Dulera哮喘新药FDA说明书(英文)

1HIGHLIGHTS OF PRESCRIBING INFORMATIONdays of stopping an MAOI intended to treat psychiatric disorders.These highlights do not include all the information needed to use In addition, do not start Cymbalta in a patient who is being treated CYMBALTA safely and effectively. See full prescribing with linezolid or intravenous methylene blue (4.1) information for CYMBALTA. •Use in patients with uncontrolled narrow-angle glaucoma (4.2)CYMBALTA (duloxetine hydrochloride) Delayed-Release Capsules for Oral Use.Initial U.S. Approval: 2004WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Increased risk of suicidal thinking and behavior in children,adolescents, and young adults taking antidepressants (5.1) • Monitor for worsening and emergence of suicidal thoughtsand behaviors (5.1) • Cymbalta is not approved for use in pediatric patients (8.4) ---------------------------RECENT MAJOR CHANGES --------------------------Dosage and Administration:Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders (2.5) 10/2012 Use of Cymbalta with Other MAOIs such as Linezolid or Methylene Blue (2.6) 10/2012 Contraindications – Monoamine Oxidase Inhibitors (4.1) 10/2012 Warnings and Precautions: Serotonin Syndrome (5.4) 10/2012 Discontinuation of Treatment with Cymbalta (5.7) 08/2012 ----------------------------INDICATIONS AND USAGE ---------------------------Cymbalta ® is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: • Major Depressive Disorder (MDD) (1.1) • Generalized Anxiety Disorder (GAD) (1.2)• Diabetic Peripheral Neuropathic Pain (DPNP) (1.3)• Fibromyalgia (FM) (1.4)• Chronic Musculoskeletal Pain (1.5)------------------------DOSAGE AND ADMINISTRATION-----------------------• Cymbalta should generally be administered once daily withoutregard to meals. Cymbalta should be swallowed whole andshould not be chewed or crushed, nor should the capsule beopened and its contents be sprinkled on food or mixed with liquids (2) Indication Starting Dose Target DoseMaximumDose MDD (2.1, 2.2)40 mg/day to 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day 120 mg/day GAD (2.1) 60 mg/day 60 mg/day (once daily) 120mg/day DPNP (2.1) 60 mg/day 60 mg/day (once daily) 60 mg/day FM (2.1)30 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain (2.1)30 mg/day 60 mg/day (once daily) 60 mg/day • Some patients may benefit from starting at 30 mg once daily (2.1) • There is no evidence that doses greater than 60 mg/day confersadditional benefit, while some adverse reactions were observed to be dose-dependent (2.1) • D iscontinuing Cymbalta: A gradual dose reduction isrecommended to avoid discontinuation symptoms (2.4, 5.7) ----------------------DOSAGE FORMS AND STRENGTHS---------------------20 mg, 30 mg, and 60 mg capsules (3)-------------------------------CONTRAINDICATIONS ------------------------------• Serotonin Syndrome and MAOIs: Do not use MAOIs intended totreat psychiatric disorders with Cymbalta or within 5 days ofstopping treatment with Cymbalta. Do not use Cymbalta within 14------------------------WARNINGS AND PRECAUTIONS -----------------------• Suicidality: Monitor for clinical worsening and suicide risk (5.1) • Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with Cymbalta. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cymbalta should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease (5.2)• Orthostatic Hypotension and Syncope: Cases have been reportedwith duloxetine therapy (5.3)• Serotonin Syndrome: Serotonin syndrome has been reported withSSRIs and SNRIs, including with Cymbalta, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort). If such symptoms occur, discontinue Cymbalta and initiate supportive treatment. If concomitant use of Cymbalta with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.4) • Abnormal Bleeding: Cymbalta may increase the risk of bleedingevents. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation (5.5, 7.4)• Severe Skin Reactions: Severe skin reactions, including erythemamultiforme and Stevens-Johnson Syndrome (SJS), can occur with Cymbalta. Cymbalta should be discontinued at the firstappearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified. (5.6)• Discontinuation: May result in symptoms, including dizziness,headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue (5.7) • Activation of mania or hypomania has occurred (5.8)• Seizures: Prescribe with care in patients with a history of seizuredisorder (5.9)• Blood Pressure: Monitor blood pressure prior to initiatingtreatment and periodically throughout treatment (5.10)• Inhibitors of CYP1A2 or Thioridazine: Should not administer withCymbalta (5.11)• Hyponatremia: Cases of hyponatremia have been reported (5.12) • Hepatic Insufficiency and Severe Renal Impairment: Should ordinarily not be administered to these patients (5.13)• Controlled Narrow-Angle Glaucoma: Use cautiously in thesepatients (5.13)• Glucose Control in Diabetes: In diabetic peripheral neuropathicpain patients, small increases in fasting blood glucose, and HbA 1c have been observed (5.13)• Conditions that Slow Gastric Emptying: Use cautiously in these patients (5.13)• Urinary Hesitation and Retention (5.14)-------------------------------ADVERSE REACTIONS------------------------------• Most common adverse reactions (≥5% and at least twice theincidence of placebo patients): nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis (6.3). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or /medwatch.-------------------------------DRUG INTERACTIONS ------------------------------• Potent inhibitors of CYP1A2 should be avoided (7.1). • Potent inhibitors of CYP2D6 may increase duloxetineconcentrations (7.2).• Duloxetine is a moderate inhibitor of CYP2D6 (7.9). ------------------------USE IN SPECIFIC POPULATIONS-----------------------• Pregnancy and Nursing Mothers: Use only if the potential benefitjustifies the potential risk to the fetus or child (2.3, 8.1, 8.3).See 17 for PATIENT COUNSELING INFORMATION and MedicationGuide Revised: 10/20122FULL PRESCRIBING INFORMATION: CONTENTS*WARNING: SUICIDAL THOUGHTS AND BEHAVIORS1 INDICATIONSANDUSAGE1.1 Major Depressive Disorder1.2 Generalized Anxiety Disorder1.3 Diabetic Peripheral Neuropathic Pain1.4 F ibromyalgia1.5 Chronic Musculoskeletal Pain2 DOSAGEANDADMINISTRATION2.1 I nitialTreatment2.2 M aintenance/Continuation/ExtendedTreatment2.3 Dosing in Special Populations2.4 D iscontinuingCymbalta2.5 Switching a Patient To or From a Monoamine OxidaseInhibitor (MAOI) Intended to Treat Psychiatric Disorders2.6 Use of Cymbalta with Other MAOIs such as Linezolid orMethylene Blue3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS4.1 Monoamine Oxidase Inhibitors (MAOIs)4.2 U ncontrolledNarrow-AngleGlaucoma5 WARNINGSANDPRECAUTIONS5.1 Suicidal Thoughts and Behaviors in Adolescents andYoung Adults5.2 H epatotoxicity5.3 Orthostatic Hypotension and Syncope5.4 S erotoninSyndrome5.5 A bnormalBleeding5.6 Severe Skin Reactions5.7 Discontinuation of Treatment with Cymbalta5.8 Activation of Mania/Hypomania5.9 S eizures5.10 Effect on Blood Pressure5.11 Clinically Important Drug Interactions5.12 H yponatremia5.13 Use in Patients with Concomitant Illness5.14 Urinary Hesitation and Retention5.15 L aboratoryTests6 ADVERSEREACTIONS6.1 Clinical Trial Data Sources6.2 Adverse Reactions Reported as Reasons forDiscontinuation of Treatment in Placebo-Controlled Trials6.3 Most Common Adverse Reactions6.4 Adverse Reactions Occurring at an Incidence of 5% orMore Among Duloxetine-Treated Patients in Placebo-Controlled Trials6.5 Adverse Reactions Occurring at an Incidence of 2% orMore Among Duloxetine-Treated Patients in Placebo-Controlled Trials6.6 Effects on Male and Female Sexual Function6.7 Vital Sign Changes6.8 W eightChanges6.9 L aboratoryChanges6.10 E lectrocardiogramChanges6.11 Other Adverse Reactions Observed During thePremarketing and Postmarketing Clinical Trial Evaluationof Duloxetine6.12 Postmarketing Spontaneous Reports7 DRUGINTERACTIONS7.1 Inhibitors of CYP1A27.2 Inhibitors of CYP2D67.3 Dual Inhibition of CYP1A2 and CYP2D67.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs,Aspirin, and Warfarin)7.5 L orazepam7.6 T emazepam7.7 Drugs that Affect Gastric Acidity7.8 Drugs Metabolized by CYP1A27.9 Drugs Metabolized by CYP2D67.10 Drugs Metabolized by CYP2C97.11 Drugs Metabolized by CYP3A7.12 Drugs Metabolized by CYP2C197.13 Monoamine Oxidase Inhibitors (MAOIs)7.14 S erotonergicDrugs7.15 A lcohol7.16 C NSDrugs7.17 Drugs Highly Bound to Plasma Protein8 USE IN SPECIFIC POPULATIONS8.1 P regnancy8.2 Labor and Delivery8.3 N ursingMothers8.4 P ediatricUse8.5 G eriatricUse8.6 G ender8.7 S mokingStatus8.8 R ace8.9 H epaticInsufficiency8.10 Severe Renal Impairment9 DRUGABUSEANDDEPENDENCE9.2 A buse9.3 D ependence10 OVERDOSAGE10.1 Signs and Symptoms10.2 M anagementofOverdose11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 P harmacodynamics12.3 P harmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES14.1 Major Depressive Disorder14.2 Generalized Anxiety Disorder14.3 Diabetic Peripheral Neuropathic Pain14.4 F ibromyalgia14.5 Chronic Musculoskeletal Pain16 HOW SUPPLIED/STORAGE AND HANDLING16.1 H owSupplied16.2 S torage17 PATIENT COUNSELING INFORMATION17.1 Information on Medication Guide17.2 Suicidal Thoughts and Behaviors17.3 M edicationAdministration17.4 Continuing the Therapy Prescribed17.5 H epatotoxicity17.6 A lcohol17.7 Orthostatic Hypotension and Syncope17.8 S erotoninSyndrome17.9 A bnormalBleeding17.10 Severe Skin Reaction17.11 Discontinuation of Treatment17.12 Activation of Mania or Hypomania17.13 Seizures17.14 Effects on Blood Pressure17.15 Concomitant Medications17.16 Hyponatremia17.17 Concomitant Illnesses17.18 Urinary Hesitancy and Retention17.19 Pregnancy and Breast Feeding17.20 Interference with Psychomotor Performance* Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATIONWARNING: SUICIDAL THOUGHTS AND BEHAVIORSAntidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)].In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)].Cymbalta is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].USAGEAND1 INDICATIONS1.1 Major Depressive DisorderCymbalta is indicated for the treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in four short-term and one maintenance trial in adults [see Clinical Studies (14.1)].A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.AnxietyDisorder1.2 GeneralizedCymbalta is indicated for the treatment of generalized anxiety disorder (GAD). The efficacy of Cymbalta was established in three short-term trials and one maintenance trial in adults [see Clinical Studies (14.2)].Generalized anxiety disorder is defined by the DSM-IV as excessive anxiety and worry, present more days than not, for at least 6 months. The excessive anxiety and worry must be difficult to control and must cause significant distress or impairment in normal functioning. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and/or sleep disturbance.1.3 Diabetic Peripheral Neuropathic PainCymbalta is indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy [see Clinical Studies (14.3)].1.4 FibromyalgiaCymbalta is indicated for the management of fibromyalgia (FM) [see Clinical Studies (14.4)].PainMusculoskeletal1.5 ChronicCymbalta is indicated for the management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain (CLBP) and chronic pain due to osteoarthritis [see Clinical Studies (14.5)].2 DOSAGE AND ADMINISTRATIONCymbalta should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Cymbalta can be given without regard to meals.Treatment2.1 InitialMajor Depressive Disorder — Cymbalta should be administered at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated [see Clinical Studies (14.1)].Generalized Anxiety Disorder — For most patients, the recommended starting dose for Cymbalta is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies (14.2)].Diabetic Peripheral Neuropathic Pain — The recommended dose for Cymbalta is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered.Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.10), and Clinical Pharmacology (12.3)].Fibromyalgia — The recommended dose for Cymbalta is 60 mg administered once daily. Treatment should begin at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.4)].Chronic Musculoskeletal Pain — The recommended dose for Cymbalta is 60 mg once daily. Dosing may be started at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.5)].Treatment2.2 M aintenance/Continuation/ExtendedMajor Depressive Disorder — It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with Cymbalta as monotherapy. Cymbalta should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)].Generalized Anxiety Disorder — It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with Cymbalta as monotherapy. Cymbalta should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].Diabetic Peripheral Neuropathic Pain — As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Cymbalta must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.Fibromyalgia — Fibromyalgia is recognized as a chronic condition. The efficacy of Cymbalta in the management of fibromyalgia has been demonstrated in placebo-controlled studies up to 3 months. The efficacy of Cymbalta was not demonstrated in longer studies; however, continued treatment should be based on individual patient response.Chronic Musculoskeletal Pain — The efficacy of Cymbalta has not been established in placebo-controlled studies beyond 13 weeks.2.3 Dosing in Special PopulationsHepatic Insufficiency — It is recommended that Cymbalta should ordinarily not be administered to patients with any hepatic insufficiency [see Warnings and Precautions (5.13) and Use in Specific Populations (8.9)].Severe Renal Impairment — Cymbalta is not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min) [see Warnings and Precautions (5.13) and Use in Specific Populations (8.10)].Elderly Patients — No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose [see Use in Specific Populations (8.5)].Pregnant Women — There are no adequate and well-controlled studies in pregnant women; therefore, Cymbalta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].Lilly maintains a pregnancy registry to monitor the pregnancy outcomes of women exposed to Cymbalta while pregnant. Healthcare providers are encouraged to register any patient who is exposed to Cymbalta during pregnancy by calling the Cymbalta Pregnancy Registry at 1-866-814-6975 or by visiting Nursing Mothers — Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended [see Use in Specific Populations (8.3)].2.4 D iscontinuingCymbaltaSymptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)].2.5 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat PsychiatricDisordersAt least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Cymbalta. Conversely, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].2.6 Use of Cymbalta with Other MAOIs such as Linezolid or Methylene BlueDo not start Cymbalta in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].In some cases, a patient already receiving Cymbalta therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Cymbalta should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Cymbalta may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.4)].The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Cymbalta is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)].3 DOSAGE FORMS AND STRENGTHSCymbalta is available as delayed release capsules:20 mg opaque green capsules imprinted with “Lilly 3235 20mg”30 mg opaque white and blue capsules imprinted with “Lilly 3240 30mg”60 mg opaque green and blue capsules imprinted with “Lilly 3237 60mg”60 mg opaque green and blue capsules imprinted with “Lilly 3270 60mg”4 CONTRAINDICATIONS4.1 Monoamine Oxidase Inhibitors (MAOIs)The use of MAOIs intended to treat psychiatric disorders with Cymbalta or within 5 days of stopping treatment with Cymbalta is contraindicated because of an increased risk of serotonin syndrome. The use of Cymbalta within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.5) and Warnings and Precautions (5.4)].Starting Cymbalta in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.6) and Warnings and Precautions (5.4)].4.2 Uncontrolled Narrow-Angle GlaucomaIn clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma [see Warnings and Precautions (5.13)].PRECAUTIONS5 WARNINGSAND5.1 Suicidal Thoughts and Behaviors in Adolescents and Young AdultsPatients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.Table 1Age Range Drug-Placebo Difference in Number of Cases ofSuicidality per 1000 Patients TreatedIncreases Compared to Placebo<18 14 additional cases18-24 5 additional cases Decreases Compared to Placebo25-64 1 fewer case≥65 6 fewer casesNo suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was notsufficient to reach any conclusion about drug effect on suicide.It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, thereis substantial evidence from placebo-controlled maintenance trials in adults with depression that the use ofantidepressants can delay the recurrence of depression.All patients being treated with antidepressants for any indication should be monitored appropriately andobserved closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initialfew months of a course of drug therapy, or at times of dose changes, either increases or decreases.The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness,impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatricpatients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatricand nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening ofdepression and/or the emergence of suicidal impulses has not been established, there is concern that such symptomsmay represent precursors to emerging suicidality.Consideration should be given to changing the therapeutic regimen, including possibly discontinuing themedication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptomsthat might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset,or were not part of the patient’s presenting symptoms.If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible,but with recognition that discontinuation can be associated with certain symptoms [see Dosage and Administration (2.4)and Warnings and Precautions (5.7) for descriptions of the risks of discontinuation of Cymbalta].Families and caregivers of patients being treated with antidepressants for major depressive disorder orother indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Cymbalta should bewritten for the smallest quantity of capsules consistent with good patient management, in order to reduce therisk of overdose.Screening Patients for Bipolar Disorder — A major depressive episode may be the initial presentation of bipolardisorder. It is generally believed (though not established in controlled trials) that treating such an episode with anantidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolardisorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior toinitiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened todetermine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including afamily history of suicide, bipolar disorder, and depression. It should be noted that Cymbalta (duloxetine) is not approvedfor use in treating bipolar depression.5.2 HepatotoxicityThere have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta. These cases havepresented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Otherpostmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patientswith chronic liver disease or cirrhosis.Cymbalta increased the risk of elevation of serum transaminase levels in development program clinical trials. Livertransaminase elevations resulted in the discontinuation of 0.3% (89/29,435) of Cymbalta-treated patients. In mostpatients, the median time to detection of the transaminase elevation was about two months. In placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.37% (132/9611) of Cymbalta-treated patients compared to 0.49% (35/7182) of placebo-treated patients. In placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.。

美国FDA批准哮喘药Advair Diskus首个仿制药上市夏训明(编译)【摘要】葛兰素史克(Glaxo SmithKline)公司的哮喘/慢性阻塞性肺病治疗药物Advair Diskus的专利到期,该药是复方药,有效成分为丙酸氟替卡松(fluticasone propionate,CAS登记号为80474-14-2)和沙美特罗(salmeterol,CAS登记号为89365-50-4),剂型为吸入性粉剂。

美国FDA于2019年1月30日批准该药的首个非专利仿制药(通用名药物)上市,适用症为用于4岁及以上患者治疗哮喘病,也可用于慢性阻塞性肺病(chronic obstructive pulmonary disease,COPD)患者治疗气流受限及减轻病情加重。

【期刊名称】《广东药科大学学报》【年(卷),期】2019(035)001【总页数】1页(P96-96)【关键词】美国FDA;哮喘药;仿制药;FDA批准;上市;salmeterol;慢性阻塞性肺病;pulmonary【作者】夏训明(编译)【作者单位】【正文语种】中文【中图分类】R95葛兰素史克(Glaxo SmithKline)公司的哮喘/慢性阻塞性肺病治疗药物AdvairDiskus的专利到期，该药是复方药，有效成分为丙酸氟替卡松(fluticasone propionate，CAS登记号为80474-14-2)和沙美特罗(salmeterol，CAS登记号为89365-50-4)，剂型为吸入性粉剂。

美国FDA于2019年1月30日批准该药的首个非专利仿制药(通用名药物)上市，适用症为用于4岁及以上患者治疗哮喘病，也可用于慢性阻塞性肺病(chronic obstructive pulmonary disease，COPD)患者治疗气流受限及减轻病情加重。

此次，仿制药巨头Mylan公司获准生产和销售3种不同剂量的Advair Diskus仿制药。

哮喘治疗药物及使用说明哮喘是一种慢性炎症性疾病，通常由特定的刺激物引起，导致气道收缩和炎症反应。

对于患有哮喘的病人来说，正确的药物治疗是非常重要的，可以帮助他们控制病情和减少哮喘发作的频率。

本文将介绍一些常用的哮喘治疗药物以及使用说明。

1. 类固醇吸入剂（ICS）类固醇吸入剂是一种主要用于控制哮喘症状的药物。

它通过减少气道炎症和肿胀来减轻哮喘的症状。

ICS的使用方法通常是通过口腔吸入剂或吸入器来进行。

患者需要按照医生的指示使用，并遵循正确的使用方法。

ICS通常需要长期使用，持续控制哮喘的症状。

2. 快速救济药物快速救济药物，例如沙丁胺醇，也称为短效β2受体激动剂（SABA），主要用于缓解哮喘发作时的紧迫感和气喘。

这些药物通过扩张气道上的平滑肌来缓解哮喘症状。

患者应该在发作时使用快速救济药物，并按照医生的建议使用正确的剂量。

3. 长效β2受体激动剂（LABA）长效β2受体激动剂通常与类固醇吸入剂联合使用，用作哮喘的控制药物。

LABA通过扩张气道上的平滑肌，帮助患者更好地控制病情。

与快速救济药物不同，LABA的作用持续时间较长，可以提供更持久的症状缓解。

LABA通常需要长期服用，但是不能用于单独治疗哮喘。

4. 白三烯受体拮抗剂（LTRA）白三烯受体拮抗剂是一种用于控制哮喘的药物，主要用于防治冷气过敏和运动诱发的哮喘。

这些药物通过阻断白三烯受体来减少炎症反应和气道收缩。

患者应该按照医生的建议正确使用LTRA，并且了解副作用以及潜在的药物相互作用。

5. 抗胆碱能药物抗胆碱能药物作为一种用于缓解气道痉挛和减少分泌物的常用药物，对于某些哮喘患者来说也是一种有效的治疗选择。

然而，对于患有狭窄性青光眼等相关疾病的患者来说，使用抗胆碱能药物需要特别谨慎，并在医生的指导下进行。

总结起来，在哮喘的治疗过程中，患者可以根据病情严重程度和医生的建议来使用不同的药物。

对于轻度哮喘，ICS可能是唯一需要的治疗药物。

对于中重度哮喘，类固醇吸入剂通常需要与快速救济药物或LABA联合使用。

FDA英文药品说明书规定项目中英对照--------------------------------------------------------------------------------药品说明书旧称description,instruction,direction.今称insert,package insert美国FDA规定其应包括十项。

一.drug names(药物名称)1.通常每种药物有三个名字(1)proprietary name（商品名称）(2)popular name（俗名）(3)chemical name（化学名）2.说明书标题多用商品名其右上角标有R者，表示registered trademark（注册商标）二.description（性状）(常用description,introduction,composition)包括药品的chemical structure（化学结构）、chemical composition（化学成分）、physical and chemical properties（物理和化学性质）三.clinical pharmacology（临床药理学）常用的还有：clinical data（临床数据）、clinical experience（临床经验）、clinical use（临床应用）、clinical observation（临床观察）、clinical effect（临床疗效）、clinical discussion（临床讨论）、mode of mechanism of action（临床机理及途径）、pharmacological actions（药理作用）、therapeutical actions（治疗作用）、bacteriology（细菌学）、microbiology（微生物学）、physiology（生理学）、toxicology（毒理学）四.indications and usage（适应证和用法）常用标题：indications,major indications,clinical indications,principal indications,condications,uses,treatment五.contraindications（禁忌证）1.常用标题contraindications,restriction on use(限制使用)2.常用词（组）pregnant women孕妇women of childbeating age育龄妇女be hypersensitive to 对......过敏者allergic reaction变态反应lactation,early infancy乳期heart,cardiac,myocardial心脏，心脏的，心肌的kidney,renal肾，肾脏的liver,hepatic肝，肝脏的insufficiency,impairment机能不全damage,danger,failure损伤，危险，衰?BR&gt;六.precautions（注意事项）常用标题:causions,remark,note,notice,attention,awakening, N.B.七.warnings（警告）常用标题：additional warnings(告戒事项)八.adverse reactions（不良反应）常用标题：side reaction（副反应）、untoward reaction（不良反应）、toxicity reaction（毒性反应）、anaphylactic reaction（过敏反应）、side effects,by-effects,after effects,undesirable effects（副作用）、double infection（双重感染）九.overdosage（用药过量）常用标题：treatment of overdosage(用药过量的治疗)十.dosage and administration（剂量用法）1.常用标题：administration procedure,method for administration,method of use,direction for use,how to use,recommendation,reconstitution（用法）posology,dosage（剂量）application and dosage,usage and dosage（用法与剂量）clinical application（临床应用）2.mode of administration(给药方式)intramuscularly肌肉注射intragluteally臀肌注射intraarterially动脉注射intravenously静脉注射intrathecally鞘内注射intracerebeospinally脑脊髓腔注射orally口服parentarally肠道外给药locally局部给药subconjunctivally结膜下给药sublingually舌下给药submucously黏膜下给药现各大药厂的说明书，项目远远超过十项，如：1.animal pharmacology and animal toxicology（动物药理学和动物毒理学）2.absorption and excretion（吸收和排泄）3.tolerance（耐受性）4.drug interactions（药物相互作用）5.storage and duration of efficacy（贮藏与失效期）6.packages（包装）7.advantages（优点）8.references（参考文献）9.further information（补充说明）10.manufacturer（生产者）。

MEDICATION GUIDESUBLOCADE(SUB-lo-kade) (buprenorphine extended-release) injection, for subcutaneous use, (CIII)What is the most important information I should know about SUBLOCADE?•Because of the serious risk of potential harm or death from self-injecting SUBLOCADE into a vein (intravenously), it is only available through a restricted program called the SUBLOCADE REMS Program.•SUBLOCADE is not available in retail pharmacies.•Your SUBLOCADE injection will only be given to you by a certified healthcare provider.•SUBLOCADE contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs.•Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose. If naloxone is given, you must call 911 or get emergency medical help right away to treat overdose or accidental use of an opioid.•SUBLOCADE may cause serious and life-threatening breathing problems. Get emergency help right away if you:•feel faint•feel dizzy•are confused•Feel sleepy or uncoordinated •have blurred vision•have slurred speech•are breathing slower than normal •cannot think well or clearlyDo not take certain medicines during treatment with SUBLOCADE. Taking other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) while on SUBLOCADE can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.•In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with SUBLOCADE.•You may have detectable levels of SUBLOCADE in your body for a long period after stopping treatment with SUBLOCADE.What is SUBLOCADE?SUBLOCADE is a prescription medicine used to treat adults with moderate to severe addiction (dependence) to opioid drugs (prescription or illegal) who:•have received treatment with an oral transmucosal (used under the tongue or inside the cheek) buprenorphine-containing medicine for 7 days and•are taking a dose that controls withdrawal symptoms for at least seven days.•SUBLOCADE is part of a complete treatment plan that should include counseling.Who should not take SUBLOCADE?Do not use SUBLOCADE if you are allergic to buprenorphine or any ingredient in the prefilled syringe (ATRIGEL® delivery system). See the end of this Medication Guide for a list of ingredients in SUBLOCADE.Before starting SUBLOCADE, tell your healthcare provider about all your medical conditions, including if you have:•trouble breathing or lung problems• a curve in your spine that affects your breathing •Addison’s disease •an enlarged prostate (men)•problems urinating•liver, kidney, or gallbladderproblems•alcoholism• a head injury or brainproblem•mental health problems•adrenal gland or thyroidgland problemsTell your healthcare provider if you are:•pregnant or plan to become pregnant. If you receive SUBLOCADE while pregnant, your baby may have symptoms of opioid withdrawal at birth that could be life-threatening if not recognized and treated. Talk to your healthcare provider if you are pregnant or plan to become pregnant.•breastfeeding or plan to breastfeed. SUBLOCADE can pass into your breast milk and harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with SUBLOCADE. Monitor your baby for increased drowsiness and breathing problems if you breastfeed during treatment with SUBLOCADE.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.How will I receive SUBLOCADE?•You will receive SUBLOCADE by your healthcare provider as an injection just under the skin (subcutaneous) of your stomach (abdomen). You will receive SUBLOCADE monthly (with at least 26 days between doses). •SUBLOCADE is injected as a liquid. After the injection, SUBLOCADE changes to a solid form called a depot. The depot may be seen or felt as a small bump under your skin at the injection site on your abdomen for several weeks. The depot will get smaller over time.•Do not try to remove the depot.•Do not rub or massage the injection site.•Try not to let belts or clothing waistbands rub against the injection site.•If you miss a dose of SUBLOCADE, see your healthcare provider to get your SUBLOCADE injection as soon as possible.What should I avoid while being treated with SUBLOCADE?•Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how SUBLOCADE affects you. Buprenorphine can cause drowsiness and slow reaction times. SUBLOCADE can make you sleepy, dizzy, or lightheaded. This may happen more often in the first few days after your injection and when your dose is changed.•You should not drink alcohol or take prescription or over-the-counter medicines that contain alcohol during treatment with SUBLOCADE, because this can lead to loss of consciousness or even death.What are the possible side effects of SUBLOCADE?SUBLOCADE can cause serious side effects, including:•Trouble breathing. Taking other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants during treatment with SUBLOCADE can cause breathing problems that can lead to coma and death. •Sleepiness, dizziness, and problems with coordination.•Physical dependence.•Liver problems. Call your healthcare provider right away if you notice any of these symptoms:•your skin or the white part of your eyes turns yellow (jaundice)•dark or “tea-colored” urine•light colored stools (bowel movements) •loss of appetite•pain, aching, or tenderness on the right side of your stomach area•nausea•Your healthcare provider should do blood tests to check your liver before you start and during treatment with SUBLOCADE.•Allergic reaction. You may have a rash, hives, swelling of your face, wheezing, low blood pressure, or loss of consciousness. Call your healthcare provider or get emergency help right away.•Opioid withdrawal. Call your healthcare provider right away if you get any of these symptoms:•shaking•sweating more than normal •feeling hot or cold more than normal •runny nose•watery eyes •goose bumps •diarrhea •vomiting •muscle aches•Decrease in blood pressure. You may feel dizzy when you get up from sitting or lying down. •The most common side effects of SUBLOCADE include:•constipation •headache •vomiting•increase in liver enzymes•nausea •injection site itching •tiredness •injection site pain•SUBLOCADE may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you. These are not all the possible side effects of SUBLOCADE.Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. General information about SUBLOCADEMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your doctor or pharmacist for information that is written for healthcare professionals.What are the ingredients in SUBLOCADE?Active ingredient: buprenorphineATRIGEL® delivery system: biodegradable 50:50 poly(DL-lactide-co-glycolide) polymer and a biocompatible solvent, N-methyl-2-pyrrolidone (NMP).© 2022, Indivior UK Limited. All Rights Reserved.SUBLOCADE® is a registered trademark of Indivior UK Limited.Manufactured by Curia Global Inc. Albany, NY 12203For more information, go to or call 1-877-782-6966.This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 08/2022。

中英双语的药品说明书药品说明书是一种专业化的文档，旨在向患者提供关于特定药物的详细信息，包括药物的配方、适应症、用法用量、不良反应、禁忌症、警告和注意事项等。

以下是一个关于药品说明书的双语参考内容。

药品说明书一、药品名称中文名称：[药品名称]英文名称：[Drug Name]二、成分中文名称：[主要成分]英文名称：[Active Ingredient]作用：[描述主要成分的功效及作用]三、适应症中文名称：[适应症]英文名称：[Indications]【中文描述用药适应症】【英文描述用药适应症】四、用法用量中文名称：[用法用量]英文名称：[Dosage and Administration]【中文描述正确用药的方法和剂量】【英文描述正确用药的方法和剂量】五、不良反应中文名称：[不良反应]英文名称：[Adverse Reactions]【中文描述可能引起的不良反应，包括常见和罕见的不良反应】【英文描述可能引起的不良反应，包括常见和罕见的不良反应】六、禁忌症中文名称：[禁忌症]英文名称：[Contraindications]【中文描述使用该药物的禁忌症】【英文描述使用该药物的禁忌症】七、警告和注意事项中文名称：[警告和注意事项]英文名称：[Warnings and Precautions]【中文描述使用该药物时需要特别注意的事项，包括特殊人群的用药注意事项】【英文描述使用该药物时需要特别注意的事项，包括特殊人群的用药注意事项】八、儿童用药指导中文名称：[儿童用药指导]英文名称：[Pediatric Use]【中文描述使用该药物给儿童用药的特殊指导】【英文描述使用该药物给儿童用药的特殊指导】九、孕妇和哺乳期妇女用药指导中文名称：[孕妇和哺乳期妇女用药指导]英文名称：[Use in Pregnant and Nursing Women]【中文描述使用该药物给孕妇和哺乳期妇女用药的特殊指导】【英文描述使用该药物给孕妇和哺乳期妇女用药的特殊指导】十、药物相互作用中文名称：[药物相互作用]英文名称：[Drug Interactions]【中文描述该药物与其他药物及物质的相互作用】【英文描述该药物与其他药物及物质的相互作用】十一、药物过量中文名称：[药物过量]英文名称：[Overdosage]【中文描述该药物过量使用的症状和处理方法】【英文描述该药物过量使用的症状和处理方法】十二、贮藏中文名称：[贮藏]英文名称：[Storage]【中文描述正确的药物贮藏方式和条件】【英文描述正确的药物贮藏方式和条件】十三、包装中文名称：[包装]英文名称：[Presentation]【中文描述药物的包装形式和包装材料】【英文描述药物的包装形式和包装材料】十四、有效期中文名称：[有效期]英文名称：[Expiry Date]【中文描述药物的有效期】【英文描述药物的有效期】十五、说明书修订日期中文名称：[说明书修订日期]英文名称：[Revision Date]【中文描述说明书的修订日期】【英文描述说明书的修订日期】以上是药品说明书的双语参考内容，用于提供给患者详细了解特定药物的信息。

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use TECFIDERA safely and effectively. See full prescribing information for TECFIDERA.TECFIDERA™ (dimethyl fumarate) delayed-release capsules, for oral useInitial U.S. Approval: 2013-------INDICATIONS AND USAGE------- TECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis (1)-------DOSAGE AND ADMINISTRATION-------∙Starting dose: 120 mg twice a day, orally, for 7 days (2)∙Maintenance dose after 7 days: 240 mg twice a day, orally (2)∙Swallow TECFIDERA capsules whole and intact. Do not crush, chew, or sprinkle capsule contents on food (2)∙Take TECFIDERA with or without food (2)-------DOSAGE FORMS AND STRENGTHS-------Delayed-release capsules: 120 mg and 240 mg (3)-------CONTRAINDICATIONS-------None (4)-------WARNINGS AND PRECAUTIONS------- TECFIDERA may cause lymphopenia. A recent CBC should be available before initiating treatment with TECFIDERA. A CBC is recommended annually, and as clinically indicated. Consider withholding treatment in patients with serious infections. (5.1, 6.1)-------ADVERSE REACTIONS-------Most common adverse reactions (incidence ≥10% and ≥2% placebo) were flushing, abdominal pain, diarrhea, and nausea (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Biogen Idec at 1-800-456-2255 or FDA at 1-800-FDA-1088 or /medwatch.-------USE IN SPECIFIC POPULATIONS-------∙Pregnancy: based on animal data, may cause fetal harm (8.1)See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labelingRevised: 03/2013FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information2.2 Blood Test Prior to Initiation of Therapy3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Lymphopenia5.2 Flushing6 ADVERSE REACTIONS6.1 Clinical Trials Experience8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use11 DESCRIPTION 12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION17.1 Dosage17.2 Flushing and Gastrointestinal (GI) Reactions17.3 Pregnancy and Pregnancy Registry17.4 Lymphocyte Counts* Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGETECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis.2 DOSAGE AND ADMINISTRATION2.1 Dosing InformationThe starting dose for TECFIDERA is 120 mg twice a day orally. After 7 days, the dose should be increased to the maintenance dose of 240 mg twice a day orally. TECFIDERA should be swallowed whole and intact. TECFIDERA should not be crushed or chewed and the capsule contents should not be sprinkled on food. TECFIDERA can be taken with or without food. Administration with food may reduce the incidence of flushing [see Clinical Pharmacology (12.3)].2.2 Blood Test Prior to Initiation of TherapyA recent complete blood cell count (CBC) (i.e., within 6 months) is recommended before initiation of therapy to identify patients with pre-existing low lymphocyte counts.3 DOSAGE FORMS AND STRENGTHSTECFIDERA is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of dimethyl fumarate. The 120 mg capsules have a green cap and white body, printed with “BG-12 120 mg” in black ink on the body. The 240 mg capsules have a green cap and a green body, printed with “BG-12 240 mg” in black ink on the body.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 LymphopeniaTECFIDERA may decrease lymphocyte counts [see Adverse Reactions (6.1)]. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x109/L (lower limit of normal 0.91x109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or 0.5x109/L.Before initiating treatment with TECFIDERA, a recent CBC (i.e., within 6 months) should be available. A CBC is recommended annually, and as clinically indicated. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.5.2 FlushingTECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) ofpatients discontinued TECFIDERA for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of TECFIDERA with food may reduce the incidence of flushing.6 ADVERSE REACTIONSThe following important adverse reactions are described elsewhere in labeling: Lymphopenia, Flushing [see Warnings and Precautions (5.1, 5.2)].6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.Adverse Reactions in Placebo-Controlled TrialsIn the two well-controlled studies demonstrating effectiveness, 1529 patients received TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies (14)].The adverse reactions presented in the table below are based on safety information from 769 patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients.Table 1:Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BIDat ≥ 2% higher incidence than placeboTECFIDERAN=769% Placebo N=771%Blood and Lymphatic System DisordersLymphopenia 2 <1 Gastrointestinal DisordersAbdominal pain Diarrhea Nausea Vomiting Dyspepsia 181412951011953Vascular DisordersFlushing 40 6 Skin and Subcutaneous Tissue DisordersPruritus RashErythema 885431InvestigationsAlbumin urine presentAspartate aminotransferase increased 6442GastrointestinalTECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA.Hepatic TransaminasesAn increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels < 3 times the upper limit of normal (ULN). Elevations of alanine aminotransferase and aspartate aminotransferase to ≥ 3 times the ULN occurred in a small number of patients treated with both TECFIDERA and placebo and were balanced between groups. There were no elevations in transaminases ≥3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo.EosinophiliaA transient increase in mean eosinophil counts was seen during the first 2 months of therapy.Adverse Reactions in Placebo-Controlled and Uncontrolled StudiesIn placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than 2 years of treatment with TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no adequate and well-controlled studies in pregnant women. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at clinically relevant doses. TECFIDERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.In rats administered DMF orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating metabolite, at the no-effect dose is approximately three times that in humans at the recommended human dose (RHD) of 480 mg/day. In rabbits administered DMF orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is approximately 5 times that in humans at the RHD.Oral administration of DMF (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses. A no-effect dose for developmental toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD.Pregnancy RegistryThere is a pregnancy registry that monitors pregnancy outcomes in women exposed to TECFIDERA during pregnancy. Encourage patients to enroll by calling 1-800-456-2255.8.3 Nursing MothersIt is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TECFIDERA is administered to a nursing woman.8.4 Pediatric UseSafety and effectiveness in pediatric patients have not been established. 8.5 Geriatric UseClinical studies of TECFIDERA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 11 DESCRIPTIONTECFIDERA contains dimethyl fumarate which is also known by its chemical name, dimethyl (E) butenedioate, (C 6H 8O 4). It has the following structure:HHOOOODimethyl fumarate is a white to off-white powder that is highly soluble in water with a molecular mass of 144.13. TECFIDERA is provided as hard gelatin delayed-release capsules for oral administration, containing 120 mg or 240 mg of dimethyl fumarate consisting of the following inactive ingredients: microcrystalline cellulose, silicified microcrystalline cellulose, croscarmellose sodium, talc, silica colloidal silicon dioxide, magnesium stearate, triethyl citrate, methacrylic acid copolymer - Type A, methacrylic acid copolymer dispersion, simethicone (30% emulsion), sodium lauryl sulphate, and polysorbate 80. The capsule shell, printed with black ink, contains the following inactive ingredients: gelatin, titanium dioxide, FD&C blue 1; brilliant blue FCF, yellow iron oxide and black iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionThe mechanism by which dimethyl fumarate (DMF) exerts its therapeutic effect in multiple sclerosis is unknown. DMF and the metabolite, monomethyl fumarate (MMF), have been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. MMF has been identified as a nicotinic acid receptor agonist in vitro .12.2 PharmacodynamicsPotential to prolong the QT intervalIn a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that dimethyl fumarate caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).12.3 PharmacokineticsAfter oral administration of TECFIDERA, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Dimethyl fumarate is not quantifiable in plasma following oral administration of TECFIDERA. Therefore all pharmacokinetic analyses related to TECFIDERA were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers.AbsorptionThe median T max of MMF is 2-2.5 hours. The peak plasma concentration (C max) and overall exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg). Following administration of TECFIDERA 240 mg twice a day with food, the mean C max of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients.A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40%. The T max was delayed from 2.0 hours to 5.5 hours. In this study, the incidence of flushing was reduced by approximately 25% in the fed state.DistributionThe apparent volume of distribution of MMF varies between 53 and 73 L in healthy subjects. Human plasma protein binding of MMF is 27-45% and independent of concentration.MetabolismIn humans, dimethyl fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. MMF, fumaric and citric acid, and glucose are the major metabolites in plasma.EliminationExhalation of CO2 is the primary route of elimination, accounting for approximately 60% of the TECFIDERA dose. Renal and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose respectively. Trace amounts of unchanged MMF were present in urine.The terminal half-life of MMF is approximately 1 hour and no circulating MMF is present at 24 hours in the majority of individuals. Accumulation of MMF does not occur with multiple doses of TECFIDERA.Specific PopulationsBody weight, gender, and age do not require dosage adjustment.No studies have been conducted in subjects with hepatic or renal impairment. However, neither condition would be expected to affect exposure to MMF and therefore no dosage adjustment is necessary.Drug Interaction StudiesNo potential drug interactions with dimethyl fumarate or MMF were identified in in vitro CYP inhibition and induction studies, or in P-glycoprotein studies. Single doses of interferon beta-1a or glatiramer acetate did not alter the pharmacokinetics of MMF. Aspirin, when administered approximately 30 minutes before TECFIDERA, did not alter the pharmacokinetics of MMF.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisCarcinogenicity studies of dimethyl fumarate (DMF) were conducted in mice and rats. In mice, oral administration of DMF (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas and papillomas of the forestomach in males and females at 200 and 400 mg/kg/day; leiomyosarcomas of the forestomach at 400 mg/kg/day in males and females; renal tubular adenomas and carcinomas at 200 and 400 mg/kg/day in males; and renal tubule adenomas at 400 mg/kg/day in females. Plasma MMF exposure (AUC) at the highest dose not associated with tumors in mice (75 mg/kg/day) was similar to that in humans at the recommended human dose (RHD) of 480 mg/day.In rats, oral administration of DMF (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. Plasma MMF AUC at the lowest dose tested was lower than that in humans at the RHD.MutagenesisDimethyl fumarate (DMF) and monomethyl fumarate (MMF) were not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. DMF and MMF were clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation. DMF was not clastogenic in the in vivo micronucleus assay in the rat.Impairment of FertilityIn male rats, oral administration of DMF (75, 250, and 375 mg/kg/day) prior to and throughout the mating period had no effect on fertility; however, increases in non-motile sperm were observed at the mid and high doses. The no-effect dose for adverse effects on sperm is similar to the recommended human dose (RHD) of 480 mg/day on a body surface area (mg/m2) basis.In female rats, oral administration of DMF (20, 100, and 250 mg/kg/day) prior to and during mating and continuing to gestation day 7 caused disruption of the estrous cycle and increases in embryolethality at the highest dose tested. The highest dose not associated with adverse effects (100 mg/kg/day) is twice the RHD on a mg/m2 basis.Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of DMF, and in a chronic oral toxicity study evaluating a combination of four fumaric acid esters (including DMF) in rats.13.2 Animal Toxicology and/or PharmacologyKidney toxicity was observed after repeated oral administration of dimethyl fumarate (DMF) in mice, rats, dogs, and monkeys. Renal tubule epithelia regeneration, suggestive of tubule epithelial injury, was observed in all species. Renal tubular hyperplasia was observed in rats with dosing for up to two years. Cortical atrophy and interstitial fibrosis were observed in dogs and monkeys at doses above 5 mg/kg/day. In monkeys, the highest dose tested (75 mg/kg/day) was associated with single cell necrosis and multifocal and diffuse interstitial fibrosis, indicating irreversible loss of renal tissue and function. In dogs and monkeys, the 5 mg/kg/day dose was associated with plasma MMF exposures less than or similar to that in humans at the recommended human dose (RHD).A dose-related increase in incidence and severity of retinal degeneration was observed in mice following oral administration of DMF for up to two years at doses above 75 mg/kg/day, a dose associated with plasma MMF exposure (AUC) similar to that in humans at the RHD.14 CLINICAL STUDIESThe efficacy and safety of TECFIDERA were demonstrated in two studies (Studies 1 and 2) that evaluated TECFIDERA taken either twice or three times a day in patients with relapsing-remitting multiple sclerosis (RRMS). The starting dose for TECFIDERA was 120 mg twice or three times a day for the first 7 days, followed by an increase to 240 mg twice or three times a day. Both studies included patients who had experienced at least 1 relapse over the year preceding the trial or had a brain Magnetic Resonance Imaging (MRI) scan demonstrating at least one gadolinium-enhancing (Gd+) lesion within 6 weeks of randomization. The Expanded Disability Status Scale (EDSS) was also assessed and patients could have scores ranging from 0 to 5. Neurological evaluations were performed at baseline, every 3 months, and at the time of suspected relapse. MRI evaluations were performed at baseline, month 6, and year 1 and 2 in a subset of patients (44% in Study 1 and 48% in Study 2).Study 1: Placebo-Controlled Trial in RRMSStudy 1 was a 2-year randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. The primary endpoint was the proportion of patients relapsed at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of new T1 hypointense lesions, number of Gd+ lesions, annualized relapse rate (ARR), and time to confirmed disability progression. Confirmed disability progression was defined as at least a 1 point increase from baseline EDSS (1.5 point increase for patients with baseline EDSS of 0) sustained for 12 weeks.Patients were randomized to receive TECFIDERA 240 mg twice a day (n=410), TECFIDERA 240 mg three times a day (n=416), or placebo (n=408) for up to 2 years. The median age was 39 years, median time since diagnosis was 4 years, and median EDSS score at baseline was 2. The median time on study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks on study drug per treatment group were 69% for patients assigned to TECFIDERA 240 mg twice a day, 69% for patients assigned to TECFIDERA 240 mg three times a day and 65% for patients assigned to placebo groups.TECFIDERA had a statistically significant effect on all of the endpoints described above and the 240 mg three times daily dose showed no additional benefit over the TECFIDERA 240 mg twice daily dose. The results for this study (240 mg twice a day vs. placebo) are shown in Table 2 and Figure 1.Table 2: Clinical and MRI Results of Study 1TECFIDERA240 mg BID Placebo P-valueClinical Endpoints N=410 N=408Proportion relapsing (primary endpoint) 27% 46% <0.0001Relative risk reduction 49%Annualized relapse rate Relative reduction 0.17253%0.364 <0.0001Proportion with disability progression Relative risk reduction 16%38%27% 0.0050MRI Endpoints N=152 N=165Mean number of new or newly enlarging T2 lesions over 2 yearsPercentage of subjects with no new or newly enlarging lesions2.645%1727%<0.0001TECFIDERA 240 mg BID Placebo P-valueNumber of Gd+ lesions at 2 years Mean (median)Percentage of subjects withlesions1lesion2lesions3 to4 lesions5 or more lesionsRelative odds reduction(percentage) 0.1 (0)93%5%<1%<1%90%1.8 (0)62%10%8%9%11%<0.0001Mean number of new T1 hypointenselesions over 2 years1.5 5.6 < 0.0001Figure 1: Time to 12-Week Confirmed Progression of Disability (Study 1)Study 2: Placebo-Controlled Trial in RRMSStudy 2 was a 2-year multicenter, randomized, double-blind, placebo-controlled study that also included an open-label comparator arm in patients with RRMS. The primary endpoint was the annualized relapse rate at 2 years. Additional endpoints at 2 years includedthe number of new or newly enlarging T2 hyperintense lesions, number of T1 hypointense lesions, number of Gd+ lesions, proportion of patients relapsed, and time to confirmed disability progression as defined in Study 1.Patients were randomized to receive TECFIDERA 240 mg twice a day (n=359), TECFIDERA 240 mg three times a day (n=345), an open-label comparator (n=350), or placebo (n=363) for up to 2 years. The median age was 37 years, median time since diagnosis was 3 years, and median EDSS score at baseline was 2.5. The median time on study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks on study drug per treatment group were 72% for patients assigned to TECFIDERA 240 mg twice a day, 70% for patients assigned to TECFIDERA 240 mg three times a day and 64% for patients assigned to placebo groups.TECFIDERA had a statistically significant effect on the relapse and MRI endpoints described above. There was no statistically significant effect on disability progression. The TECFIDERA 240 mg three times daily dose resulted in no additional benefit over the TECFIDERA 240 mg twice daily dose. The results for this study (240 mg twice a day vs. placebo) are shown in Table 3.Table 3: Clinical and MRI Results of Study 2TECFIDERA240 mg BIDPlacebo P-valueClinical Endpoints N=359 N=363Annualized relapse rate Relative reduction 0.22444%0.401 <0.0001Proportion relapsingRelative risk reduction 29%34%41% 0.0020Proportion with disability progression Relative risk reduction 13%21%17% 0.25MRI Endpoints N=147 N=144Mean number of new or newly enlarging T2 lesions over 2 yearsPercentage of subjects with no new ornewly enlarging lesions5.127%17.412%<0.0001Number of Gd+ lesions at 2 yearsMean (median)Percentage of subjects with 0lesions1lesion2lesions3 to4 lesions5 or more lesionsRelative odds reduction(percentage) 0.5 (0.0)80%11%3%3%3%74%2.0 (0.0)61%17%6%2%14%<0.0001Mean number of new T1 hypointenselesions over 2 years3.0 7.0 <0.000116 HOW SUPPLIED/STORAGE AND HANDLINGTECFIDERA is available as hard gelatin delayed-release capsules in two strengths containing either 120 mg or 240 mg of dimethyl fumarate. The green and white 120 mg capsules are printed with “BG-12 120 mg” in black ink. The green 240 mg capsules are printed with “BG-12 240 mg” in black ink. TECFIDERA is available as follows:30-day Starter Pack, (NDC 64406-007-03):7-day bottle 120 mg capsules, quantity 1423-day bottle 240 mg capsules, quantity 46120 mg capsules:7-day bottle of 14 capsules (NDC 64406-005-01)240 mg capsules:30-day bottle of 60 capsules (NDC 64406-006-02)Store at 15°C to 30°C (59 to 86°F). Protect the capsules from light. Store in original container. Once opened, discard bottles of TECFIDERA after 90 days.17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Patient Information)17.1 DosageInform patients that they will be provided two strengths of TECFIDERA when starting treatment: 120 mg capsules for the 7 day starter dose and 240 mg capsules for the maintenance dose, both to be taken twice daily. Inform patients to swallow TECFIDERA capsules whole and intact. Inform patients to not crush, chew, or sprinkle capsule contents on food. Inform patients that TECFIDERA can be taken with or without food [see Dosage and Administration (2.1)].17.2 Flushing and Gastrointestinal (GI) ReactionsFlushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most common reactions, especially at the initiation of therapy, and may decrease over time. Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI reactions, as taking TECFIDERA with food may help [see Adverse Reactions (6.1)].17.3 Pregnancy and Pregnancy RegistryInstruct patients that if they are pregnant or plan to become pregnant while taking TECFIDERA they should inform their physician.Encourage patients to enroll in the TECFIDERA Pregnancy Registry if they become pregnant while taking TECFIDERA. Advise patients to call 1-800-456-2255 for more information [see Use in Specific Populations (8.1)].17.4 Lymphocyte CountsInform patients that TECFIDERA may decrease lymphocyte counts. A recent blood test (i.e., within 6 months) should be available before they start therapy to identify patients with pre-existing low lymphocyte counts. Blood tests are also recommended annually, and as clinically indicated [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].。

DOPRAM Injection(doxapram hydrochloride injection, USP)NOT FOR USE IN NEONATESCONTAINS BENZYL ALCOHOLR x onlyDESCRIPTIONDOPRAM Injection (doxapram hydrochloride injection, USP) is a clear, colorless, sterile, non-pyrogenic, aqueous solution with pH 3.5 to 5, for intravenous administration.Each 1 mL contains:Doxapram Hydrochloride, USP ................................................................. 20 mgBenzyl Alcohol, NF (as preservative) ......................................................... 0.9%Water for Injection, USP ...........…................................................................. q.s. Doxapram Injection is a respiratory stimulant.Doxapram hydrochloride is a white to off-white, crystalline powder, sparingly soluble in water, alcohol and chloroform. Chemically, doxapram hydrochloride is 1-ethyl-4-[2-(4-morpholinyl)ethyl]-3,3-diphenyl-2-pyrrolidinone monohydrochloride, monohydrate.The chemical structure is:C24H31ClN2O2 • H2O M.W. 432.99CLINICAL PHARMACOLOGYDoxapram hydrochloride produces respiratory stimulation mediated through the peripheral carotid chemoreceptors. As the dosage level is increased, the central respiratory centers in the medulla are stimulated with progressive stimulation of other parts of the brain and spinal cord.The onset of respiratory stimulation following the recommended single intravenous injection of doxapram hydrochloride usually occurs in 20 to 40 seconds with peak effect at 1 to 2 minutes. The duration of effect may vary from 5 to 12 minutes.The respiratory stimulant action is manifested by an increase in tidal volume associated with a slight increase in respiratory rate.A pressor response may result following doxapram administration. Provided there is no impairment of cardiac function, the pressor effect is more marked in hypovolemic than in normovolemic states. The pressor response is due to the improved cardiac output rather than peripheral vasoconstriction. Following doxapram administration, an increased release of catecholamines has been noted.Although opiate-induced respiratory depression is antagonized by doxapram, the analgesic effect is not affected.INDICATIONS AND USAGEPostanesthesiaa.When the possibility of airway obstruction and/or hypoxia have been eliminated,doxapram may be used to stimulate respiration in patients with drug-inducedpostanesthesia respiratory depression or apnea other than that due to muscle relaxant drugs.b.To pharmacologically stimulate deep breathing in the postoperative patient. (Aquantitative method of assessing oxygenation, such as pulse oximetry, isrecommended.)Drug-Induced Central Nervous System DepressionExercising care to prevent vomiting and aspiration, doxapram may be used to stimulate respiration, hasten arousal, and to encourage the return of laryngopharyngeal reflexes in patients with mild to moderate respiratory and CNS depression due to drug overdosage.Chronic Pulmonary Disease Associated with Acute Hypercapnia Doxapram is indicated as a temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease. Its use should be for a short period of time (see DOSAGE AND ADMINISTRATION) as an aid in the prevention of elevation of arterial CO2 tension during the administration of oxygen.It should not be used in conjunction with mechanical ventilation.CONTRAINDICATIONSDoxapram is contraindicated in patients with known hypersensitivity to the drug or any of the injection components.Doxapram should not be used in patients with epilepsy or other convulsive disorders.Doxapram is contraindicated in patients with proven or suspected pulmonary embolism.Doxapram is contraindicated in patients with mechanical disorders of ventilation such as mechanical obstruction, muscle paresis (including neuromuscular blockade), flail chest, pneumothorax, acute bronchial asthma, pulmonary fibrosis, or other conditions resulting in restriction of the chest wall, muscles of respiration, or alveolar expansion.Doxapram is contraindicated in patients with evidence of head injury, cerebral vascular accident, or cerebral edema, and in those with significant cardiovascular impairment, uncompensated heart failure, severe coronary artery disease, or severe hypertension, including that associated with hyperthyroidism or pheochromocytoma. (See WARNINGS.)WARNINGSDoxapram should not be used in conjunction with mechanical ventilation.Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from m edications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS, Pediatric Use).In Postanesthetic Usea.Doxapram is neither an antagonist to muscle relaxant drugs nor a specific narcoticantagonist. More specific tests (eg, peripheral nerve stimulation, airway pressures, head lift, pulse oximetry, and end-tidal carbon dioxide) to assess adequacy ofventilation are recommended before administering doxapram.b.Doxapram should be administered with great care and only under careful supervisionto patients with hypermetabolic states such as hyperthyroidism orpheochromocytoma.c.Since narcosis may recur after stimulation with doxapram, care should be taken tomaintain close observation until the patient has been fully alert for ½ to 1 hour.d.In patients who have received general anesthesia utilizing a volatile agent known tosensitize the myocardium to catecholamines, administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation (seePRECAUTIONS, Drug Interactions).In Drug-Induced CNS and Respiratory DepressionDoxapram alone may not stimulate adequate spontaneous breathing or provide sufficient arousal in patients who are severely depressed either due to respiratory failure or to CNS depressant drugs, but may be used as an adjunct to established supportive measures and resuscitative techniques.In Chronic Obstructive Pulmonary DiseaseBecause of the associated increased work of breathing, do not increase the rate of infusion of doxapram in severely ill patients in an attempt to lower pCO2. PRECAUTIONSGenerala.An adequate airway is essential and airway protection should be considered sincedoxapram may stimulate vomiting.b.Recommended dosages of doxapram should be employed and maximum total dosagesshould not be exceeded. In order to avoid side effects, it is advisable to use theminimum effective dosage.c.Monitoring of the blood pressure, pulse rate, and deep tendon reflexes isrecommended to prevent overdosage.d.Vascular extravasation or use of a single injection site over an extended period shouldbe avoided since either may lead to thrombophlebitis or local skin irritation.e.Rapid infusion may result in hemolysis.f.Lowered pCO2 induced by hyperventilation produces cerebral vasoconstriction andslowing of the cerebral circulation. This should be taken into consideration on anindividual basis. In certain patients a pressor effect of doxapram on the pulmonary circulation may result in a fall of the arterial pO2 probably due to a worsening ofventilation perfusion-matching in the lungs despite an overall improvement inalveolar ventilation and a fall in pCO2. Patients should be carefully supervised taking into account available blood gas measurements.g.There is a risk that doxapram will produce adverse effects (including seizures) due togeneral central nervous system stimulation. Muscle involvement may range fromfasciculation to spasticity. Anticonvulsants such as intravenous short-actingbarbiturates, along with oxygen and resuscitative equipment should be readilyavailable to manage overdosage manifested by excessive central nervous systemstimulation. Slow administration of the drug and careful observation of the patient during administration and for some time subsequently are advisable. Theseprecautions are to assure that the protective reflexes have been restored and to prevent possible post-hyperventilation or hypoventilation.h.Doxapram should be administered cautiously to patients receiving sympathom imeticor monoamine oxidase inhibiting drugs, since an additive pressor effect may occur. i.Blood pressure increases are generally modest but significant increases have beennoted in some patients. Because of this, doxapram is not recommended for use in patients with severe hypertension (see CONTRAINDICATIONS).j.Cardiovascular effects may include various dysrhythmias. Patients receiving doxaprom should be monitored for disturbance of their cardiac rhythm.k.If sudden hypotension or dyspnea develops, doxapram should be stopped.l.Doxapram should be administered with caution to patients with significantly impaired hepatic or renal function as a reduction in the rate of metabolism or excretion ofmetabolites may alter the response.In Postanesthetic Usea.The same consideration to pre-existing disease states should be exercised as in non-anesthetized individuals. See CONTRAINDICATIONS and WARNINGS covering use in hypertension, asthma, disturbances of respiratory mechanics including airway obstruction, CNS disorders including increased cerebrospinal fluid pressure,convulsive disorders, acute agitation, and profound metabolic disorders.b.See PRECAUTIONS, Drug Interactions.In Chronic Obstructive Pulmonary Diseasea.Arrhythmias seen in some patients in acute respiratory failure secondary to chronicobstructive pulmonary disease are probably the result of hypoxia. Doxapram should be used with caution in these patients.b.Arterial blood gases should be drawn prior to the initiation of doxapram infusion andoxygen administration, then at least every ½ hour during the infusion period toprevent development of CO2 retention and acidosis in patients with chronicobstructive pulmonary disease with acute hypercapnia. Doxapram administration does not diminish the need for careful monitoring of the patient or the need forsupplemental oxygen in patients with acute respiratory failure. Doxapram should be stopped if the arterial blood gases deteriorate, and mechanical ventilation should be initiated.Drug InteractionsAdministration of doxapram to patients who are receiving sympathomimetic or monoamine oxidase inhibiting drugs may result in an additive pressor effect (see PRECAUTIONS, General).In patients who have received neuromuscular blocking agents, doxapram may temporarily mask the residual effects of these drugs.In patients who have received general anesthesia utilizing a volatile agent known to sensitize the myocardium to catecholamines, administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation (see WARNINGS).There may be an interaction between doxapram and aminophylline and between theophylline manifested by increased skeletal muscle activity, agitation, and hyperactivity.Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenic or mutagenic studies have been performed using doxapram. Doxapram did not adversely affect the breeding performance of rats.PregnancyPregnancy Category BReproduction studies have been performed in rats at doses up to 1.6 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to doxapram. There are, however, no adequate and well-controlled studies in pregnant women. Because the animals in the reproduction studies were dosed by the IM and oral routes and animal reproduction studies, in general, are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.Nursing MothersIt is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when doxapram hydrochloride is administered to a nursing woman.Pediatric UseSafety and effectiveness in pediatric patients below the age of 12 years have not been established. This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.Premature neonates given doxapram have developed hypertension, irritability, jitteriness, hyperglycemia, glucosuria, abdominal distension, increased gastric residuals, vomiting, bloody stools, necrotizing enterocolitis, erratic limb movements, excessive crying, disturbed sleep, premature eruption of teeth, and QT prolongation that has resulted in heart block. In premature neonates with risk factors such as a previous seizure, perinatal asphyxia, or intracerebral hemorrhage, seizures have occurred. In many instances, doxapram was administered following administration of xanthine derivatives such as caffeine, aminophylline or theophylline.ADVERSE REACTIONSAdverse reactions reported coincident with the administration of DOPRAM (doxapram hydrochloride, USP) include:1. Central and Autonomic Nervous SystemsPyrexia, flushing, sweating; pruritus and paresthesia, such as a feeling of warmth, burning, or hot sensation, especially in the area of genitalia and perineum;apprehension, disorientation, pupillary dilatation, hallucinations, headache, dizziness, hyperactivity, involuntary movements, muscle spasticity, muscle fasciculations,increased deep tendon reflexes, clonus, bilateral Babinski, and convulsions.2.RespiratoryDyspnea, cough, hyperventilation, tachypnea, laryngospasm, bronchospasm,hiccough, and rebound hypoventilation.3. CardiovascularPhlebitis, variations in heart rate, lowered T-waves, arrhythmias (includingventricular tachycardia and ventricular fibrillation), chest pain, tightness in chest. A mild to moderate increase in blood pressure is commonly noted and may be ofconcern in patients with severe cardiovascular diseases.4. GastrointestinalNausea, vomiting, diarrhea, desire to defecate.5. GenitourinaryStimulation of urinary bladder with spontaneous voiding; urinary retention. Elevation of BUN and albuminuria.6. Hemic and LymphaticHemolysis with rapid infusion. A decrease in hemoglobin, hematocrit, or red blood cell count has been observed in postoperative patients. In the presence of pre-existing leukopenia, a further decrease in WBC has been observed following anesthesia and treatment with doxapram hydrochloride.OVERDOSAGESigns and SymptomsSymptoms of overdosage are extensions of the pharmacologic effects of the drug. Excessive pressor effect, such as hypertension, tachycardia, skeletal muscle hyperactivity, and enhanced deep tendon reflexes may be early signs of overdosage. Therefore, the blood pressure, pulse rate, and deep tendon reflexes should be evaluated periodically and the dosage or infusion rate adjusted accordingly.Other effects may include agitation, confusion, sweating, cough, and dyspnea. Convulsive seizures are unlikely at recommended dosages. In unanesthetized animals, the convulsant dose is 70 times greater than the respiratory stimulant dose. Intravenous LD50 values in the mouse and rat were approximately 75 mg/kg and in the cat and dog were 40 to 80 mg/kg.Except for management of chronic obstructive pulmonary disease associated with acute hypercapnia, the maximum recommended dosage is 3 GRAMS/24 HOURS. (See DOSAGE AND ADMINISTRATION.)ManagementThere is no specific antidote for doxapram. Management should be symptomatic. Anticonvulsants, along with oxygen and resuscitative equipment should be readily available to manage overdosage manifested by excessive central nervous system stimulation. Slow administration of the drug and careful observation of the patient during administration and for some time subsequently are advisable. These precautions are to assure that the protective reflexes have been restored and to prevent possible post-hyperventilation or hypoventilation.There is no evidence that doxapram is dialyzable; further, the half-life of doxapram makes it unlikely that dialysis would be appropriate in managing overdose with this drug. DOSAGE AND ADMINISTRATIONNOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS)In Postanesthetic UseTable I. Dosage for postanesthetic use—I.V. and infusion.injection dose* Administrationmg/kg mg/kg mg/kg Single Injection 0.5-1 1.5 1.5 Repeat Injections(5 min. intervals)0.5-1 1.5 2 Infusion 0.5-1 – 4*Dose not to exceed 3 grams/24 hours.By I.V. Injection(See Table I. Dosage for postanesthetic use—I.V.)The recommended dose for I.V. administration is 0.5 – 1 mg/kg for a single injection and at 5-minute intervals. Careful observation of the patient during administration and for some time subsequently are advisable. The ma ximum total dosage by I.V. injection is 2 mg/kg.By InfusionThe solution is prepared by adding 250 mg of doxapram (12.5 mL) to 250 mL of dextrose 5% or 10% in water or normal saline solution. The infusion is initiated at a rate of approximately 5 mg/minute until a satisfactory respiratory response is observed, and maintained at a rate of 1 to 3 mg/minute. The rate of infusion should be adjusted to sustain the desired level of respiratory stimulation with a minimum of side effects. The maximum total dosage by infusion is 4 mg/kg, or approximately 300 mg for the average adult.In the Management of Drug-Induced CNS Depression(See Table II. Dosage for drug-induced CNS depression.)Table II. Dosage for drug-induced CNS depression.METHOD ONE Priming dose single/repeatI.V. InjectionMETHOD TWO Rate of IntermittentI.V. InfusionLevel of Depression mg/kg mg/kg/hrModerate† 2 2-3Class 0: Asleep, but can be aroused and can answer questions.Class 1: Comatose, will withdraw from painful stimuli, reflexes intact.†Moderate DepressionClass 2: Comatose, will not withdraw from painful stimuli, reflexes intact.Class 3: Comatose, reflexes absent, no depression of circulation or respiration.Method OneUsing Single and/or Repeat Single I.V. Injectionsa.Give priming dose of 2 mg/kg body weight and repeat in 5 minutes. The priming dosefor moderate depression is 2 mg/kg and the priming dose for mild depression is 1 mg/kg.b.Repeat same dose q 1 to 2h until patient wakens. Watch for relapse intounconsciousness or development of respiratory depression, since DOPRAM does not affect the metabolism of CNS-depressant drugs.c.If relapse occurs, resume injections q 1 to 2h until arousal is sustained, or totalmaximum daily dose (3 grams) is given. After maximum dose has been given (3grams), allow patient to sleep until 24 hours have elapsed from first injection ofDOPRAM, using assisted or automatic respiration if necessary.d.Repeat procedure the following day until patient breathes spontaneously and sustainsdesired level of consciousness, or until maximum dosage (3 grams) is given.e.Repetitive doses should be administered only to patients who have shown response tothe initial dose.f.Failure to respond appropriately indicates the need for neurologic evaluation for apossible central nervous system source of sustained coma.Method TwoBy Intermittent I.V. Infusiona.Give priming dose as in Method One.b.If patient wakens, watch for relapse; if no response, continue general supportivetreatment for 1 to 2 hours and repeat priming dose of DOPRAM. If some respiratory stimulation occurs, prepare I.V. infusion by adding 250 mg of DOPRAM (12.5 mL) to 250 mL of saline or dextrose solution. Deliver at rate of 1 to 3 mg/min (60 to180 mL/hr) according to size of patient and depth of coma. Discontinue DOPRAM if patient begins to waken or at end of 2 hours.c.Continue supportive treatment for ½ to 2 hours and repeat Step b.d.Do not exceed 3 grams/day.Chronic Obstructive Pulmonary Disease Associated with Acute Hypercapniaa.One vial of doxapram (400 mg) should be mixed with 180 mL of dextrose 5% or 10%or normal saline solution (concentration of 2 mg/mL). The infusion should be started at 1 to 2 mg/minute (½ to 1 mL/minute); if indicated, increase to a maximum of 3 mg/minute. Arterial blood gases should be determined prior to the onset ofdoxapram’s administration and at least every half hour during the two hours ofinfusion to insure against the insidious development of CO2-RETENTION ANDACIDOSIS. Alteration of oxygen concentration or flow rate may necessitateadjustment in the rate of doxapram infusion.b.Predictable blood gas patterns are more readily established with a continuous infusionof doxapram. If the blood gases show evidence of deterioration, the infusion ofdoxapram should be discontinued.c.ADDITIONAL INFUSIONS BEYOND THE SINGLE MAXIMUM TWO HOURADMINISTRATION PERIOD ARE NOT RECOMMENDED.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.Diluent CompatibilityDoxapram hydrochloride is compatible with 5% and 10% dextrose in water or normal saline.IncompatibilityADMIXTURE OF DOXAPRAM WITH ALKALINE SOLUTIONS SUCH AS 2.5% THIOPENTAL SODIUM, SODIUM BICARBONATE, FUROSEMIDE, OR AMINOPHYLLINE WILL RESULT IN PRECIPITATION OR GAS FORMATION. Doxapram is also not compatible with ascorbic acid, cefoperazone sodium, cefotaxime sodium, cefotetan sodium, cefuroxime sodium, folic acid, dexamethasone disodium phosphate, diazepam, hydrocortisone sodium phospate, methylprednisolone sodium, or hydrocortisone sodium succinate.Admixture of doxapram and ticarcillin disodium results in an 18% loss of doxapram in 3 hours. When doxapram is mixed with minocycline hydrochloride, there is a loss of 8% of doxapram in 3 hours and a 13% loss of doxapram in 6 hours.HOW SUPPLIEDDOPRAM Injection (doxapram hydrochloride injection, USP) containing 20 mg of doxapram hydrochloride per mL with benzyl alcohol 0.9% as the preservative is available in:20 mL multiple dose vials in packages of 6 (NDC 60977-144-02).CONTAINS BENZYL ALCOHOL.Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].ESI Stylized Logo and Dopram are trademarks of Baxter International Inc., or its subsidiaries.Manufactured byBaxter Healthcare CorporationDeerfield, IL 60015 USAFor Product Inquiry 1 800 ANA DRUG (1-800-262-3784)MLT-31/2.0。

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use SINGULAIR safely and effectively. See full prescribing information for SINGULAIR.SINGULAIR®(montelukast sodium) tablets, chewable tablets, and oral granules Initial U.S. Approval: 1998---------------------------RECENT MAJOR CHANGES --------------------------­Warnings and Precautions, Neuropsychiatric Events (5.4) 04/2010 ----------------------------INDICATIONS AND USAGE ---------------------------­SINGULAIR® is a leukotriene receptor antagonist indicated for:• Prophylaxis and chronic treatment of asthma in patients12 months of age and older (1.1).• Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older (1.2).• Relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 2 years of age and older, and perennial allergic rhinitis (PAR) in patients 6 months of age and older (1.3).-----------------------DOSAGE AND ADMINISTRATION-----------------------­Administration (by indications):• Asthma (2.1): Once daily in the evening for patients 12 months and older.• Acute prevention of EIB (2.2): 10 mg tablet at least 2 hours before exercise for patients 15 years of age and older.• Seasonal allergic rhinitis (2.3): Once daily for patients 2 years and older.• Perennial allergic rhinitis (2.3): Once daily for patients 6 months and older.Dosage (by age):• 15 years and older: one 10-mg tablet.• 6 to 14 years: one 5-mg chewable tablet.• 2 to 5 years: one 4-mg chewable tablet or one packet of 4-mg oral granules.• 6 to 23 months: one packet of 4-mg oral granules.Patients with both asthma and allergic rhinitis should take only one dose daily in the evening (2.4). For oral granules: Must administer within 15 minutes after opening the packet (with or without mixing with food) (2.5). ---------------------DOSAGE FORMS AND STRENGTHS --------------------­• SINGULAIR 10-mg Film-Coated Tablets• SINGULAIR 5-mg and 4-mg Chewable Tablets• SINGULAIR 4-mg Oral Granules-------------------------------CONTRAINDICATIONS ------------------------------­• Hypersensitivity to any component of this product (4).------------------------WARNINGS AND PRECAUTIONS-----------------------­• Do not prescribe SINGULAIR to treat an acute asthma attack.• Advise patients to have appropriate rescue medication available(5.1).• Inhaled corticosteroid may be reduced gradually. Do not abruptlysubstitute SINGULAIR for inhaled or oral corticosteroids (5.2).• Patients with known aspirin sensitivity should continue to avoidaspirin or non-steroidal anti-inflammatory agents while takingSINGULAIR (5.3).• Neuropsychiatric events have been reported with SINGULAIR.Instruct patients to be alert for neuropsychiatric events. Evaluatethe risks and benefits of continuing treatment with SINGULAIR ifsuch events occur (5.4 and 6.2).• Systemic eosinophilia, sometimes presenting with clinical featuresof vasculitis consistent with Churg-Strauss syndrome, has beenreported. These events usually, but not always, have beenassociated with the reduction of oral corticosteroid therapy (5.5and 6.2).• Inform patients with phenylketonuria that the 4-mg and 5-mgchewable tablets contain phenylalanine (5.6).------------------------------ADVERSE REACTIONS------------------------------­Most common adverse reactions (incidence ≥5% and greater thanplacebo listed in descending order of frequency): upper respiratoryinfection, fever, headache, pharyngitis, cough, abdominal pain,diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis (6.1).To report SUSPECTED ADVERSE REACTIONS, contact MerckSharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­888-4231 or FDA at 1-800-FDA-1088 or /medwatch.See 17 for PATIENT COUNSELING INFORMATION andFDA-approved patient labeling.Revised:12/2010FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE1.1 A sthma1.2 E xercise-InducedBronchoconstriction1.3 A llergicRhinitis2 DOSAGE AND ADMINISTRATION2.1 A sthma2.2 E xercise-Induced Bronchoconstriction (EIB) in Patients 15Years of Age and Older2.3 Allergic Rhinitis2.4 Asthma and Allergic Rhinitis2.5 Instructions for Administration of Oral Granules3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 A cuteAsthma5.2 Concomitant Corticosteroid Use5.3 A spirinSensitivity5.4 N europsychiatricEvents5.5 E osinophilicConditions5.6 P henylketonuria6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 P ost-MarketingExperience7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS8.1 P regnancy8.3 N ursingMothers8.4 P ediatricUse8.5 G eriatricUse8.6 H epaticInsufficiency8.7 R enalInsufficiency10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Asthma14.2 Exercise-Induced Bronchoconstriction (EIB)14.3 Allergic Rhinitis (Seasonal and Perennial)16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION17.1 Information for Patients17.2 FDA-Approved Patient Labeling*Sections or subsections omitted from the full prescribing information are not listed.(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesFULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGE1.1 AsthmaSINGULAIR1 is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older.1.2 Exercise-Induced BronchoconstrictionSINGULAIR is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older.1.3 Allergic RhinitisSINGULAIR is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older.2 DOSAGE AND ADMINISTRATION2.1 AsthmaSINGULAIR should be taken once daily in the evening. The following doses are recommended:For adults and adolescents 15 years of age and older: one 10-mg tablet.For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet or one packet of 4-mg oral granules.For pediatric patients 12 to 23 months of age: one packet of 4-mg oral granules.Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion.2.2 Exercise-Induced Bronchoconstriction (EIB) in Patients 15 Years of Age and OlderFor prevention of EIB, a single 10 mg dose of SINGULAIR should be taken at least 2 hours before exercise. An additional dose of SINGULAIR should not be taken within 24 hours of a previous dose. Patients already taking SINGULAIR daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist. Safety and effectiveness in patients younger than 15 years of age have not been established. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.2.3 Allergic RhinitisFor allergic rhinitis, SINGULAIR should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs.The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10-mg tablet.For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet or one packet of 4-mg oral granules.Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.1 Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.Copyright © 1998-2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesThe following doses for the treatment of symptoms of perennial allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10-mg tablet.For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet or one packet of 4-mg oral granules.For pediatric patients 6 to 23 months of age: one packet of 4-mg oral granules.Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.2.4 Asthma and Allergic RhinitisPatients with both asthma and allergic rhinitis should take only one SINGULAIR dose daily in the evening.2.5 Instructions for Administration of Oral GranulesSINGULAIR 4-mg oral granules can be administered either directly in the mouth, dissolved in 1 teaspoonful (5 mL) of cold or room temperature baby formula or breast milk, or mixed with a spoonful of cold or room temperature soft foods; based on stability studies, only applesauce, carrots, rice, or ice cream should be used. The packet should not be opened until ready to use. After opening the packet, the full dose (with or without mixing with baby formula, breast milk, or food) must be administered within 15 minutes. If mixed with baby formula, breast milk, or food, SINGULAIR oral granules must not be stored for future use. Discard any unused portion. SINGULAIR oral granules are not intended to be dissolved in any liquid other than baby formula or breast milk for administration. However, liquids may be taken subsequent to administration. SINGULAIR oral granules can be administered without regard to the time of meals.3 DOSAGE FORMS AND STRENGTHS• SINGULAIR 10-mg Film-Coated Tablets are beige, rounded square-shaped tablets, with code MRK 117 on one side and SINGULAIR on the other.• SINGULAIR 5-mg Chewable Tablets are pink, round, bi-convex-shaped tablets, with code MRK 275 on one side and SINGULAIR on the other.• SINGULAIR 4-mg Chewable Tablets are pink, oval, bi-convex-shaped tablets, with code MRK 711 on one side and SINGULAIR on the other.• SINGULAIR 4-mg Oral Granules are white granules with 500 mg net weight, packed in a child-resistant foil packet.4 CONTRAINDICATIONSHypersensitivity to any component of this product.5 WARNINGS AND PRECAUTIONS5.1 Acute AsthmaSINGULAIR is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with SINGULAIR can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled β-agonist.5.2 Concomitant Corticosteroid UseWhile the dose of inhaled corticosteroid may be reduced gradually under medical supervision, SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids.5.3 Aspirin SensitivityPatients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti­inflammatory agents while taking SINGULAIR. Although SINGULAIR is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate(Montelukast Sodium) Tablets, Chewable Tablets, and Oral Granulesbronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients [see Clinical Studies (14.1)].5.4 Neuropsychiatric EventsNeuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking SINGULAIR. Post-marketing reports with SINGULAIR use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving SINGULAIR appear consistent with a drug-induced effect.Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with SINGULAIR if such events occur [see Adverse Reactions (6.2)].5.5 Eosinophilic ConditionsPatients with asthma on therapy with SINGULAIR may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between SINGULAIR and these underlying conditions has not been established [see Adverse Reactions (6.2)].5.6 PhenylketonuriaPhenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame), 0.674 and 0.842 mg per 4-mg and 5-mg chewable tablet, respectively.6 ADVERSEREACTIONS6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the following description of clinical trials experience, adverse reactions are listed regardless of causality assessment.The most common adverse reactions (incidence ≥5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.Adults and Adolescents 15 Years of Age and Older with AsthmaSINGULAIR has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with SINGULAIR occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesTABLE 1Adverse Experiences Occurring in ≥1% of Patientswith an Incidence Greater than that in Patients Treated with PlaceboSINGULAIR 10 mg/day(%)(n=1955) Placebo(%) (n=1180)Body As A WholePain, abdominal 2.9 2.5Asthenia/fatigue 1.8 1.2Fever 1.5 0.9TraumaDigestive System Disorders1.0 0.8Dyspepsia 2.1 1.1Pain, dental 1.7 1.0Gastroenteritis, infectiousNervous System/Psychiatric1.5 0.5Headache 18.4 18.1DizzinessRespiratory System Disorders1.9 1.4Influenza 4.2 3.9Cough 2.7 2.4Congestion, nasalSkin/Skin Appendages Disorder1.6 1.3RashLaboratory Adverse Experiences*1.6 1.2ALT increased 2.1 2.0AST increased 1.6 1.2Pyuria 1.0 0.9* Number of patients tested (SINGULAIR and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159.The frequency of less common adverse events was comparable between SINGULAIR and placebo.The safety profile of SINGULAIR, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for SINGULAIR.Cumulatively, 569 patients were treated with SINGULAIR for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not significantly change.Pediatric Patients 6 to 14 Years of Age with AsthmaSINGULAIR has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with SINGULAIR for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of SINGULAIR in the 8-week, double-blind, pediatric efficacy trial was generally similar to the adult safety profile. In pediatric patients 6 to 14 years of age receiving SINGULAIR, the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: pharyngitis, influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The frequency of less common adverse events was comparable between SINGULAIR and placebo. With prolonged treatment, the adverse experience profile did not significantly change.In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for SINGULAIR. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving SINGULAIR, the following events not previously observed with the use of SINGULAIR in this age group occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: headache, rhinitis (infective), varicella, gastroenteritis, atopic dermatitis, acute bronchitis, tooth infection, skin infection, and myopia.(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesPediatric Patients 2 to 5 Years of Age with AsthmaSINGULAIR has been evaluated for safety in 573 pediatric patients 2 to 5 years of age in single- and multiple-dose studies. Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with SINGULAIR for at least 3 months, 230 for 6 months or longer, and 63 patients for one year or longer in clinical trials. In pediatric patients 2 to 5 years of age receiving SINGULAIR, the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis.Pediatric Patients 6 to 23 Months of Age with AsthmaSafety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been established.SINGULAIR has been evaluated for safety in 175 pediatric patients 6 to 23 months of age. The safety profile of SINGULAIR in a 6-week, double-blind, placebo-controlled clinical study was generally similar to the safety profile in adults and pediatric patients 2 to 14 years of age. In pediatric patients 6 to 23 months of age receiving SINGULAIR, the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: upper respiratory infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; and rhinitis. The frequency of less common adverse events was comparable between SINGULAIR and placebo.Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis SINGULAIR has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. SINGULAIR administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following event was reported with SINGULAIR with a frequency ≥1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving SINGULAIR vs. 1.5% of patients receiving placebo. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic RhinitisSINGULAIR has been evaluated in 280 pediatric patients 2 to 14 years of age in a 2-week, multicenter, double-blind, placebo-controlled, parallel-group safety study. SINGULAIR administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following events occurred with a frequency ≥2% and at an incidence greater than placebo: headache, otitis media, pharyngitis, and upper respiratory infection.Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis SINGULAIR has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received SINGULAIR in two, 6-week, clinical studies. SINGULAIR administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following events were reported with SINGULAIR with a frequency ≥1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.Pediatric Patients 6 Months to 14 Years of Age with Perennial Allergic Rhinitis The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this pediatric population and from adult pharmacokinetic studies.6.2 Post-Marketing ExperienceThe following adverse reactions have been identified during post-approval use of SINGULAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Blood and lymphatic system disorders: increased bleeding tendency, thrombocytopenia.Immune system disorders: hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesPsychiatric disorders: agitation including aggressive behavior or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tremor [see Warnings and Precautions (5.4)].Nervous system disorders: drowsiness, paraesthesia/hypoesthesia, seizures.Cardiac disorders: palpitations.Respiratory, thoracic and mediastinal disorders: epistaxis.Gastrointestinal disorders: diarrhea, dyspepsia, nausea, pancreatitis, vomiting.Hepatobiliary disorders: Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with SINGULAIR. Most of these occurred in combination with other confounding factors, such as use of other medications, or when SINGULAIR was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis.Skin and subcutaneous tissue disorders: angioedema, bruising, erythema nodosum, pruritus, urticaria.Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle cramps.General disorders and administration site conditions: edema.Patients with asthma on therapy with SINGULAIR may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients [see Warnings and Precautions (5.5)].7 DRUGINTERACTIONSNo dose adjustment is needed when SINGULAIR is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin, warfarin, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see Clinical Pharmacology (12.3)].8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SINGULAIR should be used during pregnancy only if clearly needed.Teratogenic Effect: No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs [see Nonclinical Toxicology (13.2)].During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with SINGULAIR during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and SINGULAIR has not been established.Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to SINGULAIR while pregnant. Patients and healthcare providers are encouraged to report any prenatal exposure to SINGULAIR by calling the Pregnancy Registry at 1-800-986-8999.8.3 Nursing MothersStudies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SINGULAIR is given to a nursing mother.8.4 Pediatric UseSafety and efficacy of SINGULAIR have been established in adequate and well-controlled studies in pediatric patients with asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are(Montelukast Sodium) Tablets, Chewable Tablets, and Oral Granulessimilar to those seen in adults [see Adverse Reactions (6.1), Clinical Pharmacology, Special Populations (12.3), and Clinical Studies (14.1)].The efficacy of SINGULAIR for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 6 months to 14 years of age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations.The safety of SINGULAIR 4-mg chewable tablets in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data [see Adverse Reactions (6.1)]. Efficacy of SINGULAIR in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. Efficacy in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age.The safety of SINGULAIR 4-mg oral granules in pediatric patients 12 to 23 months of age with asthma has been demonstrated in an analysis of 172 pediatric patients, 124 of whom were treated with SINGULAIR, in a 6-week, double-blind, placebo-controlled study [see Adverse Reactions (6.1)]. Efficacy of SINGULAIR in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma based on similar mean systemic exposure (AUC), and that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations, supported by efficacy data from a safety trial in which efficacy was an exploratory assessment.The safety of SINGULAIR 4-mg and 5-mg chewable tablets in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile [see Adverse Reactions (6.1)]. The safety of SINGULAIR 4-mg oral granules in pediatric patients as young as 6 months of age with perennial allergic rhinitis is supported by extrapolation from safety data obtained from studies conducted in pediatric patients 6 months to 23 months of age with asthma and from pharmacokinetic data comparing systemic exposures in patients 6 months to 23 months of age to systemic exposures in adults.The safety and effectiveness in pediatric patients below the age of 12 months with asthma and 6 months with perennial allergic rhinitis have not been established. The safety and effectiveness in pediatric patients below the age of 15 years with exercise-induced bronchoconstriction have not been established.Growth Rate in Pediatric PatientsA 56-week, multi-center, double-blind, randomized, active- and placebo-controlled parallel group study was conducted to assess the effect of SINGULAIR on growth rate in 360 patients with mild asthma, aged 6 to 8 years. Treatment groups included SINGULAIR 5 mg once daily, placebo, and beclomethasone dipropionate administered as 168 mcg twice daily with a spacer device. For each subject, a growth rate was defined as the slope of a linear regression line fit to the height measurements over 56 weeks. The primary comparison was the difference in growth rates between SINGULAIR and placebo groups. Growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for the SINGULAIR, placebo, and beclomethasone treatment groups were 5.67 (5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64, 5.08), respectively. The differences in growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for SINGULAIR minus placebo, beclomethasone minus placebo, and SINGULAIR minus beclomethasone treatment groups were 0.03 (-0.26, 0.31), -0.78 (-1.06, -0.49); and 0.81 (0.53, 1.09), respectively. Growth rate (expressed as mean change in height over time) for each treatment group is shown in FIGURE 1.FIGURE 1Change in Height (cm) from Randomization Visit by Scheduled Week(Treatment Group Mean ± Standard Error† of the Mean)。