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`FLONAS!:® (fluticasone propionate) Nasal Spray, 50 meg
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`Three randomized. double-blind, parallel, vehicle-controlled trials were conducted in 1 191 patients
`with perennial nonallergic rhinitis. These trials evaluated the patient-rated total nasal symptom scores
`(nasal obstruction, postnasal drip, rhinorrhea) in patients treated for 28 days of double-blind therapy
`and in one of the 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that
`patients treated with FLONASE Nasal Spray at a dose of 1 00 meg twice daily exhibited statistically
`significant decreases in total nasal symptom scores compared with patients treated with vehicle.
`Individualization of Dosage: Adult patients may be started on a 200-mcg once-a-day regimen (two
`50-meg sprays in each nostril once-a-day). An alternative 200-mcg/day dosage regimen can be given
`as 100 meg twice daily (one so-meg spray in each nostril twice-a-day).
`Individual patients will experience a variable time to onset and different degree of symptom relief. In
`4 randomized, double-blind, placebo-controlled, parallel group allergic rhinitis studies and 2 studies of
`patients in an outdoor "park" setting (park studies), a decrease in nasal symptoms in treated subjects
`compared to placebo was shown to occur as soon as 12 hours after treatment with a 200-mcg dose of
`FLONASE Nasal Spray. Maximum effect may take several days. Patients who have responded may be
`able to be maintained (after 4 to 7 days) on 100 meg/day (one spray in each nostril once daily).
`Pediatric patients (4 years of age and older) should be started with 100 meg (one spray in each
`nostril once-a-day). Treatment with 200 meg (two sprays in each nostril once daily or one spray in each
`nostril twice daily) should be reserved for pediatric patients not adequately responding to 100 meg
`daily. Once adequate control is achieved, the dosage should be decreased to 100 meg (one spray in
`each nostril) daily.
`Maximum total daily doses should not exceed two sprays in each nostril (total_ dose, 200 meg/day).
`There is no evidence that exceeding the recommended dose is more effective.
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`148 WARNINGS: The replacement of a systemic corticosteroid with a topical corticosteroid can be
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`accompanied by signs of adrenal insufficiency, and in addition some patients may experience
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`symptoms of Withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients
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`previously treated for prolonged periods with systemic corticosteroids and transferred to topical
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`corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In
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`those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid
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`treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their
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`symptoms.
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`INDICATIONS AND USAGE: FLONASE Nasal Spray is indicated for the management of the nasal
`symptoms of seasonal and perennial allergic and nonallergic rhinitis in adults and pediatric patients 4
`years of age and older.
`Safety and effectiveness of FLONASE Nasal Spray in children below 4 years of age have not been
`adequately established.
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`CONTRAINDICATIONS: FLONASE Nasal Spray is contraindicated in patients with a hypersensitivity
`to any of its ingredients.
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`APOTEX_AZFL 0060189
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`CIPLA LTD. EXHIBIT 2020 PAGE 5
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`FLONASe® (fluticasone propionate) Nasal Spray, 50 meg
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`The concomitant use of intranasal corticosteroids with other inhaled corticosteroids could increase
`the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis.
`Patients who are on immunosuppressant drugs are more susceptible to infections than healthy
`individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in
`patients on immunosuppressant doses of corticosteroids. In such patients who have not had these
`diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of
`corticosteroid administration affects the risk of developing a disseminated infection is not known. The
`contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not
`known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be
`indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be
`indicated. (See the respective package inserts for complete VZIG and IG prescribing information). If
`chickenpox develops, treatment with antiviral agents may be considered.
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`PRECAUTIONS:
`General: Rarely, immediate hypersensitivity reactions or contact dermatitis may occur after the
`administration of FLONASE Nasal Spray. Rare instances of wheezing, nasal septum perforation,
`cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal
`application of corticosteroids, including fiuticasone propionate.
`Use of excessive doses of corticosteroids may lead to signs or symptoms of hypercorticism,
`suppression of HPA function, and/or reduction of growth velocity in children or teenagers. Physicians
`should closely foHow the growth of children and ~dolescents taking corticosteroids, by any route, and
`weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth
`appears slowed.
`Although systemic effects have been minimaf with recommended doses of FLONASE Nasal Spray,
`potential risk increases with larger doses. Therefore, larger than recommended doses of FLONASE
`Nasal Spray should be avoided.
`When used at higher than recommended doses, or in rare individuals at recommended doses,
`systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such
`changes occur, the dosage of FLONASE Nasal Spray should be discontinued slowly consistent with
`accepted procedures for discontinuing oral corticosteroid therapy.
`In clinical studies with fluticasone propionate administered intranasally, the development of
`localized infections of the nose and pharynx with Candida afbicans has occurred only rarely. When
`such an infection develops, it may require treatment with appropriate local therapy and discontinuation
`of treatment with FLONASE Nasal Spray. Patients using FLONASE Nasal Spray over several months
`or longer shoulcf.be examined periodically for evidence of Candida infection or other signs· of adverse
`effects on the nasal mucosa.
`FLONASE Nasal Spray should be used with caution, if at all, in patients with active or quiescent
`tuberculous infection; untreated local or systemic fungal or bacterial, or systemic viral infections or
`parasitic infection; or ocular herpes simplex.
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`APOTEX_AZFL 0060190
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`CIPLA LTD. EXHIBIT 2020 PAGE 6
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`FLONASe® (fluticasone.propionate) Nasal Spray, 50 meg
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`Because of the inhibitory effect of corticosteroids.on wound healing, patients who have experienced
`recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until
`healing has occurred.
`Information for Patients: Patients being treated with FLONASE Nasal Spray should receive the
`following information and instructions. This information is intended to aid them in the safe and effective
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`use of this medication. It is not a disclosure of all possible adverse or intended effects.
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`Patients should be warned to avoid exposure to chickenpox or measles and. if exposed. to consult
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`their physician without delay.
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`Patients should use FLONASE Nasal Spray at regular intervals as directed since its effectiveness
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`depends on its regular use. A decrease in nasal symptoms may occur as soon as 12 hours after
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`starting therapy with FLONASE Nasal Spray. Results in several clinical trials indicate statistically
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`significant improvement within the first day or two of treatment; however, the full benefit of FLONASE
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`Nasal Spray may not be achieved until treatment has been administered for several days. The patient
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`should not increase the prescribed dosage but should contact the physician if symptoms do not
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`improve or if the condition worsens. For the proper use of the nasal spray and to attain maximum
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`improvement, the patient should read and follow carefully the accompanying patient's instructions.
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`Drug Interactions: In a placebo-controlled, crossover study in eight healthy volunteers,
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`coadministration of a single dose of orally inhaled fluticasone propionate (1 000 meg, 5 times the
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`213 maximum daily intranasal dose) with multiple doses of ketoconazole (200 mg) to steady state resulted
`in increased mean fluticasone propionate concentrations, a reduction in plasma cortisol AUC, and no
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`effect on urinary. excretion of cortisol. This interaction may be due to an inhibition of the cytochrome
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`P450 3A4 isoenzyme system by ketoconazole, which is also the route of metabolism of fluticasone
`propionate. No drug interaction studies have been conducted with FLONASE Nasal Spray; however,
`care should be exercised when fluticasone propion~te is coadministered with long-term ketoconazole
`and other known cytochrome P450 3A4 inhibitors.
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Fluticasone propionate demonstrated no
`tumorigenic potential in mice at oral doses up to 1000 meg/kg (approximately 20 times th_e maximum
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`recommended daily intranasal dose in adults and approximately 10 times the maximum recommended
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`daily intranasal dose in children on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to
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`57 meg/kg (approximately 2 times the maximum recommended daily intranasal dose in adults and
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`approximately equivalent to the maximum recommended daily intranasal dose in children on a mcg/m2
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`basis) for 104 weeks.
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`Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No
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`significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the
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`229 mouse micron~cleus test when administered at.high doses by the oral or subcutaneous routes.
`Furthermore, the compound did not delay erythroblast division in bone marrow.
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`No evidence of impairment of fertility was observed in reproductive studies conducted in male and
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`female rats at subcutaneous doses up to 50 meg/kg (approximately 2 times the maximum
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`recommended·daily intranasal dose in adults on a mcg/m2 basis). Prostate weight was significantly
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`reduced at a subcutaneous dose of 50 meg/kg.
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`CIPLA LTD. EXHIBIT 2020 PAGE 7
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`FLONASE® {fluticasone propionate) Nasal Spray, 50 meg
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`Pregnancy: Teratogenic Effects: Pregnancy Category C. Subcutaneous studies in the mouse and rat
`at 45 and 1 DO meg/kg, respectively (approximately equivalent to and 4 time~e maximum
`recommended daily intranasal dose in adults on a mcg/m2 basi ,. espectiveiY. revealed tetal toxicity
`characteristic of potent corticosteroid compounds, including embryonic growth retardation.
`omphalocele, cleft palate, and retarded cranial ossification.
`In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of
`4 meg/kg (less than the maximum recommended daily intranasal dose in adults on a mcglm2 basis) .
`r
`However, no teratogenic effects were reported at oral doses up to 3DD meg/kg (approximately 25
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`·times the maximum recommended daily intranasal dose in adults on a mcglm2 basis) of fluticasone •
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`propionate to the rabbit. No fluticasone propionate was detected in the plasma in this study, consistent
`with the established low bioavailability following oral administration (see CLINICAL
`PHARMACOLOGY).
`Fluticasone propionate crossed the placenta following oral administration of 1 DO meg/kg to rats or
`300 meg/kg to rabbits (approximately 4 and 25 times, respectively, the maximum recommended daily
`intranasal dose in adults on a mcg/m2 basis).
`There are no adequate and well-controlled studies in pregnant women. Fluticasone propionate
`should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to
`physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids
`than humans. In addition, because there is a natural increase in corticosteroid production during
`pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need
`corticosteroid treatment during pregnancy.
`Nursing Mothers: It is not known whether fluticasone propionate is excreted in human breast milk.
`When tritiated fluticasone propionate was administered to rats at a subcutaneous dose of 10 meg/kg
`(less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis), radioactivity
`was excreted in the milk. Because other. corticosteroids are excreted in human milk, caution should be
`exercised when FLONASE Nasal Spray is administered to a nursing woman.
`Pediatric Use: Five hundred (500) patients aged 4 to 11 years of age and 440 patients aged 12 to 17
`years were studied in US clinical trials with fluticasone propionate nasal spray. The safety and
`effectiveness of FLONASE Nasal Spray in children below 4 years of age have not been established.
`Oral and, to a less clear extent, inhaled and intranasal corticosteroids have been shown to have the
`potential to cause a reduction in growth velocity in children and adolescents with extended use. If a
`child or adolescent on any corticosteroid appears to have growth suppression, the possibility that they
`are particularly sensitive to this effect of corticosteroids should be considered (see PRECAUTIONS).
`Geriatric Use: f. limited number of patients aboye 6D years of age (n = 275) have . .been treated with
`FLONASE Nasal Spray in US and non-US clinical trials. While the number of patients is too small to
`permit separate analysis of efficacy and safety, the adverse reactions reported in this population were
`similar to those reported by younger patients.
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`CIPLA LTD. EXHIBIT 2020 PAGE 8
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`ADVERSE REACTIONS: In controlled US studies, more than 3300 patients with seasonal allergic.
`perennial allergic, or perennial nonallergic rhinitis received treatment with intranasal fluticasone
`propionate. In general, adverse reactions in clinical studies have been primarily associated with
`irritation of the nasal mucous membranes, and the adverse reactions were reported with
`approximately the same frequency by patients treated with the vehicle itself. The complaints did not
`usually interfere with treatment. Less than 2% of patients in clinical trials discontinued because of
`adverse events ; this rate was similar for vehicle placebo and active comparators.
`Systemic corticosteroid side effects were not reported during controlled clinical studies up to 6
`months' duration with FLONASE Nasal Spray. If recommended doses are exceeded, however, or if
`individuals are particularly sensitive, or taking FLONASE Nasal Spray in conjunction with
`administration of other corticosteroids, symptoms of hypercorticism, e.g., Cushing's syndrome, could
`occur ..
`The following incidence of common adverse reactions (>3%, where incidence in fluticasone
`propionate-treated subjects exceeded placebo) is based upon seven controlled clinical trials in which
`536 patients (57 girls and 108 boys aged 4 to 11 years, 137 female and 234 male adolescents and
`adults) were treated with FLONASE Nasal Spray 200 meg once daily over 2 to 4 weeks and two
`controlled clinical trials in which 246 patients (119 female and 127 male adolescents and adults) were
`treated with FLONASE Nasal Spray 200 meg once daily over 6 months. Also included in the table are
`adverse events from two studies in which 167 children (45 girls and 122 boys aged 4 to 11 years) were
`treated with FLONASE Nasal Spray 100 meg once daily for 2 to 4 weeks.
`
`Overall Adverse Experiences With ->3% Incidence on Fluticasone Propionate
`In Controlled Clinical Trials With FLONASE Nasal Spray
`In Patients ~4 Years With Seasonal or Perennial Allergic Rhinitis
`
`Vehicle Placebo
`(n = 758)
`o/o
`14.6
`7.2
`5.4
`2.6
`2.0
`2.9
`2.8 ·
`
`FLONASE
`FLONASE
`1 00 meg Once Daily 200 meg Once Daily
`(n = 782)
`(n = 167)
`o/o
`o/o
`16.1
`6.6
`6:0
`7.8
`6.0
`6.9
`3.2
`2.4
`4.8
`2.6
`7.2
`3.3
`' 3.8
`3.6
`
`·-
`
`Headache
`Pharyngitis
`Epistaxis
`Nasal burning/nasal irritation
`Nausea/vomiting
`Asthma symptoms
`..
`Cough
`
`Other adverse events that occurred in ~% but ~1 o/o of patients and that were more common with
`fluticasone propionate (with uncertain relationship to treatment) included: blood in nasal mucus, runny
`nose, abdominal pain, diarrhea, fever, flu-like symptoms, aches and pains, dizziness, bronchitis.
`
`(-.
`
`(
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`CIPLA LTD. EXHIBIT 2020 PAGE 9
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`(
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`.{ (.
`
`(
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`FLONASE® (fluticasone propionate) Nasal Spray, 50 meg
`
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`304
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`31 1
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`
`Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the
`following events have been identified during postapproval use of fluticasone propionate in clinical
`practice. Becai.JSe they are reported voluntarily from a population of unknown size, estimates of
`frequency cannot be made. These events have been chosen for inclusion due to either their
`seriousness, frequency of reporting, causal connection to fluticasone propionate, occurrence during
`clinical trials, or a combination of these factors.
`General: Hypersensitivity reactions, including angioedema, skin rash, edema of the face and
`tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid
`reactions, which in rare instances were severe.
`Ear, Nose, and Throat: Alteration or loss of sense of taste and/or smell and, rarely, nasal septal
`perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice
`changes.
`Eye: Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular pressure,
`and cataracts.
`
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`314
`315
`316
`317
`OVERDOSAGE: Chronic overdosage with FLONASE Nasal Spray may result in signs/symptoms of
`318
`hypercorticism (see PRECAUTIONS). Intranasal administration of 2 mg {10 times the recommended
`319
`dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated.
`320
`Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects
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`reported. Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to
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`10 mg daily for 14 days in patients were well tolerated. Adverse reactions were of mild or moderate
`323
`.
`.
`.
`severity, and incidences were similar in active and placebo treatment groups. Acute overdosage with
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`this dosage form is unlikely since one bottle of FLONASE Nasal Spray contains approximately 8 mg of
`325
`fluticasone propionate.
`326
`The oral and subcutaneous median lethal doses in mice and rats were >1000 mglkg (>20000 and
`327
`>41 000 times, respectively, the maximum recommended daily intranasal dose in adults and > 1 0000
`328
`and >20000 times, respectively, the maximum recommended daily intranasal dose in children on a
`329
`330 mg/m2 basis).
`331
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`
`DOSAGE AND ADMINISTRATION: Patients should use FLONASE Nasal Spray at regular intervals as
`directed since its effectiveness depends on its regular use.
`Adults: The recommended starting dosage in adults is two sprays (50 meg of fluticasone propionate
`each) in each nostril once-a-day (total daily dose, 200 meg). The same dosage divided into 100 meg
`given twice-a-day (e.g., 8 a.m. and 8 p.m.) is also effective. After the first few days, patients may be
`able to reduce their dosage to 100 meg (one spray in each nostril) once daily for maintenance therapy.
`..
`.
`Adolescents and Children (4 Years of Age and Older): Patients should be started with 100 meg
`(one spray in each nostril once-a-day). Patients not adequately responding to 100 meg may use
`200 meg (two sprays in each nostril). Once adequate control is achieved, the dosage should be
`decreased to 100 meg (one spray in each nostril) daily.
`
`'
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`APOTEX_AZFL 0060194
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`PTX0059-0001 0
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`CIPLA LTD. EXHIBIT 2020 PAGE 10
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`

`

`FlONASe® (fluticasone propionate) Nasal Spray, 50 meg
`
`The maximum totat daity dosage should not exceed two sprays in each nostril (200 mcglday}. (See
`Individualization of Dosage and Clinical Trials sections.)
`FLONASE Nasal Spray is not recommended for children under 4 years of age.
`Directions for Use: Illustrated patient's instructions for proper use accompany each package of
`FLONASE Nasal Spray.
`
`HOW SUPPLIED: FLONASE Nasal Spray 50 meg is supplied in an amber glass bottle providing 120
`actuations,