1. หัวหน้าหน่วยโรคภูมิแพ้ สถาบันสุขภาพเด็กแห่งชาติมหาราชินี
ชมรมโรคระบบหายใจและเวชบำบัดวิกฤตในเด็กแห่งประเทศไทย
ร่วมกับ ยูโรดรัก ลาบอราทอรีส์
พญ.มุกดา หวังวีรวงศ์
หัวหน้าหน่วยโรคภูมิแพ้
สถาบันสุขภาพเด็กแห่งชาติมหาราชินี

2. Factors altering theophylline metabolism
Effect
Physical alteration
Diet
Increase elimination
Low carbohydrate, high-protein diet
Charcoal-broiled meat
Decrease elimination
High-carbohydrate,
low-protein diet
whereas large quantities of dietary
xanthines may slow elimination ( there are of
clinical importance only if change in usual
eating patterns is sustained and extreme)
Hendeles,et al. J Pediatr 1992; 120(2):

3. Factors altering theophylline metabolism
Effect
Physical alteration
Diet
Increase
Low carbohydrate, high-protein diet
Charcoal-broiled meat
Decrease
High-carbohydrate,
low-protein diet
whereas large quantities of dietary
xanthines may slow elimination ( there are of
clinical importance only if change in usual
eating patterns is sustained and extreme)
Hendeles,et al. J Pediatr 1992; 120(2):

4. Factors altering theophylline metabolism
Effect
Bronchopulmonary dysphasia
Fever,
if sustained for> 24 hrs
Heart failure
Hyperthyroidism
Hypothyroidism
Liver disease
Decreases elimination variably; may be profound
Slow theophylline elimination by an average of ~50%
Increases elimination by an average of 20%
Decreases elimination by an average of 40%
Hendeles,et al. J Pediatr 1992; 120(2):

5. Factors altering theophylline metabolism
Effect
Drug Interaction
Allpurinol (high)
Cimetidine
Ciprofloxacin
Contraceptive pills
Carbamazepine
Slow elimination by average of 25%
Decreases elimination by average of 50%
Decreases elimination by average of 30%
(may be less with low dosage)
Increases elimination by average of 60%
Hendeles,et al. J Pediatr 1992; 120(2):

6. Factors altering theophylline metabolism
Effect
Drug Interaction
Erythromycin
Interferon
(recombinant interferon α)
Methotrexate
Mexiletine
Propranolol
Thiabendazole
Troleandomycin
Decreases elimination by average of 25%
Decreases elimination by average of 50%
Decreases elimination by average of 20%
Decreases elimination by average of 40%
Decreases elimination by average of about 65%
Decreases elimination average of 50%
( 25% on low dosage)
Hendeles,et al. J Pediatr 1992; 120(2):

7. Factors altering theophylline metabolism
Effect
Drug Interaction
Rifampin
Smoking
(cigarette or marijuana)
Isoproterenol
(intravenous infusion)
Phenobarbital
Phenytoin
Increases elimination by average of 80%
Increases elimination by average of about 50%
(effects of low tar-low nicotine cigarettes may be less)
Increases elimination by average of 20%
Increases elimination by average of 25%
Increases elimination by average of 75%
(additionally theophylline appears to inhibit
absorption of phenytoin)
Hendeles,et al. J Pediatr 1992; 120(2):

8. Clinician’s concern “Non-effect to high toxicity”
Theophylline plasma
concentration mcg/ml
Clinical Consequence
≤ 5
Absence of therapeutic effect
6-10
Sub-optimal therapeutic effect
10-20
Traditionally accepted ther.Window
>15
Anxiety, insomnia (possible)
Gastro-intestinal disturbances(possible)
>20
“Toxic effect” (CVS,GI &CNS)
>30*
Severe cardiac arrhythmias, *Fatal
>40*
Seizures,coma. *Fatal
*Sessier CN, Am j med Allegra L,Giom It Mal Tor 2006

9. After 3 days, if tolerated, ,increase dose to
Initial dosage Adults and children >1 yr or age: mg/kg/day up to a maximum of 300 mg/day
After 3 days, if tolerated, ,increase dose to
Incremental increase Adults and children > 45 kg : 400 mg/day Children <45 kg : 16 mg/kg/day up to maximum of 400 mg/day
After 3 days, if tolerated, increase dose to: i
Final dosage before serum concentration measurement Adults and children > 45 kg : 600 mg/day Children <45 kg : 20 mg/kg/day up to maximum of 600 mg/day
Check serum concentration ~4 hours after a morning dose of most slow- release products or 8 hours after a dose of a very slowly absorbed product given once every 24 hours, when no doses have been missed, added, or taken at unequal intervals for 3 days

10. Dosage adjustment based on serum concentration
Peak serum concentration
<7.5 µg/ml
7.5 to 9.9 µg/ml
10 to 14.9 µg/ml
15 to 19.9 µg/ml
Directions
Increased dose about 25%. Recheck serum theophylline concentration for guidance in further dosage adjustment.
If tolerated, increase dose ~25%
If tolerated, maintain dose. Recheck serum theophylline concentration at 6 to 12 mo. intervals
Consider 10% decrease in dose to provide greater margin of safety.
Hendeles,et al. J Pediatr 1992; 120(2):

11. Dosage adjustment based on serum concentration
Peak serum concentration
20 to 24.9 µg/ml
25 to 30 µg/ml
> 30 µg/ml
Directions
Decrease dose 10% to 25%. Recheck serum concentration after 3 days
Skip next dose and decrease subsequent doses at least 25% Recheck serum theophylline concentration after 3 days
Skip next 2 doses and decrease subsequent doses at least 50%. Recheck serum theophylline concentration for guidance in further dosage adjustment
Hendeles,et al. J Pediatr 1992; 120(2):

12. Side-effects
Most common
- anorexia
- nausea/vomiting
- headache

13. Side-effects May occur - CNS stimulation, seizures - palpitations
- tachycardia
- arrhythmia
- abdominal pain, diarrhea
- GERD
- rarely gastric bleeding

14. Side-effects
Changes in mood and personality, impaired school performance has been reported.
(Furukawa CT,et al. Lancet 1984;1:621,J allergy Clin Immunol 1988;81:83-8)
Children with asthma receiving theophylline attain scores on standardized achievement tests that, on average, match those of their non-asthmatics siblings
(Lokshin,et al.Ann Allergy 1991; 66:65.)
(Lindgren S,et al. New Engl J Med 1992;327:926-3)

15. Theophylline toxicity in children
65 cases of theophylline toxicity,aged <17 yo. were reviewed at Johns Hopkins U
Mean age 7.4 yo. (3 mo.-16 yo.)
Most common manifestations :- vomiting, tachycardia, CNS excitation
Seizures – 4 cases with serum conc. < 70 mcg/ml
Hallucinations – 2 cases associated with high serum conc.
Baker MD.J Pediatr 1986; 109:538-42

16. Dosage > 1 yr. = 12-14 mg/d max 300 mg/d
GINA 2006:- start 5 mg/d – 10mg/d
< 1 yr.
dose = (0.2)×(age in weeks) + 5.0
(mg/d)