Imitrex

Headache. 2005 Sep;45(8):1069-72.

Treatment of cluster headache attacks with less than 6 mg subcutaneous sumatriptan.

Department of Neurology, University of Munster, Germany.

BACKGROUND: Subcutaneous (SQ) sumatriptan 6 mg is effective in the treatment of acute cluster headache attacks. However, patients sometimes benefit from a dose less than 6 mg. OBJECTIVE: Therefore, we designed a prospective open study to evaluate how many patients benefit from a dose less than 6 mg SQ sumatriptan. METHODS: We enrolled 81 consecutive patients with cluster headache and recorded their use of SQ sumatriptan and oxygen. Patients regularly using SQ sumatriptan 6 mg were advised to treat attacks with doses less than 6 mg and with oxygen. Efficacy and side effects of the different treatment options (6 mg, 3 mg, 2 mg, and oxygen) were evaluated. RESULTS: As a result, 74% of the patients using SQ sumatriptan 3 mg showed efficacy and 89% reported efficacy after 2 mg. Seventy-nine percent reported side effects after the use of SQ sumatriptan 6 mg (29% severe side effects). After the use of 2 mg SQ sumatriptan, only 50% of the patients reported side effects, none of these were classified as severe. Patients' preference was 41% for 6 mg sumatriptan, 28% for doses less than 6 mg, and 31% for oxygen. CONCLUSIONS: We conclude that sumatriptan in doses less than 6 mg can be effective in the acute treatment of cluster headache attacks. We suggest that patients should have experience in their individual efficacy of sumatriptan doses less than 6 mg.

PMID: 16109122

----------

RE: TREATMENT OF CLUSTER HEADACHES WITH IMITREXÒ (SUMATRIPTAN SUCCINATE) INJECTION

SUMMARY

Imitrex^® (sumatriptan succinate) Injection was approved for the treatment of cluster headache by the FDA on May 22, 1996. Imitrex Injection is also indicated for the acute treatment of migraine attacks with or without aura in adults.

The efficacy of Imitrex Injection in the acute treatment of cluster headache was demonstrated in two randomized, double-blind, placebo-controlled, two-period crossover trials.

In both trials, the proportion of individuals gaining relief at 10 or 15 minutes was significantly greater among patients receiving 6 mg of Imitrex Injection compared to those who received placebo.

Several associated symptoms suggestive of disturbed autonomic function, including nasal congestion, rhinorrhea, lacrimation, and swelling of eyelids, disappeared in parallel with pain relief. Imitrex Injection was significantly more effective than placebo for the reduction of ipsilateral conjunctival injection (redness of the eye).

In the controlled clinical trials assessing sumatriptan’s efficacy as a treatment for cluster headache, no new significant adverse events associated with the use of Imitrex Injection were detected that had not already been identified in association with the drug’s use in migraine. Overall, the frequency of adverse events reported in the studies of cluster headache were generally lower.

One study evaluated a 12 mg dose; there was no statistically significant difference in outcome between patients randomized to the 6- and 12 mg doses.

The long-term use of Imitrex Injection for cluster headache has been evaluated in two open-label studies. Sumatriptan was found to be well tolerated and effective in the long-term treatment (up to 1 year) of cluster attacks. There was no evidence of tachyphylaxis or an increased incidence of adverse events over time.

Two open-label studies and three case reports also describe the successful use of Imitrex Injection for the treatment of cluster headache.

There has been one published open label trial that compares Imitrex^® (sumatriptan) Nasal Spray 20 mg with Imitrex Injection 6 mg in the acute treatment of cluster headache (). We are not aware of any published studies in which Imitrex Injection was compared with other active agents for the treatment of cluster headache.

Please seeIMTCTR02N for a more complete discussion of Nasal Spray for cluster…See IMTCTR03 for use in chronic paroxysmal hemicrania or hemicrania continua.,syndromes similar to cluster.

Some of the information in this letter may be outside the product labeling for Imitrex Injection. This letter is not intended to offer an opinion on the advisability of administering Imitrex Injection in a manner inconsistent with the product labeling. Please consult the product information for the complete safety and prescribing information.

BACKGROUND

Cluster headache is characterized by severe unilateral orbital, supraorbital, and temporal pain (alone or in combination), lasting 15 to 180 minutes if untreated. The pain is associated with one of the following signs, which must be present on the same side as the pain: conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, and eyelid edema. The frequency of attacks varies from one every day to 8 per day. Episodic cluster headache (ECH) occurs in periods lasting 7 days to 1 year separated by a span of 14 days or more. In chronic cluster headache (CCH) attacks occur for more than 1 year without remission or with remission lasting less than 14 days. Previously used terms for cluster headache include: erthroprosopalgia of Bing, ciliary or migrainous neuralgia (Harris), Horton’s headache, sphenopalatine headache, Vidian and Sluder’s neuralgia, and hemicrania periodica neuralgiforms ().

The prevalence of cluster headache varies with both gender and age. Men are 4.5 to 6.7 times more likely than women to be affected by cluster headache. The age of onset is approximately 27 to 31 years which is about 10 years later than the onset of migraine. Although cluster headache has not been firmly established as a familial disorder, a genetic predisposition to this disorder may be encountered in certain families. Cluster headache is one of the most severe headaches that a person can suffer from. During an attack, patients become extremely restless, agitated, pace back and forth, and have even been known to bang their head against a hard surface (). Riess et al () reported in an epidemiological survey of ECH patients in Canada that Imitrex Injection had been tried by only 26% of patients. In those patients, 93% considered it effective. Many patients with ECH had not received optimal treatment.

RESULTS OF CLINICAL TRIALS

Placebo-Controlled Double-Blind Studies

The efficacy of Imitrex Injection in the acute treatment of cluster headache was demonstrated in two randomized, double-blind, placebo-controlled, two-period crossover trials. Patients age 21 to 65 were enrolled and were instructed to treat a moderate to very severe headache within 10 minutes of onset. Patients were eligible with a history of episodic or chronic cluster headache as defined by International Headache Society (IHS) criteria and untreated attacks typically lasting 45 minutes or longer. Headache relief was defined as a reduction in headache severity to mild or no pain. Results are shown in Table 1.

Table 1: Efficacy Data From The Pivotal Cluster Headache Studies

* P<0.05.

(n = Number of headaches treated.)

Incidence Of Adverse Events in Controlled Trials of Cluster Headache

In the controlled clinical trials assessing sumatriptan’s efficacy as a treatment for cluster headache, no new significant adverse events associated with the use of sumatriptan were detected that had not already been identified in association with the drug’s use in migraine. Overall, the frequency of adverse events reported in the studies of cluster headache were generally lower. Exceptions include reports of paresthesia (5% Imitrex, 0% placebo), nausea and vomiting (4% Imitrex, 0% placebo), and bronchospasm (1% Imitrex, 0% placebo).

A more complete description of each study is discussed below.

Study 1

The Sumatriptan Cluster Headache Study Group published a double-blind, crossover study in 39 (31 male, 8 female) patients admitted to the hospital with cluster headache. The study demonstrated that Imitrex 6 mg subcutaneous (SC) was significantly more effective than placebo for the treatment of cluster headache and related symptoms.

Patients were eligible for this study if they were 18-65 years of age with a history of episodic or chronic cluster headache as defined by IHS criteria; had untreated attacks that typically lasted 45 minutes or longer; and, all prophylactic therapy was withdrawn at least one week before the study began. Hospitalization began when the patient entered a cluster period and generally lasted several days.

Patients were assessed clinically and randomly assigned to receive one of the following treatments: 1) a

single 6 mg SC injection of Imitrex for one attack followed by placebo for the second attack; or,

2) placebo for the first attack followed by Imitrex 6 mg SC for the second attack

Each injection was given within 10 minutes of the onset of the attack. The minimum interval between injections was 24 hours and the longest interval was 9 days. Rescue medication consisted of 100% oxygen given after 15 minutes followed by, if necessary, "simple" analgesics or opiates after 120 minutes. Ergotamine containing products could not be used.

Symptomatic relief was assessed at pre-determined time intervals over 120 minutes beginning 5 minutes post-injection. The primary clinical endpoint of efficacy was relief of pain from grades 2 to 4 (moderate, severe, very severe) to grade 1 or 0 (mild, no pain) within 15 minutes. Need for rescue medication, degree of functional disability, and presence or absence of ipsilateral conjunctival injection were also evaluated.

Overall, Imitrex was significantly more effective than placebo for headache relief (Tables 2 and 3). Imitrex improved functional disability (most patients given Imitrex could function normally within 30 minutes compared with 60 minutes for placebo) and reduced ipsilateral conjunctival injection (present in 36% of patients 15 minutes after Imitrex administration compared with 74% for placebo). Data for other symptoms were not reported.

Table 2: Percentage of Cluster Headache Patients With Pain Relief*

* Pain relief was defined as a reduction in severity from grades 2 to 4 (moderate to very severe) before treatment to grade 1 or 0 (mild or no pain) at 5, 10 and 15 minutes after injection.

Table 3: Percentage of Patients Totally Pain-Free

* Pain-free was defined as a reduction in severity from grades 2 to 4 (moderate to very severe) before treatment to grade 0 (no pain) at 5, 10 and 15 minutes after injection.

Imitrex was well-tolerated. Adverse events were reported in association with 26% of attacks in which placebo was given compared with 35% of attacks in which Imitrex was administered. Adverse events mainly consisted of injection site reactions (e.g., pain, swelling, erythema) dizziness, tiredness, paresthesias and hot and cold sensations.

Study 2

Ekbom et al () conducted a multinational, multicenter, randomized, double-blind, three-treatment, crossover study (N=134). This study was conducted to evaluate efficacy, safety and tolerability of two SC dosages of Imitrex (6 mg and 12 mg) and placebo for the acute treatment of cluster headache. (Please note that 6 mg is the maximum single recommended dose). Similar inclusion criteria were used during this study as previously reported. However, a further cluster headache attack was treated with alternative study medication, provided that at least 18 hours had elapsed since treatment of the first attack.

Imitrex 6 mg SC was effective and well-tolerated acute treatment for cluster headache attacks. Significant improvement in headache occurred within 5 minutes after administration of 6 mg or 12 mg Imitrex. The 12 mg dose did not result in a further relief of symptoms and was associated with an increased incidence of adverse events in comparison with the 6 mg dose. The nature of adverse events reported was similar to that previously described. The efficacy results are described in Table 4.

Table 4: Percentage of Patients with Pain Relief*

* Pain relief was defined as a reduction in severity from grades 2 to 4 (moderate to very severe) before treatment to grade 1 or 0 (mild or no pain) at 5, 10 and 15 minutes after injection.

Long-Term Studies

Study 1

Ekbom et al published the results of a 3-month multicenter, open label study in 138 patients who treated 6,353 cluster headaches with Imitrex 6 mg SC.

Methods:

Men and women aged 18 to 65 years were included if they had a history of episodic or chronic cluster headache that fulfilled the IHS diagnostic criteria and typically lasted at least 30 minutes. Patients were excluded if they experienced four or more cluster headache attacks per day, were using prophylactic agents, or had a history of abusing narcotics, ergotamines, or alcohol.

Efficacy assessments were recorded on diary cards on which patients recorded the date, the time the pain started, time treatment was administered, headache severity at the time of treatment, headache severity 15 minutes after treatment, the time that the pain resolved, and any rescue medication used. Headache severity was assessed on a 5-point scale where 0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain, and 4=very severe pain. Patients also assessed the efficacy a ineffective, poor, reasonable, or excellent and were asked if they would take sumatriptan again.

Safety assessment made throughout the study included the incidence and severity of adverse events, abnormalities in laboratory data, and changes in blood pressure, heart rate, and ECG tracings. Adverse events were defined as any untoward event experienced by the patient regardless of causality.

Results:

At least one cluster headache was treated by 138 patients (63 with chronic cluster and 75 with episodic cluster) and 57 of these remained in the study for the entire three months. In 59 patients, the cluster headache period ended before the end of the study. One patient withdrew due to an adverse event (described as lack of efficacy). Twenty-one patients were withdrawn from the study due to failure to respond (n=7), an increase in the frequency of attacks during the study (n=4), failure to return to the clinic (n=3), a desire to use prophylactic agents (n=3), and other reasons (n=4).

A median of 31 attacks per patient were treated. Two patients each treated 182 attacks. The median percentage of attacks treated, which were reduced to Grade 0 or 1 at 15 minutes, was 96% for the total population. There was no change in efficacy of sumatriptan over the three months. The median percentage of attacks that responded to sumatriptan in the first half of the study was 97% and for the second half was 100%. The median percentage of attacks in which patients were pain free (Grade 0) at 15 minutes was 68%. The median percentage of patients that required rescue medication was 0%.

Ninety-four (68%) of patients reported an adverse event at some time. In 80 cases (58%), they were considered by the investigator to be drug-related. Eighteen (13%) adverse events were graded as severe. The most commonly reported adverse events include nausea/vomiting, throat symptoms, dizziness/vertigo, malaise/fatigue, injection site reactions, headache, warm/hot sensations, chest symptoms, tingling, influenza, neck pain/stiffness, and paresthesia.

Of the 135 patients who recorded efficacy assessments at the end of the study, 88% reported sumatriptan to be "good" or "excellent" and 94% said they would take the medication again.

The authors concluded that SC sumatriptan 6 mg is a convenient, well-tolerated, long-term acute treatment for cluster headache. The authors found no evidence suggestive that the long-term use of sumatriptan was associated with an adverse event profile different from that previously reported.

Study 2

Gobel et al () published the results of a 1 year multicenter, open label study in 52 patients who treated 2,031 cluster headaches with 6 mg SC sumatriptan. The maximum dose of sumatriptan in 24 hours was 12 mg, with at least 3 hours between doses.

Methods:

Men and women aged 18 to 65 years were included if they had a history of episodic or chronic cluster headache that fulfilled the IHS diagnostic criteria. Patients were excluded if they experienced 6 or more cluster headache attacks per day, or if they had a contraindication to sumatriptan.

Both before and 15 minutes after self-injection of sumatriptan, patients documented headache intensity on a diary on a 5 point verbal scale (0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain, and 4=very severe pain). They also recorded the time until complete pain relief as well as adverse events.

Results:

A total of 2,151 attacks were treated, of which 2,031 were analyzed. The number of attacks treated ranged from 2 to 182 per patient, with a median of 24 attacks. Within 15 minutes after injection, 88% of the attacks were effectively improved and 57% of all patients were free of pain after 15 minutes. Results in the first and second halves of the one-year period are shown in Figure 1:

Forty two percent of patients (ECH: 48.6%, CCH 26.7%) were completely free of pain 15 minutes after sumatriptan in more than 90% of attacks. Seventy-seven percent of patients (ECH:78.4% , CCH:73.3%) reported treatment as satisfactory in more than 90% of attacks.

On average, the patients were pain-free within 21 minutes after injection of sumatriptan. Sixty-nine percent of patients were pain-free within 15 minutes. Seventy-three percent and 60% of patients with ECH and CCH were pain free within 15 minutes, respectively. No patient with CCH was pain-free within 5 minutes while 24.3% of patients with ECH were pain-free in this time-frame.

Thirty five patients (67%) completed the study. Adverse events were described as unpleasant, occurred soon after the injection, and disappeared rapidly without the need for treatment. The profile of adverse events is comparable with the results from other studies. In this study, the percentage of patients who experienced adverse events was 62% and lower than that observed in other studies.

The authors concluded that SC sumatriptan 6 mg is a well-tolerated, long-term acute treatment for cluster headache. The authors found no evidence suggestive that the long-term use of sumatriptan was associated with an adverse event profile different from that previously reported.

Tehindrazanarivelo () et al reported that the efficacy of Imitrex Injection was maintained in 7 patients with CCH who were followed for a 1 year period.

Pilot Studies or Case Reports

Krabbe et al () reported improvement in cluster headache pain within 30 minutes in 28 of 32 attacks in patients treated with SC sumatriptan (3-6 mg) during four open pilot studies (three SC trials, one intranasal trial [please note that an intranasal formulation is not indicated for the treatment of cluster headache.]. Marked relief of pain was evident as early as eight minutes after SC injection. Adverse effects reported were minor and transient.

Hardebo () reported that Imitrex 6 mg SC rapidly and completely relieved the pain of cluster headache in an open-label study designed to investigate the temporal effects of SC Imitrex on the pain of cluster headache and associated symptoms suggestive of disturbed autonomic function.

Thirty-four patients with a history of cluster headache (as defined by IHS criteria) administered Imitrex 6 mg SC via an auto-injector within 10 minutes after the onset of attacks (8-49 attacks treated per person). Patients were instructed to record the time lag before the pain started to cease, the time period elapsing thereafter for the pain to disappear, and the time that the accompanying autonomic symptoms (nasal congestion, rhinorrhea, lacrimation, conjunctival injection, miosis/ptosis, and swelling of eyelids) and photophobia remained after the pain had ended. Pain was completely and rapidly (beginning within 4-14 minutes) relieved in all patients. Several accompanying autonomic symptoms (nasal congestion, rhinorrhea, lacrimation, and swelling of eyelids) disappeared in parallel with the relief of pain.

The most frequently reported adverse effects consisted of a transient feeling of tension, warmth or a tingling sensation in the extremities or neck, tension around the chest, slight nausea, and irritation at the injection site. An increased frequency of attacks (up to 6 attacks per day) was noted in 13 patients, although 4 of the 13 patients experienced a spontaneous decrease in attack frequency within 5-9 days. Given the erratic course of cluster headache, which is often characterized by a pattern of increased severity of attacks in the beginning of a new cluster headache period, an increase of attacks may have been due to spontaneous disease exacerbations rather than to effects of sumatriptan. Patients had also discontinued prophylactic therapy.

Tidswell () described a 72 year old with atypical cluster headache who experienced effective and consistent responses after 10 minutes with a single injection of Imitrex 6 mg SC. An effective and consistent response was seen over a total of 6 treatments during this cluster attack interval. This patient did not report any adverse effects or difficulties using the Imitrexâ SELFdoseâ Unit (autoinjector device). The pattern of cluster headaches were typically at intervals of six weeks, with each attack lasting up to three hours and at most, a three-month pain-free interval between cluster episodes. [Please note that the use of Imitrex in patients over 65 years old has not been systematically evaluated and that Imitrex Injection is indicated for the treatment of cluster headache only when a clear diagnosis of cluster headache (episodic or chronic) exists].

Ekbom et al () reported on a 32-year-old man who received a total of 480 injections of 6 mg SC Imitrex for the treatment of acute attacks of chronic cluster headache over an eleven month period. There was no evidence of tolerance and no serious adverse events. Resolution of attacks were within 10 minutes (for 90% of the attacks treated with Imitrex) if treated with Imitrex compared with 56 minutes for untreated attacks.

Centonze et al () published a report of three male patients using higher than recommended doses of sumatriptan to manage episodic cluster headache over a one year period. The patients ranged in age from 41 to 64 years and all three treated at least three attacks daily during their cluster period. The mean duration of their cluster periods was 2 to 4 months. Each attack was treated with a 6 mg SC sumatriptan injection. No prophylactic medications were utilized due to previous treatment failures.

All three patients consistently achieved relief of their headache within 4 to 18 minutes throughout the one year period. Despite the use of higher than recommended doses, up to 24 mg in a single day, none of the patients experienced side effects. (Please note that the maximum recommended dose that may be given in 24 hours is two 6 mg injections separated by at least one hour). Furthermore, none of the patients showed any worsening of symptoms on abrupt withdrawal of therapy at the end of each cluster period.

Lainez et al ()reported the succesful use of Imitrex Injection in the treatment of a patient with continuous cluster-like headache. Cremer et al reported () the successful use of Imitrex Injection in the treatment of secondary cluster headache.

Conclusion

The efficacy of sumatriptan in the acute treatment of cluster headache was demonstrated in two randomized, double-blind, placebo-controlled, two-period crossover trials. In both trials, the proportion of individuals gaining relief at 10 or 15 minutes was significantly greater among patients receiving 6 mg of Imitrex Injection compared to those who received placebo. Several associated symptoms suggestive of disturbed autonomic function, including nasal congestion, rhinorrhea, lacrimation, and swelling of eyelids, disappeared in parallel with pain relief. In the controlled clinical trials assessing sumatriptan’s efficacy as a treatment for cluster headache, no new significant adverse events associated with the use of sumatriptan were detected that had not already been identified in association with the drug’s use in migraine. Sumatriptan was also found to be well tolerated and effective in the long-term treatment (up to 1 year) of cluster attacks. There was no evidence of tachyphylaxis or an increased incidence of adverse events over time.

Important Prescribing Information ()

The prescriber should be aware that cluster headache patients often possess one or more predictive risk factors for coronary artery disease (CAD). Sumatriptan should not be given to patients with documented ischemic or vasospastic CAD. It is strongly recommended that sumatriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, sumatriptan should not be administered.

For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of sumatriptan injection take place in the setting of a physician’s office or similar medically staffed and equipped facility. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following Imitrex Injection, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of sumatriptan and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use sumatriptan. In considering this recommendation for periodic cardiovascular evaluation, it is noted that patients with cluster headache are predominantly male and over 40 years of age, which are risk factors for CAD.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan.

REFERENCES

Enclosures: Product Information for Imitrexâ Injection. GlaxoSmithKline.

The Sumatriptan Cluster Headache Study Group. Treatment of acute cluster headache with sumatriptan. New Engl J Med 1991;325:322-326.

Ekbom K, Monstad I, Prusinski A, et al. The Sumatriptan Cluster Headache Study Group. Subcutaneous sumatriptan in the acute treatment of cluster headaches: a dose comparison study. Acta Neurol Scand 1993;88:63-69.

Revised 2/09/99 MSR

Back to top of page

RE: OPENED OR REPACKAGED IMITREX^® INJECTION

summary

Imitrex^® (sumatriptan succinate) Injection is a preservative-free product, therefore the sterility of either single-dose vials or single-dose syringe cartridges once the original container has been opened and partially used can not be assured.

Imitrex Injection is commercially available in single-dose syringe cartridges and single-dose vials. Both the syringe cartridges and the vials contain 6 mg of sumatriptan (as the succinate salt) and 3.5 mg of sodium chloride in 0.5 mL of sterile solution. Unopened syringes and vials of Imitrex Injection are stable for 24 months from the date of manufacture, when stored between 2° and 30°C (36° and 86°F) and protected from light. The product expiration date is stamped on the package and label of each vial and prefilled syringe cartridge ().

Nil et al published a study assessing the stability of Imitrex Injection when repackaged in polypropylene tuberculin syringes. Sumatriptan succinate 12 mg/mL was stable when exposed to fluorescent light or kept in the dark for 72 hours at 2–5°C and for at least 24 hours at 25°C.

Some of the information contained in this letter may be outside the product labeling for Imitrex. This letter is not intended to offer an opinion on the advisability of administering Imitrex in a manner inconsistent with product labeling. In order to allow GlaxoSmithKline to monitor the safety of Imitrex we encourage clinicians to report suspected overdoses or adverse effects to our Product Surveillance Department (888-825-5249). Please consult the enclosed product information for full prescribing details.

Published Information

Nil et al (,) published a study assessing the stability of Imitrex Injection when repackaged in polypropylene tuberculin syringes.

Imitrex Injection (12 mg/mL) was drawn up in 1 ml tuberculin syringes. Syringes were prepared in triplicate. Syringes were exposed to fluorescent light at 2–5°C (in a refrigerator) and at 25°C, as well as stored in the dark at those two temperatures.

Samples (300μL) were withdrawn and assayed at baseline, 24, 48, and 72 hours for syringes kept at refrigerator temperature, and at baseline, 8 and 24 hours for syringes at room temperature. Sumatriptan concentrations were assayed by high-performance liquid chromatography (HPLC) and compared with an analytical standard. The area under the peak was used to determine concentrations. Sumatriptan was considered stable if the concentration remained above 90% of the original concentration. At all time points, the samples did not demonstrate any significant change in stability when exposed to light or dark conditions, refrigerator or room temperatures. Visual inspection did not show any change in color or turbidity. Microbial testing was not performed.

REV0201

REFERENCEs

Enclosure: Product Information for Imitrex^® Injection.

Back to top of page

---

RE: IMITREX® INJECTION: ADMINISTRATION OF DOSES LESS THAN 6 MG

 

SUMMARY

The majority of patients in published clinical trials of subcutaneous (SC) sumatriptan received a 6 mg dose. A smaller proportion of patients receiving less than 6 mg (in dose ranging studies) obtained adequate relief and the interval to that relief was greater.

Efficacy and adverse events of Imitrex® was dose-related over the range of 1-8 mg, with pain relief being the most complete following the 6 and 8 mg doses; evaluation of safety and efficacy data in migraine patients demonstrated the optimal dose of Imitrex was 6 mg injected SC.

Although the recommended dose of Imitrex Injection is 6 mg, if side effects are dose limiting, then lower doses may be used.

In patients receiving MAO inhibitors, decreased doses of sumatriptan should be considered.

Some of the information contained in this letter may be outside the product labeling for Imitrex; therefore, this letter is not intended to offer an opinion on the advisability of administering Imitrex in a manner inconsistent with product labeling. Please consult the enclosed product information for complete safety and prescribing information.

DOSE RANGING STUDIES

Evaluation of Efficacy

Although initial results from a controlled non-U.S. trial evaluating the efficacy of Imitrex indicated that a 3 mg SC dose elicited a therapeutic effect, later U.S. and non-U.S. trials demonstrated that a 6 mg dose offered the best efficacy/safety profile.

Two multi-center dose-ranging efficacy trials, 1 U.S. and 1 non-U.S., evaluated doses of Imitrex Injection SC ranging from 1 to 8 mg in an ascending dose, parallel-group design (1, 2). A placebo control with each dose level was employed. The non-U.S. clinical trial evaluated 1, 2, and 3 mg SC doses; whereas the U.S. trial evaluated 1, 2, 3, 4, 6, and 8 mg SC doses. Six hundred eighty-five patients were evaluated in the non-U.S. trial [interim analysis of 277 patients reported previously by Ensink (3) for the Sumatriptan International Study Group]; 242 patients were evaluated in the U.S. trial.

 

TABLE 1. DOSE RESPONSE RELATIONSHIP FOR EFFICACY IN U.S. TRIAL (2,5)

Imitrex Dose (mg)	% Patients with Relief+ at 30 Minutes	% Patients with Relief+ at 1 Hour	% Patients with Relief+ at 2 Hours	Adverse Events Incidence (%)
placebo	15	24	21	55
1	40	43	40	63
2	23	57	43	63
3	47	57	60	77
4	37	50	57	80
6	63	73	70	83
8	57	80	83	93

+ Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication.

Two further studies, both parallel-group, placebo-controlled trials were conducted involving a total of 628 migraine patients who received 4 mg SC injections of Imitrex (4). The studies demonstrated a significant difference in patients treated with Imitrex compared to placebo. However, the efficacy of the higher (6 mg) dose evaluated in the U.S. trial (2) was demonstrated to be higher without a significant increase in frequency or severity of adverse events.

Evaluation of Safety

Safety, tolerance, and pharmacokinetics of subcutaneous Imitrex were first evaluated in U.S. clinical trials in 1988. An ascending-dose design was employed utilizing a placebo control with each dose level of Imitrex (1, 2, 3, or 4 mg) (4). No serious adverse events were demonstrated in healthy male volunteers receiving up to the maximum dose (4 mg). The study protocol was therefore amended and doses up to 16 mg SC were administered without serious adverse events. It was noted that the incidence of adverse events tended to increase with increasing dose.

Imitrex was well tolerated by patients during dose-ranging clinical trials. The majority of adverse events were mild and transient and appeared to be dose related (1-3). The most common adverse events reported in controlled clinical trials during dose-ranging evaluation were injection site reactions, tingling, warmth, burning, and heaviness in the head, neck and extremities. Most of the adverse events were reported to have disappeared within 30 minutes following dosage administration.

Excluding injection site reactions, 39% of placebo-treated patients in the U.S. clinical trial experienced adverse events whereas a varying percentage of Imitrex-treated patients experienced a dose-related incidence of adverse events. Of the patients who received 1 mg, 2 mg, and 3 mg Imitrex, 36%, 40%, and 52% respectively reported adverse events during the trials.

Sixty-two percent of patients who received 4 mg and 6 mg Imitrex experienced adverse events in contrast to 80% of patients who reported adverse events following an 8 mg dose (2, 3). Please refer to Table 1 for percentages of adverse events, including injection site reactions, experienced during the dose ranging study.

DOSAGE RECOMMENDATIONS

The recommended adult dose of Imitrex is 6 mg injected subcutaneously (SC). A second 6 mg injection may be administered after 1 hour if symptoms of migraine return. The maximum recommended dose in 24 hours is two 6 mg injections separated by at least 1 hour.

If side effects are dose-limiting, then lower doses of Imitrex may be used. Smaller doses of Imitrex may also prove to be effective although the proportion of patients obtaining adequate relief is decreased and the latency to that relief is greater. (See Table 1 of Product Information for dose-response relationship.)

There is a potential for monoamine oxidase (MAO) inhibitors to alter sumatriptan pharmacokinetics (increased systemic exposure). Therefore the use of Imitrex Injection in patients taking MAO inhibitors is ordinarily not recommended. In patients receiving MAO inhibitors, decreased doses of sumatriptan should be considered (5).

In patients receiving doses lower than 6 mg, only the single-dose vial dosage form should be used. Although patients may wish to save a partially used vial for future dosing, Imitrex Injection is a preservative-free solution, and sterility cannot be assured once the single-dose vial is opened.

It is strongly recommended that sumatriptan not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female who is surgically or physiologically postmenopausal, or male who is over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. In considering this recommendation, it is noted that patients with cluster headache often possess 1 or more predictive risk factors for CAD. If, during the cardiovascular evaluation, the patient's medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, sumatriptan should not be administered

For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of sumatriptan injection take place in the setting of a physician's office or similar medically staffed and equipped facility. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following Imitrex Injection, in these patient with risk factors.

DIAGNOSTIC CONSIDERATIONS

Imitrex Injection should only be used where a clear diagnosis of migraine or cluster headache has been established. Imitrex Injection is indicated for: 1) the acute treatment of migraine attacks with or without aura; and 2) the acute treatment of cluster headache episodes. Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine or cluster headache or who experience a headache that is atypical for them. There have been rare reports where patients received sumatriptan for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion. For a given attack, if a patient does not respond to the first dose of sumatriptan, the diagnosis of migraine or cluster headache should be reconsidered before administration of a second dose.

 

REFERENCEs

Visser WH, Ferrari MD, Bayliss EM, et al. Treatment of migraine attacks with subcutaneous sumatriptan: first placebo-controlled study. Cephalalgia 1992;12:308-13.

Mathew NT, Dexter J, Couch J, et al. Dose ranging efficacy and safety of subcutaneous sumatriptan in the acute treatment of migraine. Arch Neurol 1992;49:1271-76.

Ensink FBM. Subcutaneous sumatriptan in the acute treatment of migraine. J Neurol 1991;238:S66-69.

Data on file. GlaxoSmithKline.

Product Information for Imitrex® Injection. GlaxoSmithKline.

 

Enclosures: Product Information for Imitrex® Injection. GlaxoSmithKline.

Product Information for Imitrex® Tablets. GlaxoSmithKline.

Mathew NT, Dexter J, Couch J, et al. Dose ranging efficacy and safety of subcutaneous sumatriptan in the acute treatment of migraine. Arch Neurol 1992;49:1271-76.

----------

Page Last Updated:  02/17/2007