Interactions between your selected drugs

Dilantin (phenytoin) and ethosuximide (Moderate Drug-Drug)
MONITOR: Succinimides may increase serum hydantoin levels. The pharmacologic and toxic effects of hydantoins may be increased. The mechanism is not fully understood, but may be related to inhibition of the hepatic metabolism of hydantoins. In addition, phenytoin has been associated with reductions in succinimide levels.

MANAGEMENT: If a succinimide and a hydantoin must be used together, close observation for evidence of altered hydantoin effect is recommended. Patients should be advised to notify their physician if they experience symptoms of possible hydantoin toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia.


Dilantin (phenytoin) and insulin (Moderate Drug-Drug)
MONITOR: The efficacy of oral hypoglycemic agents and insulin may be diminished by certain drugs, including thiazides and other diuretics, corticosteroids, estrogens, progestins, thyroid hormones, human growth hormone, phenothiazines, atypical antipsychotics, sympathomimetic amines, protease inhibitors, phenytoin, clozapine, megestrol, danazol, isoniazid, asparaginase, pegaspargase, diazoxide, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.

MANAGEMENT: Close clinical monitoring of glycemic control is recommended if these drugs are coadministered with antidiabetic agents. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen. Dose adjustments of the hypoglycemic agent may be required.


aspirin and insulin (Moderate Drug-Drug)
MONITOR: The hypoglycemic effect of insulin may be potentiated by certain drugs, including ACE inhibitors, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, disopyramide, quinine, quinidine, MAOIs, ginseng); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); and/or inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or insulin secretagogues.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin, particularly in patients with advanced age and/or renal impairment. The insulin dosage may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.


aspirin and clopidogrel (Moderate Drug-Drug)
MONITOR: Clopidogrel has been shown to potentiate the inhibition of platelet aggregation due to aspirin. Single-dose studies have not shown a prolongation of bleeding time when aspirin was added to clopidogrel; however, the risk of gastrointestinal (GI) bleeding may be increased. A large clinical trial reported that clopidogrel 75 mg/day plus aspirin 75 to 325 mg/day for up to 1 year was associated with a higher incidence of major GI bleeding (1.3% vs 0.7% with aspirin alone). These two medications are routinely used together for their additive antiplatelet, antistroke effect. The safety of chronic administration of aspirin or other salicylates with clopidogrel has not been established.

MANAGEMENT: Until further data are available, caution is recommended, especially in patients at risk of bleeding (i.e., GI ulceration), if clopidogrel is coadministered on a long-term basis with drugs that may cause GI lesions. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, red or black stools, or bloody or coffee-ground emesis. Patients should also be counseled to avoid any other over-the-counter salicylate products.


atorvastatin and clopidogrel (Moderate Drug-Drug)
MONITOR: The concomitant administration of atorvastatin may reduce the metabolic activation of the prodrug clopidogrel and its antiplatelet effects. The proposed mechanism is competitive inhibition of CYP450 3A4 enzymatic activity, which is responsible for the conversion of clopidogrel to its active metabolite. However, data have been conflicting. In a trial with coronary stent implant patients receiving clopidogrel 75 mg/day (n=44), the percent platelet aggregation was 34% with no atorvastatin, 58% with atorvastatin 10 mg, 74% with 20 mg, and 89% with 40 mg. Results from an in vitro study suggest that equimolar concentrations of atorvastatin inhibit clopidogrel metabolism by more than 90 %. However, in a post hoc analysis of a trial with percutaneous coronary intervention patients, no statistical differences in the incidence of bleeding, stroke, myocardial infarction, or death were found at 1 year with concomitant administration of clopidogrel 75 mg/day and CYP450 3A4-metabolized HMG-CoA reductase inhibitors (n=1001, atorvastatin, lovastatin, simvastatin, cerivastatin) or other statins (n=158, pravastatin, fluvastatin).

MANAGEMENT: Until more information is available, monitoring for altered efficacy of clopidogrel may be advisable if atorvastatin is coadministered with clopidogrel. Pravastatin, fluvastatin, and rosuvastatin are not metabolized by CYP450 3A4 and are theoretically not expected to interact with clopidogrel.


Dilantin (phenytoin) and aspirin (Minor Drug-Drug)
In vitro studies suggest that salicylates may displace phenytoin from plasma protein-binding sites. The potential for phenytoin toxicity exists. The clinical significance is unknown. One case of phenytoin toxicity has been reported in a patient taking aspirin. However, clinical studies in healthy subjects and epileptic patients (taking phenytoin and 1500 mg aspirin/day) have not reported significant pharmacokinetic changes, adverse effects, or loss of seizure control.


Dilantin (phenytoin) and clopidogrel (Minor Drug-Drug)
In vitro studies have shown that high concentrations of clopidogrel inhibit CYP450 2C9 isoenzymes. The metabolism of drugs which are substrates for this enzyme may be decreased, potentiating toxicity of the substrate drug. The clinical significance and magnitude of this interaction is not known. Dose adjustments may be necessary if an interaction is suspected.

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