Felbamate was first approved in the USA in 1993. Felbamate has several mechanisms of action, including NMDA antagonism, enhancing GABA, blocking sodium channels, and blocking high-voltage activated calcium channels.

It has excellent oral bioavailability, greater than 90%. It is only 25% protein-bound, which is not clinically significant. It is metabolized via CYP 3A4. Between 40 and 50% of the absorbed dose appears unchanged in the urine and the rest as inactive metabolites and conjugates. Its half-life in monotherapy is 20–23 h. The half-life is shorter in children and also shorter in the presence of enzyme inducers. Felbamate has many interactions. It is an inhibitor of CYP 2C19, CYP 1A2, and beta-oxidation. As a result, it inhibits the metabolism and increases the serum concentration of phenobarbital, phenytoin, valproate, carbamazepine epoxide, and warfarin. On the other hand, felbamate induces CYP 3A4 and thus decreases carbamazepine level and also reduces oral contraceptive efficacy.

Felbamate is affected by enzyme-inducing antiepileptic drugs which accelerate felbamate clearance and reduce its serum concentration.

Common adverse effects of felbamate are anorexia, nausea, vomiting, and weight loss. Stomach irritation can be improved by administration with food and by the use of H2 blockers or proton pump inhibitors. Felbamate may also cause insomnia, irritability, and headache.

Felbamate was discovered to have serious idiosyncratic potential adverse effects. It may cause aplastic anemia with an estimated risk of 1 in 5000–8000 patients. Aplastic anemia has not been reported below age 13. The onset of aplastic anemia is after 2.5–6 months of treatment. It is highly unlikely to occur after one year of treatment. It has risk factors including prior cytopenia, allergy to or significant toxicity with other antiepileptic drugs, and underlying autoimmune disease [3]. Another serious idiosyncratic potential adverse effect is hepatic failure, with an estimated risk of 1 26,000-1 and 54,000. The onset of this toxicity has been after 25–959 days of treatment, with a mean of 217 days. Neither aplastic anemia nor liver failure can be prevented by monitoring of CBC and liver enzymes. Nevertheless, it is recommended to check CBC and liver function tests prior to starting felbamate, then every 2 weeks for 6 months, then every 2–3 months after 6 months, and then every 6 months after the first year.

Felbamate is a wide-spectrum antiepileptic drug, although its efficacy in generalized seizure types of idiopathic generalized epilepsy has not been evaluated in class I studies. The official FDA indications are: “Either monotherapy or adjunctive therapy in the treatment of partial seizures, with or without generalization, in adults with epilepsy and adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children.” The FDA indication specifies that “felbamate is not indicated as a first-line treatment; it is recommended only in those who respond inadequately to alternative treatments and whose epilepsy is so severe that the risk of aplastic anemia and/or liver failure is deemed acceptable.” A written informed consent is needed.

The suggested felbamate therapeutic range is 40–100 mg/L.

Gabapentin was first approved in the USA in 1994. The mechanism of action is binding to the alpha-2 delta subunit of voltage-gated calcium channels. This binding reduces the influx of calcium and reduces neurotransmitter release under hyperexcitable conditions. Despite its name, gabapentin does not interact with GABA receptors.

Gabapentin bioavailability is low, with considerable inter-subjective variability. In addition, oral bioavailability decreases with increasing gabapentin dose. For example, bioavailability is 60% after a single 300 mg dose, but only 29% for 1600 mg t.i.d. and 36% for 1200 mg p.o. q.i.d. (bioavailability improves with dividing the dose) [4]. The reason for the above is that gabapentin is transported from the gut into the bloodstream by the l-amino acid transport system, which is saturable. Gabapentin protein binding is minimal at less than 50%.

Gabapentin is not metabolized in humans. It is eliminated unchanged in the urine as a result requires dose reduction with renal impairment. Its half-life is 5–7 h.

Gabapentin has no known interactions, which is predicted by the absence of metabolism, the absence of enzyme induction or inhibition, and the absence of protein binding. However, antacids including aluminum hydroxide or magnesium hydroxide may reduce gabapentin bioavailability if taken within 2 h from gabapentin intake.

Gabapentin adverse effects include sedation, dizziness, ataxia, asthenia, and weight gain. It may cause myoclonus. It may be associated with cognitive slowing in the elderly, and emotional lability or hostility in children. It has been assigned pregnancy category C.

Gabapentin is a narrow-spectrum agent against focal seizures. It failed clinical trials against absence and primary generalized tonic–clonic seizures [5, 6]. It may cause exacerbation of myoclonus [7]. The official FDA indication is for adjunctive therapy for partial seizures. It is also approved for the treatment of postherpetic neuralgia. An extended-release preparation (gabapentin enacarbil) has been approved for the treatment of restless leg syndrome.

Lamotrigine was first approved in the USA in 1995, but was licensed in Europe in 1991. Its mechanism of action is blocking sodium channels. This secondarily results in blocking the release of glutamate. Lamotrigine also inhibits high-voltage activated calcium channels.

Lamotrigine has an excellent oral bioavailability of about 98%. The time to maximum concentration is 1–1.5 h with the immediate release preparation and 4–11 h with the extended-release preparation. Its protein binding is only 55%.

Lamotrigine is associated with a mild autoinduction. It is a weak inhibitor of dihydrofolate reductase (not clinically relevant). Lamotrigine slightly increases topiramate level and slightly decreases valproate level. However, it is markedly affected by some other drugs. Its clearance is increased in the presence of enzyme-inducing drugs, estrogen containing oral contraceptives, and pregnancy. On the other hand, lamotrigine clearance is markedly decreased by valproate.

Dose-related adverse effects include dizziness, ataxia, blurred vision, diplopia, nausea, and vomiting. Headache and tremor may also occur. Rash is seen in about 3%, but the risk is higher in children, with coadministration of valproate, with faster titration, and with higher doses. As a result of increased risk of rash with faster titration, lamotrigine has to be titrated very slowly. The rate of titration is slower in the presence of valproate.

Rare serious idiosyncratic adverse effects include Stevens–Johnson syndrome, toxic epidermal necrolysis, or hypersensitivity syndrome (1 in 4000). It is assigned pregnancy category C.

Lamotrigine is a wide-spectrum antiepileptic drug effective against partial–onset as well as generalized tonic–clonic seizures. It is FDA indicated as adjunctive therapy or for conversion to monotherapy for partial seizures, adjunctive therapy for generalized tonic–clonic seizures, and adjunctive therapy for Lennox–Gastaut syndrome. Efficacy against generalized absence seizures is less than valproate and ethosuximide. Its efficacy against myoclonic seizures is variable, and lamotrigine may exacerbate myoclonic seizures in some individuals. The recommended therapeutic range for lamotrigine is 2–20 mg/L [8].

Lamotrigine is also FDA indicated for maintenance treatment of bipolar I disorder to delay a mood episode.

Topiramate is a sulfamate-substituted monosaccharide. It was approved in the USA in 1996. It has multiple mechanisms of action including blocking of voltage-gated sodium channels, augmentation of GABA activity, antagonism of AMPA/kainate receptors, inhibition of high-voltage activated calcium channels, and weak inhibition of carbonic anhydrase activity.