THEOPHYLLINE



















TWICS trial - Theophylline vs Placebo in Patients with COPD, JAMA (2018) [PubMed abstract]
  • The TWICS trial enrolled 1578 adults with COPD who were being treated with an ICS and who had ≥ 2 exacerbations in the past year
Main inclusion criteria
  • Age ≥ 40 years
  • COPD diagnosis
  • Receiving ICS therapy
  • Smoking history ≥ 10 pack-years
  • ≥ 2 exacerbations within 12 months
Main exclusion criteria
  • Respiratory disease other than COPD
  • Significant heart disease
  • Taking drugs that interact with theophylline
Baseline characteristics
  • Average age - 68 years
  • Current smoker - 32%
  • Receiving ICS+LABA+LAMA - 80%
  • Mean FEV1 (% predicted) - 52%
  • Average # of exacerbations in past year - 3.6
Randomized treatment groups
  • Group 1 (788 patients): Theophylline 200 mg once or twice daily
  • Group 2 (779 patients): Placebo
  • Theophylline dosing was based on ideal body weight (IBW) and smoking status. Nonsmokers or smokers with IBW ≤ 60 kg took theophylline once daily. Smokers with IBW > 60 kg took theophylline twice daily.
Primary outcome: Number of COPD exacerbations requiring antibiotics, oral corticosteroids, or both during the 52-week treatment period as reported by the participant
Results

Duration: 52 weeks
Outcome Theophylline Placebo Comparisons
Primary outcome 2.24 2.23 Diff 0.01, 95%CI [−0.19 to 0.21]
COPD hospital admissions (average per patient) 0.17 0.24 Diff -0.07, 95%CI [−0.13 to -0.01]
Mean FEV1 % predicted at 52 weeks 51.5% 52.1% N/A
  • There was no significant difference in adverse reactions between the groups

Findings: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations.







  • Data from studies where levels reached > 30 mcg/ml during chronic dosing
Symptoms of theophylline toxicity
Symptom Prevalence
Sinus tachycardia 60 - 100%
Vomiting 30 - 60%
Hypokalemia 44%
Ventricular arrhythmias up to 40%
Premature ventricular contractions (PVCs) 10 - 19%
Nervousness 21%
Hyperglycemia 18%
Tremors 16%
Seizures 5 - 14%
Supraventricular tachycardia 14%
Diarrhea 14%
Atrial fib/flutter 12%
Disorientation 11%
Acid/base disturbance 5 - 9%





















  • ✝Patients with risk factors for impaired clearance: In children 1-15 years of age, the final theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day. In adolescents ≥ 16 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day
Theophylline Solution Dosing (Elixophyllin®)
Children (1 - 15 years) < 45 kg without risk factors for impaired clearance✝
Titration step Dosing
Step 1: Starting dose 12 - 14 mg/kg/day up to a maximum of 300 mg/day divided every 4 - 6 hrs
Step 2: After 3 days, if tolerated, increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day divided every 4 - 6 hrs
Step 3: After 3 more days, if tolerated, increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day divided every 4 - 6 hrs
Children > 45 kg and adults without risk factors for impaired clearance✝
Titration step Dosing
Step 1: Starting dose 300 mg/day divided every 6 - 8 hrs
Step 2: After 3 days, if tolerated, increase dose to: 400 mg/day divided every 6 - 8 hrs
Step 3: After 3 more days, if tolerated, increase dose to: 600 mg/day divided every 6 - 8 hrs

  • *Theophylline ER tablets may be taken once daily in the morning or at night. Twice daily dosing may be appropriate in some patients. Theo-24 capsules can be taken once daily in the morning. Twice daily dosing may be appropriate in some patients.
  • ✝Patients with risk factors for impaired clearance: In children 12-15 years of age, the final theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day. In adolescents ≥ 16 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day
Extended-release Tablet and Capsule Dosing (Theo-24®, Theochron®)
Children (12 - 15 years) < 45 kg without risk factors for impaired clearance✝
Titration step Dosing
Step 1: Starting dose 12 - 14 mg/kg once daily up to a maximum of 300 mg/day*
Step 2: After 3 days, if tolerated, increase dose to: 16 mg/kg once daily up to a maximum of 400 mg/day*
Step 3: After 3 more days, if tolerated and if needed, increase dose to: 20 mg/kg once daily up to a maximum of 600 mg/day*
Children > 45 kg and adults without risk factors for impaired clearance✝
Titration step Dosing
Step 1: Starting dose 300 - 400 mg once daily*
Step 2: After 3 days, if tolerated, increase dose to: 400 - 600 mg once daily*
Step 3: After 3 more days, if tolerated and if needed, increase dose to: As with all theophylline products, doses greater than 600 mg should be titrated according to blood level


Peak level
(mcg/ml)		 Dose adjustment
< 9.9 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 - 14.9 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 Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.
20 - 24.9 Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment.
25 - 30 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 overdosage treatment is indicated.
> 30 Treat overdose as indicated (see theophylline PI and contact poison control). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.