Inhibition of sodium-dependent action potentials (putative target: voltage-gated sodium channels); no IC50/Ki values reported. Radioligand binding studies showed no interactions with monoamine, acetylcholine, histamine, glycine, AMPA/kainate, NMDA, or GABA receptors [2].

Rufinamide is extensively metabolised by non-CYP450 systems with a half-life of 8-12 hours. Rufinamide’s mechanism of action is thought to be inhibition of sodium-dependent action potentials in neurons, with possible membrane-stabilising effects. Rufinamide hydrolysis is mediated primarily by human carboxylesterase (hCE) 1 and is nonsaturable up to 500 μM.

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Rufinamide given orally at 20 mg/kg every 12 h in healthy dogs should result in a plasma concentration and half-life sufficient to achieve the therapeutic level extrapolated from humans without short-term adverse effects in adult dogs. Rufinamide alleviates injury-induced mechanical allodynia for 4 hours. Rufinamide reduces peak current and stabilizes the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons in the Spared Nerve Injury neuropathic pain model in mice. Rufinamide suppresses pentylenetetrazol-induced seizures in mice (ED(50) 45.8 mg/kg) but not rats, and is active against MES-induced tonic seizures in mice (ED(50) 23.9 mg/kg) and rats (ED(50) 6.1 mg/kg). Rufinamide suppresses pentylenetetrazol-, bicuculline-, and picrotoxin-induced clonus in mice (ED(50) 54.0, 50.5, and 76.3 mg/kg, respectively). Rufinamide is partially effective in the mouse strychnine test.
In animal studies, rufinamide showed strong inhibition of maximal electroshock-, pentylenetetrazol-, bicuculline-, and picrotoxin-induced seizures. It delayed kindling and suppressed afterdischarges in amygdala-kindled cats, reduced seizure frequency in Rhesus monkeys with chronic alumina foci in motor cortex, and inhibited afterdischarges in non-kindled cat hippocampus and cortex [2].

Radioligand binding studies were performed to assess the interaction of rufinamide with various receptor systems. No significant binding was detected for monoamine, acetylcholine, histamine, glycine, AMPA/kainate, NMDA, or GABA receptors [2].

20 mg/kg; oral Dogs

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Absorption, Distribution and Excretion
The oral suspension and tablets are bioequivalent on a mg/mg basis. Lufedipine is well absorbed, but at a slow rate, and the extent of absorption decreases with increasing dose. Based on urinary excretion, a single oral dose of 600 mg lumfedipine tablets in a fed state results in at least 85% absorption. Bioavailability = 70%-85% (decreasing with increasing dose); Time to peak concentration (Tmax), in both fed and fasting states = 4-6 hours; Peak plasma concentration (Cmax), 10 mg/kg/day = 4.01 µL/mL; Peak plasma concentration (Cmax), 30 mg/kg/day = 8.68 µL/mL; AUC (0-12 hours), 10 mg/kg/day = 37.8 ± 47 µg·h/mL; AUC (0-12 hours), 30 mg/kg/day = 89.3 ± 59 µg·h/mL.
Primarily excreted via the kidneys (91%; of which 66% is CGP 47292 and 2% is the original drug) and feces (9%).
Lufedipine is uniformly distributed in erythrocytes and plasma. The apparent volume of distribution is dose-dependent and varies with body surface area. At 3200 mg/day, the apparent volume of distribution is approximately 50 L. The volume of distribution is similar in adults and children and exhibits a non-linear variation.
Metabolism/Metabolites

Lufedipine is extensively metabolized, but has no active metabolites. Its primary biotransformation pathway is hydrolysis by carboxylesterases to the inactive metabolite CGP 47292 (a carboxylic acid derivative). Small amounts of other metabolites have been detected in urine, suspected to be acylglucuronide of CGP 47292. Cytochrome P450 enzyme systems or glutathione are not involved in the metabolism of lufedipine. Lufedipine is a weak inhibitor of CYP 2E1 and a weak inducer of CYP 3A4 enzymes.

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Biological Half-Life
The elimination half-life in healthy subjects and patients with epilepsy is 6-10 hours.

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Oral bioavailability: 70% in fed state, 49% in fasted state [2].
Peak plasma concentration (Tmax): 6 h (fed), 8 h (fasted) [2].
Elimination half-life (T1/2): 8–12 h (fed or fasted) [2].
Protein binding: 34% [2].
Extensively metabolized by non-CYP450 systems via hydrolysis of the carboxylamide group to main metabolite CGP47292; only 2% excreted unchanged in urine and faeces [2].
Hepatic elimination; no hepatic enzyme induction or inhibition reported [2].
Pharmacokinetics not significantly affected by gender or age [2].

Hepatotoxicity
In premarket clinical trials, the addition of rufinamide to standard antiepileptic treatment regimens was reported to be associated only with rare ALT elevations (more than 3 times the upper limit of normal). Rufinamide was not associated with clinically significant liver injury cases, but a pooled analysis of over 200 children indicated that two patients required early discontinuation of treatment due to liver-related adverse events, one of which was described as "toxic hepatitis." Since its approval, there have been no reports of clinically significant liver injury associated with rufinamide use, but its use in epilepsy treatment is limited. Rufinamide has been associated with cases of severe skin reactions, including Stevens-Johnson syndrome, which is often accompanied by some degree of liver injury. Therefore, rufinamide may cause liver injury, but this is rare. Probability score: E (Unproven but suspected cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Since there is currently no information on the use of rufenamide during lactation, and this drug may be toxic to breastfed infants, alternative medications should be preferred, especially for breastfed newborns or premature infants.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding rate
26.3% - 34.8%, of which 90% is bound to albumin (27%).

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Most common adverse effects (vs placebo): somnolence (24% vs 13%), fatigue (20% vs 4%), tremor (12% vs 0%), dizziness (8% vs 0%), vomiting (22% vs 6%), headache (up to 8% above placebo), diplopia, diarrhoea [2].
Discontinuation rate due to adverse effects: 8.1% (rufinamide) vs 4.3% (placebo); death: 0.2% vs 0.6% [2].
Serious adverse effects: 6.3% (rufinamide) vs 3.9% (placebo), predominantly convulsions [2].
Long-term (1978 adults): headache (29.5%), dizziness (22.5%), fatigue (17.7%); discontinuation 13.2%; serious adverse effects 13.2% (seizures, pneumonia); death 0.9% (comparable to background mortality) [2].
No significant cognitive decline in attention and processing speed up to 1600 mg/day [2].
Drug-drug interactions: Valproate increases rufinamide trough concentrations and decreases clearance by 25%; phenobarbital, phenytoin, primidone increase clearance by 25% [2].
Rufinamide decreases ethinyl estradiol concentrations (oral contraceptives) [2].
Protein binding: 34% [2]. (Note: also listed under ADME)

Int J Clin Pract.2006Nov;60(11):1497-501;J Vet Pharmacol Ther.2012 Dec;35(6):529-33

Rufinamide is a heteroaryl hydrocarbon and aromatic amide. Lufedipine is a triazole derivative and an anticonvulsant used to treat epileptic seizure disorders, such as childhood epilepsy—Lennox-Gastaut syndrome. Clinical trials have shown its effectiveness in treating partial seizures. Lufedipine is a unique anticonvulsant, often used in combination with other drugs to treat severe epileptic seizure disorders. Lufedipine treatment is associated with a low incidence of transient serum enzyme elevations and rare cases of clinically significant liver injury. Drug Indications For adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. FDA Label Inovelon is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients aged 4 years and older.
Treatment of Lennox-Gastaut Syndrome

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Mechanism of Action
Lufedipine is a triazole derivative antiepileptic drug that prolongs the inactive state of voltage-gated sodium channels, thereby stabilizing the cell membrane and ultimately preventing the spread of partial seizures.

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Rufinamide (trade name Inovelon) discovered by Novartis within NIH anticonvulsant screening program; worldwide rights acquired by Eisai in 2004 [2].
Orphan drug status for Lennox-Gastaut syndrome granted by FDA and European Commission in 2004 [2].
Efficacy in partial seizures (adults/adolescents): three randomized placebo-controlled trials showed significant reduction in seizure frequency (e.g., 20.4% median decrease vs 1.6% with placebo; p=0.016) and 50% responder rate (p=0.04) [2].
Efficacy in Lennox-Gastaut syndrome: one randomized placebo-controlled trial (n=138, age 4-37) with 45 mg/kg/day showed median seizure frequency reduction 32.7% vs 11.7% placebo (p=0.0001); for tonic-atonic seizures: 42.5% vs 1.4% (p<0.0001). Efficacy comparable or higher than lamotrigine, topiramate, felbamate [2].
Open-label trial in children (n=9, age 4-16) with refractory partial seizures: 4 of 9 had ≥50% seizure reduction [2].
Should be reserved as second- or third-line therapy for partial onset seizures; beneficial for Lennox-Gastaut syndrome and possibly elderly with refractory partial seizures [2].
Not recommended for primary generalized epilepsies until further investigation [2].

C10H8F2N4O

238.19

238.066

106308-44-5

Rufinamide-d2;1129491-38-8;Rufinamide-15N,d2;1795037-48-7

129228

White to off-white solid powder

1.5±0.1 g/cm3

473.8±55.0 °C at 760 mmHg

232-234?C

240.4±31.5 °C

0.0±1.2 mmHg at 25°C

1.635

0.05

1

5

3

17

282

0

POGQSBRIGCQNEG-UHFFFAOYSA-N

InChI=1S/C10H8F2N4O/c11-7-2-1-3-8(12)6(7)4-16-5-9(10(13)17)14-15-16/h1-3,5H,4H2,(H2,13,17)

1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide

E-2080; RUF-331; E2080; CGP-33101; RUF331; CGP 33101; E 2080; RUF 331; CGP33101; Trade names: BANZEL; Inovelon.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)