Felbamate Valproate

Drugs that can increase carbamazepine serum levels include cimetidine, danazol, diltiazem, erythromycin, felbamate, clarithromycin, fluoxetine, isoniazid, niacinamide, propoxyphene, ketaconazole, itraconazole, verapamil, valproate, troleandomycin, loratadine, nicotinamide, tricyclic antidepressants, SSRIs, nefazodone, protease inhibitors. 

Phenobarbital Enhances phasic GABAa receptor responses reduces excitatory synaptic responses Nearly complete absorption not significantly bound to plasma proteins peak concentrations in Vi to 4 h no active metabolites tjy2 varies from 75 to 125 h Generalized tonic-clonic seizures, partial seizures, myoclonic seizures, generalized seizures, neonatal seizures, status epilepticus Toxicity Sedation, cognitive issues, ataxia, hyperactivity Interactions Valproate, carbamazepine, felbamate, phenytoin, cyclosporine, felodipine, lamotrigine, nifedipine, nimodipine, steroids, theophylline, verapamil, others... 

For simple and complex partial seizures and secondary generalized tonic-clonic seizures, the first line drugs are - carbamazepine, valproate and phenytoin. Second line drugs include - acetazolamide, clobazam, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxacarbamazepine, primidone, tiagabine, topiramate and vigabactin. 

For atypical absence, tonic and clonic seizures, first line treatment is with valproate and second line with acetazolamide, carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxacarbamazepine, phenobarbitone, phenytoin, primidone or topiramate. 

Mode of action. The specific site of action of felbamate is unknown. There is experimental evidence that felbamate blocks NMDA receptors, but less potently than carbamazepine, ethosuximide, phenytoin or valproate. It also modulates sodium channel conductance but does not enhance GABAergic function. In addition to its protective action against chemically induced seizures felbamate has also been shown to have a neuroprotective action in models of hypoxic ischaemia as induced by bilateral carotid ligation. 

In addition to phenytoin, carbamazepine, and lamotrigine, metabolically optimized analogs of these drugs, such as fosphenytoin and oxcarbazepine, show clinical promise. Other anticonvulsants that block sodium channels, among several mechanisms of action, include zonisamide, felbamate, topiramate, and valproate (Fig. 5). 

Plasma levels of valproate may also be Increased by felbamate, chlorpromazine, fluoxetine, fluvoxamine, topiramate, cimetidine, erythromycin, and ibuprofen... 

Nausea, vomiting, diarrhea, and changes in appetite can occur with all anticonvulsants, although they are usually transient and rarely require withdrawal. Felbamate and to a lesser extent valproate are the anticonvulsants that most often cause gastrointestinal adverse effects. 

Phenobarbital Phenytoin Primidone Felbamate Lamotrigine Tiagabide Topiramate Valproate Zonisamide Clobazam Clonazepam Diazepam usually compensated by the effect of the added drug risk of toxicity when interfering drug is discontinued drug... 

Felbamate Clonazepam Diazepam Phenobarbital Phenytoin Valproate High risk of toxicity with phenytoin, phenobarbital, and valproate Inhibition of metabolism of the affected drug... 

On the other hand, felbamate and to a lesser extent valproate inhibit a range of fiver enzymes and can increase the concentration of several drugs, leading to potentiation of their effects. 

A 32-year-old man developed infertility and a low sperm count (under 50 x 10 /1), with no motile sperm, less than 10% viability, and 100% with abnormal structure while taking valproate monotherapy for 5 years (96). Within 4 months of switching to felbamate, he and his wife conceived twin girls, and the sperm abnormalities were largely reversed. 

Lennox-Gastaut syndrome is a mixed seizure disorder combining the atypical absence seizures with tonic, tonic-clonic, or myoclonic motor patterns. The syndrome begins in childhood and usually Includes mental retardation. Although adequate control of the seizures rarely Is achieved, valproate, phenytoin, felbamate, lamotrigine, topiramate, and clonazepam have been... 

Attaining good control of tonic or atonic seizures Is difficult. Valproate, felbamate, lamotrigine, benzodiazepines, and topiramate have proven to be effective in some individuals. 

Therefore, plasma concentrations for drugs metabolized by these isoforms will be affected (see Chapter 10). Thus, the addition of phenytoin to an AED regimen can reduce their plasma levels by inducing their CYP3A4 metabolism for carbamazepine, felbamate, lamotrigine, oxcarbazepine, tiagabine, valproate, and zonisamide. Other drugs for which metabolism is induced by phenytoin include methadone, theophylline, warfarin, and oral contraceptives. On the other hand, plasma phenytoin levels are increased by carbamazepine, felbamate, cimetidine, warfarin, chloramphenicol, isoniazid, and disulfiram. Plasma phenytoin levels are decreased by rifampin, antacids, and valproate (free phenytoin levels remain the same). 

Valproate, a substrate for hepatic CYP2C19 and CYP2C9, has an extensive pattern of drug interactions. It increases the plasma concentrations of lamotrigine, CBZ, and phenobarbital and the free fraction of phenytoin by either displacing these drugs from plasma proteins or inhibiting their metabolism. Phenytoin, phenobarbital, and CBZ cause decreased plasma concentrations of valproate, whereas felbamate increases valproate levels. 

Phenobarbital, phenytoin, and possibly felbamate increase the levels of the active metabolite of mesuximide, IV-desmethylmesux-imide. Mesuximide increases the serum levels of phenobarbital and phenytoin, and decreases the levels of lamotrigine, and to a lesser extent, valproate. 

It has been suggested that phenobarbital, phenytoin and felbamate compete with mesuximide for the same metabolic mechanisms (hydroxyla-tion) in the liver. As a result each one is metabolised more slowly and therefore their levels increase. Mesuximide appears to increase the clearance of valproate, and lamotrigine (which is principally via glucuronida-tion). 

Felbamate can raise valproate serum levels causing toxicity. Valproate may slightly decrease the clearance of felbamate. 

The average steady-state valproate serum levels in 7 epileptics were raised by 28%, from 66.9 to 85.4 micrograms/mL, by felbamate 1.2 g daily, and by 54%, from 66.9 to 103 micrograms/mL by felbamate 2.4 g daily. The AUC of valproate was raised by 28% and 54% by felbamate 1.2 and 2.4 g, respectively. Valproate clearance was correspondingly reduced by felbamate. Similar effects were seen in another study.It was suggested that in children the interaction may be more marked. Many of the patients experienced nausea. Other toxic effects included lethargy, drowsiness, headaches, cognitive disturbances and low platelet counts. ... 

The clearance of felbamate was decreased 21% by valproate in one study, and another reported a significantly lower felbamate clearance in the presence of valproate. Yet another study noted only a minimal effect of valproate on felbamate clearance. ... 

---