Hypothalamic-pituitary-adrenal (HPA) aXis suppression, Cushing’s
`syndrome, and hyperglycemia. Monitor patients for these conditions and
`taper doses gradually. (5.2)
`Infections: Increased susceptibility to new infection and increased risk of
`exacerbation, dissemination, or reactivation of latent infection. (5.3)
`Ophthalmic effects: May include cataracts, infections, and glaucoma.
`Monitor intraocular pressure. (5.4)
`Elevated blood pressure, salt and water retention, and hypokalemia:
`Monitor blood pressure and sodium, potassium serum levels. (5.5)
`Behavioral and mood disturbances: May include euphoria, insomnia,
`mood swings, personality changes, severe depression, and psychosis. (5.6)
`GI perforation: Increased risk in patients with certain GI disorders. (5.7)
`Decreases in bone density: Monitor bone density in patients receiving
`long term corticosteroid therapy. (5.8)
`Live or live attenuated vaccines: Do not administer to patients receiving
`immunosuppressive doses of corticosteroids. (5.9)
`Negative effects on growth and development: Monitor pediatric patients
`on long-term corticosteroid therapy. (5.10)
`Use in pregnancy: Fetal harm can occur with first trimester use. (5.11)
`Weight gain: May cause increased appetite. (5.12)
`
`
`
`———————————DRUG INTERACTIONS-------------
`NSAIDS including aspirin and salicylates: Increased risk of
`gastrointestinal side effects. (7.14)
`
`SEE I 7 FOR PATIENT COUNSELING INFORIMATION
`REVISED: AJAY 2008
`
`NDA 22-220
`
`Page 4
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use TRIVARISTM
`safely and effectively. See full prescribing information for TRIVARISTM.
`
`TRIVARISTM (triamcinolone acetonide injectable suspension) 80 mg/mL
`Initial U. S. Approval: 1957
`
`--------INDICATIONS AND USAGE--——----—-
`TRIVARISTM is a corticosteroid indicated for:
`o
`Ophthalmic Use (1.1)
`o
`Intramuscular Use (1.2)
`o
`Intra-articular Use (1.3)
`
`O -
`
`---DOSAGE AND ADMINISTRATION-----
`o
`Intravitreal dosing: 4 mg per 0.05 mL (50 microliters of 80 mg/mL
`suspension). (2.3)
`Intramuscular dosing: Initial dose is 60 mg injected into the gluteal
`muscle. Eight injections are required to administer a 60 mg dose.
`(2.4).
`Intra-articular dosing: 2.5 to 5 mg for smaller joints and from 5 to 15 mg
`for larger joints depending on the disease being treated. (2.5)
`
`o
`
`o
`
`---DOSAGE FORMS AND STRENGTHS----
`o Single-use syringe containing 8 mg (80 mg/mL) 0ftriamcin010ne acetonide
`suspension. (3)
`
`O -
`
`------------CONTRAINDICATIONS-----------
`o
`Intramuscular corticosteroid preparations are contraindicated for
`idiopathic thrombocytopenic purpura. (4.1)
`Corticosteroids should not be used in cerebral malaria. (4.2)
`
`o
`
`O -
`
`n--WARNINGS AND PRECAUTIONS-----
`
`o
`
`TRIVARISTM is a suspension; it should not be administered intravenously.
`(5.1)
`
`
`Regeneron Exhibit 1056.001
`
`

`

`NDA 22-220
`
`Page 5
`
`FULL PRESCRIBING INFORA/[ATION' CONTENTS *
`I
`INDICATIONS AND USAGE
`Ophthalmic Use
`1 .1
`Intramuscular Use
`1.2
`Intra-articular Use
`1.3
`2 DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosing
`2.2
`General Administration
`2.3
`Intravitreal Dosing
`2.4
`Systemic Dosing
`2.5
`Intra-articula‘r Dosing
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`_
`4.1
`Idiopathlc Thrombocytopenic Purpura
`4‘2
`Cerebral Malana
`4'3
`Hypersens1t1v1ty
`5 WARNINGS AND PRECAUTIONS
`5.1
`Not for Intravenous Administration
`5.2
`Alteration in Endocrine Function
`53
`Increased Risks Related to Infections
`5 .4
`Ophthalmic Elfects
`5 .5
`Alterations in Cardiovascular/Renal Function
`5.6
`Behavioral and Mood Disturbances
`5 .7
`Use in patients with Gastrointestinal Disorders
`5.8
`Decreases in Bone Density
`5 .9
`Vaccination
`5.10 Effect on Growth and Development
`5.11
`Use in Pregnancy
`5 .12
`Neuromuscular Effects
`5.13 Kaposi’s Sarcoma
`5 .14 Intra—articular and Soft Tissue Administration
`6 ADVERSE REACTIONS
`6.1
`Allergic Reactions
`6.2
`Cardiovascular
`6.3,
`Dennatologic
`6.4
`Endocrine
`6.5
`fluid and Electrolyte Disturbances
`6.6
`Gastrointestinal
`6.7
`Metabolic
`
`7
`
`Musculoskeletal
`6 .8
`Neurologic/Psychiatric
`6.9
`Ophthalmic
`6.10
`Other
`6.1 1
`DRUG INTERACTIONS
`7.1
`Aminoglutethimide
`7.2
`Amphotericin B Injection and Potassium-depleting Agents
`7.3
`Antibiotics
`7.4
`Anticholinesterases
`7.5
`Anticoagulantsz Oral
`7.6
`Antidiabetics
`
`8
`
`Annmberc‘fl‘i“ Dmgs
`7-7
`Cholestyramine
`7.8
`Cyclospmine
`79
`Digitalis Glycosides
`7_10
`Estrogensg including Oral Contraceptives
`7.11
`Hepatic Enzyme Inducers
`7.12
`Ketoconazole
`7.13
`7.14 Nonsteroidal Anti-inflammatory Agents
`7.15
`Skin Tests
`7.16 Vaccines
`USE IN SPECIFIC POPULA TIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`84
`Pediatric Use
`8.5
`Geriatric Use
`1 0 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`_
`_
`_
`_
`_
`_
`*Sections or subsectlons omltted from the filll prescr1b1ng1nformat10n are not
`listed.
`
`Regeneron Exhibit 1056.002
`
`

`

`NDA 22-220
`
`Page 6
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`Ophthalmic Use
`1.1
`TRIVARISTM (triamcinolone acetonide
`injectable suspension) 80 mg/mL is
`indicated for:
`
`0
`
`0
`
`0
`
`o
`
`sympathetic ophthalmia,
`
`temporal arteritis,
`
`uveitis, and
`
`ocular inflammatory conditions
`unresponsive to topical
`corticosteroids.
`
`1.2
`
`Intramuscular Use
`
`Where oral therapy is not feasible,
`TRIVARISTM (triamcinolone acetonide
`injectable suspension) 80 mg/mL is
`indicated for intramuscular use as follows:
`
`Allergic states: Control of severe or
`incapacitating allergic conditions intractable
`to adequate trials of conventional treatment
`in asthma, atopic dermatitis, contact
`dermatitis, drug hypersensitivity reactions,
`perennial or seasonal allergic rhinitis, serum
`sickness, transfusion reactions.
`
`Dermatologic diseases: Bullous dermatitis
`herpetiformis, exfoliative erythroderma,
`mycosis fungoides, pemphigus, severe
`erythema multiforme (Stevens-Johnson
`syndrome).
`
`Endocrine disorders: Primary or secondary
`adrenocortical insufficiency (hydrocortisone
`or cortisone is the drug of choice; synthetic
`analogs may be used in conjunction with
`mineralocorticoids where applicable; in
`infancy, mineralocorticoid supplementation
`is of particular importance), congenital
`adrenal hyperplasia, hypercalcemia
`associated with cancer, nonsuppurative
`thyroiditis.
`
`Gastrointestinal diseases: To tide the patient
`over a critical period of the disease in
`regional enteritis and ulcerative colitis.
`
`Hematologic disorders: Acquired
`(autoimmune) hemolytic anemia, Diamond-
`Blackfan anemia, pure red cell aplasia,
`selected cases of secondary
`thrombocytopenia.
`
`Miscellaneous: Trichinosis with neurologic
`or myocardial involvement, tuberculous
`meningitis with subarachnoid block or
`impending block when used with
`appropriate antituberculous chemotherapy.
`
`Neoplastic diseases: For the palliative
`management of leukemias and lymphomas.
`
`Nervous system: Acute exacerbations of
`multiple sclerosis; cerebral edema associated
`with primary or metastatic brain tumor,
`craniotomy, or head injury.
`
`Renal diseases: To induce diuresis or
`
`remission of proteinuria in idiopathic
`nephrotic syndrome or that due to lupus
`erythematosus.
`
`Respiratory diseases: Berylliosis,
`fulminating or disseminated pulmonary
`tuberculosis when used concurrently with
`appropriate antituberculous chemotherapy,
`idiopathic eosinophilic pneumonias,
`symptomatic sarcoidosis.
`
`Rheumatic disorders: As adjunctive therapy
`for short-term administration (to tide the
`patient over an acute episode or
`exacerbation) in acute gouty arthritis; acute
`rheumatic carditis; ankylosing spondylitis;
`psoriatic arthritis; rheumatoid arthritis,
`including juvenile rheumatoid arthritis
`(selected cases may require low-dose
`maintenance therapy). For the treatment of
`dermatomyositis, polymyositis, and
`systemic lupus erythematosus.
`
`1.3
`
`Intra-articular Use
`
`The intra-articular or soft tissue
`
`administration of TRIVARISTM
`
`(triamcinolone acetonide injectable
`
`Regeneron Exhibit 1056.003
`
`

`

`NDA 22-220
`
`Page 7
`
`suspension) 80 mg/mL is indicated as
`adjunctive therapy for short-term
`administration (to tide the patient over an
`acute episode or exacerbation) in acute
`gouty arthritis, acute and subacute bursitis,
`acute nonspecific tenosynovitis,
`epicondylitis, rheumatoid arthritis, synovitis
`of osteoarthritis.
`
`2
`
`DOSAGE AND
`
`ADMINISTRATION
`
`Recommended Dosing
`2.1
`The initial dose of TRIVARISTM
`
`(triamcinolone acetonide injectable
`suspension) 80 mg/mL may vary from 2.5
`mg to 100 mg per day depending on the
`specific disease entity being treated (see
`DOSAGE AND ADMINISTRATION,
`2.3, 2.4, 2.5). However, in certain
`overwhelming, acute, life threatening
`situations, administration in dosages
`exceeding the usual dosages may be justified
`and may be in multiples of the oral dosages.
`It should be emphasized that dosage
`requirements are variable and must be
`individualized on the basis of the disease
`
`under treatment and the response of the
`patient.
`
`After a favorable response is noted, the
`proper maintenance dosage should be
`determined by decreasing the initial drug
`dosage in small decrements at appropriate
`time intervals until the lowest dosage which
`will maintain an adequate clinical response
`is reached. Situations which may make
`dosage adjustments necessary are changes in
`clinical status secondary to remissions or
`exacerbations in the disease process, the
`patient’s individual drug responsiveness,
`and the effect of patient exposure to stressful
`situations not directly related to the disease
`entity under treatment. In this latter situation
`it may be necessary to increase the dosage of
`the corticosteroid for a period of time
`consistent with the patient’ s condition. If
`after long-term therapy the drug is to be
`
`stopped, it is recommended that it be
`withdrawn gradually, rather than abruptly.
`
`2.2
`
`General Administration
`
`Strict Aseptic Technique Is Mandatory.
`Careful technique should be employed to
`avoid the possibility of entering a blood
`vessel or introducing infection.
`
`TRIVARISTM should be inspected visually
`for particulate matter and discoloration prior
`to administration.
`
`Always allow the pre-filled glass syringe to
`sit at room temperature for at least 30
`minutes before the procedure.
`
`Intravitreal Dosing
`2.3
`The recommended intravitreal dose is a
`
`single injection of4 mg per 0.05 mL (i.e., 50
`microliters of 80 mg/mL suspension).
`
`Preparation for Intravitreal Injection
`TRIVARISTM is available without an
`
`attached needle. Therefore, it is necessary
`to firmly attach a desired needle to the
`syringe. A 27 gauge 1/2 inch needle is
`suggested. Prepare the proper volume of
`TRIVARISTM to be injected by advancing
`the plunger to the single line marked on the
`pre-filled glass syringe shaft. Hold the
`syringe and the needle at an angle and
`express excess gel suspension over a sterile
`surface. The plunger is correctly positioned
`when white compound is no longer visible
`between the plunger and the fill line on the
`syringe. This will provide the recommended
`dose of 4 mg per 0.05 mL. Always check
`the needle to ensure it is firmly attached to
`the syringe before injecting the patient.
`
`The intravitreal injection procedure should
`be carried out under controlled aseptic
`conditions which include the use of sterile
`
`gloves, a sterile drape, and a sterile eyelid
`speculum (or equivalent). Adequate
`anesthesia and a broad-spectrum
`
`Regeneron Exhibit 1056.004
`
`

`

`
`
`
`
`
`NDA 22-220
`
`Page 8
`
`microbicide should be given prior to the
`injection.
`
`three or four divided doses (3.2 to 48
`mg/m2bsa/day).
`
`Following the intravitreal injection, patients
`should be monitored for elevation in
`
`intraocular pressure and for endophthalmitis.
`Monitoring may consist of a check for
`reperfusion of the optic nerve head
`immediately after the injection, tonometry
`within 30 minutes following the injection,
`and biomicroscopy between two and seven
`days following the injection. Patients
`should be instructed to report any symptoms
`suggestive of endophthalmitis without delay.
`
`Each syringe should only be used for the
`treatment of a single eye. If the contralateral
`eye requires treatment, a new syringe should
`be used and the sterile field, syringe, gloves,
`drapes, and eyelid speculum and injection
`needles should be changed before
`TRIVARISTM is administered to the other
`
`eye.
`
`Systemic Dosing
`2.4
`The suggested initial dose is 60 mg, injected
`deeply into the gluteal muscle. Atrophy of
`subcutaneous fat may occur if the injection
`is not properly given. Dosage is usually
`adjusted within the range of 40 to 80 mg,
`depending upon patient response and
`duration of relief. However, some patients
`may be well controlled on doses as low as
`20 mg or less.
`
`For adults, a minimum needle length of 11/2
`inches is recommended. In obese patients, a
`longer needle may be required. Use
`alternative sites for subsequent injections.
`Each syringe should only be used for a
`single treatment. Multiple injections are
`required to reach the recommended dose.
`In pediatric patients, the initial dose of
`triamcinolone may vary depending on the
`specific
`disease entity being treated. The range of
`initial doses is 0.11 to 1.6 mg/kg/day in
`
`
`
`
`
`
`
`
`For the purpose of comparison, the
`following is the equivalent milligram dosage
`of the various glucocorticoids:
`
`Methylprednisolone, 4
`
`
`
`These dose relationships generally apply to
`oral or intravenous administration of these
`
`compounds. When these substances or their
`derivatives are injected intramuscularly or
`into joint spaces, their relative properties
`may be greatly altered.
`
`Hay fever or pollen asthma: Patients with
`hay fever or pollen asthma who are not
`responding to pollen administration and
`other conventional therapy may obtain a
`remission of symptoms lasting throughout
`the pollen season after a single injection of
`40 to 100 mg.
`
`In the treatment of acute exacerbations of
`
`multiple sclerosis, daily doses of 160 mg of
`triamcinolone for a week followed by 64 mg
`every other day for one month, are
`recommended (see WARNINGS AND
`PRECAUTIONS, 5.12).
`
`Intra-articular Dosing
`2.5
`A single local injection of triamcinolone
`acetonide is frequently sufficient, but several
`injections may be needed for adequate relief
`of symptoms.
`
`Initial dose: 2.5 to 5 mg for smallerjoints
`and from 5 to 15 mg for larger joints,
`depending on the specific disease entity
`being treated. For adults, doses up to 10 mg
`for smaller areas and up to 40 mg for larger
`areas have usually been sufficient. Single
`
`Regeneron Exhibit 1056.005
`
`

`

`NDA 22-220
`
`Page 9
`
`injections into several joints, up to a total of
`80 mg, have been given.
`
`For treatment ofjoints, the usual intra-
`articular injection technique should be
`followed. If an excessive amount of synovial
`fluid is present in the joint, some, but not all,
`should be aspirated to aid in the relief of
`pain and to prevent undue dilution of the
`steroid. Each syringe should only be used
`for a single treatment. Multiple injections
`may be required to reach the recommended
`dose.
`
`With intra-articular administration, prior use
`of a local anesthetic may often be desirable.
`Care should be taken with this kind of
`
`injection, particularly in the deltoid region,
`to avoid injecting the gel suspension into the
`tissues surrounding the site, since this may
`lead to tissue atrophy.
`
`In treating acute nonspecif1c tenosynovitis,
`care should be taken to ensure that the
`
`injection of the corticosteroid is made into
`the tendon sheath, rather than the tendon
`substance. Epicondylitis may be treated by
`infiltrating the preparation into the area of
`greatest tenderness.
`
`3
`
`DOSAGE FORMS AND
`
`STRENGTHS
`
`Single-use 0.1 mL syringe containing 8 mg
`(80 mg/mL) of triamcinolone acetonide
`suspension.
`
`4
`
`CONTRAINDICATIONS
`
`Idiopathic Thrombocytopenic
`4.1
`Purpura
`Intramuscular corticosteroid preparations are
`contraindicated for idiopathic
`thrombocytopenic purpura.
`
`4.2
`
`Cerebral Malaria
`
`Corticosteroids should not be used in
`
`cerebral malaria.
`
`4.3
`
`Hypersensitivity
`
`TRIVARISTM (triamcinolone acetonide
`injectable suspension) 80 mg/mL is
`contraindicated in patients who are
`hypersensitive to triamcinolone or any
`components of this product.
`
`5
`
`WARNINGS AND
`
`PRECAUTIONS
`
`5.1
`
`Not for Intravenous
`
`Administration
`
`Because TRIVARISTM (triamcinolone
`acetonide injectable suspension) 80 mg/mL
`is a suspension, it should not be
`administered intravenously. Strict aseptic
`technique is mandatory.
`
`5.2
`
`Alterations in Endocrine Function
`
`Hypothalamic-pituitary-adrenal (HPA) axis
`suppression, Cushing's syndrome, and
`hyperglycemia. Monitor patients for these
`conditions with chronic use.
`
`Corticosteroids can produce reversible HPA
`aXis suppression with the potential for
`glucocorticosteroid insufficiency after
`withdrawal of treatment. Drug induced
`secondary adrenocortical insuff1ciency may
`be minimized by gradual reduction of
`dosage. This type of relative insuff1ciency
`may persist for months after discontinuation
`of therapy; therefore, in any situation of
`stress occurring during that period, hormone
`therapy should be reinstituted.
`
`Since mineralocorticoid secretion may be
`impaired, salt and/or a mineralocorticoid
`should be administered concurrently.
`Mineralocorticoid supplementation is of
`particular importance in infancy.
`
`Metabolic clearance of corticosteroids is
`
`decreased in hypothyroid patients and
`increased in hyperthyroid patients. Changes
`in thyroid status of the patient may
`necessitate adjustment in dosage.
`
`5.3
`
`Increased Risks Related to
`
`Infections
`
`Regeneron Exhibit 1056.006
`
`

`

`NDA 22-220
`
`Page 10
`
`Corticosteroids may increase the risks
`related to infections with any pathogen,
`including viral, bacterial, fungal,
`protozoan, or helminthic infections. The
`degree to which the dose, route and
`duration of corticosteroid administration
`
`correlates with the specific risks of
`infection is not well characterized,
`however, with increasing doses of
`corticosteroids, the rate of occurrence of
`infectious complications increases.
`
`Corticosteroids may mask some signs of
`infection and may reduce resistance to
`new infections.
`
`Corticosteroids may exacerbate
`infections and increase risk of
`
`disseminated infection. The use of
`
`TRIVARISTM in active tuberculosis
`
`should be restricted to those cases of
`
`fulminating or disseminated tuberculosis
`in which the corticosteroid is used for the
`
`management of the disease in
`conjunction with an appropriate
`antituberculous regimen.
`
`Chickenpox and measles can have a more
`serious or even fatal course in non-
`
`immune children or adults on
`
`corticosteroids. In children or adults who
`
`have not had these diseases, particular
`care should be taken to avoid exposure. If
`a patient is exposed to chickenpox,
`prophylaxis with varicella zoster immune
`globulin (VZIG) may be indicated. If a
`patient is exposed to measles,
`prophylaxis with pooled intramuscular
`immunoglobulin (1G) may be indicated.
`If chickenpox develops, treatment with
`antiviral agents may be considered.
`
`Corticosteroids should be used with great
`care in patients with known or suspected
`Strongyloides (threadworm) infestation.
`In such patients, corticosteroid-induced
`immunosuppression may lead to
`Strongyloides hyperinfection and
`
`dissemination with widespread larval
`migration, often accompanied by severe
`enterocolitis and potentially fatal gram-
`negative septicemia.
`
`0 Corticosteroids may exacerbate systemic
`fungal infections and therefore should not
`be used in the presence of such infections
`unless they are needed to control drug
`reactions.
`
`0 Corticosteroids may increase risk of
`reactivation or exacerbation of latent
`
`infection. If corticosteroids are indicated
`
`in patients with latent tuberculosis or
`tuberculin reactivity, close observation is
`necessary as reactivation of the disease
`may occur. During prolonged
`corticosteroid therapy, these patients
`should receive chemoprophylaxis.
`
`0 Corticosteroids may activate latent
`amebiasis. Therefore, it is recommended
`that latent or active amebiasis be ruled
`
`out before initiating corticosteroid
`therapy in any patient who has spent time
`in the tropics or in any patient with
`unexplained diarrhea.
`
`Ophthalmic Effects
`5.4
`Prolonged use of corticosteroids may
`produce posterior subcapsular cataracts,
`glaucoma with possible damage to the optic
`nerves, and may enhance the establishment
`of secondary ocular infections due to fungi
`or viruses.
`
`The use of oral corticosteroids is not
`
`recommended in the treatment of optic
`neuritis and may lead to an increase in the
`risk of new episodes.
`
`Intraocular pressure may become elevated in
`some individuals. If steroid therapy is
`continued for more than 6 weeks, intraocular
`pressure should be monitored.
`
`Regeneron Exhibit 1056.007
`
`

`

`NDA 22-220
`
`Page 11
`
`Corticosteroids should be used cautiously in
`patients with a history of ocular herpes
`simplex because of possible corneal
`perforation. Corticosteroids should not be
`used in active ocular herpes simplex.
`
`Endophlhalmitis
`The rate of infectious culture positive
`endophthalmitis is 0.5%. Proper aseptic
`techniques should always be used when
`administering triamcinolone acetonide.
`
`In addition, patients should be monitored
`following the injection to permit early
`treatment should an infection occur.
`
`5.5
`
`Alterations in
`
`Cardiovascular/Renal Function
`
`Corticosteroids can cause elevation of blood
`
`pressure, salt and water retention, and
`increased excretion of potassium and
`calcium. These effects are less likely to
`occur with the synthetic derivatives except
`when used in large doses. Dietary salt
`restriction and potassium supplementation
`may be necessary. These agents should be
`used with caution in patients with
`hypertension, congestive heart failure, or
`renal insufficiency.
`
`Literature reports suggest an association
`between use of corticosteroids and left
`
`ventricular free wall rupture after a recent
`myocardial infarction; therefore, therapy
`with corticosteroids should be used with
`
`caution in these patients.
`
`5.6
`
`Behavioral and Mood
`
`Disturbances
`
`Corticosteroid use may be associated with
`central nervous system effects ranging from
`euphoria, insomnia, mood swings,
`personality changes, and severe depression,
`to frank psychotic manifestations. Also,
`existing emotional instability or psychotic
`tendencies may be aggravated by
`corticosteroids.
`
`5.7
`
`Use in Patients with
`
`Gastrointestinal Disorders
`
`There is an increased risk of gastrointestinal
`perforation in patients with certain GI
`disorders. Signs of GI perforation, such as
`peritoneal irritation, may be masked in
`patients receiving corticosteroids.
`
`Corticosteroids should be used with caution
`
`if there is a probability of impending
`perforation, abscess or other pyogenic
`infections; diverticulitis; fresh intestinal
`anastomoses; and active or latent peptic
`ulcer.
`
`Decrease in Bone Density
`5.8
`Corticosteroids decrease bone formation and
`
`increase bone resorption both through their
`effect on calcium regulation (i.e., decreasing
`absorption and increasing excretion) and
`inhibition of osteoblast function. This,
`together with a decrease in the protein
`matrix of the bone secondary to an increase
`in protein catabolism, and reduced sex
`hormone production, may lead to inhibition
`of bone growth in children and adolescents
`and the development of osteoporosis at any
`age. Special consideration should be given
`to patients at increased risk of osteoporosis
`(i.e., postmenopausal women) before
`initiating corticosteroid therapy and bone
`density should be monitored in patients on
`long term corticosteroid therapy.
`
`5.9
`
`Vaccination
`
`Administration of live or live, attenuated
`vaccines is contraindicated in patients
`receiving immunosuppressive doses of
`corticosteroids. Killed or inactivated
`
`vaccines may be administered, however, the
`response to such vaccines can not be
`predicted. Immunization procedures may be
`undertaken in patients who are receiving
`corticosteroids as replacement therapy, e.g.,
`for Addison's disease.
`
`While on corticosteroid therapy, patients
`should not be vaccinated against smallpox.
`Other immunization procedures should not
`
`Regeneron Exhibit 1056.008
`
`

`

`NDA 22-220
`
`Page 12
`
`be undertaken in patients who are on
`corticosteroids, especially on high dose,
`because of possible hazards of neurological
`complications and a lack of antibody
`response.
`
`5.10
`
`Effect on Growth and
`
`Development
`Long-term use of corticosteroids can have
`negative effects on growth and development
`in children.
`
`Growth and development of pediatric
`patients on prolonged corticosteroid therapy
`should be carefully monitored.
`
`5.11 Use in Pregnancy
`Triamcinolone acetonide can cause fetal
`
`harm when administered to a pregnant
`woman. Human and animal studies suggest
`that use of corticosteroids during the first
`trimester of pregnancy is associated with an
`increased risk of orofacial clefts, intrauterine
`growth restriction and decreased birth
`weight. If this drug is used during
`pregnancy, or if the patient becomes
`pregnant while using this drug, the patient
`should be apprised of the potential hazard to
`the fetus. (see USE IN SPECIFIC
`POPULATIONS, 8.1).
`
`5.12 Neuromuscular Effects
`
`Although controlled clinical trials have
`shown corticosteroids to be effective in
`
`speeding the resolution of acute
`exacerbations of multiple sclerosis, they do
`not show that they affect the ultimate
`outcome or natural history of the disease.
`The studies do show that relatively high
`doses of corticosteroids are necessary to
`demonstrate a significant effect.
`(see DOSAGE AND
`ADMINISTRATION, 2.4).
`
`An acute myopathy has been observed with
`the use of high doses of corticosteroids,
`most often occurring in patients with
`disorders of neuromuscular transmission
`
`(e.g., myasthenia gravis), or in patients
`receiving concomitant therapy with
`neuromuscular blocking drugs (e.g.,
`pancuronium). This acute myopathy is
`generalized, may involve ocular and
`respiratory muscles, and may result in
`quadriparesis. Elevation of creatine kinase
`may occur. Clinical improvement or
`recovery after stopping corticosteroids may
`require weeks to years.
`
`5.13 Kaposi's Sarcoma
`Kaposi's sarcoma has been reported to occur
`in patients receiving corticosteroid therapy,
`most often for chronic conditions.
`
`Discontinuation of corticosteroids may
`result in clinical improvement.
`
`5.14
`
`Intra-articular and Soft Tissue
`
`Administration
`
`Intra-articularly injected corticosteroids may
`be systemically absorbed.
`
`Appropriate examination of any joint fluid
`present is necessary to exclude a septic
`process.
`
`A marked increase in pain accompanied by
`local swelling, further restriction ofjoint
`motion, fever, and malaise are suggestive of
`septic arthritis. If this complication occurs
`and the diagnosis of sepsis is confirmed,
`appropriate antimicrobial therapy should be
`instituted.
`
`Injection of a steroid into an infected site is
`to be avoided. Local injection of a steroid
`into a previously infected joint is not usually
`recommended.
`
`Corticosteroid injection into unstable joints
`is generally not recommended.
`
`Intra-articular injection may result in
`damage to joint tissues (see ADVERSE
`REACTIONS, 6.8).
`
`6
`
`ADVERSE REACTIONS
`
`Regeneron Exhibit 1056.009
`
`

`

`NDA 22-220
`
`Page 13
`
`(listed alphabetically under each
`subsection)
`
`The following adverse reactions may be
`associated with corticosteroid therapy:
`
`Allergic Reactions
`6.1
`Anaphylactoid reaction, anaphylaXis,
`angioedema.
`
`6.2
`
`Cardiovascular
`
`Bradycardia, cardiac arrest, cardiac
`arrhythmias, cardiac enlargement,
`circulatory collapse, congestive heart failure,
`fat embolism, hypertension, hypertrophic
`cardiomyopathy in premature infants,
`myocardial rupture following recent
`myocardial infarction (see WARNINGS
`AND PRECAUTIONS, 5.5), pulmonary
`edema, syncope, tachycardia,
`thromboembolism, thrombophlebitis,
`vasculitis.
`
`Dermatologic
`6.3
`Acne, allergic dermatitis, cutaneous and
`subcutaneous atrophy, dry scaly skin,
`ecchymoses and petechiae, edema,
`erythema, hyperpigmentation,
`hypopigmentation, impaired wound healing,
`increased sweating, lupus erythematosus-
`like lesions, purpura, rash, sterile abscess,
`striae, suppressed reactions to skin tests, thin
`fragile skin, thinning scalp hair, urticaria.
`
`6.4
`
`Endocrine
`
`Decreased carbohydrate and glucose
`tolerance, development of cushingoid state,
`glycosuria, hirsutism, hypertrichosis,
`increased requirements for insulin or oral
`hypoglycemic agents in diabetes,
`manifestations of latent diabetes mellitus,
`menstrual irregularities, secondary
`adrenocortical and pituitary
`unresponsiveness (particularly in times of
`stress, as in trauma, surgery, or illness),
`suppression of growth in pediatric patients.
`
`Congestive heart failure in susceptible
`patients, fluid retention, hypokalemic
`alkalosis, potassium loss, sodium retention.
`
`6.6
`
`Gastrointestinal
`
`Abdominal distention, bowel/bladder
`dysfunction (after intrathecal
`administration), elevation in serum liver
`enzyme levels (usually reversible upon
`discontinuation), hepatomegaly, increased
`appetite, nausea, pancreatitis, peptic ulcer
`with possible perforation and hemorrhage,
`perforation of the small and large intestine
`(particularly in patients with inflammatory
`bowel disease), ulcerative esophagitis.
`
`6.7 Metabolic
`
`Negative nitrogen balance due to protein
`catabolism.
`
`6.8 Musculoskeletal
`
`Aseptic necrosis of femoral and humeral
`heads, calcinosis (following intra-articular
`or intralesional use), Charcot-like
`arthropathy, loss of muscle mass, muscle
`weakness, osteoporosis, pathologic fracture
`of long bones, post injection flare (following
`intra-articular use), steroid myopathy,
`tendon rupture, vertebral compression
`fractures.
`
`Neurologic/Psychiatric
`6.9
`Convulsions, depression, emotional
`instability, euphoria, headache, increased
`intracranial pressure with papilledema
`(pseudotumor cerebri) usually following
`discontinuation of treatment, insomnia,
`mood swings, neuritis, neuropathy,
`paresthesia, personality changes, psychic
`disorders, vertigo. Arachnoiditis, meningitis,
`paraparesis/paraplegia, and sensory
`disturbances have occurred after intrathecal
`
`administration
`
`6.10 Ophthalmic
`Abnormal sensation in eye, anterior chamber
`cells, anterior chamber flare, cataract,
`
`6.5
`
`Fluid and Electrolyte Disturbances
`
`cataract cortical, cataract nuclear, cataract
`
`Regeneron Exhibit 1056.010
`
`

`

`NDA 22-220
`
`Page 14
`
`subcapsular, conjunctival haemorrhage,
`exophthalmos, eye irritation, eye pain, eye
`pruritus, foreign body sensation in eyes,
`glaucoma, intraocular pressure increased,
`injection site haemorrhage, lacrimation
`increased, vitreous detachment, vitreous
`floaters and rare instances of blindness
`
`associated with intravitreal or periocular
`injections.
`
`6.11 Other
`
`Abnormal fat deposits, decreased resistance
`to infection, hiccups, increased or decreased
`motility and number of spermatozoa,
`malaise, moon face, weight gain.
`
`7
`
`DRUG INTERACTIONS
`
`Aminoglutethimide
`7.1
`Aminoglutethimide may lead to a loss of
`corticosteroid-induced adrenal suppression.
`
`7.2
`
`Amphotericin B Injection and
`Potassium-depleting Agents
`When corticosteroids are administered
`
`concomitantly with potassium-depleting
`agents (i.e., amphotericin B, diuretics),
`patients should be observed closely for
`development of hypokalemia. There have
`been cases reported in which concomitant
`use of amphotericin B and hydrocortisone
`was followed by cardiac enlargement and
`congestive heart failure.
`
`7.3
`
`Antibiotics
`
`Macrolide antibiotics have been reported to
`cause a significant decrease in corticosteroid
`clearance.
`
`7.4
`
`Anticholinesterases
`
`Concomitant use of anticholinesterase
`
`agents and corticosteroids may produce
`severe weakness in patients with myasthenia
`gravis. If possible, anticholinesterase agents
`should be withdrawn at least 24 hours before
`
`initiating corticosteroid therapy.
`
`Anticoagulants, Oral
`7.5
`Coadministration of corticosteroids and
`
`warfarin usually results in inhibition of
`response to warfarin, although there have
`been some conflicting reports. Therefore,
`coagulation indices should be monitored
`frequently to maintain the desired
`anticoagulant effect.
`
`7.6
`
`Antidiabetics
`
`Because corticosteroids may increase blood
`glucose concentrations, dosage adjustments
`of antidiabetic agents may be required.
`
`Antitubercular Drugs
`7.7
`Serum concentrations of isoniazid may be
`decreased.
`
`Cholestyramine
`7.8
`Cholestyramine may increase the clearance
`of corticosteroids.
`
`Cyclosporine
`7.9
`Increased activity of both cyclosporine and
`corticosteroids may occur when the two are
`used concurrently. Convulsions have been
`reported with this concurrent use.
`
`7.10 Digitalis Glycosides
`Patients on digitalis glycosides may be at
`increased risk of arrhythmias due to
`hypokalemia.
`
`Estrogens, including Oral
`7.11
`Contraceptives
`Estrogens may decrease the hepatic
`metabolism of certain corticosteroids,
`thereby increasing their effect.
`
`7.12 Hepatic Enzyme Inducers
`(e.g., barbiturates, phenytoin,
`carbamazepine, and rifa