Can alprazolam (Xanor) or zopiclone (Imovane) be administered to a patient in dialysis? The patient

Fråga: Can alprazolam (Xanor) or zopiclone (Imovane) be administered to a patient in dialysis? The patient is concomitantly treated with citalopram (Cipramil) and levomepromazine (Nozinan).

Sammanfattning: No dosage adjustments with respect to alprazolam are considered to be necessary for patients in haemodialysis; however, especially patients on continuous peritoneal dialysis are recommended to be monitored closely for side effects and the dose should be adjusted accordingly.

Zopiclone in the dose of 7.5 mg daily has safely been used in patients with chronic renal failure. Haemodialysis of severely ill renal patients did not increase the plasma clearance of zopiclone.

Svar: A thorough search in Medline and relevant pharmacological handbooks has revealed information concerning pharmacokinetics of alprazolam and zopiclone during various stages of renal disease. Pharmacokinetics of alprazolam 0.5 and 2 mg orally were similar in normal subjects and patients on haemodialysis (HD) with the exception of higher free fraction of alprazolam in HD patients. Differences were detected in the pharmacokinetics of alprazolam in patients in continuous peritoneal dialysis (CAPD) implying a higher free fraction and a lower apparent oral clearance and free clearance in CAPD patients than in normal subjects or in HD patients. There was also a tendency for a later T-max and a longer elimination half-life in CAPD patients than in normal subjects or HD patients. Based on pharmacokinetic data of alprazolam alone, no dosage adjustments were considered to be necessary for HD patients; however CAPD patients are recommended to be monitored closely for ADRs and the dose should be adjusted accordingly (1).

In the same patient group the sensitivity to the psychomotor and memory effects of alprazolam was evaluated. The maximum memory impairment corrected for the maximal free alprazolam concentration was 4.4 per cent, 7.2 per cent and 8.9 per cent per nanogram per ml for the normal, HD and CAPD groups, respectively (p < 0.09). It is concluded that the patients receiving dialysis may show an enhanced sensitivity to some psychomotor and memory effects of alprazolam (2).

According to a common handbook, the standard dose of zopiclone, which is 7.5 mg daily, may be cautiously prescribed to patients with moderate compensated hepatic or renal insufficiency. Higher doses are not recommended in these patients. Zopiclone is said to be removed by dialysis (3).

In a comparison of the pharmacokinetics of zopiclone between 7 chronic renal failure patients and young volunteers both were given 7.5 mg nightly for 7 consecutive nights. C-max and T-max were not significantly different between the two groups but the Cmin (at 24 hours) of unchanged zopiclone was significantly higher in the chronic renal failure patients compared to the controls (8.16 +/- 5.24 vs 1.90 +/- 0.82 ng/l, p < 0.001) like the AUC values (742 +/- 212 vs 408 +/- 66.5 ng/ml). However, no evident accumulation of zopiclone appeared in the chronic renal failure patients. As in the healthy volunteers no metabolites were detected in the plasma of the chronic renal failure patients (4). In 18 patients with renal insufficiency and treated with zopiclone 7.5 mg per day, the only major modification was found to be an increased bioavailability (115 per cent vs 77 per cent) (5). Patients with severe renal failure and on zopiclone 7.5 mg (group I) were compared with moderate renal insufficiency (group II) and healthy volunteers (group III). C-max did not differ between the groups, but T-max was significantly longer in group II. Haemodialysis of the severely ill renal patients did not increase the plasma clearance of zopiclone (6).

Since the approval of alprazolam (85-02-01) and zopiclone (91-08-16), there have not been any renal side effects reported to SADRAC. 1 Schmith VD, Piraino B, Randall B, Smith RB, Kroboth PD: Alprazolam in end-stage renal disease: I. Pharmacokinetics. J Clin Pharmacol 1991; 31: 571-579 2 Schmith VD, Piraino B, Randall B, Smith RB, Kroboth PD: Alprazolam in end-stage renal disease. II. Pharmacodynamics. Clin Pharmacol Ther 1992; 51: 533-540 3 Dollery, Therapeutic drugs. 1991; I:Z7-9 4 Viron B, de Meyer M, Le Liboux A, Frydman A, Maillard F, Mignon F, Gaillot J: Steady state pharmacokinetics of zopiclone during multiple oral dosing (7.5 mg nocte) in patients with severe chronic renal failure. Int Clin Psychopharmacol 1990; 5(suppl 2): 95-104 5 Gaillot J, Le Roux Y, Houghton GW, Dreyfus JF: Critical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency. Sleep 1987; 10(suppl 1): 7-21 6 Marc-Aurele J, Caille G, Bourgoin J: Comparison of zopiclone pharmacokinetics in patients with impaired renal function and normal subjects. Effect of hemodialysis. Sleep 1987; 10(suppl 1): 22-26