How is fremanezumab used for migraine prevention, including dosing schedule, safety monitoring, common adverse effects, contraindications, and alternative therapies?

Fremanezumab for Migraine Prevention

Positioning in Treatment Algorithm

Fremanezumab is a third-line preventive medication reserved for patients who have failed first-line therapies (beta-blockers, topiramate, candesartan) and second-line options (flunarizine, amitriptyline, valproate), or when these medications are contraindicated. 1

The American College of Physicians positions fremanezumab as second-line therapy after failure of conventional preventives including beta-blockers (metoprolol, propranolol), antidepressants (amitriptyline, venlafaxine), or antiseizure medications (valproate, topiramate), driven primarily by the 100-fold cost difference rather than efficacy differences. 1, 2

In Europe, regulatory restrictions explicitly limit fremanezumab use to patients in whom other preventive drugs have failed or are contraindicated. 1

Dosing Schedule

Fremanezumab offers flexible dosing options via subcutaneous injection: 3, 4

• Monthly dosing: 225 mg subcutaneously every month
• Quarterly dosing: 675 mg subcutaneously every 3 months (single dose at baseline)

Both regimens demonstrate equivalent efficacy, allowing selection based on patient preference for injection frequency. 3, 5

Efficacy Assessment Timeline

Assess efficacy only after 3-6 months of treatment, as therapeutic benefits are not immediately apparent. 1 This contrasts with oral preventives (2-3 months) and onabotulinumtoxinA (6-9 months). 1

For chronic migraine, fremanezumab reduces headache days by approximately 4.3-4.6 days per month compared to 2.5 days with placebo at 12 weeks. 5 In the 6-month extension, reductions reached 5.1-5.5 monthly migraine days from baseline. 6

For episodic migraine, baseline monthly migraine days of 8.9-9.2 decreased to 5.3 days at 12 weeks and 4.0-4.2 days in the 6-month extension. 7

Common Adverse Effects

The most frequent adverse events are injection-site related: 7

• Injection site pain: 24% (vs 22% placebo)
• Injection site induration: 17% (vs 13% placebo)
• Injection site erythema: 16% (vs 12% placebo)

Severe adverse events occur in 3.9% of patients (vs 3.7% placebo), with no significant changes in vital signs or ECG. 7 Hepatic function abnormalities occurred in 1% of fremanezumab patients versus <1% with placebo. 5

Discontinuation rates due to adverse events are generally low across CGRP monoclonal antibodies, with 162 fewer discontinuations per 1000 treated people compared to topiramate. 2

Contraindications and Safety Monitoring

Fremanezumab has minimal absolute contraindications compared to traditional preventives. 2

Unlike other preventive medications, fremanezumab is NOT contraindicated in: 2

• Coronary heart disease (though caution advised)
• Inflammatory bowel disease
• Chronic obstructive pulmonary disease
• History of subarachnoid hemorrhage
• Pregnancy/lactation (though discussion required with patients of childbearing potential) 8

Critical cardiovascular distinction: Fremanezumab has NOT been associated with development or worsening of hypertension in post-marketing studies, unlike erenumab which carries this specific risk. 2, 8 This makes fremanezumab a safer option for patients with cardiovascular concerns.

No routine laboratory monitoring is required. 7 The medication can be continued throughout perioperative periods without interruption. 2

Treatment Duration and Discontinuation

Consider pausing treatment after 6-12 months of successful therapy to determine if preventive treatment can be stopped. 1 This minimizes unnecessary drug exposure and allows some patients to manage migraine with acute medications only.

Fremanezumab does not require tapering when discontinuing. 2

Quantify success by calculating the percentage reduction in monthly migraine days or monthly headache days of moderate-to-severe intensity. 1

Alternative Therapies

First-Line Alternatives (Try Before Fremanezumab):

• Beta-blockers: Propranolol, metoprolol, atenolol, bisoprolol 1
• Topiramate: Particularly beneficial in patients with obesity due to weight loss effects 8
• Candesartan: Angiotensin receptor blocker 1

Second-Line Alternatives:

• Flunarizine 1
• Amitriptyline 1
• Valproate (contraindicated in women of childbearing potential) 1

Other CGRP-Targeting Options:

• Other CGRP monoclonal antibodies: Erenumab, galcanezumab, eptinezumab (no direct evidence shows superiority of one over another) 2
• Oral gepants: Atogepant (daily preventive), rimegepant (acute or preventive) - patients generally prefer oral over injectable routes 2, 8

Non-Pharmacological Options:

• Non-invasive neuromodulatory devices 1
• Biobehavioral therapy 1
• Acupuncture (though not superior to sham acupuncture) 1

Cost Considerations

Annual costs for fremanezumab range from $7,071 to $22,790, representing a 100-fold increase over conventional preventives ($67-$393 annually). 2, 8 This substantial cost difference drives the recommendation to exhaust first-line options before initiating fremanezumab.

Insurance typically requires documented failure of 2-3 traditional preventives before approving CGRP therapies. 8

Clinical Pitfalls to Avoid

Do not discontinue fremanezumab prematurely for apparent inefficacy - patients must complete 3-6 months before efficacy can be properly assessed. 1

Do not use fremanezumab as first-line therapy unless all conventional preventives are contraindicated, as this violates guideline recommendations and cost-effectiveness principles. 1

Do not assume all CGRP monoclonal antibodies have identical cardiovascular safety profiles - erenumab specifically carries hypertension risk that fremanezumab does not. 2, 8