Clarithromycin Biaxin. Fluvoxamine Luvox. Grapefruit juice. Itraconazole Sporanox. Ketoconazole Nizoral. Lovastatin Mevacor. Nefazodone Serzone. Specific data support interactions between the following drugs: erythromycin and carbamazepine; cimetidine and carbamazepine or phenytoin; fluconazole and phenytoin; and rifampin and phenytoin. Serum antiepileptic drug levels should be monitored in patients who receive any of these combinations. Lithium therapy is useful for indications ranging from bipolar disorder to migraine headaches, but several interactions must be considered.
As a result, serum lithium levels increase secondary to enhanced reabsorption. If coadministration is necessary, the dosage of lithium should be reduced by 50 percent when a diuretic or an NSAID is added. Signs or symptoms of lithium toxicity involve the central nervous system drowsiness, confusion, hand tremor, blurred vision, vertigo and seizures , gastrointestinal tract nausea and vomiting and cardiovascular system arrhythmias and widening of the QRS complex.
Rifampin can increase the activity of hepatic enzymes involved in the metabolism of exogenous estrogens. Concomitant use of rifampin and oral contraceptive pills can lead to breakthrough bleeding and an increased risk of pregnancy. The interaction between oral contraceptives and other antibiotics is controversial in that no definitive studies have demonstrated contraceptive failure from such combinations. A recent retrospective study of patients who were taking an oral contraceptive and an antibiotic showed a small but insignificant increase in the risk of pregnancy.
One proposed mechanism is interruption of the enterohepatic circulation of estrogen as a result of reduced bacterial hydrolysis in the gastrointestinal tract. A variety of antibiotics have been implicated. The failure of oral contraception may be suggested by breakthrough bleeding.
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A reasonable recommendation is to remind patients that the baseline failure rate for oral contraceptives is approximately one pregnancy per woman years i. Although insufficient evidence is available to make a firm conclusion, it appears possible that oral contraception may fail while patients are taking an antibiotic. Thus, patients should be encouraged to consider using an alternative method of contraception for the duration of the cycle. Troglitazone Rezulin has been reported to reduce the plasma concentrations of oral contraceptives by 30 percent through an unknown mechanism.
Potentially fatal interactions can occur with coadministration of cisapride Propulsid and other drugs.
Cisapride has been associated with prolongation of the QT interval, torsades de pointes, syncope, cardiac arrest and sudden death. The primary agents contraindicated for use with cisapride are certain macrolide antibiotics erythromycin and clarithromycin , certain antifungal agents fluconazole, itraconazole [Sporanox] and ketoconazole [Nizoral] , one antidepressant drug nefazodone [Serzone] and certain protease inhibitors indinavir [Crixivan] and ritonavir [Norvir].
Most data on cisapride interactions are derived from case reports. However, current prescribing information warns against the coadministration of cisapride and any medications known to prolong the QT interval, such as class IA or III antiarrhythmic drugs, tricyclic antidepressants, erythromycin, clarithromycin and phenothiazines. Sildenafil Viagra is the first oral medication labeled by the U. Food and Drug Administration for the treatment of erectile dysfunction. Through inhibition of phosphodiesterase type 5, sildenafil enhances the effects of nitric oxide, potentiating penile erection after sexual arousal.
Therefore, patients with erectile dysfunction are often taking other medications. Sildenafil therapy is absolutely contraindicated in patients who are taking any form of nitrates, because of the potentiation of nitrate hypotensive effects. Sildenafil is primarily metabolized in the liver by cytochrome P 3A4.
Drugs that inhibit this enzyme, including erythromycin, cimetidine, ketoconazole and itraconazole, may increase plasma sildenafil concentrations. Sildenafil therapy should be initiated in the lowest dosage 25 mg in patients who are also taking a cytochrome P 3A4 inhibitor.
The benefits of lowering cholesterol levels for the primary and secondary prevention of coronary artery disease have been well established. Most evidence supports using drugs that inhibit 3-hydroxymethylglutaryl—coenzyme A HMG-CoA reductase in the liver, which is the main site of cholesterol synthesis. These drugs are metabolized through the cytochrome P pathway.
Concomitant use of statins and erythromycin, itraconazole, niacin or gemfibrozil Lopid can cause toxicity that manifests as elevated serum transaminase levels, myopathy, rhabdomyolysis and acute renal failure. However, the risk of toxicity increases when statins are coadministered with certain drugs. Because this risk may be dose-dependent, the dosage should be limited to the equivalent of 20 mg of lovastatin per day when any statin is given in combination with an interacting drug.
In many patients, HMG-CoA reductase inhibitors fail to lower triglyceride cholesterol levels to a desirable range. Although concomitant use of gemfibrozil or niacin with an HMG-CoA reductase inhibitor may appear clinically appropriate, these combinations have been associated with a 2 to 5 percent increase in the risk of myopathy.
If either combination is used, patients should be alert for muscle pain, tenderness or weakness. Creatine kinase levels should be measured if these symptoms occur. Lovastatin may potentiate the effects of warfarin by displacing the drug from plasma protein binding sites or inhibiting hepatic metabolism of the drug. Although potentiation of warfarin by lovastatin has been reported in at least 10 patients, controlled trials in large numbers of patients are needed to discern the clinical importance of this effect.
Over the past 15 years, selective serotonin reuptake inhibitors SSRIs have become the most commonly used antidepressant drugs.
These agents are generally well tolerated and have a more favorable side effect profile than tricyclic antidepressants. Concurrent use of SSRIs with agents metabolized by this pathway can result in increased serum concentrations of these agents. Patients already being treated with a tricyclic antidepressant may experience significant increases in plasma antidepressant concentrations and possibly antidepressant toxicity when fluoxetine Prozac is added. When concomitant use of an SSRI and a tricyclic antidepressant is required, the patient should be monitored for anticholinergic excess.
Conservative dosing of the tricyclic antidepressant should also be considered. Isolated case reports suggest that coadministration of fluoxetine and selegiline Eldepryl may result in mania and hypertension. The causal mechanism has not been established. However, selegiline is thought to produce additive serotoninergic effects, because serotonin is metabolized by MAO-A. The prescribing information for selegiline recommends that the drug not be used with SSRIs. The concomitant use of fluoxetine and non-selective MAO inhibitors has resulted in the serotonin syndrome, which is characterized by anxiety, agitation, confusion, hyperreflexia, myoclonus, diaphoresis and hyperthermia.
Several cases of serious or fatal reactions have occurred when tranylcypromine Parnate was used with fluoxetine.
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Reports of serotonin syndrome in association with tramadol and SSRI coadministration appear in the literature. At least one case report has described incoherence attributable to the combination of an SSRI and St. John's wort extract of the Hypericum perforatum plant. John's wort is mediated through inhibition of serotonin uptake or MAO antagonism. As use of this over-the-counter product increases, more data supporting clinically significant drug interactions should become available.
Given the popularity of St. John's wort, its availability and the public's propensity for self-medication, it is important to caution patients taking MAO inhibitors and SSRIs against the concomitant use of this herbal remedy. A recent report documented six cases of serotonin syndrome in patients taking fluoxetine and sumatriptan Imitrex. Another report found that the balance of documented clinical experience pertaining to the concomitant use of sumatriptan and SSRIs suggested that most patients tolerate the combination without adverse effect.
Yet another report on 14 patients discovered no significant interaction between SSRIs and sumatriptan. At least one source recommends that different triptans e. No single method is available to enable physicians to easily avoid drug interactions in clinical practice.
It can be helpful for physicians to keep files on prescribing information for new agents, maintain frequent contact with local pharmacists and have drug interaction resources readily available in the office. Several sources of information on drug interactions are described in Table 4. Complete database for drug interactions as well as clinically useful drug information; updated quarterly.