3,4-Diaminopyridine

109.13

109.13

110232

200-220-9

RU4S6E2G0J

521760

DTXSID6046715

C82687

N07XX05|N - Nervous system

29333999

64.9

-0.5

Brownish to brown-gray Crystalline Powder

1.3±0.1 g/cm3

220 °C

369.3°C at 760 mmHg

240 °C

1.676

H2O: 24 g/L (20 ºC)

Store below +30°C.

LD50 orally in Rabbit: 47 mg/kg LD50 dermal Rabbit > 200 mg/kg

Ⅱ

6.1

UN 2811 6.1/PG 2

3

25-26-36/37/38

26-28-36/37/39-45-37/39-28A-36

US7600000

T+,T,Xi

Irritant

Stable under normal temperatures and pressures.

P260-P264-P280-P284-P301 + P310-P305 + P351 + P338

H300 + H330-H311-H315-H319-H335

|Danger|H300 (94.23%): Fatal if swallowed [Danger Acute toxicity, oral]|P260, P261, P264, P270, P271, P280, P284, P301+P310, P302+P352, P304+P340, P305+P351+P338, P310, P312, P320, P321, P322, P330, P332+P313, P337+P313, P361, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 52 companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The approximate oral LD50 was >25mg/kg in rats and 100 mg/kg in mice. The approximate intravenous LD50 was 25 mg/kg in both rats and mice. Peritoneal and subcutaneous LD50 in mice were 20 mg/kg and 35 mg/kg, respectively. There is limited clinical experienced with amifampridine overdose. The manifestations of acute drug overdose may include abdominal pain, and should be responded with discontinuation of treatment and initiation of supportive care with close monitoring of viral signs. There is no specific antidote known for amifampridine. _In vitro_, amifampridine showed no clinically relevant carcinogenic or genotoxic potential. However, in a 2-year rat study, amifampridine caused small but statistically significant dose-related increases in the incidence of Schwannomas in both genders and of endometrial carcinomas in females. At doses higher than the recommended daily dose for humans, amifampridine caused a dose-related increase in the percentage of pregnant rats with stillborn offspring. Effects on the central and autonomic nervous system, increased liver and kidney weights and cardiac effects (second degree atrioventricular block) were seen in a repeat-dose toxicity studies in rats and dogs.

Amifampridine has had limited clinical use, but adverse events have been largely neurologic and gastrointestinal. Serum ALT elevations were not reported in the prelicensure studies of amifampridine but were reported as occurring in a small proportion of patients in safety reviews by the Food and Drug Administration. Nevertheless, there have been no reports of clinically apparent liver injury associated with its use. Thus, liver injury from amifampridine must be rare if it occurs at all.

There is no human data on serum protein binding of amifampridine.

Amifampridine is indicated for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and in patients aged 6 to less than 17 years of age. Nevertheless, it is important to note that at the current time only the Firdapse brand of amifampridine is indicated for the treatment of LEMS in adults and the Ruzurgi brand of amifampridine is indicated for the treatment of LEMS in patients aged 6 to less than 17 years.|FDA Label|Symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults.,

Amifampridine is an orally available potassium channel blocker that increases acetylcholine in synaptic clefts of peripheral nerve endings and is used to treat the Lambert-Eaton myasthenic syndrome. Amifampridine is associated with a low rate of transient serum enzyme elevations during therapy but has not been linked with instances of clinically apparent acute liver injury.

Myasthenia Agents

Administration of amifampridine to patients with LES in clinical trials resulted in improvement of the compound muscle action potential (CMAP), muscle function, and quantitative myasthenia gravis (QMG) score. One case of a slight prolongation of the QTc interval in male patient with LEMS and euthyroid Hashimoto’s disease treated with 90 mg of amifampridine in combination with 100 mg azathioprine was reported. I_n vitro_, amifampridine was shown to modulate cardiac conduction and induce phasic contractions in different arteries from several species. In addition, it stimulated potassium-evoked dopamine and noradrenaline release in rat hippocampal slices and upregulate acetylcholine release in the brain. It may also potentiate adrenergic and cholinergic neuromuscular transmission in the gatrointestinal tract. In a single pharmacokinetic study, no effect was observed of amifampridine phosphate on cardiac repolarization as assessed using the QTc interval. There were no changes in heart rate, atrioventricular conduction or cardiac depolarization as measured by the heart rate, PR and QRS interval durations.

Drugs used for their actions on skeletal muscle. Included are agents that act directly on skeletal muscle, those that alter neuromuscular transmission (NEUROMUSCULAR BLOCKING AGENTS), and drugs that act centrally as skeletal muscle relaxants (MUSCLE RELAXANTS, CENTRAL). Drugs used in the treatment of movement disorders are ANTI-DYSKINESIA AGENTS. (See all compounds classified as Neuromuscular Agents.)|A class of drugs that act by inhibition of potassium efflux through cell membranes. Blockade of potassium channels prolongs the duration of ACTION POTENTIALS. They are used as ANTI-ARRHYTHMIA AGENTS and VASODILATOR AGENTS. (See all compounds classified as Potassium Channel Blockers.)

Orally-administered amifampridine is rapidly absorbed in humans to reach the peak plasma concentrations within by 0.6 to 1.3 hours. A single oral dose of 20 mg amifampridine in fasted individuals resulted in mean peak plasma concentrations (Cmax) ranging from 16 to 137 ng/mL. Bioavailability is approximately 93-100% based on recoveries of unmetabolised amifampridine and a major 3-N-acetylated amifampridine metabolite in urine. Food consumption decreases amifampridine absorption and exposure with a decrease in the time to reach maximum concentrations (Tmax). It is approximated that food consumption lowers the Cmax on average by ~44% and lowers AUC by ~20%. based on geometric mean ratios. Systemic exposure to amifampridine is affected by the overall metabolic acetylation activity of NAT enzymes and NAT2 genotype. The NAT enzymes are highly polymorphic that results in variable slow acetylator (SA) and rapid acetylator (RA) phenotypes. Slow acetylators are more prone to increased systemic exposure to amifampridine, and may require higher doses for therapeutic efficacy.|Following oral administration, more than 93% of total amifampridine is renally eliminated within 24 hours. About 19% of the total renally-excreted dose is in the parent drug form, and about 74-81.7% of the dose is in its metabolite form.|In rats, orally-administered amifampridine was extensively absorbed in the gastrointestinal tract and widely distributed. Drug concentrations were highest in organs of excretion, including liver, kidney and the gastrointestinal tract, and some tissues of glandular function, such as lacrimal, salivary, mucous, pituitary and thyroid glands. Concentrations in tissues are generally similar to or greater than concentrations in plasma.|Overall clearance of amifampridine is both metabolic and renal; it is mostly cleared from the plasma via metabolism by N-acetylation.

3-N-acetylated amifampridine is the major metabolite based on _in vivo_ and _in vitro_ human studies.

The plasma elimination half-life is approximately 2.5 hours for amifampridine and 4 hours for 3-N-acetylamifampridine.

Amifampridine is a symptomatic treatment that increases acetylcholine concentrations at the neuromuscular junction. It selectively blocks presynaptic fast voltage-gated potassium channels, thereby prolonging cell membrane depolarization and action potential, and augmenting calcium transport into the nerve endings. Increased intracellular calcium enhances the exocytosis of acetylcholine-containing vesicles and enhances impulse transmission at central, autonomic, and neuromuscular synapses. Amifampridine improves muscle strength and resting compound muscle action potential (CMAP) amplitudes with an overall weighted mean difference of 1.69 mV.

3,4 Diaminopyridine

Human drugs -> Firdapse (previously Zenas) -> EMA Drug Category|Other nervous system drugs -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients