Frova

Selective Serotonin 1B/1D Receptor Agonists (Triptans)

Oral Administration

Frovatriptan is administered orally without regard to meals.

Oral Solid Formulations

The tablets should be taken with water.

Severe

serotonin syndrome / Delayed / 0-1.0
peptic ulcer / Delayed / 0-0.1
bradycardia / Rapid / 0-0.1
visual impairment / Early / 1.0
bowel ischemia / Delayed / Incidence not known
hypertensive crisis / Early / Incidence not known
ventricular fibrillation / Early / Incidence not known
ventricular tachycardia / Early / Incidence not known
myocardial infarction / Delayed / Incidence not known
arrhythmia exacerbation / Early / Incidence not known
coronary vasospasm / Early / Incidence not known
seizures / Delayed / Incidence not known
stroke / Early / Incidence not known
intracranial bleeding / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known

Moderate

constipation / Delayed / 0.1-1.0
dysphagia / Delayed / 0.1-1.0
sinus tachycardia / Rapid / 0.1-1.0
euphoria / Early / 0.1-1.0
migraine / Early / 0.1-1.0
hyperthermia / Delayed / 0-1.0
amnesia / Delayed / 0.1-1.0
confusion / Early / 0.1-1.0
dysarthria / Delayed / 0.1-1.0
ataxia / Delayed / 0.1-1.0
depression / Delayed / 0.1-1.0
hyperesthesia / Delayed / 0.1-1.0
conjunctivitis / Delayed / 0.1-1.0
myasthenia / Delayed / 0.1-1.0
hot flashes / Early / 0.1-1.0
bullous rash / Early / 0.1-1.0
dehydration / Delayed / 0.1-1.0
dyspnea / Early / 0.1-1.0
hyperacusis / Delayed / 0.1-1.0
stomatitis / Delayed / 0-0.1
hypertonia / Delayed / 0-0.1
hypotonia / Delayed / 0-0.1
hypocalcemia / Delayed / 0-0.1
hypoglycemia / Early / 0-0.1
edema / Delayed / 0-0.1
palpitations / Early / 1.0
colitis / Delayed / Incidence not known
chest pain (unspecified) / Early / Incidence not known
chest pressure syndrome / Rapid / Incidence not known
angina / Early / Incidence not known
medication overuse headache / Delayed / Incidence not known
withdrawal / Early / Incidence not known
peripheral vasoconstriction / Rapid / Incidence not known

Mild

dizziness / Early / 8.0-8.0
fatigue / Early / 5.0-5.0
flushing / Rapid / 4.0-4.0
headache / Early / 4.0-4.0
paresthesias / Delayed / 4.0-4.0
xerostomia / Early / 3.0-3.0
musculoskeletal pain / Early / 3.0-3.0
dyspepsia / Early / 2.0-2.0
hypersalivation / Early / 0.1-1.0
dysgeusia / Early / 0.1-1.0
anorexia / Delayed / 0.1-1.0
flatulence / Early / 0.1-1.0
agitation / Early / 0.1-1.0
vertigo / Early / 0.1-1.0
emotional lability / Early / 0.1-1.0
tremor / Early / 0.1-1.0
ocular pain / Early / 0.1-1.0
myalgia / Early / 0.1-1.0
muscle cramps / Delayed / 0.1-1.0
arthralgia / Delayed / 0.1-1.0
back pain / Delayed / 0.1-1.0
pruritus / Rapid / 0.1-1.0
polyuria / Early / 0.1-1.0
increased urinary frequency / Early / 0.1-1.0
polydipsia / Early / 0.1-1.0
laryngitis / Delayed / 0.1-1.0
pharyngitis / Delayed / 0.1-1.0
hyperventilation / Early / 0.1-1.0
epistaxis / Delayed / 0.1-1.0
otalgia / Early / 0.1-1.0
malaise / Early / 0.1-1.0
fever / Early / 0.1-1.0
asthenia / Delayed / 0.1-1.0
gastroesophageal reflux / Delayed / 0-0.1
dental pain / Delayed / 0-0.1
eructation / Early / 0-0.1
hiccups / Early / 0-0.1
cheilitis / Delayed / 0-0.1
syncope / Early / 0-0.1
nocturia / Early / 0-0.1
purpura / Delayed / 0-0.1
vomiting / Early / 1.0
nausea / Early / 1.0
abdominal pain / Early / 1.0
diarrhea / Early / 1.0
insomnia / Early / 1.0
dysesthesia / Delayed / 1.0
hypoesthesia / Delayed / 1.0
hyperhidrosis / Delayed / 1.0
sinusitis / Delayed / 1.0
rhinitis / Early / 1.0
tinnitus / Delayed / 1.0

Frova

Rx

Oral serotonin agonist
For acute migraine treatment; may be used off-label for menstrual migraine prophylaxis
Longer half-life and lower headache recurrence rate than other serotonin agonists

For the acute treatment of migraine with or without aura. Oral dosage Adults

2.5 mg PO as a single dose. May repeat dose after at least 2 hours if headache returns. Max: 7.5 mg/day. There is no evidence that a second dose of frovatriptan is effective for persons who do not respond to a first dose for the same headache. The safety of treating an average of more than 4 headaches/30 days has not been established.[29266] Guidelines classify frovatriptan as having established efficacy for the acute treatment of migraine.[64565]

For menstrual migraine prophylaxis†. Oral dosage Adults

5 mg PO twice daily on day 1, then 2.5 mg PO twice daily on days 2 through 6. Begin 2 days before the anticipated onset of menstrual migraine.[49929] [52569] [52570] Guidelines classify frovatriptan as having established efficacy for menstrual migraine prophylaxis.[57981]

†Indicates off-label use

Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Intermittent hemodialysis:
It is not known whether hemodialysis (or peritoneal dialysis) removes frovatriptan from plasma.

Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dihydrocodeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Acetaminophen; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Acetaminophen; Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Oxycodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxycodone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Alfentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering alfentanil with frovatriptan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Almotriptan: (Contraindicated) Almotriptan is contraindicated for use within 24 hours of treatment with frovatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
Amitriptyline: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Amphetamine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and amphetamine; dextroamphetamine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Amphetamine; Dextroamphetamine Salts: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and amphetamine; dextroamphetamine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Amphetamine; Dextroamphetamine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and amphetamine; dextroamphetamine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Aspirin, ASA; Oxycodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxycodone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Benzhydrocodone; Acetaminophen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering benzhydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Benzphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Bromocriptine: (Major) There are limited clinical trial data supporting the safety of giving a serotonin-receptor agonist ("triptan") with bromocriptine, an ergot derivative. The concomitant use of these agents with bromocriptine should be avoided. There is concern that prolonged vasospastic reactions, hypertension, tachycardia, or other side effects may occur.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Buprenorphine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Buprenorphine; Naloxone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Buspirone: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant buspirone and serotonin-receptor agonist use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Cabergoline: (Major) When possible, avoid concomitant use of serotonin-receptor agonists (triptans) within 24 hours of cabergoline administration to minimize the risk for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. The risk for vasospastic adverse reactions may be less with cabergoline, a semisynthetic ergot alkaloid derivative, than with other ergot alkaloids as cabergoline is a relatively selective dopamine agonist. In select patients, the combination of cabergoline and "triptans" has been utilized in the management of some headache types, but more data are needed regarding safety and efficacy.
Capsaicin; Metaxalone: (Moderate) Concomitant use of serotonin-receptor agonists ("triptans") and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Celecoxib; Tramadol: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Chlorpheniramine; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dihydrocodeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Citalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Clomipramine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Cocaine: (Moderate) Concomitant use of cocaine with other drugs that have CNS serotonergic properties, such as serotonin-receptor agonists, could potentiate serotonin neurotransmission, and result in serotonergic side effects or rarely, serotonin syndrome. The actions of cocaine are presumed to include inhibition of presynaptic reuptake of serotonin. In most medical use cases, cocaine would be administered topically, and this interaction would not be of concern, as serotonin-agonists for migraine are used mostly "as needed". Illicit use of cocaine is of potential concern for interactions.
Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Codeine; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Codeine; Phenylephrine; Promethazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Codeine; Promethazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Desipramine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Desogestrel; Ethinyl Estradiol: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Desvenlafaxine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering desvenlafaxine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and serotonin norepinephrine reuptake inhibitors. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Dextroamphetamine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and amphetamine; dextroamphetamine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Dextromethorphan: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Dextromethorphan; Bupropion: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Dextromethorphan; Guaifenesin: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Dextromethorphan; Quinidine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Doxepin: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Drospirenone; Ethinyl Estradiol: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Droxidopa: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
Duloxetine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant duloxetine and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Eletriptan: (Contraindicated) Eletriptan is contraindicated for use within 24 hours of treatment with frovatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
Ergot alkaloids: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
Escitalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Ethinyl Estradiol; Norelgestromin: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Ethinyl Estradiol; Norgestrel: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Etonogestrel; Ethinyl Estradiol: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Fenfluramine: (Moderate) Use fenfluramine and serotonin receptor agonists with caution due to an increased risk of serotonin syndrome. Monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fluoxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Fluvoxamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Guaifenesin; Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Homatropine; Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Hydrocodone; Ibuprofen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Hydrocodone; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Hydromorphone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydromorphone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Ibuprofen; Oxycodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxycodone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Imipramine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Isocarboxazid: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with isocarboxazid. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue frovatriptan and isocarboxazid and initiate symptomatic treatment if serotonin syndrome occurs.
Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Levomilnacipran: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and serotonin norepinephrine reuptake inhibitors. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Levonorgestrel; Ethinyl Estradiol: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Levorphanol: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levorphanol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Linezolid: (Major) Linezolid is an antibiotic that is also a reversible, non-selective inhibitor of MAO and should not be administered with serotonin-receptor agonists. The monoamine oxidase type A enzyme metabolizes serotonin. Non-selective MAO inhibitors increase the plasma concentrations of these drugs and some of their active metabolites, thus increasing levels of serotonin. This interaction could lead to serotonin syndrome. The manufacturers of serotonin agonists contraindicate the administration of their drugs to patients receiving non-selective MAO inhibitors like linezolid or within 2 weeks of discontinuation of a MAO inhibitor.
Lisdexamfetamine: (Major) Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation or dosage increase, during concomitant lisdexamfetamine and serotonin-receptor agonist use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk of serotonin syndrome.
Lithium: (Major) If concurrent use is necessary, monitor for the emergence of serotonin syndrome and inform patients of the increased risk. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment should be implemented. There is an increased risk of serotonin syndrome during concurrent use of drugs with central serotonergic properties such as lithium and serotonin-receptor agonists. Signs and symptoms of serotonin syndrome include autonomic instability (e.g., labile blood pressure, tachycardia, diaphoresis, dizziness, hyperthermia), mental status changes (e.g., delirium, confusion, coma), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), gastrointestinal effects (e.g., nausea, vomiting, diarrhea), seizures, and in rare cases, death.
Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, serotonin-receptor agonists. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
Meperidine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering meperidine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Metaxalone: (Moderate) Concomitant use of serotonin-receptor agonists ("triptans") and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Methadone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering methadone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Methamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as methamphetamine and serotonin-receptor agonists. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Methylene Blue: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Milnacipran: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering milnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and serotonin norepinephrine reuptake inhibitors. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Mirtazapine: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
Morphine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering morphine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Morphine; Naltrexone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering morphine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Nalbuphine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering nalbuphine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Naratriptan: (Contraindicated) Naratriptan is contraindicated for use within 24 hours of treatment with frovatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
Nefazodone: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Norethindrone; Ethinyl Estradiol: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Norgestimate; Ethinyl Estradiol: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Nortriptyline: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Olanzapine; Fluoxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Oliceridine: (Moderate) If concomitant use of oliceridine and serotonin-receptor agonists is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Oxycodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxycodone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Oxymorphone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxymorphone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Ozanimod: (Major) Coadministration of ozanimod with serotonin receptor agonists "triptans" is not recommended due to the potential for hypertensive crisis or serotonin syndrome. If coadministration is necessary, closely monitor patients for hypertension and serotonergic effe

cts. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis or serotonin syndrome. Serotonin receptor agonists may increase blood pressure by increasing serotonin concentrations.
Paroxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Perphenazine; Amitriptyline: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Phenelzine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with phenelzine. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue frovatriptan and phenelzine and initiate symptomatic treatment if serotonin syndrome occurs.
Promethazine; Dextromethorphan: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Protriptyline: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Rasagiline: (Minor) Use together with caution. Serotonin syndrome has been reported during administration of serotonin-receptor agonists ("triptans") and non-selective monoamine oxidase inhibitors (MAOIs). Unlike some serotonin-receptor agonists, frovatriptan is not a substrate for MAO; therefore, its metabolism is not affected by MAOIs. Therefore, MAOI-based interactions appear to be less likely with frovatriptan. Since rasagiline selectively inhibits MAO-B at recommended doses, no interaction with frovatriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing rasagiline doses. Monitor for potential serotonin-related side effects. If serotonin syndrome occurs, discontinue all serotonergic agents and institute appropriate treatment.
Remifentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Rizatriptan: (Contraindicated) Rizatriptan is contraindicated for use within 24 hours of treatment with frovatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
Safinamide: (Moderate) Safinamide and serotonin-receptor agonists, also known as triptans, should be used together with caution. Serotonin syndrome has been reported during administration of serotonin-receptor agonists and non-selective monoamine oxidase inhibitors (MAOIs). Since safinamide selectively inhibits MAO-B at recommended doses, no interaction with serotonin-receptor agonists would be expected with normal prescription use. However, monitoring for serotonin-related side effects is advisable since the potential for serotonin syndrome exists. If serotonin syndrome occurs, discontinue all serotonergic agents and institute appropriate treatment.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives.
Selective serotonin reuptake inhibitors: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Selegiline: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with transdermal selegiline, orally disintegrating selegiline tablets, and high doses of oral selegiline capsules and tablets. Since selegiline oral tablets and capsules selectively inhibit MAO-B at recommended doses, no interaction with frovatriptan would be expected with normal prescription use. However, MAO-B selectivity decreases with increasing doses, therefore, an interaction may occur with high dose treatment. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue frovatriptan and selegiline and initiate symptomatic treatment if serotonin syndrome occurs.
Sertraline: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
St. John's Wort, Hypericum perforatum: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Sufentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sufentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sumatriptan: (Contraindicated) Sumatriptan is contraindicated for use within 24 hours of treatment with frovatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
Sumatriptan; Naproxen: (Contraindicated) Sumatriptan is contraindicated for use within 24 hours of treatment with frovatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
Tapentadol: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tapentadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and serotonin-receptor agonists such as frovatriptan. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO. The monoamine oxidase (MAO) type A enzyme metabolizes serotonin. Non-selective traditional MAO inhibitors increase the plasma concentrations of these drugs and some of their active metabolites, thus increasing levels of serotonin. Serious CNS reactions, such as serotonin syndrome, have been reported during the concurrent use of linezolid, which is structurally similar to tedizolid, and psychiatric medications that enhance central serotonergic activity; therefore, caution is warranted with concomitant use of other agents with serotonergic activity. This interaction could lead to 'serotonin syndrome' (presenting as agitation, restlessness, aggressive behavior, insomnia, poor concentration, headache, paresthesia, incoordination, worsening of obsessive thoughts or compulsive behavior, nausea, abdominal cramps, diarrhea, palpitations, or chills). The manufacturers of serotonin agonists contraindicate the administration of their drugs to patients receiving non-selective MAO inhibitors or within 2 weeks of discontinuation of a MAO inhibitor.
Tramadol: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tramadol; Acetaminophen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tranylcypromine: (Contraindicated) Due to the risk of serotonin syndrome, tranylcypromine is contraindicated for use with frovatriptan. Tranylcypromine should not be used within 4 to 5 half-lives of discontinuing treatment with frovatriptan.
Trazodone: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant trazodone and serotonin-receptor agonist use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Tricyclic antidepressants: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Trimipramine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Tryptophan, 5-Hydroxytryptophan: (Contraindicated) Combining medications that potentiate serotonin neurotransmission, such as serotonin-receptor agonists and tryptophan, could result in serotonin syndrome. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever.
Venlafaxine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant venlafaxine and serotonin-receptor agonist use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Vilazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vilazodone with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) with serotonin-receptor agonists. Of the 27 cases reviewed by the FDA, 2 were considered life-threatening and 13 required hospitalization. Some patients had used the combination previously without incident. Eight of 27 cases involved a recent dose increase or addition of another serotonergic drug to the regimen, with a median onset of 1 day (range: 10 minutes to 6 days). It is thought that the interaction between SNRIs or SSRIs and serotonin-receptor agonists is the result of increased serotonergic activity by each of the drug classes. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. At least 6 patients taking an SSRI antidepressant are known to have received sumatriptan for migraine where no apparent adverse effects were seen. In another case report, the addition of fluoxetine lead to loss of migraine control with sumatriptan. Patients receiving vilazodone and a serotonin-receptor agonist should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Vortioxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vortioxetine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonergic antidepressants with the serotonin-receptor agonists. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the sertonergic antidepressant or the addition of other serotonergic medications to an existing antidepressant regimen.
Zolmitriptan: (Contraindicated) Zolmitriptan is contraindicated for use within 24 hours of treatment with frovatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.

Frova/Frovatriptan Oral Tab: 2.5mg

Adults

7.5 mg/day PO for acute migraine treatment.

Geriatric

7.5 mg/day PO for acute migraine treatment.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Frovatriptan is a selective agonist of vascular serotonin (5-hydroxytryptamine 1B/1D; 5-HT1B/D) receptors. Frovatriptan has no significant activity at other 5-HT receptors, GABA-mediated channels, or benzodiazepine receptors. The mechanisms involved in the pathogenesis of migraine are not clearly understood, therefore making it difficult to determine the precise mechanism of serotonin-agonists (i.e., 'triptans') in the treatment of migraine. Multiple pharmacological actions have been derived that appear important for antimigraine effects.. 'Triptans' stimulate presynaptic 5-HT1D receptors, an action that inhibits both dural vasodilation and inflammation. They directly inhibit trigeminal nuclei cell nociceptive neurotransmission via 5-HT1B/D receptor agonism within the trigeminocervical complex of the brainstem and upper spinal cord. Vascular 5-HT1B receptor agonism results in vasoconstriction of painfully dilated intracranial extracerebral vessels.. In general, second-generation 'triptans' are less likely to aggravate the coronary 5-HT1B receptor than sumatriptan, which should reduce the incidence of chest pain or other cardiac effects in patients with normal coronary circulation. However, in therapeutic use such events have been rarely reported with all agents.

Frovatriptan is administered orally. It exhibits minimal protein binding (roughly 15%). The mean elimination half-life is 26 hours. Frovatriptan is primarily metabolized by cytochrome P450 1A2. Unlike most other 5-HT1 agonists, it is not an inhibitor of monoamine oxidase (MAO) or hepatic cytochrome P450 microsomal isozymes (e.g., 2C9, 2C19, 2D6, 2E1, 3A4), and, therefore, appears to have fewer drug interactions than other drugs in the class. Frovatriptan has several metabolites and only one, desmethyl frovatriptan, has a reported affinity (although, low) for the 5-HT1 receptor. Approximately 30% of the oral dose is eliminated renally and 60% is excreted in the feces.
 
Affected cytochrome P450 isoenzymes: CYP1A2
Frovatriptan is a substrate of the hepatic cytochrome isoenzyme CYP1A2; however clinically significant interactions with CYP1A2 inhibitors are not likely due to its' wide therapeutic range in addition to its partial renal elimination.
 

Oral Route

The absolute bioavailability of frovatriptan is low and, although it has no impact on dosing, varies according to gender, 20% in males and 30% in females. Peak plasma levels of frovatriptan occur 2—4 hours after oral administration; food has no significant affects on frovatriptan's bioavailability, but it does delay the Tmax by 1 hour.

Pregnancy

There are no data on the developmental risk associated with frovatriptan use during human pregnancy. Women with migraines may be at increased risk of preeclampsia during pregnancy. Based on animal data, frovatriptan may cause fetal harm. In animal studies where pregnant rats were given frovatriptan at doses higher than those used clinically throughout organogenesis, increased embryofetal mortality and an increased incidence of fetal malformations were observed at the highest dose; decreased fetal body weights and increased incidences of fetal structural variations associated with growth impairment were observed at all doses. The lowest effect dose for embryofetal developmental toxicity in rats (100 mg/kg/day) is approximately 130-times the maximum recommended human dose (MRHD) of 7.5 mg/day on a body surface area basis. When pregnant rabbits were given frovatriptan at doses higher than those used clinically throughout organogenesis, increased embryofetal mortality occurred. The no-effect dose for embryofetal developmental toxicity in rabbits (5 mg/kg/day) is approximately 13-times the MRHD on a body surface area basis.

There are no data on the presence of frovatriptan in human milk, the effects of frovatriptan 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 frovatriptan and any potential adverse effects on the breast-fed infant from frovatriptan or the underlying maternal condition. In general, if a nursing mother requires an antimigraine serotonin agonist, other agents with shorter half-lives may be preferred. Previous American Academy of Pediatrics (AAP) recommendations considered sumatriptan as compatible with breast-feeding, and sumatriptan may be an alternative to frovatriptan for the acute treatment of migraines in breast-feeding mothers.[27500] [29266]