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Slow-Release Theophylline: Do Not Substitute
I POINT...
I
Siow-Relea'se Theophylline: Do Not Substitute By LesUe Hendeles, PharmO' nent brain damage, and death can tion, dosage, and dosing jntervalfor occur at very high concentrations a specific product should be titrated (I.e., >40 mcg/mI). Patients who mecarefully under controlled condimultiple-source drugs. However, tabolize theophyUine rapidly (chil· tiorrs to achieve maximum potential . benefit with minimal risk of toxicdrug product selection should not dren and cigarette or marijuana ity.l Once dosing is established, be practiced for slow~release theo- smokers) are especially vulnerable phyHine for control of chronic to, large fluctuations in serum con- changes in any of these conditions, including. a change in the product, asthma, because bioequivalency centrations (see figure). and interchangeability of the differFood affects the rate and/or ex- may alter serum theophylline· conent products cannot be assumed. , tent of absorption of theophylline centrations, thus impairing control At least 30 different brands and in different ways, depending on the , of asthma or. causing toxicity. 2 . Therefore; --It-. is 'recommended several generic versions of slow-re- formulation: With one product, food lease theophylline products are· may cause dose-dumping of toxic that phannacists: ' available cin the-United States, but amounts and. theophylline in the • Dispense only the identified significant and potentially impor- blood; whereas with another prod- product; tant. differences in rate and extent uct blood levels may. drop too low if • Explain to patients why another of absorption have been found taken after a meal.! Until more ' product should not be used in place among the available fonnulations. 1 I studies have established the effects of the previously used product. When these differences result in of food 'and,other variables. on most Even in states. where it is' legal changes in serum concentrations, of the available slow~release prod- for a pharmacist to select one brand serious problems can arise. 2 Low ucts, one product cannot be as- of slow.;.release theophylline product serum concentrations (< 10 .mcg/mn sumed 'to be bioequivalent and in- over another, such action could place the pharmacist in jeopardy of can result in increased asthmatic I terchangeable with another. symptoms,'and high concentrations Because of the narrow therapeu- civil liability if the patient ·· is (>20 mcg/mI) may cause nausea, tic range of theophylline (1~20 harmed. 4 ® vomiting, headache, nervousness, I meg/m!), the interpatient variabiland insomnia. Life-threateningcar- I i ty. in rate.of metabolism, and differ- References diac arrhythmias, seizures, perma- enees in extent and rate of absorp- 1. L. Hendeles and M. Weinberger, Sen many states, phannacists are 'urged or required by law to select Igeneric or less expensive brands of
I
I
-Een -
30
~
>. ..c a. 0
o
•
Phyllocontin Siophyilin Gyrocaps
•
Theolair SR
20 15
..c
10
E =s
5
Q)
Plain Tablets .
o Theo-Our 300
::i
Q)
•
25
l~
Q)
\n
0
0
2.
3
4
5
6
7
8
9
10
1' 1
12
Time (hours) Predicted steady-state serum concentrations' for an average child t ih.=3.7 hours, Vd = 0.5 liter/kg) receiving plain uncoated tablets and four slow-release products at 12-hour dosing tntervals. Adjusting dose rather than dosing interval will not alter percentage fluctuation. From Reference 3.
22
lection of a Slow Release Theophylline Product, J Allergy Clin Immurwl, 78, 743 (1986). 2. J .R. Baker et aI., Clinical Relevance of the Substitution of Different Brands of Sustained-Release Theophylline, J Allergy Clin Immurwl, 81, 664 (1988). 3. M: Weinberger et aI., Relationship of Formation and Dosing Interval to Fluctuation of Serum Theophylline Concentration in Children with Chronic Asthma, Pediatr~ 99,. 145 (1981). 4. J. Shacknai, Liability for Substituting Generic' for Brand N arne Drugs, U. S. Pharmacist, 11 ~ 18 (1986):
Leslie Hendeles, PharmD, is professor, pharmacy and pediatrics, University of Florida, Gainesville.
American Pharmacy, Vol. NS29, No.3 March 1989/182
I
Siow-Relea'se Theophylline: Do Not Substitute By LesUe Hendeles, PharmO' nent brain damage, and death can tion, dosage, and dosing jntervalfor occur at very high concentrations a specific product should be titrated (I.e., >40 mcg/mI). Patients who mecarefully under controlled condimultiple-source drugs. However, tabolize theophyUine rapidly (chil· tiorrs to achieve maximum potential . benefit with minimal risk of toxicdrug product selection should not dren and cigarette or marijuana ity.l Once dosing is established, be practiced for slow~release theo- smokers) are especially vulnerable phyHine for control of chronic to, large fluctuations in serum con- changes in any of these conditions, including. a change in the product, asthma, because bioequivalency centrations (see figure). and interchangeability of the differFood affects the rate and/or ex- may alter serum theophylline· conent products cannot be assumed. , tent of absorption of theophylline centrations, thus impairing control At least 30 different brands and in different ways, depending on the , of asthma or. causing toxicity. 2 . Therefore; --It-. is 'recommended several generic versions of slow-re- formulation: With one product, food lease theophylline products are· may cause dose-dumping of toxic that phannacists: ' available cin the-United States, but amounts and. theophylline in the • Dispense only the identified significant and potentially impor- blood; whereas with another prod- product; tant. differences in rate and extent uct blood levels may. drop too low if • Explain to patients why another of absorption have been found taken after a meal.! Until more ' product should not be used in place among the available fonnulations. 1 I studies have established the effects of the previously used product. When these differences result in of food 'and,other variables. on most Even in states. where it is' legal changes in serum concentrations, of the available slow~release prod- for a pharmacist to select one brand serious problems can arise. 2 Low ucts, one product cannot be as- of slow.;.release theophylline product serum concentrations (< 10 .mcg/mn sumed 'to be bioequivalent and in- over another, such action could place the pharmacist in jeopardy of can result in increased asthmatic I terchangeable with another. symptoms,'and high concentrations Because of the narrow therapeu- civil liability if the patient ·· is (>20 mcg/mI) may cause nausea, tic range of theophylline (1~20 harmed. 4 ® vomiting, headache, nervousness, I meg/m!), the interpatient variabiland insomnia. Life-threateningcar- I i ty. in rate.of metabolism, and differ- References diac arrhythmias, seizures, perma- enees in extent and rate of absorp- 1. L. Hendeles and M. Weinberger, Sen many states, phannacists are 'urged or required by law to select Igeneric or less expensive brands of
I
I
-Een -
30
~
>. ..c a. 0
o
•
Phyllocontin Siophyilin Gyrocaps
•
Theolair SR
20 15
..c
10
E =s
5
Q)
Plain Tablets .
o Theo-Our 300
::i
Q)
•
25
l~
Q)
\n
0
0
2.
3
4
5
6
7
8
9
10
1' 1
12
Time (hours) Predicted steady-state serum concentrations' for an average child t ih.=3.7 hours, Vd = 0.5 liter/kg) receiving plain uncoated tablets and four slow-release products at 12-hour dosing tntervals. Adjusting dose rather than dosing interval will not alter percentage fluctuation. From Reference 3.
22
lection of a Slow Release Theophylline Product, J Allergy Clin Immurwl, 78, 743 (1986). 2. J .R. Baker et aI., Clinical Relevance of the Substitution of Different Brands of Sustained-Release Theophylline, J Allergy Clin Immurwl, 81, 664 (1988). 3. M: Weinberger et aI., Relationship of Formation and Dosing Interval to Fluctuation of Serum Theophylline Concentration in Children with Chronic Asthma, Pediatr~ 99,. 145 (1981). 4. J. Shacknai, Liability for Substituting Generic' for Brand N arne Drugs, U. S. Pharmacist, 11 ~ 18 (1986):
Leslie Hendeles, PharmD, is professor, pharmacy and pediatrics, University of Florida, Gainesville.
American Pharmacy, Vol. NS29, No.3 March 1989/182