Fremanezumab is an injectable calcitonin gene-related peptide (CGRP) receptor antagonist indicated for migraine prophylaxis in adults. In 3-month clinical trials of patients with episodic migraine, fremanezumab significantly reduced monthly migraine days in comparison to placebo; monthly migraine days were reduced by 3.7 days, 3.4 days, and 2.2 days for fremanezumab once monthly, once quarterly, and placebo, respectively, from a baseline of approximately 9 days/month for each group. At month 3, fremanezumab-treated chronic migraine patients experienced significant reductions in monthly migraine days of at least moderate severity of 4.6 days for monthly and 4.3 days for quarterly dosing from baselines of approximately 13 days/month vs. placebo. A 50% or greater reduction in monthly migraine days was achieved by 44.4% to 47.7% of episodic migraineurs and 37.6% to 40.8% of chronic migraineurs who were treated with fremanezumab compared to 27.9% of episodic migraineurs and 18.1% of chronic migraineurs given placebo.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the fremanezumab solution is cloudy, discolored, or contains particles. Fremanezumab is a clear to opalescent, colorless to slightly yellow solution.
Subcutaneous Administration
-Fremanezumab is intended for patient self-administration. Provide proper training to patients and/or caregivers on how to prepare and administer fremanezumab, including aseptic technique.
-Before administration, allow fremanezumab to sit at room temperature for at least 30 minutes protected from direct sunlight. Do not warm using a heat source such as hot water or microwave. Do not use if the product has been at room temperature for 7 days or more.
-Do not shake.
-Clean injection site on the abdomen, thigh, or upper arm with an alcohol wipe and allow skin to dry.
-Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting directly into raised, thick, red, or scaly skin patch or lesion, or areas with scars or stretch marks.
-If using the same body area for the 3 separate injections needed for the 675 mg dose, ensure the injections are not at same location used for the previous injection.
-Do not coadminister fremanezumab with other injectable drugs at the same injection site.
-When switching between monthly and quarterly dosage options, administer the first dose of the new regimen on the next scheduled date of administration.
-If a dose is missed, give the next dose as soon as possible. Subsequently, schedule from the date of the last dose.
-Storage: After removing fremanezumab from the refrigerator, it can be stored at room temperature up to 86 degrees F (30 degrees C) for up to 7 days. Discard if not used within 7 days after removal from refrigerator. Do not place back in refrigerator once stored at room temperature.
Single-dose, Prefilled Syringe
-Always hold syringe by the barrel.
-Pull needle cap straight out and away from body.
-Pinch injection site skin firmly between thumb and fingers.
-Hold the pinch, and insert the syringe into skin at 45 to 90 degrees.
-Using slow and constant pressure, push the plunger rod all the way down with thumb until the prefilled syringe stops moving.
-When done, release thumb, and gently lift syringe off the skin.
-Discard the prefilled syringe in a FDA-cleared sharps disposal container. Do not discard in household trash.
Single-dose, Prefilled Autoinjector
-Pull the protective cap straight off the autoinjector.
-Place the autoinjector at a 90-degree angle against the skin.
-Press the autoinjector down onto the skin for approximately 30 seconds to deliver the dose.
-A click will be heard when the injection starts and approximately 15 seconds into the injection. Wait 10 seconds after the second click before removing the autoinjector from the skin to ensure all of the dose is injected. The blue plunger will fill the viewing window when the dose is delivered.
-Discard the prefilled autoinjector in a FDA-cleared sharps disposal container. Do not discard in household trash.
An injection site reaction, including injection site pain, induration, and erythema, was the most frequent adverse reaction reported during 2 double-blind, placebo-controlled, 3-month studies of fremanezumab and the 1-month follow-up period after those studies. Injection site reactions occurred in 43% of patients who received fremanezumab 225 mg (with or without a loading dose of 675 mg) once monthly (n = 290), 45% of patients who received fremanezumab 675 mg once quarterly (n = 667), and 38% of placebo-treated patients (n = 668). Injection site reactions were the most common reason for treatment discontinuation (1%).
Hypersensitivity reactions including rash, pruritus, drug hypersensitivity, and urticaria were reported with fremanezumab during clinical trials. Most reactions were mild to moderate; however, some required corticosteroid treatment or fremanezumab discontinuation. Most reactions were reported within hours to 1 month after administration. Anaphylactoid reactions and angioedema have been reported during postmarketing experience with fremanezumab. Consider discontinuing fremanezumab and institute appropriate therapy if a hypersensitivity reaction occurs.
As with all therapeutic proteins, there is the potential for immunogenicity and antibody formation. In clinical trials of fremanezumab, treatment-emergent anti-fremanezumab antibodies developed in 0.4% of patients (6/1,701) during clinical trials (1 of whom developed neutralizing antibodies at day 84) and 1.6% of patients (30/1,888) during the ongoing long-term open-label study. Of the 30 patients with anti-fremanezumab antibodies in the open-label study, 17 patients had neutralizing activity in their post-dose samples. Although the data did not demonstrate an impact of anti-fremanezumab antibody development on the efficacy or safety of fremanezumab, data are too limited to make definitive conclusions.
Constipation was reported with fremanezumab in postmarketing experience.
Alopecia was reported with fremanezumab in postmarketing experience.
Fremanezumab is contraindicated in patients with serious hypersensitivity to fremanezumab or any of the excipients. Anaphylaxis and angioedema have been reported with fremanezumab.
There are no adequate data on the developmental risk associated with fremanezumab use during human pregnancy. Fremanezumab has a half-life of approximately 31 days, which should be taken into consideration for women who are pregnant or who intend to become pregnant while using the drug. No adverse developmental effects were observed when rabbits were given fremanezumab throughout organogenesis or when rats were given fremanezumab prior to and during mating and throughout pregnancy and lactation at doses associated with exposures approximately 2 to 3 times that in humans at a dose of 675 mg. Women with migraine may be at increased risk of preeclampsia during pregnancy. There is a pregnancy exposure registry that monitors outcomes in women exposed to fremanezumab during pregnancy. Health care providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-833-927-2605 or visiting www.tevamigrainepregnancyregistry.com.
There are no data on the presence of fremanezumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fremanezumab and any potential adverse effects on the breast-fed infant from fremanezumab or the underlying maternal condition.
General dosing information
-When switching between monthly and quarterly dosage options, administer the first dose of the new regimen on the next scheduled date of administration.
Guideline indications for initiating migraine prevention with monoclonal antibodies to calcitonin gene-related peptide (CGRP) or its receptor:
-Migraine with or without aura (4 to 7 monthly headache days) and inability to tolerate or inadequate response to an 8-week trial of at least 2 evidence-based preventative treatments and at least moderate disability defined by Migraine Disability Assessment Score (MIDAS) more than 11 or Headache Impact Test Score (HIT-6) more than 50
-Migraine with or without aura (8 to 14 monthly headache days) and inability to tolerate or inadequate response to an 8-week trial of at least 2 evidence-based preventative treatments
-Chronic migraine and inability to tolerate or inadequate response to an 8-week trial of at least 2 evidence-based preventative treatments or inability to tolerate or inadequate response to a minimum of 2 quarterly injections (6 months) of onabotulinumtoxinA
Evidence-based migraine preventative treatments with established or probable efficacy include:
-Topiramate
-Divalproex sodium/valproate sodium
-Beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol
-Tricyclic antidepressant: amitriptyline, nortriptyline
-Serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine
Guideline criteria for continuation of migraine prevention with monoclonal antibodies to CGRP or its receptor after 3 months or more (monthly dosing) or 6 months or more (quarterly dosing):
-Reduction in mean monthly headache days of 50% or more relative to pretreatment baseline (diary documentation or healthcare provider attestation) or
-Clinically meaningful improvement, defined by MIDAS reduction of 5 points or more with a baseline score of 11 to 20 or reduction of 30% or more with baseline score more than 20, HIT-6 reduction of 5 points or more, or Migraine Physical Function Impact Diary (MPFID) reduction of 5 points or more
For migraine prophylaxis:
Subcutaneous dosage:
Adults: 225 mg subcutaneously once monthly or 675 mg subcutaneously every 3 months. Guidelines classify fremanezumab as having established efficacy for migraine prophylaxis.
Maximum Dosage Limits:
-Adults
225 mg/month or 675 mg every 3 months subcutaneously.
-Geriatric
225 mg/month or 675 mg every 3 months subcutaneously.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Fremanezumab products.
Fremanezumab is a human immunoglobulin G2 (IgG2) monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor. CGRP is distributed throughout the nervous system, and it is concentrated at anatomical sites, such as the trigeminovascular system, which are involved in migraine pathophysiology. Centrally, CGRP is involved in nociceptive transmission through second and third order neurons and pain modulation in the brainstem. Peripherally, CGRP mediates vasodilation through smooth muscle receptors. CGRP concentrations are elevated during acute migraine attacks and may be chronically elevated in chronic migraineurs.
Fremanezumab is administered subcutaneously. Steady-state is achieved by 6 months after both monthly and quarterly dosing regimens. Fremanezumab has an apparent volume of distribution of 6 L, suggesting minimal distribution to extravascular tissues. Fremanezumab is degraded by enzymatic proteolysis into small peptides and amino acids. Fremanezumab apparent clearance is approximately 0.141 L/day. The half-life of fremanezumab is 31 days.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Subcutaneous Route
After single fremanezumab doses of 225, 675, or 900 mg, the median Tmax was 5 to 7 days. Dose-proportionality was observed between 225 to 900 mg. The median accumulation ratio based on once-monthly and once-quarterly dosing regimens is approximately 2.3 and 1.2, respectively.
-Special Populations
Hepatic Impairment
Hepatic impairment is not expected to affect the pharmacokinetics of fremanezumab. A population pharmacokinetic analysis of integrated data from fremanezumab clinical trials did not reveal a difference in fremanezumab pharmacokinetics in patients with mild hepatic impairment (n = 4), relative to those with normal hepatic function. There were no patients with severe hepatic impairment in fremanezumab clinical trials.
Renal Impairment
Renal impairment is not expected to affect the pharmacokinetics of fremanezumab.
Geriatric
The pharmacokinetics of fremanezumab were not affected by age.
Gender Differences
The pharmacokinetics of fremanezumab were not affected by gender.
Ethnic Differences
The pharmacokinetics of fremanezumab were not affected by race.
Obesity
The pharmacokinetics of fremanezumab were not affected by weight.