Catosal

Dosage Form: FOR ANIMAL USE ONLY
CatosalTM

(10% Butaphosphan+cyanocobalamin)

Sterile Injectable Solution

CAUTION: Federal law (U.S.A.) restricts this drug to use by or on the order of a licensed veterinarian.

INDICATIONS :

CatosalTM is a source of Vitamin B12 and phosphorus for prevention or treatment of deficiencies of these nutrients in cattle, swine, horses and poultry.

Contains Per mL:

1-( n-Butylamino)-1-methylethyl phosphonous acid

(Butaphosphan)......................................................100 mg

Cyanocobalamin (Vitamin B12)...........................0.05 mg

n-Butyl alcohol (as preservative).............................30 mg

Butaphosphan provides 17.3 mg of phosphorus in 1 mL of CatosalTM solution.

PRECAUTIONS:

Use standard aseptic procedures during administration of injections. Volumes of more than 10mL should be split and given at separate intramuscular or subcutaneous sites.

For customer service or to obtain product information, including a Material Safety Data Sheet, call 1-800-633-3796. For medical emergencies or to report adverse reactions, call 1-800-422-9874.

Catosal Dosage and Administration

Give by subcutaneous, intramuscular or intravenous injection according to the following table:

Repeat daily as needed.
Cattle	1 - 2 mL per 100 lbs body weight
Calves	2 - 4 mL per 100 lbs body weight
Horses	1 - 2 mL per 100 lbs body weight
Swine	2 - 5 mL per 100 lbs body weight
Piglets	1 - 2.5 mL per animal
Poultry	1 - 3 mL per Liter drinking water

HUMAN WARNINGS:

For animal use only. Keep out of reach of children.

RESIDUE WARNINGS:

This product has a zero day withdrawal period for meat, milk, and eggs.

STORAGE CONDITIONS:

Store at temperatures below 30°C (86°F), avoiding freezing.

Bayer, the Bayer Cross and Catosal are trademarks of Bayer.

Patent Pending.

81177490                                                                    14226

© 2008 Bayer HealthCare LLC                  Printed in USA

Principal Display Panel

Principal Display Panel

Catosal  enrofloxacin  solution

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 0859-2350 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BUTAFOSFAN (BUTAFOSFAN) BUTAFOSFAN 100 mg  in 1 mL CYANOCOBALAMIN (CYANOCOBALAMIN) CYANOCOBALAMIN 0.05 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength BUTYL ALCOHOL 30 mg  in 1 mL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0859-2350-01 100 mL In 1 BOTTLE None 2 0859-2350-02 250 mL In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Unapproved drug other		01/20/2009

Labeler - Bayer HealthCare LLC Animal Health Division (152266193)

Revised: 05/2009Bayer HealthCare LLC Animal Health Division

Serevent

Generic Name: Salmeterol Xinafoate
Class: Selective beta-2-Adrenergic Agonists
VA Class: RE102
Chemical Name: ±-4-Hydroxy-α1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol compd. with 1-hydroxy-2-naphthalenecarboxylic acid (1:1)
Molecular Formula: C₂₅H₃₇NO₄•C₁₁ H₈O₃
CAS Number: 94749-08-3

Special Alerts:

[Posted 02/18/2010] FDA notified healthcare professionals and consumers that, due to safety concerns, FDA is requiring a risk management strategy (REMS) and class-labeling changes for all Long-Acting Beta-Agonists (LABAs). The REMS will require a revised Medication Guide written specifically for patients, and a plan to educate healthcare professionals about the appropriate use of LABAs. These changes are based on FDA's analyses of studies showing an increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma.

Healthcare professionals are reminded that to ensure the safe use of these products:

• 
  

  Single-ingredient LABAs should only be used in combination with an asthma controller medication; they should not be used alone.

  
  


• 
  

  LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.

  
  


• 
  

  LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller medication.

  
  


• 
  

  Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure compliance with both medications.

  
  

FDA has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when used appropriately with an asthma controller medication in patients who need the addition of LABAs. FDA believes the safety measures recommended will improve the safe use of these drugs. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for salmeterol to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of salmeterol and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

• 
  

  Possible increase in asthma-related deaths in patients receiving long-acting β₂-adrenergic bronchodilators, including salmeterol, in addition to usual asthma therapy.^{188 221 226 227 241 242 248 249}

  
  


• 
  

  Reserve use of long-acting β₂-adrenergic agonists in patients with asthma for those whose disease is inadequately controlled with other anti-asthma therapy (e.g., low to medium dosage of inhaled corticosteroids) or whose disease severity warrants treatment with 2 maintenance therapies.^{188 221 247 248 249 250 251} (See Increased Risk of Asthma-related Death under Cautions.)

  
  

Introduction

Bronchodilator; a relatively selective, long-acting β₂-adrenergic agonist.^{1 2 3 5 188}

Uses for Serevent

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Bronchospasm in Asthma

Long-term prevention of bronchospasm in patients with reversible obstructive airway disease (e.g., asthma) whose symptoms are not adequately managed with other controller therapy (e.g., low to medium dosage of inhaled corticosteroids) or whose disease severity warrants treatment with 2 maintenance therapies.^{222 247 248} Not indicated in patients whose asthma can be successfully managed with occasional use of inhaled, short-acting β₂-adrenergic agonists or in those whose asthma can be successfully managed by inhaled corticosteroids or other controller drugs accompanied by occasional use of an inhaled, short-acting β₂-adrenergic agonist.^{188 221 250 251 a} (See Increased Risk of Asthma-related Death under Cautions.)

Fixed combination of salmeterol and fluticasone propionate recommended in patients who have not responded adequately to low to medium dosages of inhaled corticosteroids without a long-acting β₂-adrenergic agonist or in patients who are already taking an inhaled corticosteroid and a long-acting β₂-adrenergic agonist separately.²⁴⁹ Fixed combination should not be used in patients whose asthma can be successfully managed by inhaled corticosteroids accompanied by occasional use of inhaled, short-acting β₂-adrenergic agonists.^{188 221 250 251 a}

Salmeterol should not be used as initial or sole therapy for asthma and is not a substitute for corticosteroids;^{247 248 249} corticosteroid therapy should not be stopped or reduced in dosage when salmeterol is initiated.^{1 226 247} (See Concomitant Anti-inflammatory Therapy under Cautions.)

Not to be used for immediate relief of bronchospasm or in patients with substantially worsening or acutely deteriorating asthma.^{1 154 188 221 247 248 249 250 251} (See Acute Exacerbations of Asthma or COPD under Cautions.)

Exercise-induced Bronchospasm

Prevention of exercise-induced bronchospasm.^{1 12 21 91 105 172 188 214}

Consider alternative therapy if twice-daily dosing is not effective.^{1 188}

Bronchospasm in COPD

Long-term symptomatic treatment of reversible bronchospasm associated with moderate to severe COPD (e.g., FEV₁ less than 80% of predicted), including chronic bronchitis and emphysema.^{1 182 183 238 239}

Fixed combination of salmeterol and fluticasone propionate for maintenance treatment of airflow obstruction in COPD associated with chronic bronchitis.²²¹

Benefit of therapy with fixed combination of salmeterol and fluticasone propionate for >6 months not established.²²¹ Reevaluate patients receiving long-term therapy (>6 months) periodically to assess continuing benefits and risks.²²¹

Not to be used for immediate relief of acute exacerbations of COPD.^{1 154 188 221} Use a short-acting inhaled β₂-agonist intermittently (as needed) for acute symptoms of COPD.^{238 239} (See Acute Exacerbations of Asthma or COPD under Cautions.)

Serevent Dosage and Administration

General

• 
  

  When salmeterol therapy is initiated, regular use of short-acting, inhaled β₂-agonists should be discontinued,^{1 97 113 188} and such agents should be used only for relief of acute symptoms of asthma or COPD that are not controlled by salmeterol.^{1 97 113 188 221}

  
  


• 
  

  Failure to respond to a previously effective dosage may indicate seriously worsening asthma; extra/increased doses are not recommended.^{1 111 112} (See Acute Exacerbations of Asthma or COPD under Cautions.) Consult clinician.^{1 113 188}

  
  


• 
  

  Therapy with salmeterol in fixed combination with fluticasone propionate should be initiated in asthmatic patients ≥12 years of age whose disease severity warrants treatment with 2 maintenance therapies, including those maintained on noncorticosteroid therapy.²²¹

  
  

Administration

Oral Inhalation

Administer by oral inhalation using a special oral inhaler (Diskus device) that delivers powdered salmeterol xinafoate alone (Serevent Diskus) or in fixed combination with fluticasone propionate (Advair Diskus) from foil-wrapped blisters.^{188 221}

Administer twice daily, approximately every 12 hours (morning and evening).^{1 188 221}

Oral Inhalation Powder

Hold the Diskus device in one hand, put the thumb of the other hand on the thumbgrip, and push the thumbgrip until the mouthpiece appears and snaps into position.^{189 a}

To release powdered drug into the exit port, hold the inhaler in a level, horizontal position and depress the lever on the Diskus in a direction away from the patient.^{188 189 a}

To avoid releasing and wasting additional doses of the drug, do not close the Diskus device, play with the lever, or advance the lever more than once.^{189 a} A dose counter will advance each time the lever is depressed.¹⁸⁹

Exhale completely, place the mouthpiece of the inhaler between the lips, and inhale deeply and rapidly through the inhaler with a steady, even breath.^{188 189 190 a} Remove the inhaler from the mouth and hold the breath for 10 seconds before slowly exhaling.^{189 a}

Do not exhale into the Diskus device.^{188 189 190 221 a}

Spacer devices are not recommended with the Serevent or Advair Diskus inhaler.^{188 221 a}

Close the inhalation device and reset for the next dose by sliding the thumbgrip toward the patient as far as it will go.^{189 221 a} Do not wash the inhaler.^{188 189 221} Do not take inhaler apart.^{188 190 221}

Discard the inhaler when every blister of salmeterol alone or in fixed combination with fluticasone propionate has been used.^{188 190 221} Alternatively, discard the inhaler 6 or 4 weeks after removal of salmeterol alone or in fixed combination with fluticasone propionate, respectively, from its foil overwrap pouch.^{188 190 221 a}

Rinse the mouth without swallowing after inhalation of salmeterol in fixed combination with fluticasone propionate.²²¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as salmeterol xinafoate; dosage expressed in terms of salmeterol.¹

Each blister in the Serevent or Advair Diskus device contains 50 mcg of salmeterol as salmeterol xinafoate inhalation powder.^{188 221} However, the precise amount of drug delivered to the lungs depends on factors such as the patient’s inspiratory flow.^{188 221}

Pediatric Patients

Asthma

Oral Inhalation

Serevent Diskus: 50 mcg (1 inhalation) twice daily in children ≥4 years of age.^{188 221}

Fixed combination of salmeterol and fluticasone propionate in children 4–11 years of age: Initially, 50 mcg of salmeterol and 100 mcg of fluticasone propionate twice daily in those inadequately controlled with an inhaled corticosteroid.²²¹

Fixed combination of salmeterol and fluticasone propionate in children ≥12 years of age: Initially, 50 mcg of salmeterol and 100 mcg of fluticasone propionate (1 inhalation) twice daily, for children not currently receiving an orally inhaled corticosteroid;²²¹ after 2 weeks, if asthma control is inadequate, increasing the dosage of fluticasone propionate may provide additional asthma control.²²¹ In patients currently receiving inhaled corticosteroid, salmeterol 50 mcg twice daily and a fluticasone propionate dosage based on the dosage of the inhaled corticosteroid currently in use²²¹ . (see Table 1.)

Table 1. Recommended Dosage of Advair Diskus for Adolescents ≥12 Years of Age Taking Inhaled Corticosteroids

Inhaled Corticosteroid	Current Daily Dosage of Inhaled Corticosteroid (mcg)	Recommended Strength of Fluticasone Propionate Contained in Advair Diskus (with 50 mcg of Salmeterol) at Twice-Daily Dosage (mcg)
Beclomethasone Dipropionate HFA Inhalation Aerosol	≤160	100
	320	250
	640	500
Budesonide Inhalation Aerosol	≤400	100
	800–1200	250
	1600	500
Flunisolide Inhalation Aerosol	≤1000	100
	1250–2000	250
Flunisolide HFA Inhalation	≤320	100
	640	250
Fluticasone Propionate HFA Inhalation Aerosol	≤176	100
	440	250
	660–880	500
Fluticasone Propionate Inhalation Powder	≤200	100
	500	250
	1000	500
Mometasone Furoate Inhalation Powder	220	100
	440	250
	880	500
Triamcinolone Acetonide	≤1000	100
	1100–1600	250

Exercise-induced Bronchospasm

Oral Inhalation

50 mcg (1 inhalation) administered via the Serevent Diskus device at least 30 minutes before exercise for children ≥4 years of age.¹⁸⁸

Adults

Asthma

Oral Inhalation

Serevent Diskus: 50 mcg (1 inhalation) twice daily.¹⁸⁸

Fixed combination of salmeterol and fluticasone propionate: Initially, 50 mcg of salmeterol and 100 mcg of fluticasone propionate (1 inhalation) twice daily, in patients not currently receiving an orally inhaled corticosteroid;²²¹ after 2 weeks, if asthma control is inadequate, increasing the dosage of fluticasone propionate may provide additional asthma control.²²¹ In patients currently receiving inhaled corticosteroid, salmeterol 50 mcg twice daily and a fluticasone proprionate dosage based on the dosage of the inhaled corticosteroid currently in use.²²¹ (see Table 2.)

Table 2. Recommended Dosage of Advair Diskus for Adults Taking Inhaled Corticosteroids

Inhaled Corticosteroid	Current Daily Dosage of Inhaled Corticosteroid (mcg)	Recommended Strength of Fluticasone Propionate Contained in Advair Diskus (with 50 mcg of Salmeterol) at Twice-Daily Dosage (mcg)
Beclomethasone Dipropionate HFA Inhalation Aerosol	≤160	100
	320	250
	640	500
Budesonide Inhalation Aerosol	≤400	100
	800–1200	250
	1600	500
Flunisolide Inhalation Aerosol	≤1000	100
	1250–2000	250
Flunisolide HFA Inhalation	≤320	100
	640	250
Fluticasone Propionate HFA Inhalation Aerosol	≤176	100
	440	250
	660–880	500
Fluticasone Propionate Inhalation Powder	≤200	100
	500	250
	1000	500
Mometasone Furoate Inhalation Powder	220	100
	440	250
	880	500
Triamcinolone Acetonide	≤1000	100
	1100–1600	250

If control of asthma is inadequate 2 weeks after initiation of therapy at the initial dosage, a higher strength may provide additional asthma control.²²¹

Exercise-induced Bronchospasm

Oral Inhalation

Serevent Diskus: 50 mcg (1 inhalation) administered at least 30 minutes before exercise.¹⁸⁸

COPD

Oral Inhalation

Serevent Diskus: 50 mcg (1 inhalation) twice daily.¹⁸⁸

Fixed combination of salmeterol and fluticasone propionate: 50 mcg (1 inhalation) of salmeterol with 250 mcg of fluticasone propionate twice daily administered via the Advair Diskus device.²²¹

Use of dosages higher than those recommended (50 mcg of salmeterol and 250 mcg of fluticasone propionate twice daily) produces no additional improvement in lung function.²²¹

Prescribing Limits

Pediatric Patients

Asthma

Oral

Children ≥4 years of age receiving Serevent Diskus: Maximum 50 mcg (1 inhalation) twice daily.¹⁸⁸

Children 4–11 years of age receiving fixed combination of salmeterol and fluticasone propionate: Maximum 50 mcg of salmeterol and 100 mcg of fluticasone propionate twice daily.²²¹

Children or adolescents ≥12 years of age receiving fixed combination of salmeterol and fluticasone propionate: Maximum 50 mcg of salmeterol and 500 mcg of fluticasone propionate (1 inhalation) twice daily.²²¹

Exercise-induced Bronchospasm

Oral Inhalation

Serevent Diskus: 50 mcg (1 inhalation) twice daily (every 12 hours) in children ≥4 years of age.¹⁸⁸

Adults

Asthma

Oral Inhalation

Serevent Diskus: Maximum 50 mcg (1 inhalation) twice daily.¹⁸⁸

Fixed combination of salmeterol and fluticasone propionate: Maximum 50 mcg of salmeterol and 500 mcg of fluticasone propionate (1 inhalation) twice daily.²²¹

Exercise-induced Bronchospasm

Oral Inhalation

Serevent Diskus: 50 mcg (1 inhalation) twice daily (every 12 hours).¹⁸⁸

COPD

Oral Inhalation

Serevent Diskus: 50 mcg (1 inhalation) twice daily.¹⁸⁸

Fixed combination of salmeterol and fluticasone propionate: 50 mcg of salmeterol (1 inhalation) twice daily in fixed combination with fluticasone propionate (250 mcg).²²¹

Special Populations

Hepatic Impairment

Decreased clearance.¹

Monitor patients closely; however, dosage adjustments not required.¹

Renal Impairment

Pharmacokinetics have not been studied; dosage adjustments not required.^{1 154 156 188 221}

Geriatric Patients

Salmeterol in fixed combination with fluticasone propionate: Dosage adjustments not recommended solely because of age in geriatric patients.²²¹

Cautions for Serevent

Contraindications

• 
  

  Known hypersensitivity to salmeterol xinafoate or any ingredients in the formulations.^{1 56 57 59 188}

  
  

Warnings/Precautions

Warnings

Increased Risk of Asthma-related Death

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Data from a large study (Salmeterol Multi-center Asthma Research Trial [SMART]) evaluating the safety of salmeterol in patients with asthma suggest that the drug may be associated with an increased risk of asthma-related life-threatening events, including death, in certain patients,^{1 188 221 226 227 248 249} particularly African Americans^{1 188 221 226 227 221 242 248 249} and patients not receiving concomitant inhaled corticosteroid therapy.^{226 227 246} Because of similar mechanisms of action among β₂-adrenergic agonists, it is possible that the increased risk of asthma-related life-threatening events represents a class effect of these drugs.^{1 188 221 228 246} Data from the SMART study are insufficient to determine whether concurrent use of inhaled corticosteroids provides protection from or modifies the risk of asthma-related adverse effects.^{188 221 228} It is not known whether the rate of death is increased in patients with COPD receiving long-acting β₂-adrenergic agonists.¹⁸⁸

Add long-acting bronchodilators such as salmeterol to asthma therapy only when symptoms have not responded adequately to other asthma controller drugs such as low- or medium-dose corticosteroids or in patients whose disease severity warrants treatment with 2 maintenance therapies.^{188 221 247 248 249 250 251} Concomitant use of inhaled corticosteroids recommended by current asthma management guidelines and most experts in patients with asthma who require more than intermittent therapy with inhaled β-agonist bronchodilators.^{25 40 44 110 136 137 156 157 222 226 227}

Acute Exacerbations of Asthma or COPD

Do not initiate therapy in patients with acutely deteriorating or substantially worsening asthma, which may be life-threatening, or in patients with acute symptoms of COPD.^{1 154 188 221 247 248 249 250 251} Do not initiate salmeterol therapy in patients with severe asthma (e.g., unresponsive to usual medications, increasing need for inhaled short-acting β-agonists, marked increase in symptoms, recent emergency room visits, sudden or progressive deterioration in pulmonary function).^{1 154 188 221} Serious acute respiratory events, including fatalities, have been reported.^{1 188 247 248 249 250 251}

Failure to respond to a previously effective dosage may indicate substantially worsening asthma.^{1 154 188 221} Promptly reevaluate asthma therapy if inadequate control of symptoms persists with supplemental short-acting β₂-agonist bronchodilator therapy.^{1 113 134 156 188 214 222 247 248 249 250 251} Do not use extra/increased doses of salmeterol alone or in fixed combination with fluticasone propionate in such situations.^{1 8 113 188 221} Do not use extra doses of salmeterol or other long-acting inhaled β₂-adrenergic agonists (e.g., formoterol) for maintenance therapy of asthma, COPD, or for any other reason.²²¹

If asthma deteriorates in patients receiving salmeterol in fixed combination with fluticasone propionate, prompt reevaluation of asthma therapy is required.^{221 248 249 250 251} Consider increasing the strength of the fixed combination (higher strengths contain higher dosages of fluticasone propionate only), adding additional inhaled corticosteroids, or initiating systemic corticosteroids.^{221 248 249 250 251}

Excessive Doses

Fatalities associated with excessive use of inhaled sympathomimetic drugs.^{1 64 81 110 111 112 115 119 188} For treatment of COPD, do not use higher than recommended dosages of salmeterol in fixed combination with fluticasone propionate, as increased risks of systemic effects exist.²²¹

Patients receiving salmeterol alone or in fixed combination with fluticasone propionate should not use additional salmeterol or other long-acting inhaled β₂-adrenergic agonists for the prevention of exercise-induced bronchospasm or the maintenance treatment of asthma or COPD.^{188 221}

Concomitant Anti-inflammatory Therapy

Salmeterol therapy is not a substitute for inhaled or oral corticosteroids.^{1 188} Possible worsening of asthma if corticosteroid dosage is reduced or discontinued when salmeterol therapy is initiated.^{1 2 5 16 20 40 42 43 45 61 62 63 72 85 97 113 188}

Consider early initiation of concomitant anti-inflammatory therapy (e.g., corticosteroids) since β₂-adrenergic agonists alone may not provide adequate control of asthma in many patients.¹ Continue corticosteroid therapy even if the patient feels better as a result of initiating or increasing salmeterol dosage.^{1 188} Changes in corticosteroid dosage recommended only after clinical evaluation of the patient.¹

Particular care is needed during and after transfer of patients from systemic to inhaled corticosteroid therapy since death resulting from adrenal insufficiency has occurred during such transfer.²²¹ Do not use orally inhaled salmeterol in fixed combination with fluticasone propionate to transfer patients from systemic corticosteroid therapy since such a transfer may unmask conditions previously suppressed by systemic corticosteroid therapy, such as rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.²²¹

Respiratory Effects

Possible symptoms of laryngeal spasm, irritation, or swelling (e.g., stridor, choking).^{1 188} Possible acute bronchospasm;^{1 56 59 111 112 116 153 154 156} may represent a hypersensitivity reaction. (See Sensitivity Reactions under Cautions.)^{17 20 56 57 59 114}

Discontinue therapy immediately if bronchoconstriction occurs and institute alternative therapy.^{1 153 156 188}

Cardiovascular Effects

Possible clinically important changes in SBP and/or DBP, rapid heart rate, ECG changes, palpitations, or chest pain.^{1 154 156 188}

May require discontinuance of the drug.^{1 13 188 210} Use with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertension, thyrotoxicosis, and in those who are unusually responsive to sympathomimetic amines.^{1 187 188 210}

Sensitivity Reactions

Immediate hypersensitivity reactions (e.g., urticaria, rash/skin eruption, contact dermatitis, anaphylaxis, and angioedema) have been reported.^{1 188} Possible acute bronchospasm; frequently occurs with the first use of a new oral inhalation aerosol canister.^{1 56 59 111 112 116 153 154 156} (See Respiratory Effects under Cautions.)

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Nervous System Effects

Possible CNS stimulation and adverse nervous system effects^{1 2 13 15 19 188} including headache,^{1 16 17 19 23 52} tremor,^{1 16 17 102 107 182} nervousness^{1 154 156} , dizziness/giddiness,^{147 152} or excitement.^{1 106}

Some nervous system effects may require discontinuance of the drug.^{1 106} Use with caution in patients with seizure disorders and in those who are unusually responsive to sympathomimetic amines.^{1 187 188 210}

Metabolic Effects

Possible hypokalemia (usually transient and dose-related);^{2 15 19 25 33 37 42 43} may increase risk of arrhythmias.¹ (See Cardiovascular Effects under Cautions.) Supplemental potassium therapy generally is not required.¹

Possible dose-related hyperglycemia may occur rarely.^{2 15 19 25 33 37}

Use of Fixed Combination

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether salmeterol is distributed into milk.^{1 188} Discontinue nursing or the drug.^{1 188}

Pediatric Use

Safety and efficacy of salmeterol oral inhalation powder in children 4–11 years of age with asthma have been evaluated for periods up to 1 year.^{188 221} Current data suggest that such children may receive the same dosage as adults for the treatment of asthma or exercise-induced bronchospasm.^{188 221}

Use of salmeterol in fixed combination with fluticasone propionate in children 4–11 years of age is supported by data from one clinical trial and from extrapolation of efficacy data from older patients.²²¹ Safety and efficacy of such a combination in children <4 years of age not established.²²¹

Geriatric Use

Adverse effect profile similar to that in younger adults.^{1 77 82 92 188 221}

Use with caution in geriatric patients who have concomitant cardiovascular disease.^{1 188 221} (See Cardiovascular Effects under Cautions.) Dosage adjustments not needed based solely on age.^{1 154 156 188 221}

Hepatic Impairment

Predominantly metabolized in the liver; possible increased plasma concentrations in patients with hepatic impairment.¹

Close monitoring of such patients recommended.¹

Renal Impairment

Effects on pharmacokinetics of salmeterol not investigated.¹

Common Adverse Effects

Headache, tremor, cough.^{114 154 182}

Interactions for Serevent

Specific Drugs

Drug	Interaction	Comments
β2-Adrenergic agonists, short acting	Potential for increased cardiovascular adverse effects, but such effects less likely with a selective β2-adrenergic agonist like salmeterol110 115 116 117 118 120	Safety of concomitant use of > 8 inhalations of supplemental, short-acting β2-agonist therapy with salmeterol inhalation therapy has not been established1
β-Adrenergic blocking agents	Potential for antagonism of pulmonary effects resulting in severe bronchospasm in asthmatic patients1 154 156 188	If concomitant therapy required, consider cautious use of cardioselective β-adrenergic blocking agents1 188
Corticosteroids	Concomitant corticosteroid use may maintain and/or restore sensitivity of β-adrenergic receptors1 78 132 133 151
MAO inhibitors	Potential for increased effect of salmeterol on the vascular system1	Extreme caution recommended with concomitant therapy or in patients receiving salmeterol within 2 weeks of discontinuance of these agents1
Diuretics, nonpotassium-sparing	Potential for additive hypokalemia and/or ECG changes, especially when the recommended β-agonist dose is exceeded1	Cautious use recommended1 188
Tricyclic antidepressants	Potential for increased effect of salmeterol on the vascular system1	Extreme caution recommended with concomitant therapy or in patients receiving salmeterol within 2 weeks of discontinuance of these agents1
Xanthine derivatives	Potential for increased cardiotoxic effects with concomitant administration of sympathomimetic agents and aminophylline but not theophylline1 123 124 154

Serevent Pharmacokinetics

Absorption

Bioavailability

Most of an orally inhaled drug actually is swallowed.^{1 2 38 39 188} The bronchodilating action of orally inhaled sympathomimetic agents is believed to result from a local action of the portion of the dose that reaches the bronchial tree.^{1 2 38 39 188} Low or undetectable systemic concentrations of the drug occur after inhalation of the recommended dosage and are not predictive of therapeutic effects.^{1 39 188}

Onset

Time to onset of effective bronchodilation is 30 or 60 minutes with salmeterol in fixed combination with fluticasone propionate²²¹ or the oral inhalation powder, respectively.¹⁸⁸ Maximum benefit may not be achieved for 1 week or longer after initiating treatment with salmeterol in fixed combination with fluticasone propionate.²²¹ Maximum improvement in forced expiratory volume in 1 second (FEV₁) generally occurs within 3 hours after administration of oral inhalation powder.¹⁸⁸

Duration

Clinically important improvements are maintained for up to 12 hours in most patients receiving the oral inhalation powder.

ProAmatine

midodrine hydrochloride

Dosage Form: tablet
ProAmatine®

(midodrine hydrochloride)

Tablets

Warning: Because ProAmatine® can cause marked elevation of supine blood pressure, it should be used in patients whose lives are considerably impaired despite standard clinical care. The indication for use of ProAmatine® in the treatment of symptomatic orthostatic hypotension is based primarily on a change in a surrogate marker of effectiveness, an increase in systolic blood pressure measured one minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of ProAmatine®, principally improved ability to carry out activities of daily living, have not been verified.

DESCRIPTION

Name: ProAmatine®(midodrine hydrochloride) Tablets

Dosage Form: 2.5-mg, 5-mg and 10-mg tablets for oral administration

Active Ingredient: Midodrine hydrochloride, 2.5 mg, 5 mg and 10 mg

Inactive Ingredients: Colloidal Silicone Dioxide NF, Corn Starch NF, FD&C Blue No. 2 Lake (10-mg tablets), FD&C Yellow No. 6 Lake (5-mg tablet), Magnesium Stearate NF, Microcrystalline Cellulose NF, Talc USP

Pharmacological Classification: Vasopressor/Antihypotensive

Chemical Names (USAN: Midodrine Hydrochloride): (1) Acetamide, 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-monohydrochloride, (±)-;

(2) (±)-2-amino-N-(β-hydroxy-2,5-dimethoxyphenethyl)acetamide monohydrochloride

BAN, INN, JAN: Midodrine

Structural formula:

Molecular formula: C12H18N2O4HCl; Molecular Weight: 290.7

Organoleptic Properties: Odorless, white, crystalline powder

Solubility: Water: Soluble

Methanol: Sparingly soluble

pKa: 7.8 (0.3% aqueous solution) pH: 3.5 to 5.5 (5% aqueous solution)

Melting Range: 200 to 203°C

CLINICAL PHARMACOLOGY

Mechanism of Action: ProAmatine® forms an active metabolite, desglymidodrine, that is an alpha1-agonist, and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors. Desglymidodrine diffuses poorly across the blood-brain barrier, and is therefore not associated with effects on the central nervous system.

Administration of ProAmatine® results in a rise in standing, sitting, and supine systolic and diastolic blood pressure in patients with orthostatic hypotension of various etiologies. Standing systolic blood pressure is elevated by approximately 15 to 30 mmHg at 1 hour after a 10-mg dose of midodrine, with some effect persisting for 2 to 3 hours. ProAmatine® has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure.

Pharmacokinetics:ProAmatine® is a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine, formed by deglycination of midodrine. After oral administration, ProAmatine® is rapidly absorbed. The plasma levels of the prodrug peak after about half an hour, and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%. The bioavailability of desglymidodrine is not affected by food. Approximately the same amount of desglymidodrine is formed after intravenous and oral administration of midodrine. Neither midodrine nor desglymidodrine is bound to plasma proteins to any significant extent.

Metabolism and Excretion: Thorough metabolic studies have not been conducted, but it appears that deglycination of midodrine to desglymidodrine takes place in many tissues, and both compounds are metabolized in part by the liver. Neither midodrine nor desglymidodrine is a substrate for monoamine oxidase.

Renal elimination of midodrine is insignificant. The renal clearance of desglymidodrine is of the order of 385 mL/minute, most, about 80%, by active renal secretion. The actual mechanism of active secretion has not been studied, but it is possible that it occurs by the base-secreting pathway responsible for the secretion of several other drugs that are bases (see also Potential for Drug Interactions).

Clinical Studies

Midodrine has been studied in 3 principal controlled trials, one of 3-weeks duration and 2 of 1 to 2 days duration. All studies were randomized, double-blind and parallel-design trials in patients with orthostatic hypotension of any etiology and supine-to-standing fall of systolic blood pressure of at least 15 mmHg accompanied by at least moderate dizziness/lightheadedness. Patients with pre-existing sustained supine hypertension above 180/110 mmHg were routinely excluded. In a 3-week study in 170 patients, most previously untreated with midodrine, the midodrine-treated patients (10 mg t.i.d., with the last dose not later than 6 P.M.) had significantly higher (by about 20 mmHg) 1-minute standing systolic pressure 1 hour after dosing (blood pressures were not measured at other times) for all 3 weeks. After week 1, midodrine-treated patients had small improvements in dizziness/lightheadedness/unsteadiness scores and global evaluations, but these effects were made difficult to interpret by a high early drop-out rate (about 25% vs 5% on placebo). Supine and sitting blood pressure rose 16/8 and 20/10 mmHg, respectively, on average.

In a 2-day study, after open-label midodrine, known midodrine responders received midodrine 10 mg or placebo at 0, 3, and 6 hours. One-minute standing systolic blood pressures were increased 1 hour after each dose by about 15 mmHg and 3 hours after each dose by about 12mmHg; 3-minute standing pressures were increased also at 1, but not 3, hours after dosing. There were increases in standing time seen intermittently 1 hour after dosing, but not at 3 hours.

In a 1-day, dose-response trial, single doses of 0, 2.5, 10, and 20 mg of midodrine were given to 25 patients. The 10- and 20-mg doses produced increases in standing 1- minute systolic pressure of about 30 mmHg at 1 hour; the increase was sustained in part for 2 hours after 10 mg and 4 hours after 20 mg. Supine systolic pressure was =200 mmHg in 22% of patients on 10mg and 45% of patients on 20 mg; elevated pressures often lasted 6 hours or more.

Special Populations

A study with 16 patients undergoing hemodialysis demonstrated that ProAmatine® is removed by dialysis.

INDICATIONS AND USAGE

ProAmatine® is indicated for the treatment of symptomatic orthostatic hypotension (OH). Because ProAmatine® can cause marked elevation of supine blood pressure (BP>200 mmHg systolic), it should be used in patients whose lives are considerably impaired despite standard clinical care, including non-pharmacologic treatment (such as support stockings), fluid expansion, and lifestyle alterations. The indication is based on ProAmatine®'s effect on increases in 1-minute standing systolic blood pressure, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of ProAmatine®, principally improved ability to perform life activities, have not been established. Further clinical trials are underway to verify and describe the clinical benefits of ProAmatine®.

After initiation of treatment, ProAmatine® should be continued only for patients who report significant symptomatic improvement.

CONTRAINDICATIONS

ProAmatine® is contraindicated in patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis. ProAmatine® should not be used in patients with persistent and excessive supine hypertension.

WARNINGS

Supine Hypertension: The most potentially serious adverse reaction associated with ProAmatine® therapy is marked elevation of supine arterial blood pressure (supine hypertension). Systolic pressure of about 200 mmHg were seen overall in about 13.4% of patients given 10 mg of ProAmatine®. Systolic elevations of this degree were most likely to be observed in patients with relatively elevated pre-treatment systolic blood pressures (mean 170 mmHg). There is no experience in patients with initial supine systolic pressure above 180 mmHg, as those patients were excluded from the clinical trials. Use of ProAmatine® in such patients is not recommended. Sitting blood pressures were also elevated by ProAmatine® therapy. It is essential to monitor supine and sitting blood pressures in patients maintained on ProAmatine®.

PRECAUTIONS

General

The potential for supine and sitting hypertension should be evaluated at the beginning of ProAmatine® therapy. Supine hypertension can often be controlled by preventing the patient from becoming fully supine, i.e., sleeping with the head of the bed elevated. The patient should be cautioned to report symptoms of supine hypertension immediately. Symptoms may include cardiac awareness, pounding in the ears, headache, blurred vision, etc. The patient should be advised to discontinue the medication immediately if supine hypertension persists.

Blood pressure should be monitored carefully when ProAmatine® is used concomitantly with other agents that cause vasoconstriction, such as phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine, or pseudoephedrine.

A slight slowing of the heart rate may occur after administration of ProAmatine®, primarily due to vagal reflex. Caution should be exercised when ProAmatine® is used concomitantly with cardiac glycosides (such as digitalis), psychopharmacologic agents, beta blockers or other agents that directly or indirectly reduce heart rate. Patients who experience any signs or symptoms suggesting bradycardia (pulse slowing, increased dizziness, syncope, cardiac awareness) should be advised to discontinue ProAmatine® and should be re-evaluated.

ProAmatine® should be used cautiously in patients with urinary retention problems, as desglymidodrine acts on the alpha-adrenergic receptors of the bladder neck.

ProAmatine® should be used with caution in orthostatic hypotensive patients who are also diabetic, as well as those with a history of visual problems who are also taking fludrocortisone acetate, which is known to cause an increase in intraocular pressure and glaucoma.

ProAmatine® use has not been studied in patients with renal impairment. Because desglymidodrine is eliminated via the kidneys, and higher blood levels would be expected in such patients, ProAmatine® should be used with caution in patients with renal impairment, with a starting dose of 2.5 mg (see DOSAGE AND ADMINISTRATION). Renal function should be assessed prior to initial use of ProAmatine®.

ProAmatine® use has not been studied in patients with hepatic impairment. ProAmatine® should be used with caution in patients with hepatic impairment, as the liver has a role in the metabolism of midodrine.

Information for Patients

Patients should be told that certain agents in over-the-counter products, such as cold remedies and diet aids, can elevate blood pressure, and therefore, should be used cautiously with ProAmatine®, as they may enhance or potentiate the pressor effects of ProAmatine® (see Drug Interactions). Patients should also be made aware of the possibility of supine hypertension. They should be told to avoid taking their dose if they are to be supine for any length of time, i.e., they should take their last daily dose of ProAmatine® 3 to 4 hours before bedtime to minimize nighttime supine hypertension.

Laboratory Tests

Since desglymidodrine is eliminated by the kidneys and the liver has a role in its metabolism, evaluation of the patient should include assessment of renal and hepatic function prior to initiating therapy and subsequently, as appropriate.

Drug Interactions

When administered concomitantly with ProAmatine®, cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia.

The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine®. Therefore, caution should be used when ProAmatine® is administered concomitantly with agents that cause vasoconstriction.

ProAmatine® has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with ProAmatine®. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine®.

Potential for Drug Interaction

It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desyglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies have been conducted in rats and mice at dosages 3 to 4 times the maximum recommended daily human dose on a mg/m2 basis, with no indication of carcinogenic effects related to ProAmatine®. Studies investigating the mutagenic potential of ProAmatine® revealed no evidence of mutagenicity. Other than the dominant lethal assay in male mice, where no impairment of fertility was observed, there have been no studies on the effects of ProAmatine® on fertility.

Pregnancy

Pregnancy Category C. ProAmatine® increased the rate of embryo resorption, reduced fetal body weight in rats and rabbits, and decreased fetal survival in rabbits when given in doses 13 (rat) and 7 (rabbit) times the maximum human dose based on body surface area (mg/m2). There are no adequate and well-controlled studies in pregnant women. ProAmatine® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects have been observed in studies in rats and rabbits.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ProAmatine® is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

The most frequent adverse reactions seen in controlled trials were supine and sitting hypertension; paresthesia and pruritus, mainly of the scalp; goosebumps; chills; urinary urge; urinary retention and urinary frequency.

The frequency of these events in a 3-week placebo-controlled trial is shown in the following table:

Adverse Events

	Placebo n=88		Midodrine n=82
Event	# of reports	% of patients	# of reports	% of patients
Total # of reports	22		77
Paresthesia1	4	4.5	15	18.3
Piloerection	0	0	11	13.4
Dysuria2	0	0	11	13.4
Pruritis3	2	2.3	10	12.2
Supine hypertension4	0	0	6	7.3
Chills	0	0	4	4.9
Pain5	0	0	4	4.9
Rash	1	1.1	2	2.4

1 Includes hyperesthesia and scalp paresthesia

2 Includes dysuria (1), increased urinary frequency (2), impaired urination (1), urinary retention (5), urinary urgency (2)

3 Includes scalp pruritus

4 Includes patients who experienced an increase in supine hypertension

5 Includes abdominal pain and pain increase

Less frequent adverse reactions were headache; feeling of pressure/fullness in the head; vasodilation/flushing face; confusion/thinking abnormality; dry mouth; nervousness/anxiety and rash. Other adverse reactions that occurred rarely were visual field defect; dizziness; skin hyperesthesia; insomnia; somnolence; erythema multiforme; canker sore; dry skin; dysuria; impaired urination; asthenia; backache; pyrosis; nausea; gastrointestinal distress; flatulence and leg cramps.

The most potentially serious adverse reaction associated with ProAmatine® therapy is supine hypertension. The feelings of paresthesia, pruritus, piloerection and chills are pilomotor reactions associated with the action of midodrine on the alpha-adrenergic receptors of the hair follicles. Feelings of urinary urgency, retention and frequency are associated with the action of midodrine on the alpha-receptors of the bladder neck.

OVERDOSAGE

Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention. There are 2 reported cases of overdosage with ProAmatine®, both in young males. One patient ingested ProAmatine® drops, 250 mg, experienced systolic blood pressure greater than 200 mmHg, was treated with an IV injection of 20 mg of phentolamine, and was discharged the same night without any complaints. The other patient ingested 205 mg of ProAmatine® (41 5-mg tablets), and was found lethargic and unable to talk, unresponsive to voice but responsive to painful stimuli, hypertensive and bradycardic. Gastric lavage was performed, and the patient recovered fully by the next day without sequelae.

The single doses that would be associated with symptoms of overdosage or would be potentially life-threatening are unknown. The oral LD50 is approximately 30 to 50 mg/kg in rats, 675 mg/kg in mice, and 125 to 160 mg/kg in dogs.

Desglymidodrine is dialyzable.

Recommended general treatment, based on the pharmacology of the drug, includes induced emesis and administration of alpha-sympatholytic drugs (e.g., phentolamine).

DOSAGE AND ADMINISTRATION

The recommended dose of ProAmatine® is 10 mg, 3 times daily. Dosing should take place during the daytime hours when the patient needs to be upright, pursuing the activities of daily living. A suggested dosing schedule of approximately 4-hour intervals is as follows: shortly before, or upon arising in the morning, midday and late afternoon (not later than 6 P.M.). Doses may be given in 3-hour intervals, if required, to control symptoms, but not more frequently. Single doses as high as 20 mg have been given to patients, but severe and persistent systolic supine hypertension occurs at a high rate (about 45%) at this dose. In order to reduce the potential for supine hypertension during sleep, ProAmatine® should not be given after the evening meal or less than 4 hours before bedtime. Total daily doses greater than 30 mg have been tolerated by some patients, but their safety and usefulness have not been studied systematically or established. Because of the risk of supine hypertension, ProAmatine® should be continued only in patients who appear to attain symptomatic improvement during initial treatment.

The supine and standing blood pressure should be monitored regularly, and the administration of ProAmatine® should be stopped if supine blood pressure increases excessively.

Because desglymidodrine is excreted renally, dosing in patients with abnormal renal function should be cautious; although this has not been systematically studied, it is recommended that treatment of these patients be initiated using 2.5-mg doses.

Dosing in children has not been adequately studied.

Blood levels of midodrine and desglymidodrine were similar when comparing levels in patients 65 or older vs. younger than 65 and when comparing males vs. females, suggesting dose modifications for these groups are not necessary.

HOW SUPPLIED

ProAmatine® is supplied as 2.5-mg, 5-mg and 10-mg tablets for oral administration. The 2.5-mg tablet is white, round, and biplanar, with a bevelled edge, and is scored on one side with "RPC" above and "2.5" below the score, and "003" on the other side. The 5-mg tablet is orange, round, and biplanar, with a bevelled edge, and is scored on one side with "RPC" above and "5" below the score, and "004" on the other side. The 10-mg is blue, round, and biplanar, with a bevelled edge, and is scored on one side with "RPC" above and "10" below the score, and "007" on the other side.

2.5-milligram Tablets: NDC 54092-003-01 Bottle of 100

5.0-milligram Tablets: NDC 54092-004-01 Bottle of 100

10-milligram Tablets: NDC 54092-007-01 Bottle of 100

Store at 25°C (77°F)

Excursions permitted to 15-30 °C (59-86 °F)

[see USP Controlled Room Temperature]

Manufactured for

Shire US Inc., One Riverfront Place, Newport, KY, 41071, USA

by NYCOMED Austria GmbH

© 2003 Shire US Inc.

Rev. 10/03

003 0107 006

Rx only

Container Labels

2.5mg Bottle Label

5mg Bottle Label

10mg Bottle Label

2.5mg Carton Label

5mg Carton Label

10mg Carton Label

ProAmatine  midodrine hydrochloride  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 54092-003 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MIDODRINE HYDROCHLORIDE (MIDODRINE) MIDODRINE HYDROCHLORIDE 2.5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   STARCH, CORN   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   TALC

Product Characteristics Color white (white) Score 2 pieces Shape ROUND (ROUND) Size 7mm Flavor Imprint Code RPC;2;5;003 Contains

Packaging # NDC Package Description Multilevel Packaging 1 54092-003-01 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019815	09/06/1996

ProAmatine  midodrine hydrochloride  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 54092-004 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MIDODRINE HYDROCHLORIDE (MIDODRINE) MIDODRINE HYDROCHLORIDE 5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   STARCH, CORN   FD&C YELLOW NO. 6   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   TALC

Product Characteristics Color orange (orange) Score 2 pieces Shape ROUND (ROUND) Size 7mm Flavor Imprint Code RPC;5;004 Contains

Packaging # NDC Package Description Multilevel Packaging 1 54092-004-01 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019815	09/06/1996

ProAmatine  midodrine hydrochloride  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 54092-007 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MIDODRINE HYDROCHLORIDE (MIDODRINE) MIDODRINE HYDROCHLORIDE 10 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   STARCH, CORN   FD&C BLUE NO. 2   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   TALC

Product Characteristics Color blue (blue) Score 2 pieces Shape ROUND (ROUND) Size 7mm Flavor Imprint Code RPC;10;007 Contains

Packaging # NDC Package Description Multilevel Packaging 1 54092-007-01 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019815	03/20/2002

Labeler - Shire US Manufacturing Inc. (964907406)

Registrant - Shire US Inc. (622467447)

Establishment
Name	Address	ID/FEI	Operations
Nycomed Austria GmbH		300689002	MANUFACTURE

Revised: 10/2009Shire US Manufacturing Inc.

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