Table 3 Potential contraindications of anti-CGRP/rec mAbs based on physiological data & clinical evidence
Physiological CGRP functions | Potential contraindications | Experimental / clinical evidence | RECOMMENDATION |
|---|---|---|---|
Protective vasodilatation and proangiogenic effect (reviews: 5,6) Antioxydant and homeostatic properties (reviews: 7,8) | Ischemic stroke | Gepants worsen ischemic cerebral outcome in mice [147] No effect on vasodilatory / contractile responses of human cerebral arteries (erenumab) [148] 1 case with cerebral proliferative angiopathy (erenumab) [152] 1 case with reversible cerebral vasospasm (erenumab + triptan + contraceptive pill) [153] | Contraindicated if recent stroke Not recommended if history of stroke (precautionary principle) |
Coronary artery disease | No worsening of angina (1 erenumab dose) [149] Vascular safety profile in RCTs similar to placebo (erenumab) [150] No case reports [151] | Contraindicated if recent myocardial infarction or unstable angina Not recommended if history of myocardial infarction (precautionary principle) | |
Raynaud’s | 5,3% with microvascular complications (5 cases erenumab, 3 galcanezumab, 1 fremanezumab) (2 with sclerodermia) [157] More prevalent than with triptans or beta-blockers in WHO VigiBase® [156] | Contraindicated if severe Raynaud’s with microvascular lesions and/or sclerodermia | |
Arterial hypertension | 62 cases (erenumab) reported to FDA in 2 years (31% had pre-existing hypertension) [160] Incidence not different from placebo in RCTs (erenumab) [159] Significant overall rise in blood pressure, de novo hypertension in 4/109 (3.7%) patients on erenumab, 0/87 with fremanezumab [161] Blood pressure worsening in 23.3% of 335 patients with erenumab [162] | Surveillance of blood pressure Erenumab not recommended in severe and/or uncontrolled hypertension | |
Peripheral artery disease | No case reports [151] | Not recommended if severe (precautionary principle) | |
Venous thrombosis/embolism | No case reports [151] | Not recommended if recent (precautionary principle) | |
Reversible cerebral vasoconstriction syndrome | 1 case report (erenumab) [163] | Not recommended (precautionary principle) | |
Erectile dysfunction | 1 case report (galcanezumab) [164] | Surveillance | |
Vasoregulation of utero-placental blood flow & feto-placental development (163) Penetration in milk during lactation (143) | Pregnancy Lactation | No deleterious effect in monkeys (erenumab) [166] Fetal mortality increase and growth decrease with s.c. infusion of CGRP8 − 37 (a CGRP receptor antagonist) in pregnant rats [167] No deleterious effect in case reports (erenumab) [168] and 92 safety reports [169] No signal in WHO pharmacovigilance database (VigiBase®) [170] | Contraindicated (precautionary principle) |
Regulation of gastro-intestinal tract motility & mucosal integrity (169) | GI motility disorders | Calcrl gene expression 5x higher in enteric neurons than in vascular cells/sensory neurons [173] 17% of 24,573 adverse effects related to GI disorders In FAERS 2019 in [174] Constipation prevalent (20%) with erenumab, but discontinuation rare [15] CGRP causes gastrointestinal hyperactivity | Erenumab not recommended if severe constipation Surveillance in Irritable Bowel Syndrome |
Peptic ulcer, inflammatory bowel disease | No signal in databases | Surveillance in Inflammatory Bowel Disease | |
Proliferation of keratinocytes, VEGF upregulation & reduction of inflammatory mediators (143) | Cutaneous lesions | Impaired wound healing (erenumab-1 case) [176] Severe ecchymosis (erenumab + fish oil) in 1 case (177) Alopecia: women, non-serious, case reports and signal in FAERS (all 4 mAbs) [178,179,180] | Not recommended if severe skin lesions or poor wound healing (precautionary principle) Surveillance in vasculitis & bleeding disorders Not recommended in women with abnormal hair loss |