Phenytoin Ciclosporin

A report of severe gingival overgrowth in a kidney transplant patient was attributed to the additive adverse effects of ciclosporin and phenytoin. Ciclosporin was replaced by tacrolimus, which may have fewer oral adverse effects, and almost complete reversal of gingival overgrowth was achieved within 6 months. ... 

Omeprazole can inhibit the metabolism of drugs metabolised mainly by the cytochrome P-450 enzyme subfamily 2C (diazepam, phenytoin), but not of those metabolished by subfamilies lA (caffeine, theophylline), 2D (metoprolol, propranolol), and 3A (ciclosporin, lidocaine (lignocaine), quinidine). Since relatively few drugs are metabolised mainly by 2C compared with 2D and 3A, the potential for omeprazole to interfere with the metabolism of other drugs appears to be limited, but the half lives of diazepam and phenytoin are prolonged as much as by cimetidine. 

CICLOSPORIN ANTI EPILEPTICS -BARBITURATES, CARBAMAZEPINE, PHENYTOIN L plasma concentrations of ciclosporin, with risk of transplant rejection Due to induction of metabolism of ciclosporin by these drugs. The potency of induction varies Monitor for signs of rejection of transplants. Monitor ciclosporin levels to ensure adequate therapeutic concentrations and t dose when necessary... 

Inducers of UGT include carbamazepine, phenobarbital, phenytoin and rifampin. Inhibitors of UGTs include amitriptyline, chlorpromazine, ciclosporin, clomipramine, diazepam, lorazepam, nitrazepam and valproic acid,... 

With phenytoin, reduced absorption can contribute to the fall in ciclosporin concentrations. 

Gingival hyperplasia, similar to that seen with phenytoin and ciclosporin, is a rare but well-recognized adverse effect of nifedipine (88). It has also been reported in patients taking felodipine (89,90), nitrendipine (SEDA-16, 200), and verapamil (91), suggesting that this adverse effect is a class effect. Only one case of gingival hyperplasia related to calcium channel blockers was reported to the Norwegian Adverse Drug Reaction Committee up to 1991, despite their widespread use (92). However,... 

The observation that 5 patients taking ciclosporin needed dosage increases while taking phenytoin prompted a further study in 6 healthy subjects. Phenytoin 300 or 400 mg daily reduced the maximum ciclosporin blood levels and AUC by 37% (from 1325 to 831 micrograms/L) and 47%, respectively. ... 

Other reports describe patients who needed two- to fourfold increases in their ciclosporin dosages when they were given phenytoin. " ... 

Another report describes an increase in ciclosporin levels from 512 to 810 nanograms/mL after phenytoin and phenobarbital were replaced by sodium valproate. ... 

In 5 cases an interacting antiepileptic was successfully replaced by sodium valproate, see Carbamazepine, Phenobarbital and Phenytoin, above.However, sodium valproate may not always be without problems because interstitial nephritis was suspected in one patient with a renal graft taking ciclosporin and valproate, and fatal valproate-induced hepatotoxicity occurred in another patient taking ciclosporin. ... 

It is thought that phenytoin, - carbamazepine and phenobarbital increase the metabolism of the ciclosporin by the liver (hepatic cytochrome P450 oxygenase system) thereby decreasing the serum levels. Oxcarbazepine produced only small reductions in ciclosporin levels, and the effect is probably due to weak induction of the cytochrome P450 isoenzyme CTT3A. Phenytoin also possibly reduces the absorption of the ciclosporin. ... 

None of these interactions is extensively documented but all appear to be established and of clinical importance. Serum ciclosporin levels should be well monitored if carbamazepine, phenobarbital or phenytoin are added and the ciclosporin dosage increased appropriately. Primidone is metabolised to phenobarbital by the liver, and therefore would be expected to reduce ciclosporin levels. Information about oxcarbazepine is very limited but small reductions in its dose, together with an increase in ciclosporin dose, may be adequate to control any interaction. However, more study is required before oxcarbazepine can be recommended as a suitable alternative. The effects of the interaction may persist for a week or more after the anticonvulsant is withdrawn. Sodium valproate seems not to alter ciclosporin levels, but the case reports of nephritis and hepatotoxicity suggest some caution is warranted. 

---