Drug Interactions with Cimetidine and Theophylline
Cimetidine Drug Interactions
Cimetidine is a potent inhibitor of multiple cytochrome P450 enzymes (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4), making it prone to numerous clinically significant drug interactions that require dose adjustments or alternative medication selection. 1
Major Interactions Requiring Dose Reduction or Avoidance
| Drug/Drug Class | Interaction Type | Clinical Consequence | Management Recommendation |
|---|---|---|---|
| Theophylline | Metabolic inhibition via CYP1A2 | Decreased theophylline clearance by 30%, increased half-life by 64%, risk of toxicity (nausea, vomiting, seizures, arrhythmias) | Reduce theophylline dose by 30% or more; monitor serum levels closely [1,2,3,4] |
| Warfarin | Metabolic inhibition | Increased anticoagulant effect, bleeding risk | Monitor prothrombin time; may require warfarin dose reduction [2,5] |
| Propranolol | Metabolic inhibition | Increased beta-blocker effects, bradycardia, hypotension | Reduce propranolol dose by approximately 25% [2,3] |
| Phenytoin | Metabolic inhibition | Phenytoin toxicity (ataxia, nystagmus, confusion) | Monitor phenytoin levels; reduce dose as needed [1] |
| Benzodiazepines (diazepam, triazolam) | Metabolic inhibition | Increased sedation, respiratory depression | Consider dose reduction or alternative benzodiazepine [1,2] |
| Quinidine | Metabolic inhibition | Increased quinidine levels, cardiac arrhythmias | Monitor quinidine levels; reduce dose [2] |
| Lidocaine | Metabolic inhibition | Increased lidocaine toxicity (CNS effects, arrhythmias) | Monitor clinically; reduce lidocaine dose [2] |
| Procainamide | Metabolic inhibition | Increased procainamide levels | Monitor drug levels; adjust dose [2] |
| Clopidogrel | Competitive CYP2C19 inhibition | Reduced antiplatelet effect, increased thrombotic risk | Avoid combination if possible; consider alternative H2 blocker (ranitidine, famotidine) [1] |
Macrolide Antibiotics
| Drug | Interaction | Management |
|---|---|---|
| Erythromycin | Listed as interacting drug | Consider alternative antibiotic [1] |
| Clarithromycin | Potential interaction | Avoid combination when possible [1] |
Antimigraine Medications
| Drug | Interaction | Management |
|---|---|---|
| Rizatriptan | Cimetidine increases rizatriptan levels | Avoid combination; use alternative H2 blocker or reduce rizatriptan to 5 mg maximum [1] |
Antimalarial Agents
| Drug | Interaction | Management |
|---|---|---|
| Chloroquine/Hydroxychloroquine | Cimetidine increases drug levels | Monitor for increased toxicity (retinopathy, cardiotoxicity) [1] |
Drugs with Reduced Absorption
| Drug | Interaction | Management |
|---|---|---|
| Ketoconazole | Reduced absorption due to increased gastric pH | Separate administration; consider alternative antifungal [2] |
| Iron supplements | Reduced absorption | Separate administration by 2+ hours [2] |
Theophylline Drug Interactions
Theophylline has a narrow therapeutic index (10-20 mcg/mL) and is metabolized primarily by CYP1A2 and CYP3A4, making it highly susceptible to drug interactions that can cause life-threatening toxicity or therapeutic failure. 3
Drugs That INCREASE Theophylline Levels (Require Dose Reduction)
| Drug/Drug Class | Mechanism | Theophylline Dose Adjustment | Clinical Monitoring |
|---|---|---|---|
| Cimetidine | CYP1A2 inhibition | Reduce by 30% or more | Monitor serum levels; watch for nausea, vomiting, tremor, tachycardia, seizures [1,2,3,4,6] |
| Erythromycin | CYP3A4 inhibition | Reduce by 25% | Monitor serum levels [3] |
| Troleandomycin | Potent CYP3A4 inhibition | Reduce by 50% | Monitor closely for toxicity [3] |
| Ciprofloxacin | CYP1A2 inhibition | Reduce dose; monitor levels | Risk of theophylline toxicity [1,3] |
| Oral contraceptives | Metabolic inhibition | Reduce by 30% or more | Monitor serum levels [3] |
| Propranolol | Multiple mechanisms | Reduce by 25% | Monitor for toxicity [3] |
| Allopurinol (high doses) | Xanthine oxidase inhibition | Reduce by 20% | Monitor serum levels [3] |
Drugs That DECREASE Theophylline Levels (Require Dose Increase)
| Drug/Drug Class | Mechanism | Theophylline Dose Adjustment | Clinical Monitoring |
|---|---|---|---|
| Phenobarbital | CYP enzyme induction | Increase by 30% | Monitor for loss of bronchodilation [3] |
| Phenytoin | CYP enzyme induction | Increase by 40-50% | Monitor serum levels [3] |
| Carbamazepine | CYP enzyme induction | Increase by 40-50% | Monitor therapeutic effect [3] |
| Rifampin | CYP enzyme induction | Increase by 20-25% | Monitor serum levels [1,3] |
| Isoniazid | Variable effect | Increase by 20-25% | Monitor levels; can also increase levels in some patients [3] |
Drugs with Conflicting Evidence or No Significant Interaction
| Drug | Interaction Status |
|---|---|
| Digoxin | Conflicting evidence; no established clinically significant interaction [1,7] |
| Ranitidine | No significant effect on theophylline clearance [3] |
| Famotidine | No cytochrome P450 interaction [1,3] |
| Metoprolol | No significant effect [3] |
| Amoxicillin | No interaction [3] |
| Tetracycline | No interaction [3] |
Critical Clinical Pitfalls
Age-related interactions: The cimetidine-theophylline interaction is more pronounced in older adults (age 54-70 years), requiring greater dose reductions 5
Time to steady state: When cimetidine is added to theophylline therapy, new steady-state theophylline levels are reached by day 5, and the interaction resolves within 5 days after cimetidine discontinuation 5, 4
Immediate effect: Cimetidine's effect on theophylline begins immediately upon first dose and progresses over 8 days of continued use 4
Alternative H2 blockers: Ranitidine, famotidine, and nizatidine do not significantly interact with theophylline or other CYP-metabolized drugs and are preferred alternatives 1, 3
Theophylline toxicity signs: Monitor for nausea, vomiting, tremor, tachycardia, seizures, and arrhythmias when any interacting drug is added 6