A review of frovatriptan for the treatment of menstrual migraine

Figures & data

Table 1 International Headache Society classification of menstrual migraine

Pure menstrual migraine without aura^Citation11
Diagnostic criteria
A.	Attacks, in a menstruating woman, fulfilling criteria for migraine without aura and criterion (B) below
B.	Documented and prospectively recorded evidence over at least three consecutive cycles has confirmed that attacks occur exclusively on day 1±2 (ie, days −2 to +3) of menstruation in at least two out of three menstrual cycles and at no other times of the cycle
Menstrually related migraine without aura^Citation11
Diagnostic criteria
A.	Attacks, in a menstruating woman, fulfilling criteria for migraine without aura and criterion B below
B.	Documented and prospectively recorded evidence over at least three consecutive cycles has confirmed that attacks occur on day 1±2 (ie, days −2 to +3) of menstruation in at least two out of three menstrual cycles and additionally, at other times of the cycle

Notes: For the purposes of ICHD-3 beta, menstruation is considered to be endometrial bleeding resulting from either the normal menstrual cycle or from the withdrawal of exogenous progestogens, as in the use of combined oral contraceptives or cyclical hormone replacement therapy. The first day of menstruation is day 1, and the preceding day is day −1; there is no day 0.

Abbreviation: ICHD, International Headache Society Classification of Headache Disorders.

Figure 1 Headache recurrence vs half-life for different triptans, after 2 hours.

Notes: Copyright © 2003, John Wiley and Sons. Reproduced with permission from Géraud G, Keywood C, Senard JM. Migraine headache recurrence: relationship to clinical, pharmacological, and pharmacokinetic properties of triptans. Headache. 2003;43(4):376–388;^{52 †}after 4 hours.

Figure 2 Pain relief following treatment with frovatriptan versus almotriptan, rizatriptan, or zolmitriptan.

Abbreviations: CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel.

Figure 3 Pain-free response following treatment with frovatriptan versus almotriptan, rizatriptan, or zolmitriptan.

Abbreviations: CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel.

Figure 4 Relapse following 2-hour pain-free response after treatment with frovatriptan versus almotriptan, rizatriptan, or zolmitriptan.

Abbreviations: CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel.

Table 2 Clinical trials of frovatriptan for acute treatment of menstrual migraine: post hoc analyses of three placebo-controlled RCTs

Study	Intervention	Results of primary end points
Allais et al (2011)^Citation65	Frovatriptan 2.5 mg (73 attacks); zolmitriptan 2.5 mg (65 attacks)	Pain relief at 2 hours: 52% frovatriptan; 53% zolmitriptan (NS)
		Pain-free at 2 hours: 22% frovatriptan; 26% zolmitriptan (NS)
		Pain relief at 24 hours: 83% frovatriptan; 82% zolmitriptan (NS)
		Pain-free at 24 hours: 74% frovatriptan; 69% zolmitriptan (NS)
		Relapse within 24 hours: 15% frovatriptan; 22% zolmitriptan (P<0.05)
Bartolini et al (2012)^Citation66	Frovatriptan 2.5 mg (77 attacks); almotriptan 12.5 mg (78 attacks)	Pain relief at 2 hours: 36% frovatriptan; 41% almotriptan (NS)
		Pain-free at 2 hours: 19% frovatriptan; 29% almotriptan (NS)
		Pain relief at 24 hours: 62% frovatriptan; 67% almotriptan (NS)
		Pain-free at 24 hours: 60% frovatriptan; 67% almotriptan (NS)
		Relapse within 24 hours: 8% frovatriptan; 21% almotriptan (P<0.05)
Savi et al (2011)^Citation67	Frovatriptan 2.5 mg (49 attacks); rizatriptan 5 mg (59 attacks)	Pain relief at 2 hours: 58% frovatriptan; 64% rizatriptan (NS)
		Pain-free at 2 hours: 31% frovatriptan; 34% rizatriptan (NS)
		Pain relief at 24 hours: 81% frovatriptan; 74% rizatriptan (NS)
		Pain-free at 24 hours: 67% frovatriptan; 61% rizatriptan (NS)
		Relapse within 24 hours: 10% frovatriptan; 32% rizatriptan (P<0.01)
Allais et al (2012)^Citation68	Pooled data from Frovatriptan 2.5 mg (199 attacks); almotriptan 12.5 mg/rizatriptan 5 mg/zolmitriptan 2.5 mg (202 attacks)^Citation63^–^Citation65	Pain relief at 2 hours: 37% frovatriptan; 43% other triptans (NS)
		Pain-free at 2 hours: 23% frovatriptan; 30% other triptans (NS)
		Pain relief at 24 hours: 37% frovatriptan; 43% other triptans (NS)
		Pain-free at 24 hours: 23% frovatriptan; 30% other triptans (NS)
		Relapse within 24 hours: 11% frovatriptan; 24% other triptans (P<0.05)
Allais et al (2013)^Citation69	Oral contraceptive-induced migraine in pooled data from frovatriptan 2.5 mg (73 attacks); almotriptan 12.5 mg/rizatriptan 5 mg/zolmitriptan 2.5 mg (71 attacks)^Citation63^–^Citation65	Pain relief at 2 hours: 51% frovatriptan; 48% other triptans (NS)
		Pain-free at 2 hours: 25% frovatriptan; 28% other triptans (NS)
		Pain relief at 24 hours: 83% frovatriptan; 76% other triptans (NS)
		Pain-free at 24 hours: 71% frovatriptan; 60% other triptans (P<0.05)
		Relapse within 24 hours: 17% frovatriptan; 27% other triptans (P<0.05)

Notes: Pain relief: decrease in migraine from severe or moderate to mild or no headache. Pain-free: absence of migraine 2 hours after intake of one dose of study drug ± rescue medication. Relapse: migraine occurring 24 hours after the previous episode, with a migraine-free period between the two attacks.

Abbreviations: NS, nonsignificant; RCT, randomized controlled trial.

Table 3 Clinical trials of frovatriptan for perimenstrual prophylaxis

Study	Intervention	Diagnosis established	Baseline number of attacks	Primary endpoint	Results	Comments
Placebo-controlled RCT
Silberstein et al 2004^Citation72	Crossover treatment of three PMPs; start 2 days before predicted MM; duration 6 days Safety population: n=546 ITT population: n=506 Frovatriptan 2.5 mg QD (n=505); frovatriptan 2.5 mg BID (n=501); PCB (n=501)	Review of patient’s history: >1 year history of MM; attack frequency of ≥3 out of 4 PMPs in the previous year MM defined as migraine on days −2 to +4	Mean MM frequency in previous 12 months =1.4 (range 7 to 12)	Incidence of MM during each treated PMP	Frovatriptan QD 52%; frovatriptan BID 41%; PCB 67% (P<0.0001 BID and QD vs PCB; P<0.001 BID vs QD)	Diagnosis was derived from women’s responses to study screening questions, without the use of confirmation headache diaries 36.4% treated 2 days before anticipated MM; 69.3% treated 1–3 days before anticipated MM
Brandes et al 2009^Citation73	Parallel treatment of three PMPs; start 2 days before predicted MM; duration 6 days Safety population: frovatriptan 2.5 mg QD (n=152); frovatriptan 2.5 mg BID (n=103); PCB (n=161) ITT population: frovatriptan 2.5 mg QD (n=149); frovatriptan 2.5 mg BID (n=101); PCB (n=160)	Patients with difficult to treat MM and a documented history of MM in at least 2 of the three previous cycles MM defined as migraine that started on day −2 to +3 of menstruation	Mean MM frequency in previous three cycles =2.9 (SD 0.4)	Mean number of headache-free PMPs per patient	Frovatriptan QD 0.69; frovatriptan BID 0.92; PCB 0.42 (P<0.0001 [BID] and P<0.01 [QD] vs PCB)	34% treated within one day of correct timing for all three PMPs Accurate predication associated with greater efficacy; number of MM-free PMPs improved by 213% [BID] and 100% [QD] vs PCB
Post hoc analysis of placebo-controlled RCT
Silberstein et al 2009^Citation74	Crossover treatment of three PMPs; start 2 days before predicted MM; duration 6 days Safety population n=195; ITT population n=179 Frovatriptan 2.5 mg QD (n=177); frovatriptan 2.5 mg BID (n=175); PCB (n=187)	Review of patient’s history: >1-year history of MM; attack frequency of ≥ three out of four PMPs in the previous year MM defined as migraine on days −2 to +4	Mean MM frequency in previous 12 months =11.5 (median 12.0)	Incidence of MM during each treated PMP	Frovatriptan QD 51.3%; frovatriptan BID 37.7%; PCB 67.1% (P<0.001 [BID] and P<0.002 [QD] vs PCB; P=0.01 BID vs QD)	Diagnosis was derived from women’s responses to study screening questions, without the use of confirmation headache diaries

Abbreviations: BID, twice daily; ITT, intention to treat; MM, menstrual migraine (pure menstrual or menstrually-related migraine); PCB, placebo; PMP, perimenstrual period; QD, once daily; RCT, randomized controlled trial; SD, standard deviation; vs, versus.

Figure 5 Perimenstrual prophylaxis with frovatriptan: incidence of no migraine occurring during the treated perimenstrual period.

Abbreviations: BID, twice daily; CI, confidence interval; df, degrees of freedom; QD, once daily; M-H, Mantel-Haenszel; vs, versus.

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