Amerge - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Amerge - Scientific Information

Manufacture: GlaxoSmithKline
Country: United States
Condition: Migraine, Migraine Headache (Migraine)
Class: Antimigraine agents
Form: Tablets
Ingredients: croscarmellose sodium, hydroxypropyl methylcellulose, indigo carmine aluminium lake (FD&C Blue No. 2) [2.5 mg tablet only], iron oxide yellow [2.5 mg tablet only], lactose, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin

Pharmaceutical Information

Drug Substance

Proper name: naratriptan hydrochloride
Chemical name: 2-[3-(1-Methyl-piperidin-4-yl)-1H-indol-5-yl]-ethanesulphonic acid methylamide hydrochloride
Molecular formula: C17H25N3O2S•HCl
Molecular mass: 371.9
Structural formula:
Physicochemical properties: Naratriptan hydrochloride is a white to pale yellow microcrystalline solid with a melting point of 246°C. Its solubility in water (25°C) is 35 mg/mL. It has a pKa of 9.7 (piperidinyl nitrogen), and its pH (1% aqueous solution) is 6.3

Clinical Trials

Four double-blind, placebo-controlled, dose-ranging clinical trials evaluated the safety and efficacy for AMERGE at oral doses ranging from 0.1 to 10 mg in a total of 3160 adult patients with migraine attacks characterized by moderate or severe pain. The minimal effective dose was 1.0 mg. In three of the four clinical trials, a higher overall rate of headache relief was achieved with a 2.5 mg dose. Single doses of 5 mg and higher are not recommended due to an increased incidence of adverse events. Onset of significant headache relief (defined as no or mild pain) became apparent at 60-120 minutes after these doses. AMERGE also relieved the nausea, phonophobia and photophobia associated with migraine attacks.

The following table shows the 4 hour efficacy results obtained for the recommended doses of AMERGE in 2 of the 4 dose-ranging efficacy studies. In Study 1, patients were randomized to receive placebo or a particular dose of AMERGE for the treatment of a single migraine attack according to a parallel group design, whereas in Study 2, patients were randomized to receive each of the treatments for separate migraine attacks according to a crossover design. In both studies, patients who achieved headache relief at 240 minutes post-dose, but experienced a worsening of severity between 4 and 24 hours post-dosing were permitted to take a second dose of double-blind medication identical to the first.

Table 1 Results at 240 Minutes Post First Dose
Parameter Study 1 Study 2
Placebo (n=107) AMERGE 1 mg (n=219) AMERGE 2.5 mg (n=209 Placebo (n=602) AMERGE 1 mg (n=595) AMERGE 2.5 mg (n=586)
Pain relief (0/1)1 27% 52%* 66%* 33% 57%* 68%*
Pain free (0)2 10% 26%* 43%* 15% 33%* 45%*
Nausea free 56% 71%* 77%* 54% 69%* 75%*
Photophobia free 34% 57%* 67%* 33% 53%* 61%*
Phonophobia free 36% 55%* 65%*
Clinical disability (0/1)3 49% 62%* 72%* 50% 70%* 76%*

1Pain relief is defined as a reduction in headache severity from grade 3 or 2 (severe or moderate) to grade 1 or 0 (mild or no pain).

2Pain free is defined as a headache severity score of 0 (no pain).

3Clinical disability is measured on a 4-point scale (0=able to function normally, 1=ability mildly impaired, 2=ability severely impaired, 3=bed rest required).

Photophobia and phonophobia collected as one measure.

* p<0.01 versus placebo

p<0.01 versus AMERGE 1 mg. Note comparisons were not performed for any parameter other than pain relief and pain free in study 1 and for pain relief in study 2

*Statistical comparisons were not performed.

Significant headache relief was sustained for over 24 hours. Data from four placebo controlled studies (n=3160) showed that of the patients who achieved headache relief with AMERGE Tablets 2.5 mg, 72% to 83% did not experience recurrence of headache between 4 and 24 hours post-dosing.

Subgroup analyses of the overall population of patients participating in the placebo-controlled trials indicate that the efficacy of AMERGE was unaffected by migraine type (with/without aura), gender, oral contraceptive use or concomitant use of common migraine prophylactic drugs (e.g. beta-blockers, calcium channel blockers, tricyclic antidepressants). In a long-term, repeated dose, open study of 417 patients (all were initiated on a 2.5 mg dose of AMERGE but were given the option to titrate down to a 1 mg dose if 2.5 mg was not well tolerated), a total of 15,301 attacks were treated (mean number of treated attacks/patient of 36 for the 2.5 mg dose and 8 for the 1 mg dose) over a period of up to 12 months. Headache response was sustained (as judged by the proportion of attacks treated with AMERGE resulting in headache relief). The median percentage of attacks per patient requiring a second dose for headache recurrence was 8%. Of the 417 patients treating attacks, 10 patients opted for a dosage reduction.

Detailed Pharmacology

Animal

Naratriptan has been shown to have a high affinity for human recombinant 5-HT1B (pKi=8.7) and 5-HT1D (pKi=8.3) receptors. Naratriptan appears to act as an agonist at these receptors, causing selective vasoconstriction of isolated intracranial blood vessels from dogs in in vitro models (ED50=0.07-0.11 µM). In anaesthetised dogs, naratriptan treatment was associated with a dose-dependent decrease in carotid arterial blood flow in association with an increase in carotid arterial vascular resistance. The cumulative dose required to produce 50% of its own maximum vasoconstriction was 19 µg/kg i.v. Naratriptan was also associated with increases in vascular resistance in the femoral, renal, vertebral and coronary artery beds, although these effects were less than at the cranial artery.

Naratriptan caused vasoconstriction of isolated coronary arteries obtained from anaesthetised monkeys (ED50=30-47 nM) and from humans (ED50=170 nM) undergoing heart transplantation. In addition, naratriptan inhibits plasma protein extravasation from blood vessels in the dura following trigeminal nerve stimulation in anaesthetised rats resulting in a decrease of the neurogenic inflammation response (ID50=4.1 µg/kg i.v.). In anaesthetized cats, naratriptan (30-100 µg/kg i.v.) gains access to the central nervous system (CNS) and inhibits trigeminal nerve firing. Naratriptan does not exert a generalized analgesic effect.

In rats receiving oral (50 mg/kg) or intravenous (24 mg/kg) naratriptan, the main acute effects consisted of behavioural depression. In dogs receiving the drug by means of oral (1 mg/kg) or intravenous (0.3 mg/kg) routes, the predominant acute effects consisted of mydriasis, hind limb stiffness, increased barking and tachycardia. Effects seen in the rate occurred at exposures around 40 (oral based on AUC) and 400 (intravenous based on Cmax) times that seen in humans following a single 5 mg (tablet) dose; whilst the main effects in the dog occurred at exposures around 5 (oral based on AUC) and 11 (intravenous based on Cmax) times that seen in humans.

No evidence was found to suggest that naratriptan would interfere with pentobarbitone metabolism; nor was it seen to produce symptoms characteristic of 5-HT behavioural syndrome when administered together with a monoamine oxidase inhibitor (parglyine), a 5-HT reuptake inhibitor (fluoxetine) or lithium.

The absorption, distribution and excretion of naratriptan are similar in rats, mice, rabbits, dogs and humans. Oral bioavailability has been determined to be 39% in the rat and 68% in the dog. The time to peak plasma concentrations following oral administration varies from less than 1 hour in the dog to 3 to 4 hours in the rat. The elimination half-life ranges from 0.7 hours in the rabbit to 4.6 hours in the mouse.

The drug undergoes limited metabolism with unchanged naratriptan being the predominant plasma component in all species studied, as well as the major urinary component in humans, dogs, rats and mice. The majority of metabolites have been characterized and are shown to be excreted rapidly in the urine. The metabolism of naratriptan in humans is most similar to that in the dog, with the N-oxide of naratriptan as the major metabolite. None of the metabolites tested, including the N-oxide, demonstrated any significant pharmacological activity at vascular 5-HT1 receptors.

Plasma protein binding was low in all species studied (21-35%). Drug-related material was widely distributed throughout most tissues following oral or intravenous administration to the rat with highest concentrations being observed in the gastrointestinal tract, liver, kidneys and bladder. Only trace concentrations were detected in the brain and central nervous system following intravenous dosing. Following oral dosing, radioactive drug-related material in central nervous tissues was undetectable. Low levels of radioactivity persisted in the eyes (of pigmented animals, probably associated with melanin), testes, liver and kidney (and in some cases, bladder and thyroid) at later time-points (up to 168 hours after dosing). Radioactive drug-related material was still detected in the eyes 3 months post-administration (last time point studied).

Drug-related material has been shown to cross the placenta in pregnant rats and rabbits. Following oral administration, the ratio of drug-related radioactivity in foetal tissue to maternal plasma ranged from 0.2 to 1.9 in rats and 0.3 to 0.7 in rabbits. Naratriptan is likewise distributed into the milk of lactating rats. At 2 hours post oral gavage dosing levels in milk were 3.5 times higher than maternal plasma levels.

Following oral administration to the dog, approximately 65-75% of the dose was excreted in the urine and 22-32% in the feces. For mice and rats, urinary excretion accounted for 30-40% of the dose while 50-60% was excreted in the feces.

Toxicology

Acute Toxicology

Naratriptan was shown to have low acute toxicity. Mice and rats of both sexes appeared equally sensitive to the effects of naratriptan. Maximum oral non-lethal dosages of >1000 mg/kg and approximately 750 mg/kg were established for the mouse and rat, respectively. Maximum non-lethal dosages for both species were in the range of ≥180 to 225 mg/kg and ≥30 to 40 mg/kg for the subcutaneous and intravenous routes, respectively.

Clinical signs were indicative of behavioural depression and effects on the central nervous system, consistent with finding seen with sumatriptan. Target organ toxicity was seen in the testes/epididymides at an oral dose of 340 mg/kg, in the rat only. All treatment-related effects occurred at dosages significantly greater than the maximum oral dose proposed for clinical use (2 x 2.5 mg/day).

Long Term Toxicology and Carcinogenicity

Naratriptan has low acute toxicity and is well tolerated in repeat dose studies in the rat and dog at dosages, and resulting systemic exposures (based on AUC), considerably higher than those achieved in humans.

In rats, increased mortality was observed following repeat oral administration for up to 29 weeks at a systemic exposure ranging from approximately 400 to 1000 times that seen in humans following an oral (tablet) dose of 5 mg. At the same exposure level, effects on the testes and epididymides, a slight reduction in prostrate weight, changes in the female reproductive tract (atrophic or cystic ovaries and vaginal anoestrus) and atrophy of the granular ducts of the submandibular salivary glands (predominantly in females) were observed. The effects in females, together with the changes in oestrus cycles seen in the oral fertility study, are considered indicative of a disturbance in hormonal balance. The effects were mild and with the exception of the testicular/epididymal atrophy, showed recovery after a treatment-free period. At the no effect level for these findings, systemic exposure was approximately 70 to 100 times that seen in humans following an oral (tablet) dose of 5 mg.

In the dog, two high dosage (5 mg/kg/day) males were killed towards the end of the oral 12 month study following repeated convulsive episodes, but neurological and historical examination revealed no significant findings. The beagle is recognized as having a high incidence of primary epilepsy and no similar findings were seen in the other animals at this dosage. Transient changes in the pre-corneal tear film were observed following repeated oral or intravenous administration. These effects were considered to be pharmacologically mediated and have been seen previously with sumatriptan. They were not associated with any histological damage to the cornea or surrounding tissue.

In a carcinogenicity study, naratriptan (90 mg/kg/day) caused an increased incidence of proliferative lesions of the thyroid gland in the rat only. At the maximum oral dosage with no oncogenic effect (20 mg/kg/day), systemic exposure was up to approximately 100 times that seen in humans following an oral (tablet) dose of 5 mg. In mice, an increased incidence of hypophyseal adenoma was reported in females and Harderian gland adenoma in males at the intermediate dosage only (65 mg/kg/day). Naratriptan was therefore considered not to be oncogenic in the mouse up to a dosage of 200 mg/kg/day.

Mutagenicity

Naratriptan, or naratriptan spiked with certain synthetic or degradation impurities, was not mutagenic in any of the in vitro or in vivo used, presenting no detectable genetic hazard or clastogenic effect. Naratriptan can be nitrosated in vitro in the World Health Organization Nitrosation Assay Procedure test to form an N-nitroso derivative, which is a bacterial mutagen. Exposure to the N-nitroso derivative of naratriptan was demonstrated in the stomach of nitrite-supplemented rats in a specially designed carcinogenicity study. However, the generation in situ this nitrosated product was not associated with any carcinogenic potential in the liver or gastrointestinal tract.

Reproduction and Teratology

In the oral fertility study in rats, naratriptan resulted in maternal toxicity, which was associated with increased pre-implantation loss, foetal growth retardation, delayed foetal ossification and reduced survival of F1 pups at the high dosage (340 mg/kg/day). However, overall reproductive performance of the F0 and F1 generations and development of the F1 and F2 generations were unaffected by treatment with naratriptan.

Naratriptan was not teratogenic in the rat or rabbit. In the rat, maternal toxicity was seen, which was accompanied by slight increases in early post-implantation loss and minor skeletal effects. In the Dutch rabbit, maternal toxicity was accompanied by increases in pre- and post-implantation loss and at all dosages (1, 5 and 30 mg/kg p.o.), minor skeletal effects and variations in the position of the cervico-thoracic vasculature. In the New Zealand White rabbit, however, the embryonic loss and effects on the foetal vasculature were not reproducible despite exposure to identical doses, and maternal toxicity was accompanied only by an increased incidence of minor skeletal variants.

In the peri-/post-natal study, maternal toxicity, which was accompanied by reduced survival of F1 pups, was seen at the high dosage (340 mg/kg/day), together with some transient effects on early post-natal development, which reversed after weaning. However, parturition, outcome of pregnancy, reproductive performance of the F1 generation and F2 embryonic development were unaffected by treatment with naratriptan.

Local Tolerance

In local tolerance studies, naratriptan hydrochloride was slightly irritant to the rabbit eye and produced no significant irritant reactions, when applied topically to intact skin in the guinea pig, but was slightly irritant on abraded skin. The sensitizing potential of the compound in the guinea pig, if any, was considered to be very low. In addition, neither naratriptan hydrochloride nor a naratriptan-protein mixture showed any activity in either an active systemic anaphylaxis test or passive cutaneous anaphylaxis test in guinea pigs.