Amber Elam, Pharm.D.

PGY-1 Pharmacy Resident

Drug Information Question #2
Theophylline sustained action (SA) is the theophylline formulation that is carried and stocked by the
United States Veterans Affairs Consolidated Mail Outpatient Pharmacy (CMOP), in Charleston, South
Carolina. However, as of March 8, 2016, theophylline SA 200mg was reported to be on long term
manufacturer backorder. Since the medication will be on backorder for an unknown amount of time
and patients will continue to require this medication for maintenance treatment, a therapeutic
alternative is warranted in the meantime. The theophylline formulation listed within the Veterans
Affairs National Drug File is Theo-24.
Question: Is it appropriate to use Theo-24 in place of theophylline SA while it is on
manufacturer backorder? If administration and therapeutic interchange is appropriate,
what conversion factor should be used when converting theophylline SA to Theo-24?
Per package inserts for multiple controlled or extended release theophylline formulations, stabilized
patients currently controlled on an oral theophylline formulation, can be converted to a different
oral formulation on a mg-to-mg basis. When converting from an immediate or controlled-release
product to an extended-release product, the patient should remain on the same total daily dose
with only the interval being adjusted based on the formulation type.
Although theophylline formulations have pharmacokinetic properties similar to other theophylline
formulations, ensuring therapeutic interchangeability between all formulation types is not possible.
Interchanging controlled, sustained or extended release products for another at the same dosage
may result in significant variation in serum theophylline concentration, possibly leading to a subtherapeutic or toxic level. The equivalent content of the active ingredient, anhydrous theophylline,
is what determines the serum concentration and clinical response and efficacy. If converting to a
different theophylline formulation or product, it involves a change in the anhydrous theophylline
equivalence. Due to the significant variability in extended release product characteristics,
pharmacists should not substitute one brand for another without consulting the prescribing
physician unless the product has proven bioequivalence. Careful monitoring is required when
changing to a different theophylline brand/manufacturer or formulation. Serum levels should be
closely monitored and the dose should be adjusted accordingly.
In addition to variability of formulation types, a large number of patient factors may influence
theophylline metabolism and levels, such as: age, gender, cigarette smoking, concomitant
medications, other chronic disease states, renal function, hepatic function, and wide patient
variability in theophylline metabolic clearance. There is considerable patient-to-patient variation in
total daily theophylline doses required to achieve therapeutic and safe levels. Each patients
optimal maintenance dose should be individualized to achieve clinical symptomatic response and
maintain therapeutic serum theophylline levels.
Studies have been conducted comparing different theophylline formulations, dosing,
bioavailability, and serum concentrations. Kanthawatana S., et al. conducted a study to assess
the pharmacokinetic characteristics and bioavailability after a single oral dose of 3 different
sustained release theophylline formulations. The study was a randomized, 4-period, crossover
design. Each of the following treatments was given as a single dose during each study visit at

weekly intervals: Theo-Dur, Theo-24, and Xanthium. Twelve healthy volunteers were
enrolled in the study.

Parameter

Theo-Dur

Theo-24

Xanthium

Tmax (hr)

8.2 1.3 (6-10)

11.5 2.7 (8-16)*

10.7 1.8 (6-12)*

Cmax (ug/ml)

12.7 1.5 (10.3-15)

10.0 2.6 (6.4-13.9)*

7.6 1.2 (6.3-9.2)*$

T (hr)

9.4 1.3 (7.4-11.5)

13.8 4.0 (7.2-18.9)*

12.9 3.2 (8.0-19.1)*

MRT

17.7 1.8 (14.5-20.3)

25.9 6.2 (16.9-36.4)*

21.8 6.0 (15.4-36.2)*

0.075 0.011 (0.060.055 0.018 (0.0370.094)

0.097)*
$
*p < 0.05 vs. Theo-Dur;
p < 0.05 vs. Theo-24

0.057 0.014 (0.0360.086)*

Kel (hr-1)

Overall, the three sustained release formulations were shown to be effective and reliable in their
slow-release properties but had differences in their pharmacokinetic properties, with
bioavailability being a parameter that was found to be significantly lower in the xanthium group
and would require higher doses. Close monitoring of serum theophylline concentrations is
strongly recommended when switching between theophylline formulations.
Ideally, monitoring of serum theophylline concentrations should be conducted in all patients in
order to achieve a dose that will provide maximum potential clinical benefit with minimal risk of
adverse events and toxicity. Therapeutic levels are generally considered to be between 5-15
mcg/mL. Theophylline levels of 20mcg/mL or greater are high associated with toxicity, although
symptoms of toxicity can occur below the cutoff.
Summary Recommendation:
Theophylline SA can be converted to Theo-24 on a mg-to-mg basis, same dose patient is currently
taking at the time of conversion; however, these agents are not bioequivalent or interchangeable
and can result in significant theophylline level concentrations, despite patient being well controlled
on the first formulation. For this reason, patients being converted from one formulation of
theophylline to another should be closely monitored and a baseline theophylline level should be
drawn before the conversion is made. Once conversion is made, theophylline level should be
checked every 5-7 days to ensure concentration is therapeutic and not toxic. Once patient is
stabilized on the new formulation at dose, maintain therapeutic dose and continue to monitor and
recheck serum theophylline level every 6-12 months or sooner if needed.

References:
Asian Pac J Allergy Immunol. 1996 Jun;14(1):13-8. A single-dose comparison of three slowrelease theophylline oral preparations in healthy Thai volunteers.