Drug Interactions between Capozide 50/15 and Lithonate

MONITOR CLOSELY: Coadministration with angiotensin converting enzyme (ACE) inhibitors may increase serum lithium concentrations and the risk for lithium toxicity. Several mechanisms may be involved, one of which is reduced renal lithium clearance due to natriuresis secondary to the inhibition of aldosterone and angiotensin II by ACE inhibitors. The combination may also cause renal dysfunction secondary to volume depletion during chronic therapy, which can further impair lithium clearance. The interaction was suspected in cases of lithium toxicity that occurred up to several weeks after the initiation of ACE inhibitor therapy. A retrospective study of 20 patients also found that addition of an ACE inhibitor to stable lithium therapy resulted in a mean 26% decrease in lithium clearance and a 35% increase in steady-state serum lithium concentrations. The average decline in lithium clearance was less in patients under 50 years of age than in older patients (13% vs. 31%). Four of the patients also demonstrated symptoms consistent with lithium toxicity and required dosage reduction or drug discontinuation. In contrast, a pharmacokinetic study found no significant effect of enalapril (5 mg twice a day for 10 days) on the steady-state serum lithium levels of 9 healthy volunteers receiving lithium 450 mg every 12 hours. Thus, it appears the interaction may not be completely predictable and may depend on factors such as dosages of the drugs, duration of therapy, age, and underlying medical conditions such as congestive heart failure or renal impairment. In addition, the interaction may be exacerbated by sodium restriction, dehydration, or concomitant use of diuretics or nonsteroidal anti-inflammatory drugs (NSAIDs).

MANAGEMENT: Given the narrow therapeutic index of lithium, caution is advised during coadministration with ACE inhibitors, particularly in the elderly or patients with other risk factors (e.g., sodium restriction, renal impairment, congestive heart failure, dehydration, concomitant use of diuretics or NSAIDs). Pharmacologic response and serum lithium levels should be monitored more closely whenever an ACE inhibitor is added to or withdrawn from therapy, and the lithium dosage adjusted as necessary. Empiric reductions of both drugs may be appropriate during initial therapy. Renal function should also be monitored regularly. Patients should be advised to seek medical attention if they experience potential signs and symptoms of lithium toxicity such as drowsiness, dizziness, confusion, muscle weakness, vomiting, diarrhea, polydipsia, polyuria, tinnitus, tremor, ataxia, and blurred vision.

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GENERALLY AVOID: Thiazide diuretics may cause a rapid increase in serum lithium levels and potentiate the risk of lithium toxicity. The exact mechanism is unknown but may be related to the sodium loss induced by thiazide diuresis, which produces a compensatory increase in proximal tubular reabsorption of sodium along with lithium. In a study of 22 patients receiving bendroflumethiazide 2.5 mg or hydroflumethiazide 25 mg daily for the treatment of edema, mean renal clearance of a single 600 mg dose of lithium carbonate was reduced by 24% during thiazide diuretic therapy compared to before or after diuretic therapy. A similar reduction in renal lithium clearance has been reported in studies with chlorothiazide. There have also been case reports of patients developing lithium toxicity shortly after initiation of various thiazide diuretics including bendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide and indapamide, either alone or in combination with other diuretics. Up to severalfold increases in serum lithium levels have been observed, usually within several days to 2 weeks but occasionally longer. The risk for lithium toxicity may be further increased during concomitant sodium restriction.

MANAGEMENT: Thiazide diuretics should generally not be prescribed to patients receiving lithium unless close monitoring of serum lithium levels and electrolytes can be rendered. Lithium dose reductions may be required. Patients should be advised to notify their physician if they experience potential signs and symptoms of lithium toxicity such as drowsiness, dizziness, muscle weakness, vomiting, diarrhea, thirst, polyuria, tinnitus, tremor, ataxia, and blurred vision. Some investigators have suggested that loop diuretics are safer with lithium than thiazide diuretics, although supporting data are limited.

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MONITOR: Although they are frequently combined in clinical practice, diuretics and angiotensin converting enzyme (ACE) inhibitors may have additive effects. Coadministration makes hypotension and hypovolemia more likely than does either drug alone. Some ACE inhibitors may attenuate the increase in the urinary excretion of sodium caused by some loop diuretics. Some patients on diuretics, especially those on dialysis or a dietary salt restriction, may experience acute hypotension with lightheadedness and dizziness after receiving the first dose of the ACE inhibitor. In addition, ACE inhibitors may cause renal insufficiency or acute renal failure in patients with sodium depletion or renal artery stenosis.

MANAGEMENT: Monitoring of blood pressure, diuresis, electrolytes, and renal function is recommended during coadministration. The possibility of first-dose hypotensive effects may be minimized by initiating therapy with small doses of the ACE inhibitor, or either discontinuing the diuretic temporarily or increasing the salt intake approximately one week prior to initiating an ACE inhibitor. Alternatively, the patient may remain under medical supervision for at least two hours after the first dose of the ACE inhibitor, or until blood pressure has stabilized.

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