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

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):177-83.

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):177-83.

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):177-83.

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):177-83.

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):177-83.

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):177-83.

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.1988 Allegra L,Giom It Mal Tor 2006

After 3 days, if tolerated, ,increase dose to Initial dosage Adults and children >1 yr or age: 12-14 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

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):177-83.

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):177-83.

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

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

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)

Theophylline toxicity in children 65 cases of theophylline toxicity,aged <17 yo. were reviewed at Johns Hopkins U. 1974-1985 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

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)