pms-Sumatriptan Mechanism of Action





Full Prescribing Info
Pharmacology: Mechanism of Action: Sumatriptan succinate has been shown to be effective in relieving migraine headache. Sumatriptan is an agonist for a vascular 5-hydroxytryptamine1D (5-HT1D) receptor subtype (a member of the 5-HT1 family), and has only weak affinity for 5-HT1A receptors and no significant activity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, 5-HT5A, or 5-HT7 receptor subtypes, or at alpha1-, alpha2-, or beta-adrenergic; dopamine1 or dopamine2; muscarinic; or benzodiazepine receptors.
The therapeutic activity of sumatriptan succinate in migraine is generally attributed to its agonist activity at 5-HT1B/5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1 receptor agonists in migraine. One theory suggests that activation of 5-HT1 receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is believed to be correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT1 receptors on perivascular fibres of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. These theories are not mutually exclusive.
Experimental data from animal studies show that sumatriptan also activates 5-HT1 receptors on peripheral terminals of the trigeminal nerve, which innervates cranial blood vessels. This causes the inhibition of neuropeptide release. It is thought that such an action may contribute to the anti-migraine action of sumatriptan in humans.
Cardiovascular Effects: In vitro studies in human isolated epicardial coronary arteries suggest that the predominant contractile effect of 5-HT is mediated via 5-HT2 receptors. However, 5-HT1 receptors also contribute to some degree to the contractile effect seen. Transient increases in systolic and diastolic blood pressure (up to 20 mmHg) of rapid onset (within minutes), have occurred after intravenous administration of up to 64 μg/kg (3.2 mg for 50 kg subject) to healthy volunteers. These changes were not dose related and returned to normal within 10-15 minutes. Following oral administration of 200 mg or intranasal administration of 40 mg, however, mean peak increases in blood pressure were smaller and of slower onset than after intravenous or subcutaneous administration.
Pharmacodynamics: Significant relief begins about 10-15 minutes following subcutaneous injection, 15 minutes following intranasal administration and 30 minutes following oral administration.
Clinical Trials: Comparative Bioavailability Studies: A two-way crossover, single dose, fasting, comparative bioavailability study of pms-SUMATRIPTAN 100 mg tablets was performed versus GlaxoSmithKline, IMITREX 100 mg Tablets. The study was conducted in 24 healthy fasted subjects. There were no withdrawals. Bioavailability data were measured and the results are summarized in the following table: See Table 1.

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Migraine: The efficacy of sumatriptan succinate tablets for the treatment of migraine was established in four multicentre, randomized, placebo-controlled studies. Patients enrolled and treated in these studies were primarily female (84%), Caucasian (98%) and with a mean age of 40 years (range of 18 to 65 years). Patients were instructed to treat a moderate to severe headache. In Study 2, up to three doses were permitted to treat a single attack within a 24-hour period, non-responders could take a second dose at two hours, while any recurrence of migraine could be treated with a third dose. Studies 1, 3 and 4 were designed to allow for the treatment of up to three attacks.
Headache relief at two hours was statistically significantly greater for all sumatriptan succinate groups when compared to placebo (see Table 2).

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In study 4, the 50 mg (p=0.002) and 100 mg (p=0.003) groups had significantly more patients experience headache relief compared to the 25 mg group at 2 hours.
For patients with migraine-associated nausea, photophobia and/or phonophobia at baseline, there was a decreased incidence of these symptoms following administration of sumatriptan succinate tablets compared to placebo.
Menstrually-Associated Migraine: Two multicentre, randomized, placebo-controlled studies evaluated sumatriptan succinate 50 mg and 100 mg tablets administered during the mild phase of a menstrually-associated migraine attack. A total of 816 subjects with a mean age of 37 (18-65 years of age), with at least a 1-year history of migraine, and a 6-month history of regularly occurring MAM, were enrolled and treated. MAM was defined as any migraine beginning on Day-2, to +4 with day 1 = the first day of flow. Patients were instructed to treat a single mild, moderate or severe headache within one hour of mild pain onset.
A statistically significantly higher proportion of patients following sumatriptan succinate 50 mg and 100 mg achieved pain-free status at 2 hours post-dose compared with placebo in the treatment of menstrually-associated migraine (see Table 3).

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For patients with migraine-associated nausea, photophobia and/or phonophobia at baseline, there was a decreased incidence of these symptoms following administration of sumatriptan succinate compared to placebo.
Detailed Pharmacology: Animal Pharmacodynamics: The action of sumatriptan has been studied in a range of isolated preparations in vitro, all known to contain different 5-HT receptor subtypes.
In Beagle dog isolated saphenous vein known to contain 5-HT1 receptors, sumatriptan had a mean EC502 of 302 nM, while 5-HT had an EC50 of 44 nM.
2molar concentrations required to produce 50% of the maximum response.
In cat isolated saphenous vein, sumatriptan (concentrations of up to 10 μM) had no activity on 5-HT1 receptors, suggesting that sumatriptan is a highly selective agonist at some, but not all, 5-HT1 receptors. The contrasting action of sumatriptan at these receptor sites in the Beagle dog and cat isolated saphenous veins provides evidence that 5-HT1 receptors are heterogeneous.
Sumatriptan displayed virtually no activity at 5-HT2 receptors mediating contraction of the rabbit isolated aorta (concentrations up to 50 μM) and at 5-HT3 receptors mediating depolarization of the rat isolated vagus nerve (concentrations up to 100 μM).
The selectivity of sumatriptan was further confirmed by studies in dog isolated saphenous vein, and in dog and primate isolated basilar artery. In these assays sumatriptan was resistant to the selective 5-HT2 and 5-HT3 receptor antagonists, ketanserin and MDL72222, respectively. Radioligand binding studies provide yet additional support for the high degree of specificity of sumatriptan. Sumatriptan was shown to have a high affinity for some 5-HT1 binding sites, notably the 5-HT1D subtype, and no significant affinity for other neurotransmitter binding sites such as, 5-HT1A, 5-HT1C, 5-HT2, 5-HT3, alpha1, alpha2, beta1, dopamine D1 and D2, muscarinic and benzodiazepine receptors. In the human isolated basilar artery, methiothepin specifically and equally antagonized the contractile effects of both 5-HT and sumatriptan, suggesting that sumatriptan and 5-HT contract this artery by activating the same receptor type. This receptor appears to be identical to the 5-HT1 receptor which mediates contraction of the dog isolated saphenous vein and cerebral blood vessels in both the dog and primate.
Sumatriptan selectively reduced the extravasation of plasma proteins in the dura mater of rats and guinea pigs, in response to trigeminal nerve stimulation.
Although an inhibitory effect on neurotransmitter release from trigeminal nerve endings is implicated, the action of sumatriptan would still predominantly involve a direct vasoconstrictive action on dural blood vessels, which could be expected to inhibit extravasation. In fact, such a vasoconstrictive action during a migraine attack could also increase the threshold for activating perivascular nerve afferents by reducing pressure on edematous pain-sensitive vessels within the cranium.
The major metabolite of sumatriptan in humans and other animal species, GR49336, has no pharmacological activity at 5-HT1 receptors or other vascular 5-HT receptor subtypes.
Sumatriptan (1 to 1000 μg/kg, iv) produced a selective long-lasting and dose-dependent decrease in carotid arterial blood flow, in vivo (anaesthetized Beagles), with little or no change in arterial blood pressure. The dose of sumatriptan producing 50% of its maximum vasoconstrictor action was 39 ± 8 μg/kg, iv. Maximal vasoconstrictor responses were achieved with intravenous doses between 300 to 1000 μg/kg.
The vasoconstrictor action of sumatriptan in the carotid arterial circulation of anesthetized Beagles is mediated by the activation of 5-HT1 receptors since it was antagonized by methiothepin, a selective 5-HT1 receptor blocker.
Sumatriptan (30 to 1000 μg/kg, iv) produced a dose-dependent reduction in the proportion of cardiac output passing through arteriovenous anastomoses (AVAs) in anaesthetized cats.
At doses up to 1000 μg/kg iv, sumatriptan had little effect upon vascular resistance in a variety of other vascular beds. In contrast, the administration of ergotamine (30 μg/kg) caused marked increases in vasoconstriction in most vascular beds examined.
Sumatriptan did not modify efferent vagal activity by either a central action or by interference with cholinergic neurotransmission from vagal nerve endings in the myocardium of anaesthetized cats.
It had no antinociceptive effects in rodents, and is, therefore, unlikely that its effectiveness in alleviating migraine headache is due to a generalized analgesic action.
In conscious monkeys, at cumulative doses of up to 1000 μg/kg, there were no significant effects on arterial blood pressure, heart rate, ECG or respiratory rate that could be attributed to the intravenous administration of sumatriptan.
Sumatriptan up to 1 mg/kg had little or no effect upon either pulmonary artery or esophageal pressure in Beagle dogs. There was also little or no effect upon total peripheral resistance, and only a slight increase in cardiac output and stroke volume.
In the rat, sumatriptan (1 and 10 mg/kg, ip) caused a dose-related increase in the rate of gastric emptying, the magnitude of this effect being comparable with that obtained with metoclopramide at doses of 5 to 20 mg/kg, ip.
Human Pharmacodynamics: Administration of subcutaneous sumatriptan 6 mg twice daily for 5 days to healthy subjects caused slight increases in mean systolic and diastolic blood pressures (6-8 mmHg) while heart rate decreased slightly (1-7 bpm).
Vasopressor effects were also evident following oral administration, with mean peak increases being somewhat smaller and of slower onset than after parenteral administration. A single oral dose of 200 mg sumatriptan caused significant increases in both systolic and diastolic blood pressures (16 mmHg and 5 mmHg, respectively); however, further dosing (200 mg three times daily for a further 7 days) did not cause any additional vasopressor effects.
In hypertensive patients with common or classical migraine, small, transient increases in both systolic and diastolic blood pressure (maximum mean increase: 6/6 mmHg) occurred shortly after subcutaneous doses of 6 mg, but resolved within 60 minutes. A dose-related increase of 14 mmHg in systolic blood pressure was found in elderly patients given 200 mg oral sumatriptan.
Sumatriptan had no effect on cardiac function in migraine patients when given as a 64 μg/kg intravenous infusion. Exercise tests were performed after each infusion showing that sumatriptan had no effect on left ventricular ejection fraction either at rest or after exercise, and no differences were noted between placebo and sumatriptan.
Pharmacokinetics: Pharmacokinetic parameters following oral administration is shown in Table 4.
Inter-patient and intra-patient variability was noted in most pharmacokinetic parameters assessed. (See Table 4.)

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Absorption/Metabolism: Sumatriptan is rapidly absorbed after oral administration. The low oral bioavailability is primarily due to metabolism (hepatic and pre-systemic) and partly due to incomplete absorption. The oral absorption of sumatriptan is not significantly affected either during migraine attacks or by food.
In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme. In studies conducted in a limited number of patients, MAO inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure.
Excretion: Non-renal clearance of sumatriptan accounts for about 80% of the total clearance. The major metabolite, the indole acetic acid analogue of sumatriptan, is mainly excreted in the urine where it is present as a free acid (35%) and the glucuronide conjugate (11%). It has no known 5-HT1 or 5-HT2 activity. Minor metabolites have not been identified.
Special Populations and Conditions: Geriatrics: No differences have been observed between the pharmacokinetic parameters in healthy elderly volunteers and those in younger volunteers (less than 65 years old).
Animal Pharmacokinetics: Absorption of radiolabelled drug-related material following single-dose oral administration of sumatriptan was both rapid and extensive in mice, rats, rabbits and dogs. Oral bioavailabilities of 37% in rat (5 mg/kg), 23% in rabbit (5 mg/kg) and 58% in dog (I mg/kg) indicate that first-pass metabolism is moderate to high in these species. In dogs, this was supported by low metabolic clearance relative to hepatic blood flow. Following intravenous administration, the parent compound was rapidly eliminated from the plasma of mice, rats and rabbits (t1/2 ≤ 1.2 h) and less rapidly in dogs (t1/2 = 2.1h). Active tubular secretion of sumatriptan occurred in the kidneys of rats and rabbits but not in the dog, where clearance was primarily metabolic.
The repeat-dose pharmacokinetics of sumatriptan in the mouse, rat, rabbit and dog were generally consistent with the single-dose data. Plasma levels attained in these species showed that sumatriptan concentrations were linearly-related to oral doses up to 160 mg/kg in mice, 200 mg/kg in rats (subcutaneous doses up to 25 mg/kg), 400 mg/kg in rabbits and 100 mg/kg in dogs (subcutaneous doses up to 24 mg/kg).
Following intranasal administration to the rat or dog, plasma concentrations of sumatriptan peaked at approximately 30 minutes; in the monkey it peaked at 15 minutes. A second peak was observed in some animals at 90 to 120 minutes, suggesting absorption of a swallowed portion of the dose.
The maximum concentrations of sumatriptan detected in plasma following oral or subcutaneous administration to dogs were 35- and 75-fold higher, respectively, than were measured in human plasma following standard therapeutic doses.
There was no evidence of accumulation or enzyme inhibition/induction in any of the species studied.
Radioactive drug-related material was widely distributed throughout the body following both oral and intravenous administration of radiolabelled sumatriptan. Transfer into the central nervous system was limited.
Drug-related material was cleared rapidly from all tissues with the exception of the eye in which it appeared to be bound to the melanin in the uveal tract.
The binding of sumatriptan to plasma proteins over the concentration range 10 to 1000 ng/mL was low, 21% or less, in all species studied. Erythrocyte-associated 14C-GR43175 was reversibly bound.
Placental transfer studies in rat and rabbit showed that in both species the fetuses were exposed to low levels of drug-related material. Sumatriptan and drug-related material were secreted into the milk of lactating rats and were present at higher concentrations than those seen in maternal plasma.
Following oral administration to the rabbit and dog, and intravenous administration to the dog, and intranasal administration to the rat and dog, the indole acetic acid derivative GR49336 was the major metabolite formed.
This metabolite was also a major component in the urine of rats after both oral and intravenous and intranasal administration and in rabbits after intravenous administration, indicating that oxidative deamination is the major metabolic pathway in all animal species studied.
Metabolism of the methylaminosulphonylmethyl side chain resulting in the formation of an N-demethylated derivative of sumatriptan was apparent in the urine of the mouse, rat, and rabbit but not in the dog.
The major route of excretion was via the urine in the mouse, rabbit and dog following oral and intravenous administration and in the rat following intravenous dosing only.
Following oral administration to rats, the major route of excretion of drug-related material was via the feces.
Toxicology: Acute Toxicity: Administration of single oral doses of sumatriptan up to 2000 mg/kg in rats and 1200 mg/kg in mice was well tolerated.
Dogs also survived high oral doses of sumatriptan (500 mg/kg).
In subcutaneous studies, a dose of 2 mg/kg to rats was lethal. Dogs received subcutaneous doses of 20 and 100 mg/kg which were non-lethal. The reactions to treatment were similar irrespective of species or route of administration. Apart from local damage at the injection sites, there were no macroscopic or microscopic changes noted in any tissue (Table 5). (See Table 5.)

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Long Term Studies: Subacute toxicity studies were conducted for periods up to 6 weeks in RH rats. Sumatriptan was given orally (by gavage) at doses up to 500 mg/kg/day and given subcutaneously at doses up to 81 mg/kg/day.
Clinical signs observed following oral administration were generally minor and transient in nature and occurred predominantly at 500 mg/kg/day. These signs included post-dosing erythema, mydriasis, ataxia, salivation, subdued temperament, postural changes and moist eyes.
Reactions were similar in subcutaneous studies in rats receiving doses of sumatriptan up to 81 mg/kg/day. Local irritation at the injection site was accompanied by a marked inflammatory response, local necrosis, hemorrhage, infiltration, granulation tissue formation and local muscle degeneration and repair. These reactions were dose dependent.
In dogs administered oral sumatriptan (1 to 100 mg/kg/day) in studies up to 6 weeks, clinical signs observed included head shaking, scratching, salivation, trembling, agitated behaviour, vocalization, mydriasis and vasodilation. These effects were dose-related. The dogs also developed tachycardia lasting for several hours, often followed by bradycardia. No changes in ECG were detected.
Subcutaneous administration of sumatriptan (1 to 16 mg/kg/day) up to 6 weeks in dogs caused injection site reactions similar to the reactions described in rats.
Chronic toxicity studies were carried out for 24 weeks and 72 weeks in rats and 26 and 60 weeks in dogs.
In both the 24-week and 72-week studies in rats receiving sumatriptan doses of 5, 50 and 500 mg/kg/day orally, clinical signs were similar to those seen in previous oral toxicity studies in rats and were mild and transient in nature.
Animals of each sex receiving 50 and 500 mg/kg/day gained weight more rapidly than controls. This was considered to be related to increased food consumption.
Small reductions in cholesterol levels were frequently noted at 500 mg/kg/day. As well, dose-related increases in urine-specific gravity were seen throughout the 72-week study at 500 mg/kg/day. These increases were of no toxicological significance. Cessation of treatment showed good evidence of recovery.
There were no macroscopic or histological treatment-related findings in any of the organs in either study.
A long term repeat-dose subcutaneous toxicity study of 24 weeks duration was performed in RH rats receiving sumatriptan at doses of 1, 8 and 64 mg/kg/day.
There was occasional temporary appearance of masses at the injection sites in the animals receiving the highest dose of sumatriptan. Evidence of injection site injury was also apparent in the recovery animals. Rats in this group showed signs of neutrophilia and lymphocytosis.
Injection site reactions in animals in the high-dose group were similar to those reported during previous toxicity studies.
Studies of 26 and 60 weeks at oral doses of 2, 10 and 50 mg/kg/day were performed in Beagle dogs.
A moderate increase in heart rate was observed in the intermediate (10 mg/kg/day) dose group (60 week study) and in the high (50 mg/kg/day) dose group (26 and 60 week studies). The increase lasted for up to 7 hours after dosing and a dose related decrease in heart rate was evident 24 hours after dosing, at 10 and 50 mg/kg/day. There were no changes in rhythm. Animals of either sex receiving 50 mg/kg/day showed slight reductions in body weight gain in both studies.
In the 60-week study, a dose-related incidence of transient changes was noted on the surface of the cornea. However, these changes were not considered to be treatment-related as evidenced by microscopic examination.
Organ weight analyses revealed significantly increased heart weights in all groups of treated females in the 26-week study. There were no treatment-related effects on organ weights in the 60-week study.
A long term repeat-dose subcutaneous study of 24 weeks duration was performed in the Beagle dog at doses of 1, 3.5 and 12 mg/kg/day. Injection site reactions included oedema, marked hemorrhage, moderate/chronic inflammation and minimal arteritis. Some minimal injection site changes were also seen in treated animals after a 5-week recovery period.
Transient dose-related changes in the precorneal tear film of treated dogs were observed. There was, however, no histological evidence of damage to the cornea or surrounding tissues.
Analysis of hematological parameters revealed a slight lowering of some red cell parameters in the high-dose (12 mg/kg/day) group. No reticulocyte response was evident. Although no effect on total leucocyte count was observed, lymphocyte numbers were generally lower and neutrophils were generally slightly higher at this dose level. The only change observed during the recovery period was a statistically significantly reduced hemoglobin level in the males.
Carcinogenicity: The carcinogenic potential of sumatriptan was evaluated in a 78-week oncogenicity study conducted in mice given oral doses of 10, 60 and 160 mg(base)/kg/day. There were two groups (102 mice each) given the vehicle only.
Tumours were found in more than half of the male mice and in less than half of the females across all groups. There was a statistically significant increase in the incidence of non-fatal hemolymphoreticular tumours observed in males at the dose of' 60 mg/kg/day group only when compared with controls. Since there was no dose relationship, this increase was considered to be of no toxicological significance. There was no evidence that administration of sumatriptan at any of the dose levels caused any alteration in the incidence of any specific tumours or non-neoplastic lesions.
A 104-week study was conducted in the Sprague-Dawley rat given oral doses of 10, 60 and 360 mg (base)/kg/day. Two control groups of 100 animals each were given vehicle control only.
There was a significant increase in the incidence of non-fatal adrenal medullary tumours (benign and malignant pheochromocytomas) in males given doses of 10 and 60 mg/kg/day and in males dosed at 360 mg/kg/day. A significant increase in the incidence of benign testicular interstitial (Leydig) cell tumours occurred when compared with controls. Adrenal medullary tumours also increased significantly in females dosed at 60 and 360 mg/kg/day. Comparison of both types of tumours with historical control data indicated that the observations were within the expected background range for the species and that long-term exposure to sumatriptan does not induce any treatment-related increases in the incidences of any tumours for the species tested.
Mutagenicity: Sumatriptan produced no detectable or reproducible mutagenic potential above that seen in controls, in studies conducted in vitro with mutant strains of Salmonella typhimurium, Escherichia coli, or Saccharomyces cerevisiae with or without a rat hepatic drug metabolizing enzyme system. In addition, no statistically significant clastogenic effects were seen in vitro using cultured human peripheral lymphocytes at a maximum dose of 1000 μg/mL in the presence of the rat hepatic drug metabolism enzyme system or in vivo in a rat micronucleus test, at a maximum dosage of 1000 mg/kg.
Sumatriptan showed only weak cytotoxic activity at the highest concentration of 5000 μg/mL tested in vitro with V-79 mammalian cells.
Reproduction and Teratology: In organogenesis studies, oral doses of up to 500 mg/kg/day in the rat were without adverse effects upon fetal parameters measured, but an oral dose of 1000 mg/kg/day in the rat, proved toxic to both dams and embryos.
Two oral organogenesis studies were conducted in rabbits, one using daily oral doses of 5, 25 or 100 mg/kg/day and the other using 5, 15 or 50 mg/kg/day. Sumatriptan was administered from days 8 to 20 of pregnancy.
In the first study, there were no adverse effects at the two lower doses. At the highest dose (100 mg/kg), there was a severe decrease in maternal body weight gain indicating that this dose is maternally toxic. A non-significant increase in post-implantation intra-uterine death from 8.3% in the untreated control group to 21.2% in the high-dose (background range in untreated control animals 1.7% to 15.2%) was observed. In addition there was an increased incidence of subtle variations in the position of certain blood vessels emanating from the aortic arch. In the untreated control these were present at 5.5% of fetuses (3 out of 10 litters affected). At the maternally toxic dose of 100 mg/kg, 23.1% of fetuses had these variations (4 out of 5 litters affected). This type of change is commonly found in untreated control animals (historical control incidence 17.5%; proportion of litters affected 44 out of 91), and does not compromise either health or survival.
In the second oral study, the findings were similar to those seen in the first study. There were no adverse effects at the two lower doses. At the highest dose (50 mg/kg), there was a severe decrease in maternal body weight gain. There were also various fetal effects ascribed to maternal toxicity. There was a slight reduction in mean fetal weight (37.7 g in control, 35.3 g at 50 mg/kg); small increases in the incidence of common skeletal variants (control incidence 8.8%; at 50 mg/kg 20.8%; background mean 6.2%; background range 1.3% - 13.3%) and again an increased incidence of positional changes of certain aortic arch blood vessels; (control incidence 12.8%, 3 out of 20 litters affected; at 50 mg/kg 25%, 10 out of 14 litters affected).
Placental transfer studies in pregnant rabbits have shown that sumatriptan can cross the placental barrier in small amounts. After a 5 mg/kg oral dose, 71.2 ng sumatriptan per gram of fetus was detected. The blood levels at this dose were 172 - 269 ng/mL. At the maternally toxic dose of 50 mg/kg in rabbits, blood levels reached 3180-6750 ng/mL.
Organogenesis studies conducted using intravenous doses of up to 12.5 mg/kg/day in rats revealed fused ribs at a dose of 2.5 mg/kg/day and rudimentary tail and dilatation of the renal pelvis at a dose of 12.5 mg/kg/day. The treatment had no adverse effects on either the dams or the fetuses and the malformations were considered unrelated to treatment since they are known to occur spontaneously in the control groups of the rat strain employed.
Rabbits were also studied using intravenous doses of up to 8.0 mg/kg/day which revealed no teratological response. However, in the first study a statistically significant dose-related increasing trend in prenatal mortality was seen due to apparent maternal toxicity. In the second study, using intravenous doses up to 2.0 mg/kg/day, no maternal toxicity or increased prenatal mortality were observed.
Fertility studies conducted in rats with oral doses of up to 500 mg/kg/day and subcutaneous doses of up to 60 mg/kg/day indicated that there were no adverse effects upon the reproductive performance of the treated, parental generation, or upon the growth and development of two successive untreated generations.
In peri- and postnatal studies conducted in rats given oral doses of up to 1000 mg/kg/day and subcutaneous doses of up to 81 mg/kg/day, no toxicological adverse effects that may have been relevant to the peri- and postnatal development of their offspring were seen. However, oral administration of 1000 mg/kg/day during periods of pregnancy and lactation resulted in a decrease in maternal and fetal body weight.
A comprehensive evaluation of the effects of sumatriptan on reproduction indicates that the compound is devoid of teratogenic potential in the rat. In addition, there were no adverse effects on fertility or postnatal development. In rabbit oral reproduction studies, there were increased incidences of variations in cervico-thoracic blood vessel configuration in the fetuses, but these were only seen at maternally toxic doses in which blood levels were in excess of 50 times those seen after therapeutic doses in humans. A direct association with sumatriptan treatment is considered unlikely but cannot be excluded. The relevance to humans is unknown.
Local Tolerance: The subcutaneous and intramuscular administration of 1 mL of a solution of sumatriptan (50 mg/mL) to rabbits produced no overt signs of irritancy and caused only slight necrotic changes in the deepest layers of the subcuticular muscle. While the subcutaneous lesions healed in a rapid and uncomplicated manner, the intramuscular lesions were moderately slow to heal.
At a lower concentration (2.5 mg/mL) no signs of subcutaneous or intramuscular irritancy were apparent.
In inhalation toxicity studies (dog, monkey), no irritants of the nasal passages or respiratory tract tissues were identified after intranasal administration of sumatriptan.
Skin and Eye Irritancy: Sumatriptan produced little or no irritant reaction when applied topically to the skin of guinea pigs and was a non-irritant in the rabbit eye.
Sumatriptan was shown to be devoid of detectable skin sensitizing potential in guinea pigs; subjected to a 12-day induction period (0.05 mL of a 10% solution, applied epicutaneously) prior to challenge with sumatriptan.
Dependence Liability: The physical dependence liability of sumatriptan was assessed in Cynomolgus monkeys at an oral dose of 5 mg/kg, the lowest tolerable dose causing mild to moderate CNS effects.
The behavioural changes observed upon withdrawal of sumatriptan were limited in number, sporadic, unsustained and not observed in all animals. It would appear that sumatriptan does not share with compounds such as opiates and benzodiazepines the ability to cause physical dependence.
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