Aminophylline

Aminophylline Manufacturers

• Actavis Mid Atlantic Llc
  

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  Aminophylline | Actavis Mid Atlantic Llc

  

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  General Considerations:

  The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

  Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (See Table V). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady state. Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI). Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS).

  If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS), serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours.

  Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

  Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.

  Table V. Dosing initiation and titration (anhydrous theophylline equivalent listed in parentheses).*,†

  A. Infants <1 year old.

  A. 1. Initial Dosage.

  a. Premature Neonates:

  i. <24 days postnatal age; 1.0 (**1.17) mg/kg every 12 hr

  ii.≥ 24 days postnatal age; 1.5 (**1.75) mg/kg every 12 hr

  b. Full term infants and infants up to 52 weeks of age:

  A. 1. a. Total theophylline daily dose (mg) = [(0.2) x age in weeks)+5.0] x (Kg body Wt).

  {**Total aminophylline daily dose (mg) = [(0.23 x age in weeks) + 5.0] x (Kg body Wt).

  i. up to age 26 weeks; divide dose into 3 equal amounts administered at 8 hour intervals.

  ii. >26 weeks of age; divide dose into 4 equal amounts administered at 6 hour intervals.

  2. Final Dosage.

  Adjusted to maintain a peak steady-state serum theophylline concentration of 5-10 mcg/mL in neonates and 10-15 mcg/mL in older infants (see Table VI). Since the time required to reach steady-state is a function of theophylline half-life, up to 5 days may be required to achieve steady-state in a premature neonate while only 2-3 days may be required in a 6 month old infant without other risk factors for impaired clearance in the absence of a loading dose. If a serum theophylline concentration is obtained before steady-state is achieved, the maintenance dose should not be increased, even if the serum theophylline concentration is <10 mcg/mL.

  B. Children (1-15 years) and adults (16-60 years) without risk factors for impaired clearance. Titration Step Children <45 kg Children > 45 kg and adults 1.  Starting Dosage 12-14 (**14-16.3) mg/kg/day up to a maximum of 300 (**350) mg/day divided Q4-6 hrs* 300 (**350) mg/day divided Q6-8 hrs* 2.  After 3 days, if tolerated, increase dose to: 16 (**18.7) mg/kg/day up to a maximum of 400 (**466.7) mg/day divided Q4-6 hrs* 400 (**466.7) mg/day divided Q6-8 hrs* 3.  After 3 more days, if tolerated, increase dose to: 20 (**23.3) mg/kg/day up to a maximum of 600 (**700) mg/day divided Q4-6 hrs* 600 (**700) mg/day divided Q6-8 hrs*

  C.Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And

  Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations:

  In children 1-15 years of age, the final aminophylline dose should not exceed 16 (**18.7) mg/kg/day up to a maximum of 400 (**466.7) mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.

  In adolescents ≥ 16 years and adults, including the elderly, the final aminophylline dose should not exceed 400 (**466.7) mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.

  D.Loading Dose for Acute Bronchodilatation:

  An inhaled beta-2 selective agonist, alone or in combination with a systemically administered corticosteroid, is the most effective treatment for acute exacerbations of reversible airways obstruction. Theophylline is a relatively weak bronchodilator, is less effective than an inhaled beta-2 selective agonist and provides no added benefit in the treatment of acute bronchospasm. If an inhaled or parenteral beta agonist is not available, a loading dose of an oral immediate release theophylline can be used as a temporary measure. A single 5 (**5.8) mg/kg dose of aminophylline, in a patient who has not received any theophylline in the previous 24 hours, will produce an average peak serum theophylline concentration of 10 mcg/mL (range 5-15 mcg/mL). If dosing with theophylline is to be continued beyond the loading dose, the guidelines in Sections A.1.b., B.3, or C., above, should be utilized and serum theophylline concentration monitored at 24 hour intervals to adjust final dosage.

  *  Patients with more rapid metabolism, clinically identified by higher than average dose

  requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals.

  †  For products containing theophylline salts, the appropriate dose of the theophylline salt should

  be substituted for the anhydrous theophylline dose. To calculate the equivalent dose for theophylline salts, divide the anhydrous theophylline dose listed below by 0.65 for oxtriphylline, and by 0.5 for the calcium salicylate and sodium glycinate salts. Each 5 mL contains 105 mg of anhydrous aminophylline (equivalent to 90 mg of anhydrous theophylline).

  Table VI. Dosage adjustment guided by serum theophylline concentration. Peak Serum Concentration Dosage Adjustment <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after three days for further dosage adjustment. 10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen. 15-19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated. 20-24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. 25-30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage). >30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

  Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS).

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  General Considerations:
  
  The steady-state serum theophylline concentration is a function of the infusion rate and the rate of theophylline clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance. For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. The dose of theophylline must be individualized on the basis of serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.
  
  When theophylline is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose. Because of rapid distribution into body fluids, the serum concentration (C) obtained from an initial loading dose (LD) is related primarily to the volume of distribution (V), the apparent space into which the drug diffuses:
  
  C = LD/V
  
  If a mean volume of distribution of about 0.5 L/kg is assumed (actual range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of theophylline administered as a loading dose over 30 minutes results in an average 2 mcg/mL increase in serum theophylline concentration. Therefore, in a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg (5.7 mg/kg as aminophylline), calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a loading dose becomes necessary in the patient who has already received theophylline, estimation of the serum concentration based upon the history is unreliable, and an immediate serum level determination is indicated. The loading dose can then be determined as follows:
  
  D = (Desired C - Measured C) (V)
  
  where D is the loading dose, C is the serum theophylline concentration, and V is the volume of distribution. The mean volume of distribution can be assumed to be 0.5 L/kg and the desired serum concentration should be conservative (e.g., 10 mcg/mL) to allow for the variability in the volume of distribution. A loading dose should not be given before obtaining a serum theophylline concentration if the patient has received any theophylline in the previous 24 hours.
  
  A serum concentration obtained 30 minutes after an intravenous loading dose, when distribution is complete, can be used to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy. Once a serum concentration of 10 to 15 mcg/mL has been achieved with the use of a loading dose(s), a constant intravenous infusion is started. The rate of administration is based upon mean pharmacokinetic parameters for the population and calculated to achieve a target serum concentration of 10 mcg/mL (see Table V). For example, in non-smoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr (0.5 mg/kg/hr as aminophylline) at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline (5.7 mg/kg as aminophylline) followed by a constant intravenous infusion of 0.8 mg/kg/hr (1.0 mg/kg/hr as aminophylline). Since there is large interpatient variability in theophylline clearance, serum concentrations will rise or fall when the patient’s clearance is significantly different from the mean population value used to calculate the initial infusion rate. Therefore, a second serum concentration should be obtained one expected half-life after starting the constant infusion (e.g., approximately 4 hours for children age 1 to 9 and 8 hours for nonsmoking adults; See Table I for the expected half-life in additional patient populations) to determine if the concentration is accumulating or declining from the post loading dose level. If the level is declining as a result of a higher than average clearance, an additional loading dose can be administered and/or the infusion rate increased. In contrast, if the second sample demonstrates a higher level, accumulation of the drug can be assumed, and the infusion rate should be decreased before the concentration exceeds 20 mcg/mL. An additional sample is obtained 12 to 24 hours later to determine if further adjustments are required and then at 24-hour intervals to adjust for changes, if they occur. This empiric method, based upon mean pharmacokinetic parameters, will prevent large fluctuations in serum concentration during the most critical period of the patient’s course.
  
  In patients with cor pulmonale, cardiac decompensation, or liver dysfunction, or in those taking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr (21 mg/hr as aminophylline) unless serum concentrations can be monitored at 24-hour intervals. In these patients, 5 days may be required before steady-state is reached.
  
  Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.
  
  Table V contains initial theophylline infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for final theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.

  
  

  Table V. Initial Theophylline Infusion Rates Following an Appropriate Loading Dose.

  Patient population                        Age                     Theophylline infusion rate
  

                                                                              (mg/kg/hr)*†

  Neonates                              Postnatal age up to 24 days      1 mg/kg q12h/‡

                                             Postnatal age beyond 24 days    1.5 mg/kg q12h/‡

  Infants                                 6-52 weeks old                           mg/kg/hr=(0.008)(age in weeks) +

                                                                                                0.21

  Young Children                     1-9 years                                    0.8

  Older Children                     9-12 years                                    0.7

  Adolescents                        12-16 years                                    0.7

  (cigarette or marijuana smokers)

  Adolescents (nonsmokers)   12-16 years                                 0.5§

  Adults                                    16-60 years                               0.4§

  (otherwise healthy nonsmokers)

  Elderly                                    greater than 60 years               0.3 ı

  Cardiac decompensation,                                                       0.2 ı

  cor pulmonale, liver

  dysfunction, sepsis with

  multiorgan failure,

  or shock

  *To achieve a target concentration of 10 mcg/mL Aminophylline=theophylline/0.8. Use ideal body weight for obese patients.

  †Lower initial dosage may be required for patients receiving other drugs that decrease theophylline clearance(e.g., cimetidine).

  ‡To achieve a target concentration of 7.5 mcg/mL for neonatal apnea.

  §Not to exceed 900 mg/day, unless serum levels indicate the need for a larger dose.

  ıNot to exceed 400mg/day, unless serum levels indicate the need for a larger dose.

  
  

  Table VI. Final Disage Adjustment Guided by Serum Theophylline Concentration

  Peak Serum                                                       Dosage Adjustment

  Concentration

  less than 9.9 mcg/mL      If symptoms are not controlled and current dosage is tolerated, increase

                                       infusion rate about 25%.  Recheck serum contration after 12 hours in
  

                                       children and 24 hours in adults for further dosage adjustment.

  10 to 14.9 mcg/mL        If symptoms are controlled and current dosage is tolerated, maintain infusion

                                      rate and recheck serum concentration at 24 hour intervals.¶  If symptoms are

                                       not controlled and current dosage is tolerated consider adding additional
  

                                    medications(s) to treatment regimen.

  15-19.9 mcg/mL        Consider 10% decrease in infusion rate to provide greater margin of safety

                                      even if current dosage is tolerated.¶

  20-24.9 mcg/mL       Decrease infusion rate by 25% even if no adverse effects are present.

                                   Recheck serum concentration after 12 hours in children and 24 hours in
  

                                    adults to guide further dosage adjustment.

  25-30mcg/mL            Stop infusion for 12 hours in children and 24 hours in adults and decrease
  

                                    subsequent infusion rate at least 25% even if no adverse effects are present.

                                    Recheck serum concentration after 12 hours in children and 24 hours in
  

                                    adults to guide further dosage adjustment.  If symptomatic, stop infusion and
  

                                    consider whether overdose treatment is indicated (see recommendations for

                                    Chronic overdosage).

  greater than 30 mcg/mL   Stop the infustion and treat overdose as indicated (see recommendations for

                                         chronic overdosage).  If theophylline is subsequently resumed, decrease
  

                                          infusion rate by at least 50% and recheck serum concentration after 12 hours

                                          in children and 24 hours in adults to guide further dosage adjustment.

  ¶Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g. sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS).

  Intravenous Admixture Incompatibility:
  
  Although there have been reports of aminophylline precipitating in acidic media, these reports do not apply to the dilute solutions found in intravenous infusions. Aminophylline injection should not be mixed in a syringe with other drugs but should be added separately to the intravenous solution.
  
  When an intravenous solution containing aminophylline is given “piggyback”, the intravenous system already in place should be turned off while the aminophylline is infused if there is a potential problem with admixture incompatibility.
  
  Because of the alkalinity of aminophylline containing solutions, drugs known to be alkali labile should be avoided in admixtures. These include epinephrine HCl, norepinephrine bitartrate, isoproterenol HCl and penicillin G potassium. It is suggested that specialized literature be consulted before preparing admixtures with aminophylline and other drugs.
  
  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless solution is clear and container is undamaged. Discard unused portion. Do not use if crystals have separated from solution.
  
  

  
  

  
  

  
  

                                                                             
  

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  General Considerations:
  The steady-state serum theophylline concentration is a function of the infusion rate and the rate of theophylline clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance. For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. The dose of theophylline must be individualized on the basis of serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. When theophylline is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose. Because of rapid distribution into body fluids, the serum concentration (C) obtained from an initial
  loading dose (LD) is related primarily to the volume of distribution (V), the apparent space into which the drug diffuses:
  C = LD/V
  If a mean volume of distribution of about 0.5 L/kg is assumed (actual range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of theophylline administered as a loading dose over 30 minutes results in an average 2 mcg/mL increase in serum theophylline concentration. Therefore, in a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg (5.7 mg/kg as aminophylline), calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a loading dose becomes necessary in the patient who has already received theophylline, estimation of the serum concentration based upon the history is unreliable, and an immediate serum level determination is indicated. The loading dose can then be determined as follows:
  D = (Desired C - Measured C) (V)
  where D is the loading dose, C is the serum theophylline concentration, and V is the volume of distribution. The mean volume of distribution can be assumed to be 0.5 L/kg and the desired serum concentration should be conservative (e.g., 10 mcg/mL) to allow for the variability in the volume of distribution. A loading dose should not be given before obtaining a serum theophylline concentration if the patient has received any theophylline in the previous 24 hours. A serum concentration obtained 30 minutes after an intravenous loading dose, when distribution is complete, can be used to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy. Once a serum
  concentration of 10 to 15 mcg/mL has been achieved with the use of a loading dose(s), a constant intravenous infusion is started. The rate of administration is based upon mean pharmacokinetic parameters for the population and calculated to achieve a target serum concentration of 10 mcg/mL (see Table V). For example, in non-smoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr (0.5 mg/kg/hr as aminophylline) at the completion of the loading dose, on average, will result in a steadystate concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline (5.7 mg/kg as aminophylline) followed by a constant intravenous infusion of 0.8 mg/kg/hr (1.0 mg/kg/hr as aminophylline). Since there is large interpatient variability in
  theophylline clearance, serum concentrations will rise or fall when the patient’s clearance is significantly different from the mean population value used to calculate the initial infusion rate. Therefore, a second serum concentration should be obtained one expected half-life after starting the constant infusion (e.g., approximately 4 hours for children age 1 to 9 and 8 hours for nonsmoking adults; See Table I for the expected half-life in additional patient populations) to determine if the concentration is accumulating or declining from the post loading dose level. If the level is declining as a result of a higher than average clearance, an additional loading dose can be administered and/or the infusion rate increased. In contrast, if the second sample demonstrates a higher level, accumulation of the drug can be assumed, and the infusion rate should be decreased before the concentration exceeds 20 mcg/mL. An additional sample
  is obtained 12 to 24 hours later to determine if further adjustments are required and then at 24-hour intervals to adjust for changes, if they occur. This empiric method, based upon mean pharmacokinetic parameters, will prevent large fluctuations in serum concentration during the most critical period of the patient’s course. In patients with cor pulmonale, cardiac decompensation, or liver dysfunction, or in those taking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr (21 mg/hr as aminophylline) unless serum concentrations can be monitored at 24-hour intervals. In these patients, 5 days may be required before steady-state is reached.
  Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains initial theophylline infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for final theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.

  Table V. Initial Theophylline Infusion Rates Following an Appropriate Loading Dose. Patient population Age Theophylline infusion rate (mg/kg/hr)*† Neonates
  
  Postnatal age up to 24 days
  Postnatal age beyond 24 days
  1 mg/kg q 12h/‡
  1.5 mg/kg q12 h/‡
  Infants
  6-52 weeks old
  mg/kg/hr=(0.008) (age in weeks) + 0.21
  Young children
  1-9 years
  0.8
  Older children
  9-12 years
  0.7
  Adolescents
  (cigarette or marijuana
  smokers)
  12-16 years
  
  
  0.7
  Adolescents (nonsmokers)
  12-16 years
  0.5 §
  Adults
  (otherwise healthy
  nonsmokers)
  16-60 years
  
  
  0.4§
  
  
  Elderly
  greater than 60 years
  0.3#
  Cardiac decompensation,
  cor pulmonale, liver
  dysfunction, sepsis with
  multiorgan failure,
  or shock
  
  0.2#
  * To achieve a target concentration of 10 mcg/mL Aminophylline=theophylline/0.8. Use ideal body weight for obese patients.
  
  † Lower initial dosage may be required for patients receiving other drugs that decrease theophylline clearance (e.g., cimetidine).
  
  ‡ To achieve a target concentration of 7.5 mcg/mL for neonatal apnea.
  
  § Not to exceed 900 mg/day, unless serum levels indicate the need for a larger dose.
  
  # Not to exceed 400 mg/day, unless serum levels indicate the need for a larger dose.
  
  
  Table VI. Final Dosage Adjustment Guided by Serum Theophylline Concentration Peak Serum
  Concentration Dosage Adjustment
  less than 9.9 mdg/mL
  If symptoms are not controlled and current dosage is tolerated,
  increase infusion rate about 25%. Recheck serum concentration
  after 12 hours in children and 24 hours in adults for further dosage
  adjustment.
  10 to 14.9
  mcg/mL
  If symptoms are controlled and current dosage is tolerated,
  maintain infusion rate and recheck serum concentration at 24 hour
  intervals.¶ If symptoms are not controlled and current dosage is
  tolerated consider adding additional medication(s) to treatment
  regimen.
  15 - 19.9 mcg/mL
  Consider 10% decrease in infusion rate to provide greater margin
  of safety even if current dosage is tolerated.¶
  20 - 24.9 mcg/mL
  Decrease infusion rate by 25% even if no adverse effects are
  present. Recheck serum concentration after 12 hours in children
  and 24 hours in adults to guide further dosage adjustment.
  25 - 3- mcg/mL
  Stop infusion for 12 hours in children and 24 hours in adults
  and decrease subsequent infusion rate at least 25% even if no
  adverse effects are present. Recheck serum concentration after 12
  hours in children and 24 hours in adults to guide further dosage
  adjustment. If symptomatic, stop infusion and consider whether
  overdose treatment is indicated (see recommendations for chronic
  overdosage).
  greater than 30 mcg/mL
  Stop the infusion and treat overdose as indicated (see
  recommendations for chronic overdosage). If theophylline is
  subsequently resumed, decrease infusion rate by at least 50% and
  recheck serum concentration after 12 hours in children and 24
  hours in adults to guide further dosage adjustment.
  ¶ Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS).
  
  Intravenous Admixture Incompatibility:
  Although there have been reports of aminophylline precipitating in acidic media, these reports do not apply to the dilute solutions found in intravenous infusions. Aminophylline injection should not be mixed in a syringe with other drugs but should be added separately to the intravenous solution. When an intravenous solution containing aminophylline is given “piggyback”, the intravenous system already in place should be turned off while the aminophylline is infused if there is a potential problem with admixture incompatibility. Because of the alkalinity of aminophylline containing solutions, drugs known to be alkali labile should be avoided in admixtures. These include epinephrine HCl, norepinephrine bitartrate, isoproterenol HCl and penicillin G potassium. It is suggested that specialized literature be consulted before preparing admixtures with aminophylline and other drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless solution is clear and container is undamaged. Discard unused portion. Do not use if crystals have separated from solution.
  
  

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• West-ward Pharmaceutical Corp
  

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  Aminophylline | West-ward Pharmaceutical Corp

  

  ---

  General Considerations:

  The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

  Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (See Table V). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady state. Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI). Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS).

  If the patient's symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS), serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours.

  Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

  Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.

  Table V. Dosing initiation and titration ╖ [*Aminophylline equivalent in (*)]  

  ╖ Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals.

   A. Children (1-15 years) and adults (16-60 years) without risk factors for impaired clearance.  Titration Step  Children < 45 kg  Children > 45 kg and adults  1. Starting Dosage  12-14 (*15.2-17.7) mg/kg/day up to a maximum of 300 (*380)mg/day divided Q4-6 hrs ╖  300 (*380) divided Q6-8 hrs ╖  2. After 3 days, if tolerated,,
  increase dose to:  16 (*20.3) mg/kg/day up to a maximum of 400 (*507) mg/day divided Q4-6 hrs ╖  400 (*507) mg/day divided Q6-8 hrs ╖  3. After 3 more days, if tolerated.
  increase dose to:  20 (*25.3) mg/kg/day up to a maximum of 600 mg (*760) mg/day divided Q4-6 hrs ╖  600 (*760) mg/day divided Q6-8 hrs ╖
  
  
   

  B.Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations: In children 1-15 years of age, the final theophylline dose should not exceed 16 (*20.3) mg/kg/day up to a maximum of 400 (*507) mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.

  In adolescents ≥16 years and adults, including the elderly, the final theophylline dose should not exceed 400 (*507) mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.
  
  
  

   

  C.Loading Dose for Acute Bronchodilatation: An inhaled beta-2 selective agonist, alone or in combination with a systemically administered corticosteroid, is the most effective treatment for acute exacerbations of reversible airways obstruction. Theophylline is a relatively weak bronchodilator, is less effective than an inhaled beta-2 selective agonist and provides no added benefit in the treatment of acute bronchospasm. If an inhaled or parenteral beta agonist is not available, a loading dose of an oral immediate release theophylline can be used as a temporary measure. A single 5 mg/kg dose of theophylline, in a patient who has not received any theophylline in the previous 24 hours, will produce an average peak serum theophylline concentration of 10 mcg/mL (range 5-15 mcg/mL). If dosing with theophylline is to be continued beyond the loading dose, the guidelines in Sections A.3, or B., above, should be utilized and serum theophylline concentration monitored at 24 hour intervals to adjust final dosage.

  Table VI. Dosage adjustment guided by serum theophylline concentration.  

  ¶ Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS).

   Peak Serum
  Concentration  Dosage Adjustment  <9.9 mcg/mL  If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after three days for further dosage adjustment  10 to 14.9 mcg/mL  If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.  15-19.9 mcg/mL  Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.¶  20-24.9 mcg/mL  Decrease dose by 25% eyen if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment.  25-30 mcg/mL  Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage).  >30 mcg/mL  Treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

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  General Considerations:

  The steady-state serum theophylline concentration is a function of the infusion rate and the rate of theophylline clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance. For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. The dose of theophylline must be individualized on the basis of serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

  When theophylline is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose. Because of rapid distribution into body fluids, the serum concentration (C) obtained from an initial loading dose (LD) is related primarily to the volume of distribution (V), the apparent space into which the drug diffuses:

  C = LD/V

  If a mean volume of distribution of about 0.5 L/kg is assumed (actual range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of theophylline administered as a loading dose over 30 minutes results in an average 2 mcg/mL increase in serum theophylline concentration. Therefore, in a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg (5.7 mg/kg as aminophylline), calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a loading dose becomes necessary in the patient who has already received theophylline, estimation of the serum concentration based upon the history is unreliable, and an immediate serum level determination is indicated. The loading dose can then be determined as follows:

  D = (Desired C - Measured C) (V)

  where D is the loading dose, C is the serum theophylline concentration, and V is the volume of distribution. The mean volume of distribution can be assumed to be 0.5 L/kg and the desired serum concentration should be conservative (e.g., 10 mcg/mL) to allow for the variability in the volume of distribution. A loading dose should not be given before obtaining a serum theophylline concentration if the patient has received any theophylline in the previous 24 hours.

  A serum concentration obtained 30 minutes after an intravenous loading dose, when distribution is complete, can be used to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy. Once a serum concentration of 10 to 15 mcg/mL has been achieved with the use of a loading dose(s), a constant intravenous infusion is started. The rate of administration is based upon mean pharmacokinetic parameters for the population and calculated to achieve a target serum concentration of 10 mcg/mL (see Table V). For example, in non-smoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr (0.5 mg/kg/hr as aminophylline) at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline (5.7 mg/kg as aminophylline) followed by a constant intravenous infusion of 0.8 mg/kg/hr (1.0 mg/kg/hr as aminophylline). Since there is large interpatient variability in theophylline clearance, serum concentrations will rise or fall when the patient’s clearance is significantly different from the mean population value used to calculate the initial infusion rate. Therefore, a second serum concentration should be obtained one expected half-life after starting the constant infusion (e.g., approximately 4 hours for children age 1 to 9 and 8 hours for nonsmoking adults; See Table I for the expected half-life in additional patient populations) to determine if the concentration is accumulating or declining from the post loading dose level. If the level is declining as a result of a higher than average clearance, an additional loading dose can be administered and/or the infusion rate increased. In contrast, if the second sample demonstrates a higher level, accumulation of the drug can be assumed, and the infusion rate should be decreased before the concentration exceeds 20 mcg/mL. An additional sample is obtained 12 to 24 hours later to determine if further adjustments are required and then at 24-hour intervals to adjust for changes, if they occur. This empiric method, based upon mean pharmacokinetic parameters, will prevent large fluctuations in serum concentration during the most critical period of the patient’s course.

  In patients with cor pulmonale, cardiac decompensation, or liver dysfunction, or in those taking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr (21 mg/hr as aminophylline) unless serum concentrations can be monitored at 24-hour intervals. In these patients, 5 days may be required before steady-state is reached.

  Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

  Table V contains initial theophylline infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for final theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.

  Table V. Initial Theophylline Infusion Rates Following an Appropriate Loading Dose.

  Patient population

  Age

  Theophylline infusion rate (mg/kg/hr)*† 

  Neonates

  Postnatal age up to 24 days

  Postnatal age beyond 24 days

  1 mg/kg q12h/‡

  1.5 mg/kg q12h/‡

  Infants

  6-52 weeks old

  mg/kg/hr= (0.008)(age in weeks) + 0.21

  Young children

  1-9 years

  0.8

  Older children

  9-12 years

  0.7

  Adolescents

  (cigarette or marijuana

  smokers)

  12-16 years

  0.7

  Adolescents (nonsmokers)

  12-16 years

  0.5 §

  Adults

  (otherwise healthy

  nonsmokers)

  16-60 years

  0.4 §

  Elderly

  >60 years

  0.3 ı

  Cardiac decompensation,

  cor pulmonale, liver

  dysfunction, sepsis with

  multiorgan failure,

  or shock

  0.2 ı

  * To achieve a target concentration of 10 mcg/mL Aminophylline=theophylline/0.8. Use ideal body weight for obese patients.

  † Lower initial dosage may be required for patients receiving other drugs that decrease theophylline clearance (e.g., cimetidine).

  ‡ To achieve a target concentration of 7.5 mcg/mL for neonatal apnea.

  § Not to exceed 900 mg/day, unless serum levels indicate the need for a larger dose.

  ı Not to exceed 400 mg/day, unless serum levels indicate the need for a larger dose.

  Table VI. Final Dosage Adjustment Guided by Serum Theophylline Concentration

  Peak Serum Concentration

  Dosage Adjustment

  <9.9 mcg/mL

  If symptoms are not controlled and current dosage is tolerated, increase infusion rate about 25%. Recheck serum concentration after 12 hours in children and 24 hours in adults for further dosage adjustment.

  10 to 14.9 mcg/mL

  If symptoms are controlled and current dosage is tolerated, maintain infusion rate and recheck serum concentration at 24 hour intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.

  15-19.9 mcg/mL

  Consider 10% decrease in infusion rate to provide greater margin of safety even if current dosage is tolerated.¶

  20-24.9 mcg/mL

  Decrease infusion rate by 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment.

  25-30 mcg/mL

  Stop infusion for 12 hours in children and 24 hours in adults and decrease subsequent infusion rate at least 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment. If symptomatic, stop infusion and consider whether overdose treatment is indicated (see recommendations for chronic overdosage).

  
  

  >30 mcg/mL

  Stop the infusion and treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease infusion rate by at least 50% and recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment.

  ¶ Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS).

  Intravenous Admixture Incompatibility:

  Although there have been reports of aminophylline precipitating in acidic media, these reports do not apply to the dilute solutions found in intravenous infusions. Aminophylline injection should not be mixed in a syringe with other drugs but should be added separately to the intravenous solution.

  When an intravenous solution containing aminophylline is given “piggyback”, the intravenous system already in place should be turned off while the aminophylline is infused if there is a potential problem with admixture incompatibility.

  Because of the alkalinity of aminophylline containing solutions, drugs known to be alkali labile should be avoided in admixtures. These include epinephrine HCl, norepinephrine bitartrate, isoproterenol HCl and penicillin G potassium. It is suggested that specialized literature be consulted before preparing admixtures with aminophylline and other drugs.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless solution is clear and container is undamaged. Discard unused portion. Do not use if crystals have separated from solution.

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  Before Sodium Chloride Injection, USP, 0.9% is used as a vehicle for the administration of a drug, specific references should be checked for any possible incompatibility with sodium chloride. The volume of the preparation to be used for diluting or dissolving any drug for injection is dependent on the vehicle concentration, dose and route of administration as recommended by the manufacture.

  Sodium Chloride Injection, USP, 0.9% is also indicated for use in flushing intravenous catheters. Prior to and after administration of the medication, the intravenous catheter should be flushed in its entirety with Sodium Chloride Injection, USP, 0.9%. Use in accord with any warnings or precautions appropriate to the medication being administered. Parental drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  INSTRUCTIONS FOR USE

  To open ampuls, using gauze, place thumb and forefinger on color line, break at constriction.

  Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of Lidocaine Hydrochloride Injection, USP for various types of anesthetic procedures. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. When larger volumes are required only solutions containing epinephrine should be used, except in those cases where vasopressor drugs may be contraindicated.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Lidocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures. The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient. In all cases the lowest concentration and smallest dose that will produce the desired result should be given. Dosages should be reduced for children and for elderly and debilitated patients and patients with cardiac and/or liver disease.

  The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (i.e., total dose) of local anesthetic used. Thus, an increase in volume and concentration of Lidocaine Hydrochloride Injection will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia. However, increasing the volume and concentration of Lidocaine Hydrochloride Injection may result in a more profound fall in blood pressure when used in epidural anesthesia. Although the incidence of side effects with lidocaine is quite low, caution should be exercised when employing large volumes and concentrations, since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected.

  For intravenous regional anesthesia, only the 50 mL single-dose vial containing 0.5% Lidocaine Hydrochloride Injection, USP should be used.

  Epidural Anesthesia

  For epidural anesthesia, only the following available specific products of Lidocaine Hydrochloride Injection by Hospira are recommended:

  1%. . . . . . . . . . . . . . . . . . . . 30 mL single-dose teartop vials

  1.5%. . . . . . . . . . . . . . . . . . . . . . . 20 mL single-dose ampuls

  2%. . . . . . . . . . . . . . . . . . . . . . . . . 10 mL single-dose ampuls

  Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block provided they are employed as single dose units. These solutions contain no bacteriostatic agent. In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2−3 mL of the indicated concentration per dermatome).

  Caudal and Lumbar Epidural Block: As a precaution against the adverse experiences sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2−3 mL of 1.5% lidocaine hydrochloride should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block. The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter. Epinephrine, if contained in the test dose (10−15 mcg have been suggested), may serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient "epinephrine response" within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure. Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of Lidocaine Hydrochloride Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

  In the event of the known injection of a large volume of local anesthetic solutions into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

  Maximum Recommended Dosages

  NOTE: The products accompanying this insert do not contain epinephrine.

  Adults: For normal healthy adults, the individual maximum recommended dose of lidocaine HCl with epinephrine should not exceed 7 mg/kg (3.5 mg/lb) of body weight and in general it is recommended that the maximum total dose not exceed 500 mg. When used without epinephrine, the maximum individual dose should not exceed 4.5 mg/kg (2 mg/lb) of body weight and in general it is recommended that the maximum total dose does not exceed 300 mg. For continuous epidural or caudal anesthesia, the maximum recommended dosage should not be administered at intervals of less than 90 minutes. When continuous lumbar or caudal epidural anesthesia is used for non-obstetrical procedures, more drug may be administered if required to produce adequate anesthesia.

  The maximum recommended dose per 90 minute period of lidocaine hydrochloride for paracervical block in obstetrical patients and non-obstetrical patients is 200 mg total. One-half of the total dose is usually administered to each side. Inject slowly five minutes between sides. (See also discussion of paracervical block in PRECAUTIONS).

  For intravenous regional anesthesia, the dose administered should not exceed 4 mg/kg in adults.

  Children: It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight. For example, in a child of 5 years weighing 50 lbs., the dose of lidocaine HCl should not exceed 75 — 100 mg (1.5 — 2 mg/lb). The use of even more dilute solutions (i.e., 0.25 — 0.5%) and total dosages not to exceed 3 mg/kg (1.4 mg/lb) are recommended for induction of intravenous regional anesthesia in children.

  In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. In some cases it will be necessary to dilute available concentrations with 0.9% sodium chloride injection in order to obtain the required final concentration.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions that are discolored and/or contain particulate matter should not be used.

  Table 1

  Recommended Dosages of Lidocaine Hydrochloride Injection, USP for Various Anesthetic

  Procedures in Normal Healthy Adults

  Lidocaine Hydrochloride Injection, USP (without Epinephrine)

  Procedure

  Conc. (%)

  Vol. (mL)

  Total Dose (mg)

  Infiltration

  Percutaneous

  0.5 or 1.0

  1−60

  5−300

  Intravenous Regional

  0.5

  10−60

  50−300

  Peripheral Nerve Blocks, e.g.

  Brachial

  1.5

  15−20

  225−300

  Dental

  2.0

  1−5

  20−100

  Intercostal

  1.0

  3

  30

  Paravertebral

  1.0

  3−5

  30−50

  Pudendal (each side)

  1.0

  10

  100

  Paracervical

  Obstetrical Analgesia

  (each side)

  1.0

  10

  100

  Sympathetic Nerve Blocks, e.g.

  Cervical (stellate ganglion)

  1.0

  5

  50

  Lumbar

  1.0

  5−10

  50−100

  Central Neural Blocks

  Epidural*

  Thoracic

  1.0

  20−30

  200−300

  Lumbar

  Analgesia

  1.0

  25−30

  250−300

  Anesthesia

  1.5

  15−20

  225−300

  2.0

  10−15

  200−300

  Caudal

  Obstetrical Analgesia

  1.0

  20−30

  200−300

  Surgical Anesthesia

  1.5

  15−20

  225−300

  *Dose determined by number of dermatomes to be anesthetized (2 to 3 mL/dermatome).

  THE ABOVE SUGGESTED CONCENTRATIONS AND VOLUMES SERVE ONLY AS A GUIDE. OTHER VOLUMES AND CONCENTRATIONS MAY BE USED PROVIDED THE TOTAL MAXIMUM RECOMMENDED DOSE IS NOT EXCEEDED.

  Sterilization, Storage and Technical Procedures: Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, zinc, copper, etc.) should not be used for skin or mucous membrane disinfection as they have been related to incidence of swelling and edema. When chemical disinfection of multi-dose vials is desired, either isopropyl alcohol (91%) or 70% ethyl alcohol is recommended. Many commercially available brands of rubbing alcohol, as well as solutions of ethyl alcohol not of USP grade, contain denaturants which are injurious to rubber and, therefore, are not to be used. It is recommended that chemical disinfection be accomplished by wiping the vial stopper thoroughly with cotton or gauze that has been moistened with the recommended alcohol just prior to use.

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  General Considerations:

  The steady-state serum theophylline concentration is a function of the infusion rate and the rate of theophylline clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance. For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. The dose of theophylline must be individualized on the basis of serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

  When theophylline is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose. Because of rapid distribution into body fluids, the serum concentration (C) obtained from an initial loading dose (LD) is related primarily to the volume of distribution (V), the apparent space into which the drug diffuses:

                                C = LD/V

  If a mean volume of distribution of about 0.5 L/kg is assumed (actual range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of theophylline administered as a loading dose over 30 minutes results in an average 2 mcg/mL increase in serum theophylline concentration. Therefore, in a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg (5.7 mg/kg as aminophylline), calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a loading dose becomes necessary in the patient who has already received theophylline, estimation of the serum concentration based upon the history is unreliable, and an immediate serum level determination is indicated. The loading dose can then be determined as follows:

                                 D = (Desired C - Measured C) (V)

  where D is the loading dose, C is the serum theophylline concentration, and V is the volume of distribution. The mean volume of distribution can be assumed to be 0.5 L/kg and the desired serum concentration should be conservative (e.g., 10 mcg/mL) to allow for the variability in the volume of distribution. A loading dose should not be given before obtaining a serum theophylline concentration if the patient has received any theophylline in the previous 24 hours.

  A serum concentration obtained 30 minutes after an intravenous loading dose, when distribution is complete, can be used to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy. Once a serum concentration of 10 to 15 mcg/mL has been achieved with the use of a loading dose(s), a constant intravenous infusion is started. The rate of administration is based upon mean pharmacokinetic parameters for the population and calculated to achieve a target serum concentration of 10 mcg/mL (see Table V). For example, in non-smoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr (0.5 mg/kg/hr as aminophylline) at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline (5.7 mg/kg as aminophylline) followed by a constant intravenous infusion of 0.8 mg/kg/hr (1.0 mg/kg/hr as aminophylline). Since there is large interpatient variability in theophylline clearance, serum concentrations will rise or fall when the patient’s clearance is significantly different from the mean population value used to calculate the initial infusion rate. Therefore, a second serum concentration should be obtained one expected half-life after starting the constant infusion (e.g., approximately 4 hours for children age 1 to 9 and 8 hours for nonsmoking adults; See Table I for the expected half-life in additional patient populations) to determine if the concentration is accumulating or declining from the post loading dose level. If the level is declining as a result of a higher than average clearance, an additional loading dose can be administered and/or the infusion rate increased. In contrast, if the second sample demonstrates a higher level, accumulation of the drug can be assumed, and the infusion rate should be decreased before the concentration exceeds 20 mcg/mL. An additional sample is obtained 12 to 24 hours later to determine if further adjustments are required and then at 24-hour intervals to adjust for changes, if they occur. This empiric method, based upon mean pharmacokinetic parameters, will prevent large fluctuations in serum concentration during the most critical period of the patient’s course.

  In patients with cor pulmonale, cardiac decompensation, or liver dysfunction, or in those taking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr (21 mg/hr as aminophylline) unless serum concentrations can be monitored at 24-hour intervals. In these patients, 5 days may be required before steady-state is reached.

  Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

  Table V contains initial theophylline infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for final theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.

  Table V. Initial Theophylline Infusion Rates Following an Appropriate Loading Dose. * To achieve a target concentration of 10 mcg/mL Aminophylline=theophylline/0.8. Use ideal body weight for obese patients.
  † Lower initial dosage may be required for patients receiving other drugs that decrease theophylline clearance (e.g., cimetidine).
  ‡ To achieve a target concentration of 7.5 mcg/mL for neonatal apnea.
  § Not to exceed 900 mg/day, unless serum levels indicate the need for a larger dose.
  ı  Not to exceed 400 mg/day, unless serum levels indicate the need for a larger dose.

  Patient population

  Age

  Theophylline infusion rate (mg/kg/hr)*† 

  Neonates

  Postnatal age up to 24 days

  Postnatal age beyond 24 days

  1 mg/kg q12h/‡

  1.5 mg/kg q12h/‡

  Infants

  6-52 weeks old

  mg/kg/hr= (0.008)(age in weeks) + 0.21

  Young children

  1-9 years

  0.8

  Older children

  9-12 years

  0.7

  Adolescents

    (cigarette or marijuana

    smokers)

  12-16 years

  0.7

  Adolescents (nonsmokers)

  12-16 years

  0.5 §

  Adults

    (otherwise healthy

    nonsmokers)

  16-60 years

  0.4 §

  Elderly

  >60 years

  0.3 ı

  Cardiac decompensation,

    cor pulmonale, liver

    dysfunction, sepsis with

    multiorgan failure,

    or shock

  0.2 ı

  Table VI. Final Dosage Adjustment Guided by Serum Theophylline Concentration ¶     Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS).

  Peak Serum Concentration

  Dosage Adjustment

  <9.9 mcg/mL

  If symptoms are not controlled and current dosage is tolerated, increase infusion rate about 25%. Recheck serum concentration after 12 hours in children and 24 hours in adults for further dosage adjustment.

  10 to 14.9 mcg/mL

  If symptoms are controlled and current dosage is tolerated, maintain infusion rate and recheck serum concentration at 24 hour intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.

  15-19.9 mcg/mL

  Consider 10% decrease in infusion rate to provide greater margin of safety even if current dosage is tolerated.¶

  20-24.9 mcg/mL

  Decrease infusion rate by 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment.

  25-30 mcg/mL

  Stop infusion for 12 hours in children and 24 hours in adults and decrease subsequent infusion rate at least 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment. If symptomatic, stop infusion and consider whether overdose treatment is indicated (see recommendations for chronic overdosage).

  >30 mcg/mL

  Stop the infusion and treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease infusion rate by at least 50% and recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment.

  Intravenous Admixture Incompatibility:

  Although there have been reports of aminophylline precipitating in acidic media, these reports do not apply to the dilute solutions found in intravenous infusions. Aminophylline injection should not be mixed in a syringe with other drugs but should be added separately to the intravenous solution.

  When an intravenous solution containing aminophylline is given “piggyback”, the intravenous system already in place should be turned off while the aminophylline is infused if there is a potential problem with admixture incompatibility.

  Because of the alkalinity of aminophylline containing solutions, drugs known to be alkali labile should be avoided in admixtures. These include epinephrine HCl, norepinephrine bitartrate, isoproterenol HCl and penicillin G potassium. It is suggested that specialized literature be consulted before preparing admixtures with aminophylline and other drugs.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless solution is clear and container is undamaged. Discard unused portion. Do not use if crystals have separated from solution.

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