Abstract
Introduction
A series of investigations, including placebo-controlled, comparative and long-term extension studies, have established not only the antimigraine efficacy of the novel 5-HT1B/1D receptor agonist rizatriptan, but also its safety and tolerability. These investigations have demonstrated that rizatriptan is well tolerated and constitutes a safe medicine to treat the acute attack of migraine.
The tolerability of rizatriptan in these studies was evaluated by determining the incidence of adverse events and the discontinuation of the drug caused by them. On the other hand, the safety of the compound was investigated by evaluating possible modifications in blood pressure, heart rate and ECG, as well as in the haematology and clinical chemistry.
An adverse event in these studies was defined as any unfavourable or unintended change in the structure, function and chemistry of the body, or worsening of a pre-existing condition. All the unfavourable or unintended changes were reported as adverse events, regardless of their relationship to the use of study medication.
Adverse events were reported in three different ways:
All the adverse events regardless of the relationship to the drug given.
Drug-related adverse events. The possible relationship between the adverse event and the administration of the drug was determined by the clinician who judged if the adverse advent was possibly, probably, or definitely related to the given medication.
Adverse events were defined as serious when they:
resulted in death
were immediately life threatening
resulted in permanent or substantial disability
resulted in or prolonged hospitalization
resulted in a congenital anomaly or cancer
were the result of an overdose.
All the patients enrolled in clinical trials with the compound were instructed to keep a complete diary and, in case they experienced any unexpected symptom, they were instructed to describe it, noting the date and time of onset and its duration. The patients were instructed to record the adverse events at the same time when they registered the efficacy of the medication. The clinical investigators assessed the adverse events in terms of their severity (severe, moderate or mild) and their relationship with the study medication (definitely, probably or possibly drug-related, or probably not and definitely not related to the medication).
Safety of rizatriptan in short-term trials
Treatment with the triptans constitutes a very safe way to control the acute attack of migraine. Sumatriptan has been used in 100 million migraine attacks in more than 5 million patients. In all these attacks, there were 31 fatal events considered to be cardiovascular and/or cerebro-vascular related, mortality was only one in 160 000 patients and one in 3 225 000 attacks. Most of these cases were due to an inappropriate prescription of the compound (1).
Data from two Phase lib dose-finding studies in about 1000 patients, who received oral rizatriptan tablets in the dose range 2.5-40 mg, suggested that 10 mg rizatriptan was optimal (efficacy vs. adverse events) for the acute treatment of migraine and that a dose of 2.5 mg was subtherapeutic (2, 3). Subsequently, several studies have been carried out to determine the efficacy of rizatriptan 5 and 10 mg in which its safety and tolerability were also investigated. There were two placebo-controlled studies and three comparative studies with sumatriptan 100 mg, naratriptan 2.5 mg and zolmitriptan 2.5 mg. The results of a study carried out in an adolescent population, as well as of those corresponding to a long-term extension study, in this case comparing rizatriptan with standard care, were also considered. In general, the incidences of clinical adverse experiences were consistent across trials, mild or moderate in intensity and transient in nature
The most common drug-related adverse events following a single dose of rizatriptan in a placebo-controlled study were somnolence, dizziness and asthenia or fatigue (Table 1). They seemed to be dose dependent and were rather transient and mild in nature (4).
Most common clinical adverse events (in percentage) in patients following a single dose of placebo or rizatriptan 5 and 10 mg
Symptoms were heaviness, pain, pressure and tightness. Data from (4).
In the study in which rizatriptan wafer was given to migraine patients, somnolence, asthenia/fatigue and paresthesia had an incidence that was significantly higher following a single dose of rizatriptan 5 or 10 mg than placebo. However, the actual overall incidence of adverse events was rather low, between 3 and 6%, comparable with that in the tablet study (5).
In the study comparing rizatriptan 10 mg with sumatriptan 100 mg, similar adverse events were observed: somnolence, dizziness, asthenia or fatigue (6). In both groups, the effects were very similar (Table 2). The only difference was a higher prevalence of nausea (9%) in the sumatriptan group.
Adverse events reported in more than 5% of patients receiving placebo, rizatriptan 10 mg or sumatriptan 100 mg (expressed in percentage)
P<0.05 vs. rizatriptan 10 mg.
P<0.001 vs. placebo.
P<0.05 vs. sumatriptan 100 mg.
Data from (6).
In the comparison between rizatriptan 10 mg and naratriptan 2.5 mg, the incidence of adverse events was somewhat lower for the naratriptan group (7) while in the comparison of rizatriptan 10 mg with zolmitriptan 2.5 mg, there was a similar incidence of adverse events in terms of somnolence, dizziness or asthenia/fatigue (8).
In the study carried out in adolescents, when a rather low dose of 5 mg rizatriptan was given to 12-17 year-old migraineurs, there was a very low incidence of adverse events that were comparable in the placebo and in the rizatriptan groups. This suggests that rizatriptan is well tolerated in a younger population (9).
Safety of rizatriptan in long-term studies
In the long-term extension studies, there were 24 013 attacks treated with rizatriptan 10 mg and 8128 attacks treated with medications used for standard care. In this group of patients, the physicians prescribed anti-migraine medications such as subcutaneous or oral sumatriptan, NSAIDs, paracetamol, barbiturates, opiates, isometheptene or ergot derivatives (10).
The most common adverse events reported in the long-term extension studies for standard care and for rizatriptan, used intermittently for up to a year, were of a similar type and had a comparable incidence in both groups (Table 3).
Most common clinical adverse events (adjusted incidence in percentage) in extension studies in patients receiving standard care or rizatriptan 5 or 10 mg
Data from (10).
The rate of discontinuation related to adverse events in the extension studies, was somewhat higher for rizatriptan 10 mg (4%) than for standard care (2%). This was probably due to the fact that while for patients treated with rizatriptan the only choice was to continue or discontinue the medication, those receiving standard care were allowed to change the treatment instead of interrupting it. There were no clinically relevant changes in long-term controlled clinical trials with respect to either cardiovascular parameters and laboratory findings.
Concerning serious adverse events, there was only one patient that experienced musculoskeletal pain in the shoulder in the long-term extension study who was hospitalized. Because of this fact, the patient's complaint was categorized as a serious adverse event. She continued to take further doses of rizatriptan without any incident.
In conclusion, the efficacy of rizatriptan was well balanced with a very favourable tolerability profile, since the compound was well tolerated by most patients and no clinically relevant changes in ECG parameters were observed. Moreover, it was found that the tolerability was unaffected by common medications used for migraine prophylaxis or by oral contraceptives.
Footnotes
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Based on a presentation to the Symposium held during the IX Meeting of the International Headache Society, Barcelona, Spain, 24 June 1999.