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Vascular Headache Suppressants, Ergot Derivativecontaining (Systemic)

This monograph includes information on the following:

1) Dihydroergotamine
2) Ergotamine
3) Ergotamine and Caffeine
4) Ergotamine, Caffeine, and Belladonna Alkaloids *
5) Ergotamine, Caffeine, Belladonna Alkaloids, and Pentobarbital *
6) Ergotamine, Caffeine, and Cyclizine *
7) Ergotamine, Caffeine, and Dimenhydrinate *
8) Ergotamine, Caffeine, and Diphenhydramine *

VA CLASSIFICATION
Dihydroergotamine
Primary: CN105
Secondary: CV900

Ergotamine
Primary: CN105

Ergotamine and Caffeine
Primary: CN105

Ergotamine, Caffeine, and Belladonna Alkaloids
Primary: CN105

Ergotamine, Caffeine, Belladonna Alkaloids, and Pentobarbital
Primary: CN105

Ergotamine, Caffeine, and Cyclizine
Primary: CN105

Ergotamine, Caffeine, and Dimenhydrinate
Primary: CN105

Ergotamine, Caffeine, and Diphenhydramine
Primary: CN105


Note: Controlled substance classification—

Canada—Ergotamine, Belladonna Alkaloids, Caffeine, and Pentobarbital—C.
Commonly used brand name(s): Cafergot3; Cafergot-PB5; Cafertine3; Cafetrate3; D.H.E. 451; Dihydroergotamine-Sandoz1; Ercaf3; Ergo-Caff3; Ergodryl8; Ergomar2; Ergostat2; Gotamine3; Gravergol7; Gynergen2; Medihaler Ergotamine2; Megral6; Migergot3; Wigraine3.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.



Category:


Vascular headache suppressant—Dihydroergotamine; Ergotamine; Ergotamine and Caffeine; Ergotamine, Caffeine, and Belladonna Alkaloids; Ergotamine, Caffeine, Belladonna Alkaloids, and Pentobarbital; Ergotamine, Caffeine, and Cyclizine; Ergotamine, Caffeine, and Dimenhydrinate; Ergotamine, Caffeine, and Diphenhydramine;

Thrombosis prophylaxis adjunct—Dihydroergotamine;

Antihypotensive—Dihydroergotamine
Note: Some headache specialists question the validity of the term ``vascular headache'' because a correlation between dilatation of cerebral blood vessels and symptoms of migraine or cluster headaches has not been demonstrated conclusively. {87}5 A clinical distinction between vascular, tension-type, and coexisting migraine and tension-type (``mixed'') headaches may be difficult to ascertain in some patients. {87}4

;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Headache, vascular (treatment)—Ergot derivative–containing headache suppressants are indicated in the treatment of vascular headaches, such as migraine (with or without aura), cluster headache (histaminic cephalalgia, migrainous neuralgia, ciliary neuralgia, Horton's headache), and migraine variants. {87}3 {87}2 {87}1 {87}0 {92}9 {92}8 {92}7 {92}6 {92}5 {92}4 {92}3 {92}2 {92}1 {92}0
—For migraine: Ergot derivative–containing headache suppressants are used to relieve (abort) acute migraine headaches {14}9 {14}8 in patients who report that sufficient relief is not obtained with analgesics (e.g., acetaminophen, aspirin, other nonsteroidal anti-inflammatory drugs [NSAIDs]). {14}7 {14}6 {14}5 When incapacitating migraines occur more frequently than twice a month, {14}4 {14}3 {14}2 additional prophylactic treatment is recommended to reduce the severity and duration, as well as the number, of headaches. However, too frequent use of an ergotamine–containing headache suppressant may cause tolerance, leading to decreased efficacy, and physical dependence, leading to more frequent headaches (including withdrawal [rebound] headaches and chronic, intractable headaches) and medication abuse. {14}1 {14}0 {76}9 {76}8 {76}7 {76}6 {76}5 {76}4 {76}3 Chronic use of ergot derivatives may also cause peripheral vasospasm, which may lead to arterial insufficiency, ischemia, and even gangrene. {76}2 {76}1 {76}0 {87}9 {87}8 {87}7 Therefore, these agents are not recommended for long-term migraine prophylaxis. {87}6 {87}5 {87}4 {87}3 {87}2 {87}1 Beta-adrenergic blocking agents, {87}0 {92}9 {92}8 {92}7 {92}6 calcium channel blocking agents, {92}5 {92}4 {92}3 {92}2 {92}1 tricyclic antidepressants, {92}0 {76}9 {76}8 {76}7 {76}6 monoamine oxidase inhibitors, {76}5 {76}4 {76}3 {76}2 {76}1 methysergide, {76}0 {87}9 {87}8 {87}7 {87}6 pizotyline (pizotifen [not commercially available in the U.S.]), {87}5 {87}4 and sometimes cyproheptadine {87}3 {87}2 {87}1 {87}0 (especially in children) {92}9 are used for prophylaxis.
—Parenteral dihydroergotamine is used for rapid relief of severe, refractory migraine, including status migrainosus {92}8 {92}7 {92}6 {92}5 {92}4 {92}3 and chronic, intractable headaches resulting from overuse of ergotamine or analgesics. {92}2 Some physicians consider it the treatment of choice in status migrainosus. {92}1 Prophylactic treatment may also be needed to reduce recurrences. {92}0 {24}
—For cluster headache: Ergot derivative–containing headache suppressants are indicated to abort headaches in patients who experience episodic or chronic cluster headaches. {15} {19} {21} {22} {24} These headaches may occur daily, often more than once a day, for several months (a cluster period), followed by a headache-free interval. {15} {19} {20} {21} Cluster headaches often are unresponsive to simple analgesics. {19} Prophylactic therapy is advisable during cluster periods, but many of the agents commonly used for migraine prophylaxis are ineffective in reducing the frequency or severity of cluster headaches (especially chronic cluster headaches), or lose efficacy after 1 or 2 cluster periods. {19} {21} [Ergotamine is therefore used prophylactically during cluster periods]1 , alone or concurrently with a calcium channel blocking agent, usually verapamil, and/or lithium. {15} {17} {20} {21} Prophylactic administration of ergotamine during cluster periods is not likely to cause dependence of the type associated with its chronic use by migraine patients. {21} {76}
—Ergot derivative–containing headache suppressants are generally not used in the treatment of chronic paroxysmal hemicrania, a cluster headache variant. Indomethacin is highly effective in relieving and preventing these headaches, {15} {19} {20} {21} and is considered the agent of choice for management of this condition. {21}

Note: Other measures that may reduce the need for medication in headache patients include identification and avoidance of headache precipitants (for migraine or cluster headaches) {18} {19} {20} {21} and relaxation and/or biofeedback techniques (for migraine). {18}


[Thrombosis, deep venous (prophylaxis adjunct)]1and
[Thromboembolism, pulmonary (prophylaxis adjunct)]1—Dihydroergotamine is used in combination with low-dose heparin for the prevention of postoperative deep-vein thrombosis and pulmonary embolism following elective orthopedic procedures, such as total hip replacement, or major abdominal, thoracic, or pelvic surgery. {25} {26} {27} {28} {29} {30} Prophylactic therapy with heparin is generally reserved for high-risk patients, such as patients with a history of thromboembolism or patients requiring prolonged immobilization following surgery, especially if they are 40 years of age or older. {31} The combination of dihydroergotamine and heparin may be more effective than low-dose heparin alone in some cases, e.g., in hip replacement surgery. {27} {28} {29} However, this combination of medications has been reported to cause serious complications, including severe peripheral ischemia, probably resulting from dihydroergotamine-induced vasospasm. {32} {33} {34} {35} Especially careful patient selection and careful monitoring throughout therapy are required to reduce the risk of such complications. {34}

[Hypotension, orthostatic (prophylaxis and treatment)]1—Dihydroergotamine is used to prevent or treat orthostatic hypotension that may occur in conjunction with spinal or epidural anesthesia. {36} It is also used to treat orthostatic hypotension due to autonomic insufficiency or other causes. {37} {38} {39} {40} {41}

Unaccepted
Dihydroergotamine, ergotamine, and ergotamine-containing combinations are not recommended for long-term migraine prophylaxis. {04} {06} {08} {09} {10} {15}

Although ergotamine has oxytocic effects, it is not used clinically to produce these effects because other ergot alkaloids are more effective and less toxic. {16}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Pharmacology/pharmacokinetics information for the adjuvants present in headache suppressant formulations (caffeine, belladonna alkaloids, cyclizine, dimenhydrinate, diphenhydramine, and pentobarbital) is limited to brief descriptions of the effects that may be pertinent to treatment of patients with vascular headaches. Gastric stasis that accompanies migraine headaches tends to inhibit absorption of orally administered medications and may therefore alter their pharmacokinetic profiles. {19} {42} For additional information on the actions of these agents, see—
Caffeine: Caffeine (Systemic) .
Belladonna alkaloids: Anticholinergics/Antispasmodics (Systemic) .
Cyclizine: Cyclizine (Systemic) .
Dimenhydrinate: Antihistamines (Systemic) .
Diphenhydramine: Antihistamines (Systemic) .
Pentobarbital: Barbiturates (Systemic) .


Physicochemical characteristics:
Source—
{43}    Dihydroergotamine: Synthetic
    Ergotamine: Semisynthetic alkaloid; derived from ergot, a product of the parasitic fungus Claviceps purpurea
Molecular weight—
{44}    Dihydroergotamine mesylate: 679.79
    Ergotamine tartrate: 1313.43
    Caffeine: 194.19
    Cyclizine hydrochloride: 302.85
    Dimenhydrinate: 469.97
    Diphenhydramine hydrochloride: 291.82
    Pentobarbital sodium: 248.26

Mechanism of action/Effect:


Dihydroergotamine and Ergotamine:

These ergot derivatives interact with several neurotransmitter receptors, including alpha-adrenergic, serotonergic (tryptaminergic), and dopaminergic receptors. {04} {16} {18} Both agonistic (or partial agonistic) and antagonistic actions have been reported at different receptor types or subtypes. {04} {16} {45} {46} These medications directly stimulate vascular smooth muscle, {02} {04} {07} {08} {10} causing constriction of both arteries and veins, {03} {04} {16} and depress vasomotor centers in the brain. {03} {04} {07} {08} Dihydroergotamine's adrenergic blocking actions are somewhat more pronounced, and its vasoconstrictive actions (especially in arteries) are less pronounced, than those of ergotamine. {01} {02} {15}


Vascular headache suppressant—

Ergot derivative–induced decreases in the firing of serotonergic (5-hydroxytryptaminergic, 5-HT) neurons may be responsible for headache suppression. {82} Specifically, it is thought that agonist activity at the 5-HT 1D receptor subtype provides relief of acute headache, whereas antagonist activity at the 5-HT 2 receptor subtype provides headache prophylaxis. {45} {46} It has been proposed that constriction of cerebral blood vessels by the ergot derivative (resulting from alpha-adrenergic stimulation as well as from activity at 5-HT receptors) reduces the pulsation in cerebral arteries that may be responsible for the pain of vascular headaches. {03} {04} {10} {15} {16} {18} However, studies have not consistently shown a significant correlation between dilatation of cerebral blood vessels and pain or other symptoms of migraine or cluster headaches, or between the vasoconstrictive effect of an ergot derivative and relief of these headaches. {82}

Dihydroergotamine and ergotamine may decrease hyperperfusion in the area of the basilar artery, {16} but they do not reduce cerebral hemispheric blood flow. {03} {04} {16}



Thrombosis prophylaxis adjunct and Antihypotensive—

Dihydroergotamine's constrictive effect on capacitance (venous) vasculature is significantly greater than its constrictive effect on resistance (arterial) vasculature. As a result, the velocity of venous blood flow in the legs is increased, venous return to the heart is enhanced, venous pooling (which may increase the risk of thrombus formation) is reduced, and arterial blood pressure is maintained or increased. {02} {16} {25} {29} {30} {37} It has also been proposed that dihydroergotamine may enhance the effects of heparin in preventing thrombosis. {47}




Caffeine:

Caffeine constricts the cerebral vasculature and decreases both cerebral blood flow and the oxygen tension of the brain. {16} However, it is believed that the caffeine in many ergotamine-containing formulations acts primarily by increasing both the rate and extent of absorption of orally or rectally administered ergotamine, {07} {08} {15} {17} {18} {19} {20} {37} thereby hastening the onset of action and increasing the effect of ergotamine. {08} {37}



Belladonna alkaloids:

Belladonna alkaloids are used in headache suppressant formulations for their antiemetic effects, because nausea and vomiting may occur in association with the migraine headache and/or as a result of ergotamine administration. {07}



Cyclizine and Dimenhydrinate and Diphenhydramine:

These antihistamines are used in headache suppressant formulations for their antiemetic and sedative effects.



Pentobarbital:

This barbiturate is used in headache suppressant formulations for its sedative effects. {07}



Other actions/effects:


Dihydroergotamine and Ergotamine:

These medications may cause nausea and vomiting via direct stimulation of the chemoreceptor trigger zone. {19}

Like other ergot derivatives, dihydroergotamine and ergotamine stimulate uterine smooth muscle {03} {04} {16} via an action on alpha-adrenergic receptors and/or 5-HT receptors. {16} Ergotamine is much more potent than dihydroergotamine as a uterine stimulant. {16}

Peripheral vasoconstriction induced by dihydroergotamine and ergotamine may lead to decreased blood flow in various organs, {03} {04} increased peripheral vascular resistance, and increased blood pressure. {03} {04} {05} {16} However, with the doses usually used in the treatment of migraine or cluster headaches, increases in blood pressure are usually slight. {03} {04} {16}

Large doses of dihydroergotamine and ergotamine may cause constriction of the coronary vasculature and bradycardia. These effects may result from increased vagal activity as well as direct actions on the myocardium and the vasculature. {05} {37}



Caffeine:

Caffeine has central nervous system (CNS) stimulant activity and may therefore inhibit sleep. Because sleep contributes to relief of migraine headaches, this action may be detrimental to the patient. {19}



Belladonna alkaloids:

Belladonna alkaloids have anticholinergic activity. {37}



Cyclizine and Dimenhydrinate and Diphenhydramine:

These medications have antihistaminic, anticholinergic, and CNS depressant activities. {37}



Pentobarbital:

Barbiturates have CNS depressant activity. {15} {37}


Absorption:


Dihydroergotamine:

Intramuscular or subcutaneous: Rapid. {42} {48}



Ergotamine:

Oral: Slow, incomplete, {10} {15} {16} {37} {43} and subject to wide interpatient variability. {43} Absorption is inhibited by the gastric stasis that accompanies migraine headaches. {19} {42} Concurrent administration of caffeine increases the rate and extent of absorption. {08} {15} {17} {18} {37} {42} Metoclopramide may also increase ergotamine absorption by accelerating gastrointestinal motility (and may also be useful as an antiemetic). {15} {42} Extensive first-pass metabolism of ergotamine also reduces bioavailability. {16} {37}

Rectal: More rapid and extensive than after oral administration; {15} {16} increased by concurrent administration of caffeine. {08} {16}

Sublingual: Very poor. {15} {16} {42}


Distribution:

Ergotamine is distributed into breast milk. {03} {04} {37}

Protein binding:


Dihydroergotamine:

Very high (about 90%). {37}



Ergotamine:

Very high (93 to 98%). {08} {10}


Biotransformation:


Dihydroergotamine:

Hepatic; extensive, {02} {15} {37} with considerable first-pass metabolism. {15} The principal metabolite, 8´-hydroxy-dihydroergotamine, is pharmacologically active. {15} {83}



Ergotamine:

Hepatic; {03} {04} {08} {10} {16} {37} extensive, {08} {37} with considerable first-pass metabolism. {16} {37} At least some of the metabolites are pharmacologically active. {15}


Half-life:

Note: Reported values vary widely, depending on the route of administration and study methodology. {42} {43} {48} {84} Values obtained after administration of radiolabeled dihydroergotamine or ergotamine represent metabolites as well as the parent compound, whereas values determined via specific radioimmunoassay (RIA) represent only the parent compound. {42} {43} At least 2 RIAs have been used to assess pharmacokinetics of dihydroergotamine, one of which is more sensitive (able to detect significantly smaller quantities of the compound) than the other. {84}



Distribution:


Dihydroergotamine—

Intravenous—1 to 1.35 minutes in one study; {42} 4 minutes in a second study. {84} Different doses and RIAs were used in the 2 studies.

Subcutaneous—Approximately 1 hour, measured via RIA. {48}



Ergotamine—

2.7 hours, determined following oral administration of radiolabeled ergotamine. {08} {37} {42}




Elimination:


Dihydroergotamine—

Intravenous—

Alpha phase: Approximately 23 to 33 minutes in one study; {42} 1.45 hours in a second study. {84} Different doses and RIAs were used in the 2 studies.

Beta phase: Approximately 15 hours, measured via the more sensitive RIA. {84}

Subcutaneous—About 7.25 hours, measured via RIA. {48}

Values ranging between 18 and 32 hours have been reported after administration of radiolabeled dihydroergotamine by various routes. {02} {15} {37}



Ergotamine: Determined after oral administration of radiolabeled ergotamine—

Alpha phase: Approximately 2 hours. {03} {04}

Beta phase: Approximately 21 hours. {08} {10} {37} {42}



Onset of action:


Acute headaches:

Note: For relief of acute migraine or cluster headaches, the onset of action is highly dependent on the duration of the headache prior to initiation of therapy {03} {04} {15} {16} {18} as well as on the route of administration. The most rapid onset of action is achieved when the medication is administered as soon as the first symptoms appear (during the prodrome, for migraine with aura). {03} {04} {16} {18}



Dihydroergotamine—

Intramuscular—15 to 30 minutes. {01} {02}

Intravenous—Variable; usually less {85} than 5 minutes. {76}



Time to peak concentration:


Dihydroergotamine:

Intramuscular: About 30 minutes. {42}

Intravenous: About 3 minutes. {42}

Subcutaneous: 15 {48} to 45 minutes. {42} {48}



Ergotamine:

Oral, administered without caffeine: About 2 hours. {42}

Oral, administered concurrently with caffeine: About 60 {49} to 70 {15} {16} minutes.

Rectal, administered concurrently with caffeine: About 1 hour. {42}

Note: The pharmacokinetics of ergotamine after oral or rectal administration have been studied in healthy subjects {15} {16} and in migraine patients who were not experiencing an attack at the time of the study. {42} {49} During a migraine headache, peak concentrations after oral administration are likely to occur less rapidly than reported above, because the gastric stasis that accompanies migraine headaches inhibits absorption of medications. {19} {42}
In a study investigating the association between pharmacokinetic variables and efficacy of ergotamine in migraine patients who were not experiencing an attack at the time of the study, plasma concentrations measured after a single oral or rectal dose of each patient's usual ergotamine-containing medication were subject to wide interindividual variability. Peak plasma concentrations of ergotamine occurred earlier, were higher, and were maintained for a longer time in patients who reported a good therapeutic response to their medications than in patients who reported a poor therapeutic response to the same medications. In most patients reporting a good therapeutic response, plasma concentrations of 200 picograms per mL or higher were measured within 1 hour after administration. {49}



Time to peak effect


Relief of acute headache:

Dihydroergotamine: Parenteral—15 minutes to 2 hours. {16}

Ergotamine: Oral—Variable; usually within 1 to 2 hours, {94} but up to 5 hours in some patients. {16}


Duration of action:


Dihydroergotamine—Vasoconstrictive and antihypotensive effects:

About 8 hours, following intravenous or subcutaneous administration. {83}


Elimination:


Dihydroergotamine—
        Primarily via hepatic metabolism, followed by fecal (biliary) elimination of metabolites. {37} Only 5 {48} to 10% {37} of a dose is excreted in the urine, with only trace amounts being excreted in the urine as unchanged dihydroergotamine. {15}



Ergotamine—
        Primarily via hepatic metabolism, followed by fecal (biliary) elimination of metabolites. {15} About 4% of an oral dose is excreted in the urine {15} {37} within 96 hours. {37} Only trace amounts are eliminated in the urine and feces as unmetabolized ergotamine. {03} {04} {16} After sublingual administration, ergotamine is also eliminated, erratically, in saliva. {03} {04}
        In dialysis—Ergotamine is dialyzable. {03} {37}



Precautions to Consider

Note: Information in this section concerning the adjuvants present in ergotamine-containing headache suppressant formulations (caffeine, belladonna alkaloids, cyclizine, dimenhydrinate, diphenhydramine, and pentobarbital) is limited to brief summaries of the major precautions that may apply to their use in doses recommended for treatment of vascular headaches. For more complete information that may apply, especially if these agents are ingested frequently or in higher-than-recommended doses, see—
Caffeine: Caffeine (Systemic) .
Belladonna alkaloids: Anticholinergics/Antispasmodics (Systemic) .
Cyclizine: Cyclizine (Systemic) .
Dimenhydrinate: Antihistamines (Systemic) .
Diphenhydramine: Antihistamines (Systemic) .
Pentobarbital: Barbiturates (Systemic) .


Mutagenicity


Dimenhydrinate:

Mutagenicity screening tests showed dimenhydrinate to be mutagenic in bacterial systems, but not mammalian systems. There are no human data showing that the medication is mutagenic. {51}


Pregnancy/Reproduction

Note: Information concerning use of adjuvants present in ergotamine-containing combinations by pregnant women is not included in this section because the potential adverse effects of ergotamine preclude the use of these combinations during pregnancy.


Pregnancy—

Dihydroergotamine

Use during pregnancy is not recommended because dihydroergotamine stimulates the uterine musculature, {01} {02} although it has much less oxytocic activity than ergotamine. {37} Also, constriction of the placental vasculature may cause fetotoxicity by reducing uterine blood flow. {15}



Ergotamine

Use during pregnancy is not recommended because of ergotamine's potent oxytocic activity. {03} {04} {05} {06} {07} {08} {09} {10} {15} {18} Ergotamine's uterine stimulating action {03} {04} and its vasoconstrictive activity, {03} {04} {10} which may lead to reduced uterine blood flow, {15} may both be harmful to the fetus. Although a definite causal relationship has not been established, use of ergotamine by pregnant women may have caused fetal growth retardation, intrauterine fetal deaths, miscarriages, and intestinal obstruction resulting in the death of a neonate. {52} {53}

In animal studies, ergotamine has caused retarded fetal growth and increases in the number of resorptions and intrauterine deaths. {03} {04}

FDA Pregnancy Category X. {03}


Dihydroergotamine and Ergotamine
Ergot alkaloids are distributed into breast milk and have the potential to cause adverse effects (e.g., vomiting, diarrhea, weak pulse, unstable blood pressure, seizures) in the infant. These medications may also inhibit lactation. {03} {04} {06} {08} {09} {10}


Caffeine:

Caffeine is distributed into breast milk in small amounts. However, it is recommended that breast-feeding mothers limit their total daily intake of caffeine to 360 mg, because accumulation of caffeine in the infant, leading to hyperactivity, wakefulness, and other signs of caffeine stimulation, may occur when a breast-feeding mother ingests large quantities of caffeine. {54}



Belladonna alkaloids and Cyclizine and Dimenhydrinate and Diphenhydramine:

Because of their anticholinergic activity, these medications have the potential to inhibit lactation. {37} Dimenhydrinate is distributed into breast milk in small amounts. {51} Cyclizine may also be distributed into breast milk. {37}



Pentobarbital:

Barbiturates are distributed into breast milk in small amounts and may cause sedation or other signs of CNS depression in the infant. {55}


Pediatrics


Dihydroergotamine:

Although appropriate studies have not been done in the pediatric population, dihydroergotamine is being used to treat severe migraine headache in children as young as 6 years of age. No pediatrics-specific problems have been reported. {56} {76} However, it is recommended that an ergot derivative be used with caution and only in patients who are unresponsive to less toxic medications. {15}



Ergotamine:

Ergotamine is being used in patients 6 years of age and older. {08} {09} {76} No pediatrics-specific problems have been documented to date. However, it is recommended that an ergot derivative be used with caution and only in patients who are unresponsive to less toxic medications. {15}



Caffeine:

Appropriate studies on the relationship of age to the effects of caffeine have not been performed in children up to 12 years of age. However, no pediatrics-specific problems have been documented to date.



Belladonna alkaloids:

Young children are especially susceptible to the toxic effects of anticholinergics. {15} {37} An increased response to anticholinergics has been reported in children with spastic paralysis or brain damage. {37}



Cyclizine and Dimenhydrinate and Diphenhydramine:

A paradoxical reaction characterized by hyperexcitability may occur in children taking antihistamines. {37}



Pentobarbital:

Some children react to barbiturates with paradoxical excitement. {15}



Geriatrics



Dihydroergotamine and Ergotamine:

Caution is recommended in the elderly, {20} who are more likely to have occlusive peripheral vascular disease, and are therefore more likely to be adversely affected by peripheral vasoconstriction, than are younger adults. This increases the risk of hypothermia and other ischemic complications. The risk of cardiac ischemia is also increased in geriatric patients. {86} Elderly patients are also more likely to have age-related renal function impairment, which requires caution in patients receiving these medications. {57}



Belladonna alkaloids:

Geriatric patients may respond to usual doses of these medications with excitement, agitation, drowsiness, or confusion. {37}



Belladonna alkaloids and Cyclizine and Dimenhydrinate and Diphenhydramine:

Caution is recommended when these medications are used in the elderly, who are especially sensitive to anticholinergic side effects. Also, the risk of precipitating undiagnosed glaucoma in the elderly must be considered. {37} Dizziness, sedation, and hypotension are also more likely to occur in elderly patients receiving antihistamines {58} such as cyclizine, dimenhydrinate, and diphenhydramine.



Pentobarbital:

Excitement, depression, and confusion may be more likely to occur in elderly patients, who are generally more susceptible than younger adults to the effects of barbiturates. {55}


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Barbiturates such as pentobarbital induce hepatic chromosomal enzymes and may thereby increase the metabolism and decrease the efficacy of many medications that are metabolized by these enzymes. {55} The most clinically significant interactions have been reported with adrenocorticoids, corticotropin, coumarin- or indandione-derivative anticoagulants, anticonvulsants (carbamazepine, divalproex sodium, valproic acid), and estrogen-containing oral contraceptives (see Barbiturates [Systemic] ). Although occasional use of a pentobarbital-containing headache suppressant may not cause significant interference with the effects of most of these agents, selection of a formulation that does not contain pentobarbital may be advisable in some cases. {76}


For dihydroergotamine and ergotamine
Antibiotics, macrolide, especially

Erythromycin
Troleandomycin    (these antibiotics may inhibit the metabolism of the ergot derivative and increase the risk of vasospasm {02} {03} {04} {06} {08} {09} {10} {37} {59})


Beta-adrenergic blocking agents    (peripheral vasoconstriction and vasospastic reactions have occurred in a few patients receiving a beta-adrenergic blocking agent for migraine prophylaxis after administration of usual doses of dihydroergotamine {60} or ergotamine; {04} {08} {10} {61} {62} although most patients are able to tolerate the combination of medications without ill effects, closer monitoring of patients receiving both types of medication may be warranted {61})


» Ergot alkaloids, other or
» Vasoconstrictors, systemic, other, such as:
Cocaine
Epinephrine, parenteral
Metaraminol
Methoxamine
Norepinephrine
Phenylephrine, parenteral or
» Vasoconstrictor-containing local anesthetic solutions    (concurrent use with dihydroergotamine or ergotamine may produce peripheral vascular ischemia and gangrene and is not recommended {76})

    (the pressor effect of sympathomimetic pressor amines may be potentiated, resulting in possible severe hypertension and rupture of cerebral blood vessels {03})


Nitroglycerin    (the vasoconstrictive effect of dihydroergotamine or ergotamine may oppose the vasodilating effect of nitroglycerin, thereby reducing nitroglycerin's efficacy as an antianginal agent {61})

    (nitroglycerin may also reduce hepatic metabolism of dihydroergotamine {61})


Smoking, tobacco    (administration of ergotamine to a patient who smokes heavily may increase the risk of peripheral vascular ischemia because nicotine also constricts blood vessels {76})


For formulations containing caffeine
Caffeine from any other dietary or medicinal source or
CNS stimulation–producing medications, other (See Appendix II )    (excessive CNS stimulation, which may lead to nervousness, irritability, insomnia, or possibly convulsions or cardiac arrhythmias, may occur; close observation is recommended)


Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine and selegiline    (the sympathomimetic side effects of caffeine may lead to cardiac arrhythmias or severe hypertension when large doses are used concurrently with MAO inhibitors; even small doses may cause tachycardia and a slight increase in blood pressure {63})


For formulations containing belladonna alkaloids, cyclizine, dimenhydrinate, diphenhydramine, or pentobarbital
Anticholinergics or other medications with anticholinergic activity, other (See Appendix II ) or
CNS depression–producing medications, other (See Appendix II ), including alcohol    (the risk of additive anticholinergic effects must be considered when any medication having anticholinergic activity is used concurrently with belladonna alkaloids, cyclizine, dimenhydrinate, or diphenhydramine {51} {58})

    (the risk of additive CNS depression must be considered when any medication having CNS depressant activity is used concurrently with cyclizine, dimenhydrinate, diphenhydramine, or pentobarbital {51} {55} {58})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
For belladonna alkaloids
» Gastric acid secretion test    (belladonna alkaloids may antagonize the effects of pentagastrin and histamine in the evaluation of gastric acid secretory function; administration of belladonna alkaloids during the 24 hours preceding the test is not recommended {37})

For caffeine
Myocardial perfusion studies, dipyridamole-assisted    (caffeine may inhibit the effects of dipyridamole on myocardial blood flow, thereby interfering with test results; patients should be advised to avoid caffeine for at least 12 hours prior to the test {64} {65} {66} {68})


Urate, serum, determinations    (false-positive elevations may occur when measured by the Bittner method {67})

For cyclizine, dimenhydrinate, and diphenhydramine
Skin tests using allergen extracts    (cyclizine, dimenhydrinate, and diphenhydramine may inhibit the cutaneous histamine response, thereby producing false-negative results; it is recommended that these medications not be administered for at least 72 hours before testing {37})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:

For dihydroergotamine and ergotamine:
» Angioplasty, recent or contemplated or
» Vascular surgery, especially arterial, recent or contemplated    (increased risk of ischemia {47})


» Hypertension, severe, uncontrolled    (may be aggravated {24})


Risk-benefit should be considered when the following medical problems exist

For dihydroergotamine and ergotamine:
Allergic reaction to dihydroergotamine or ergotamine, history of
» Coronary artery disease,{01}{02}{03}{04}{05}{06}{07}{08}{09}{10}{37} especially:
» Angina pectoris, unstable or vasospastic,{04}{06}{15}{18} or other indication of coronary ischemia{15}{18}    (vasospasm may aggravate existing angina pectoris, or cause angina pectoris or myocardial infarction)


Diarrhea—for suppository dosage forms{18}    (impaired absorption of medications)


» Hepatic function impairment{01}{02}{03}{04}{05}{06}{07}{08}{09}{10}{15}{18}    (impaired metabolism may result in ergot poisoning)


» Hypertension, not optimally controlled{01}{02}{03}{04}{05}{06}{07}{08}{09}{10}{15}{24}{37}    (may be aggravated)


Hyperthyroidism{87}    (possible increased risk of ergotism)


Malnutrition{02}{04}{05}{06}{10}{15}{88}    (risk of ergotism may be increased because malnutrition-associated metabolic disturbances may lead to increased concentrations of the ergot derivative and/or to hyperreactivity to the medication)


» Peripheral vascular disease, occlusive, or{01}{02}{03}{04}{05}{06}{07}{08}{09}{10}{15}{18}
» Pruritus, severe, especially when associated with hepatic disease,{02}{03}{04}{06}{10} or
» Sepsis or other severe infection{01}{02}{03}{04}{05}{06}{07}{08}{09}{10}{15}{18}    (increased risk of complications associated with vasospasm)


» Renal function impairment{01}{02}{03}{04}{05}{06}{07}{08}{09}{10}{15}{18}
Caution is also recommended in geriatric patients, who may be especially susceptible to complications associated with vasospasm and to hypothermia.
For dihydroergotamine only, when used concurrently with low-dose heparin for prophylaxis against perioperative thrombotic complications (in addition to the medical problems listed above):
» Trauma    (increased risk of vasospastic reactions, especially in an injured extremity of patients with multiple fractures {37} {69})


For formulations containing caffeine:
» Anxiety disorders, including
Agoraphobia
Panic attacks    (increased risk of anxiety, nervousness, fear, nausea, palpitation, rapid heartbeat, restlessness, and trembling {70})


» Cardiac disease, severe    (high doses of caffeine are not recommended because of an increased risk of tachycardia or extrasystoles, which may lead to heart failure)


» Insomnia    (may be potentiated; this effect may be particularly detrimental to patients with a vascular headache, because sleep also helps relieve headache {19})


» Peptic ulcer    (may be aggravated {37})


Sensitivity to caffeine
For formulations containing belladonna alkaloids, cyclizine, dimenhydrinate, or diphenhydramine:
Any condition in which the anticholinergic effects of these medications may be detrimental,{37} such as:
Bladder neck obstruction
Gastrointestinal tract obstructive disease
Glaucoma, not optimally controlled, or predisposition to
Prostatic hypertrophy
Urinary retention
Sensitivity to the agent considered for use

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure    (close monitoring is recommended when multiple doses of dihydroergotamine are administered for relief of chronic, intractable headache; antihypertensive therapy may be needed to assure that the patient is normotensive when each dose is given and/or to treat any rise in blood pressure that occurs after dihydroergotamine administration {24})


Electrocardiographic monitoring    (recommended, especially during the first few doses in patients older than 60 years of age, when multiple doses of dihydroergotamine are administered intravenously for relief of chronic, intractable headache {83} {92})


Examination of extremities and
Palpation of peripheral pulses    (recommended periodically during therapy to detect vasospasm or ischemia in patients using frequent doses, especially when dihydroergotamine is administered daily as an adjunct to heparin prophylaxis against postoperative thrombotic complications or to treat orthostatic hypotension {71} and when multiple doses of dihydroergotamine are administered intravenously for relief of chronic, intractable headache {92})




Side/Adverse Effects

Note: Most side/adverse effects are dose-related and are usually relieved by a reduction in dose or withdrawal of the medication. {24} {37}
Although acute ergot poisoning is rare, patient sensitivity to the effects of ergotamine varies widely and symptoms of ergot toxicity (peripheral ischemia, paresthesia, headache, nausea and vomiting) may occur even with usual doses. {04} {07} {37}
Nausea and vomiting may be caused by migraine headaches as well as by an ergot derivative. {06} {15} {19}
The risk of side effects being induced by recommended doses of the adjuvants in ergotamine-containing combination formulations has not been determined. In general, it is expected that such effects, even in overdose situations, would be overshadowed by those of ergotamine. {07} However, with acute overdose of formulations containing belladonna alkaloids, cyclizine, dimenhydrinate, or diphenhydramine, the possibility of severe symptoms associated with their anticholinergic activity should be considered. Also, with acute overdose of formulations containing pentobarbital, the possibility of severe CNS depression should be considered.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Edema, localized (swelling of face, fingers, feet, and/or lower legs)

Incidence less frequent or rare
    
Cardiovascular effects, specifically angina pectoris, coronary vasospasm–induced{01}{02}{03}{04}{05}{06}{07} (chest pain)
    
fast or slow heartbeat{03}{04}{08}{10}{37}
    
increase or decrease in blood pressure{03}{04}{07}{08}{10}
    
rapid, weak pulse{08}{10}
    
ischemia, cerebral{15} (anxiety, confusion)
    
ischemia, peripheral vasospasm–induced{01}{02}{03}{04}{05}{06}{07}{08}{09}{10}{15}{37} (itching of skin; numbness and tingling of fingers, toes, or face; pain in arms, legs, or lower back, especially pain in calves and/or heels upon exertion; pale, bluish-colored, or cold hands or feet; weak or absent pulses; weakness in legs)
    
and vasospasm, ocular{04}{06} (changes in vision; miosis)
Note: Myocardial infarction and cerebral infarction have also been reported. {04} {15}





Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
CNS effects (dizziness or drowsiness occurring without other signs and symptoms of overdose [especially with formulations containing cyclizine, dimenhydrinate, diphenhydramine, or pentobarbital]; {03}{07}{08}{10}rarely, nervousness, racing thoughts, and restlessness)—these dysphoric effects may be especially severe with repetitive administration of intravenous dihydroergotamine and metoclopramide for intractable headaches{15}
    
dryness of mouth —especially likely with formulations containing belladonna alkaloids
    
may also occur with formulations containing cyclizine, dimenhydrinate, or diphenhydramine
    
diarrhea, nausea, or vomiting —occurring without other signs and symptoms of overdose{03}{04}{07}{08}{10}
    
peripheral vascular effects, mild and lasting 1 hour or less (cold fingers or toes,{01}{02}{03}{04}{05}{06}{07} itching of skin,{03}{04}{05}{07} numbness or tingling of fingers or toes{03}{04}{08}{09}{10}{12} , weakness in the legs{01}{02} occurring without other signs and symptoms of ischemia)



Those indicating possible withdrawal and the need for medical attention if they occur after medication is discontinued
    
Headache —severe withdrawal (rebound) headaches may occur in migraineurs who overuse ergotamine; they are generally most severe for the first 24 to 48 hours, and usually last about 72 hours, after the last dose of ergotamine,{87} and may lead to increased use of ergotamine and/or analgesics{03}{04}{07}{16}{17}{18}{24} , dependence, and chronic, intractable headaches{15}{16}




Overdose
For specific information on the agents used in the management of vascular headache, suppressants, ergot derivative-containing overdose, see
   • Charcoal, Activated (Oral-Local) monograph;
   • Diazepam or Lorazepam in Benzodiazepines (Systemic) monograph;
   • Ipecac (Oral-Local) monograph;
   • Neostigmine in Antimyasthenics (Systemic) monograph;
   • Nitroglycerin in Nitrates (Systemic) monograph;
   • Nitroprusside (Systemic) monograph; and/or
   • Physostigmine (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose

Note: Cerebral ischemia and/or peripheral ischemia may be signs of acute or chronic overdose. {07} {15} {37} {43} Continued chronic use of an ergot derivative after early signs and symptoms of peripheral ischemia appear may lead to gangrene (red or violet blisters on skin of hands or feet may be first signs) {03} {04} {06} {07} {15} {16} {37} {43} or to thrombotic complications. {04} {16} {43}
In addition to vision changes associated with ocular vasospasm listed above, one case of reversible bilateral papillitis with ring scotomata has been reported in chronic overdose. {07}

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
CNS toxicity{03}{04}{07}{08}{10} (convulsions; severe confusion, dizziness, or drowsiness; weakness; one-sided paralysis; loss of consciousness)
    
diarrhea, vomiting, stomach pain or bloating{03}{04}{07}{08}{10}
    
respiratory depression{04}{10} (shortness of breath)
Note: After an acute overdose has been ingested, CNS and gastrointestinal manifestations, hypotension, and tachycardia may occur within a few hours, but signs and symptoms of peripheral ischemia may not appear until the next day. {89}
Hypotension and sometimes shock {03} {04} {07} {08} {10} may occur following initial hypertension.



Chronic
    
Fibrosis, pleural or retroperitoneal{72}{73}{74}{75} (shortness of breath; chest pain)—reported in isolated patients
    
loss of appetite
    
nausea or vomiting, severe or continuing{43}
    
headache
    
rectal ulceration (abdominal pain, irregular bowel movements, rectal discomfort, difficulty in moving bowels)
Note: Increased frequency and/or severity of migraine headaches may indicate tolerance to ergotamine. Frequent use of ergotamine by migraineurs may also lead to the development of chronic, intractable headaches with both migrainous and nonmigrainous manifestations. {03} {04} {08} {10} {15} {17} {19} These chronic headaches will not subside as long as ergotamine and/or analgesics continue to be taken. {24} If specific treatment (e.g., intravenous dihydroergotamine) is not given after other headache-aborting medications are discontinued, the headaches usually become worse (being most severe on the third or fourth day) and may persist for 2 weeks or longer. {24}
Rectal ulceration has been reported with chronic overuse of the rectal suppository dosage form of ergotamine and caffeine. {77}




Treatment of overdose
To decrease absorption of orally administered ergotamine— Emesis may be induced with of syrup of ipecac. Alternatively, the stomach may be emptied via gastric lavage, provided that pharyngeal and laryngeal reflexes are present and the patient is conscious. If the patient is unconscious, gastric lavage should be performed only after intubation with a cuffed endotracheal tube has been performed. Activated charcoal, {95} {97} in water or a saline cathartic, {97} such as sodium or magnesium sulfate in water, {04} {08} {10} {97} may then be introduced and left in the stomach.

To enhance elimination—There is no evidence that forced diuresis accelerates elimination of either dihydroergotamine {02} or ergotamine. {04} {08} {10} However, ergotamine is dialyzable. {03}

Specific treatmement—

For convulsions: Administering a benzodiazepine such as diazepam or lorazepam {96} is recommended. The fact that intravenous benzodiazepines may cause circulatory depression when administered intravenously must be kept in mind. See the package inserts or Diazepam or Lorazepam in Benzodiazepines (Systemic) for specific dosing guidelines for use of these products.

For maintaining pulmonary ventilation: Mucus secretions may be removed via pharyngeal and tracheal suction. Oxygen may be administered if necessary, keeping in mind that further respiratory depression and hypercapnia may occur in the presence of hypoventilation hypoxia unless respiration is assisted. Very severe cases may require endotracheal intubation and tracheostomy, with or without assisted respiration. {04} {08} {10}

For hypotension (in acute intoxication, may occur following initial hypertension): Mild to moderate hypotension may respond to positioning the patient in the Trendelenburg position and/or administering intravenous fluids. {04} {08} Volume expanders may be administered if necessary. {08} {10} Vasopressors may be considered if hypotension is very severe, {04} {08} {10} keeping in mind the hazards of administering such substances in the presence of ergot derivative–induced peripheral vasoconstriction.

For peripheral vasospasm or ischemia: Warmth should be applied to ischemic extremities, taking care to avoid excessive heat. {04} {07} {08} {10} If necessary, a vasodilator may be administered, keeping in mind the risk of administering vasodilators in the presence of hypotension. {03} {04} {07} {08} {10} {37} Severe ischemia may require intravenous or intra-arterial nitroprusside; severe coronary ischemia or vasospasm may require intravenous nitroglycerin. {89} Less severe cases may respond to oral vasodilators. Prazosin and captopril have been reported effective in a few patients. See the package inserts or Nitroglycerin in Nitrates (Systemic) or Nitroprusside (Systemic) for specific dosing guidelines for use of these products.

Careful nursing measures designed to prevent tissue damage should be instituted. {04} {08} {10} Anticoagulant therapy may be warranted if ischemia is present, especially if the patient is unconscious {03} {04} {08} {10}; some emergency care physicians recommend low-dose heparin for ergot-induced vasospasm, even when arterial thrombosis has not been documented. {89} {97} Severe ischemia or gangrene unresponsive to treatment may require vascular surgery, catheter dilation, or even amputation. {37}

Monitoring—Monitoring vital signs; monitoring cardiac rhythm (if vital signs are abnormal or the patient has a history of cardiovascular disease). {89}

Supportive care—Supportive measures required to maintain pulmonary ventilation and correct hypotension; and measures to reduce additional absorption of orally ingested ergotamine, if an acute overdose had been ingested within the past 4 hours; {04} {08} {10} and (in both acute and chronic intoxications) measures to ascertain the presence and/or extent of ischemia {89} and to maintain adequate circulation. {03} {04} {07} {08} {10} If no indication of vasospasm or ischemia is present 6 hours or longer {95} following ingestion of an acute overdose, the patient should be informed about typical signs and symptoms, and instructed to seek medical attention immediately if they occur on a delayed basis. {89}


For belladonna alkaloid–containing combinations:
Specific treatment—

Use of physostigmine or neostigmine methylsulfate to reverse severe anticholinergic symptoms {94}. See package inserts or Neostigmine in Antimyasthenics (Systemic) or Physostigmine (Systemic) for specific dosing guidelines for use of these products.



Pentobarbital–containing formulations:
To enhance elimination—If renal function is normal, inducing forced diuresis, which may increase barbiturate elimination. Alkalinization of the urine increases renal excretion of some barbiturates. {76}

Instituting hemodialysis or hemoperfusion in severe barbiturate poisoning or if the patient is anuric or in shock. However, hemodialysis or hemoperfusion is not recommended as a routine procedure. {76}

Specific treatment—Administering chest physiotherapy. If pneumonia is suspected, appropriate cultures should be taken and antibiotics administered. Also, appropriate care should be taken to prevent hypostatic pneumonia, decubiti, aspiration, and other complications that may occur with altered states of consciousness. {76}

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Headache Medicines, Ergot Derivative-containing (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to any ingredient in the product considered for use

Pregnancy—Use is not recommended because ergot derivatives have oxytocic activity, which may lead to miscarriage, and vasoconstrictive activity, which may result in fetotoxicity





Breast-feeding—Ergot alkaloids are distributed into breast milk and may cause adverse effects in the infant; ergot alkaloids and medications having anticholinergic activity (belladonna alkaloids, cyclizine, dimenhydrinate, diphenhydramine) may also inhibit lactation; caffeine and pentobarbital are also distributed into breast milk and may cause CNS stimulation or CNS depression, respectively





Use in children—Pediatrics-specific problems have not been reported in children 6 years of age or older, but dihydroergotamine and ergotamine are recommended only for patients unresponsive to less toxic medications; young children, especially those with spastic paralysis or brain damage, may be especially susceptible to the effects of belladonna alkaloids; also, risk of paradoxical hyperexcitability in children receiving cyclizine, dimenhydrinate, diphenhydramine, or pentobarbital






Use in the elderly—Increased risk of hypothermia and other adverse effects associated with ergot derivative-induced peripheral and coronary vasoconstriction; increased susceptibility to effects of medications with anticholinergic activity and to barbiturates
Other medications, especially other vasoconstrictors (including other ergot alkaloids and vasoconstrictors present in local anesthetic solutions)
Other medical problems, especially angina pectoris or other coronary artery disease, hepatic function impairment, hypertension, severe infection, peripheral vascular disease, pruritus, renal function impairment, and recent or contemplated angioplasty or vascular surgery (for dihydroergotamine and ergotamine); anxiety disorders (e.g., agoraphobia, panic attacks), severe cardiac disease, insomnia, or peptic ulcer (for caffeine-containing formulations)

Proper use of this medication
» Importance of not using more medication than the amount prescribed; risk of habituation with too frequent use and of peripheral vasoconstriction or other signs and symptoms of ergotism with acute or chronic overdosage

» Taking at first sign of headache (prodromal stage, for migraine with aura)

» Lying down in a quiet, dark room after taking initial dose

» Compliance with prophylactic therapy, if prescribed

Proper administration techniques for—

Dihydroergotamine injection

Ergotamine inhalation: Reading patient directions; shaking container after removing cap; exhaling, placing mouthpiece in mouth aimed at back of throat, simultaneously inhaling and pressing vial down into the adapter; holding breath as long as possible after inhaling medication

Ergotamine sublingual tablets: Allowing to dissolve under tongue; not chewing or swallowing whole; not eating, drinking, or smoking while tablet is dissolving

Ergotamine-containing rectal suppositories

If dividing suppository dosage form: Dividing lengthwise into pieces of equal size; easier to accomplish if suppositories have been refrigerated

» Proper dosing

» Proper storage

Precautions while using this medication
» Checking with physician if usual dose fails to relieve headaches, or if frequency and/or severity of headaches increases; possibility that tolerance to or dependence on the medication has developed, leading to withdrawal (rebound) or chronic headaches

Avoiding alcohol, which aggravates headache

Avoiding smoking because nicotine constricts blood vessels

Avoiding exposure to excessive cold, which may intensify peripheral vasoconstriction

Notifying physician if infection develops; severe infection may cause increased sensitivity to medication

For ergotamine inhalation—Possible hoarseness or throat irritation, which may be prevented by gargling and rinsing mouth after use; checking with physician if continuing or bothersome

Possible interferences with laboratory tests; not taking caffeine for 12 hours prior to dipyridamole-assisted myocardial perfusion study, belladonna alkaloids for 24 hours prior to gastric acid secretion test, and cyclizine, dimenhydrinate, or diphenhydramine for 72 hours prior to skin tests using allergen extracts

» For formulations containing cyclizine, dimenhydrinate, diphenhydramine, or pentobarbital

Caution when driving or doing jobs requiring alertness because of possible dizziness, lightheadedness, or drowsiness, especially if taking other CNS depressants concurrently

For formulations containing belladonna alkaloids, cyclizine, dimenhydrinate, or diphenhydramine

Possible dryness of mouth, nose, and throat; using sugarless candy or gum, ice, or saliva substitute for relief


Side/adverse effects
Signs and symptoms of potential side effects, especially edema, fast or slow heartbeat, cerebral or peripheral ischemia, gangrene, and coronary or ocular vasospasm


General Dosing Information
Abortive therapy is most effective when initiated at the first symptoms of a migraine attack {01} {02} {03} {04} {05} {06} {07} {08} {09} {10} {15} {16} {18} (during the prodrome, for migraine with aura). {15} {18} Delay in starting treatment increases the required dose {03} {04} {16} and prolongs the onset of action {16} of the ergot derivative.

After the first dose has been administered, it is recommended that the patient lie down and relax in a quiet, darkened room, {37} because this contributes to relief of migraines. {19}

To reduce the risk of adverse effects, the ergot derivative should be used in the lowest dose that provides adequate relief of headache. {03} {04} {05} {07} {08} {16} However, individual sensitivity to the effects of ergot derivatives varies, and signs and symptoms of toxicity may occur in some patients even with usual doses. {03} {04} {07} {37} Therapy should be withdrawn at the first sign of vasospasm. {15}

Analgesics, antiemetics, antianxiety agents, and/or sedatives may be used concurrently with the ergot derivative, if needed, for relief of an acute migraine attack. {15} {17} {18} {19} Regimens used for relief of severe, refractory migraine utilize metoclopramide {18} {19} {23} {24} or prochlorperazine {19} together with intravenous dihydroergotamine. However, medications having the potential to cause habituation (e.g., opioid analgesics, barbiturates, benzodiazepines) should be used with caution {15} {18} {19} and as infrequently as possible. {19}

Atropine, {03} metoclopramide, {19} {23} {24} {56} or a phenothiazine antiemetic {03} {19} may be administered to prevent or relieve nausea and vomiting induced by an ergot derivative or by the migraine itself.

Tolerance to the effects of ergotamine may develop in migraineurs, leading to an increased dosage requirement, {03} {04} {15} {16} {18} dependence, {03} {04} {15} {19} {24} withdrawal (rebound) or chronic, intractable headaches, {15} {16} {17} {18} {19} and abuse of the medication. {07} {24} {81} The caffeine in many ergotamine-containing formulations may contribute to the development of dependence and withdrawal or chronic, intractable headaches, {78} {79} {80} and the pentobarbital in some formulations may also be habit-forming. {09} However, repetitive administration of intravenous dihydroergotamine over a 2- to 3-day period for treatment of chronic, intractable headaches associated with dependence on ergotamine or analgesics has not been reported to increase or prolong dependence. {76}

To reduce the risk of dependence, it is recommended that ergotamine not be administered to migraine patients more frequently than every fifth day. {18}

For rectal dosage forms only
Ergotamine-containing rectal suppositories are torpedo-shaped and are not scored. To assure proper dosage when a portion of a suppository is to be administered, the suppository should be cut lengthwise into pieces of equal size. This is easier to accomplish when the suppository has been refrigerated. {90}

For treatment of adverse effects
Treatment of headaches associated with dependence on ergotamine may involve:

   • Discontinuation of ergotamine and other headache medications, {19} {23} even acetaminophen or aspirin; {24} {81} in-patient treatment may be necessary during detoxification. {15} {18} {24}
   • Repetitive intravenous administration of dihydroergotamine (in conjunction with metoclopramide) is recommended by some headache specialists to relieve chronic, intractable headaches. {24}
   • Naproxen, alone {15} or together with amitriptyline, {81} may help relieve the headache pain. Overuse of acetaminophen or aspirin, especially in formulations containing caffeine in addition to the analgesic, may have contributed to the development of withdrawal headaches or chronic, intractable headaches; therefore, use of these agents is not recommended. {81}
   • Appropriate treatment for symptoms of withdrawal from other substances frequently used or abused by chronic headache patients may also be needed. {24}
   • Initiation or adjustment of appropriate prophylactic treatment is recommended to reduce the number and severity of future headaches. {24} {83}
   • After a headache-prone patient has been detoxified from ergotamine and/or other abused substances, intramuscular or subcutaneous dihydroergotamine is recommended for treating future acute migraine headaches. {83}

DIHYDROERGOTAMINE

Summary of Differences


Category/indications:
May be agent of choice for treatment of status migrainosus or other severe, refractory headaches, including chronic headaches associated with dependence on ergotamine or analgesics.

Also, indicated as a thrombosis prophylaxis adjunct, being used concurrently with low-dose heparin to prevent postoperative thrombotic complications.

Also, indicated as an antihypotensive, to prevent or treat orthostatic hypotension.



Pharmacology/pharmacokinetics:
Mechanism of action/effects—Adrenergic blocking actions are somewhat more pronounced, and vasoconstrictive actions less pronounced, than those of ergotamine.

Other actions/effects—Much less potent as a uterine stimulant than ergotamine.

Time to peak effect—Relieves acute headache in 15 minutes to 2 hours.

Duration of action—Subcutaneous or intravenous: About 8 hours.



Precautions:
Medical considerations/contraindications—When used concurrently with heparin to prevent postoperative thrombotic complications, caution also needed if trauma of an extremity is present because of the increased risk of vasospastic reactions.

Patient monitoring—

Blood pressure monitoring needed when medication is administered repetitively for treatment of severe, intractable headache.

Examination of extremities and palpation of peripheral pulses recommended when medication is administered daily for prophylaxis against postoperative thrombotic complications (concurrently with heparin) or for treatment of orthostatic hypotension.



Additional Dosing Information
See also General Dosing Information.

Dihydroergotamine is administered via intramuscular, {01} {02} {15} intravenous, {01} {15} {18} {19} {23} {24} {56} or subcutaneous {02} {15} {25} injection. Intra-arterial injection must be avoided. {02}

When dihydroergotamine is used in conjunction with heparin for prophylaxis against postoperative thrombotic complications, all of the precautions pertinent to use of heparin must also be kept in mind. {25}


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

DIHYDROERGOTAMINE MESYLATE INJECTION USP

Usual adult dose
Acute migraine or cluster headache (outpatient treatment)
Intramuscular (preferred) or subcutaneous, 1 mg at the start of the attack. May be repeated in one hour, if needed. {87} The maximum recommended daily dose is 3 mg. {01} {02}

Intravenous, 500 mcg (0.5 mg) at the start of the attack, administered in conjunction with an antiemetic. May be repeated in one hour, if necessary. {87} The maximum recommended daily dose is 2 mg. {01} {02}


Chronic, intractable headache (inpatient treatment)
Intravenous, initially 500 mcg (0.5 mg), administered over one minute, three to five minutes after intravenous administration of an antiemetic (10 mg of metoclopramide is most commonly used). {19} {23} {24} {83} The dosage of dihydroergotamine and/or the antiemetic should be adjusted as needed to reduce the occurrence of side effects (especially to prevent nausea and vomiting) while providing adequate control of the headache; {24} {83} up to 1 mg of dihydroergotamine may be given for subsequent doses if needed and tolerated. {83} This regimen may be repeated every eight hours until relief is obtained {19} {23} {24} {83}, although an antiemetic is usually no longer needed after six doses of dihydroergotamine have been administered. {83} One specialist recommends an additional two or three doses of dihydroergotamine, administered at twelve-hour intervals after the headache is relieved, to reduce the likelihood of headache recurrence. {24}

[Thrombosis prophylaxis adjunct]1
To be administered concurrently with 5000 USP Units of subcutaneously administered heparin:

Abdominal, thoracic, or pelvic surgery—Subcutaneous, 500 mcg (0.5 mg) two hours prior to surgery, then every twelve hours for five to seven days. {25}

Total hip replacement surgery—Subcutaneous, 500 mcg (0.5 mg) two hours prior to surgery, then every eight hours for seven to fourteen days. {25}

[Prevention of orthostatic hypotension associated with spinal or epidural anesthesia]1
Intravenous, 500 mcg (0.5 mg), administered a few minutes prior to the anesthetic. {36}

[Treatment of orthostatic hypotension]1
Intramuscular, 1 mg once a day. {40}

Subcutaneous, 6.5 to 13 mcg (0.0065 to 0.013 mg) per kg of body weight once a day, in the morning. Breakthrough episodes of hypotension may occur after meals when this dose is used, but can be prevented by oral administration of 250 mg of caffeine one-half hour before meals. {38}



Usual adult prescribing limits
Vascular headache suppressant (migraine or cluster [acute])—6 mg per week. {01} {02}

Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe])
Children 6 years of age and older:

Intramuscular or subcutaneous, 500 mcg (0.5 mg) at the start of the attack. May be repeated in one hour if needed. {87}

Intravenous, 250 mcg (0.25 mg) at the start of the attack. May be repeated in one hour if needed. {87}


Note: Another regimen that has been advocated for treatment of children and adolescents with severe, acute migraine consists of:
For children 6 to 9 years of age—Intravenous, 100 to 150 mcg (0.1 to 0.15 mg), with one or two additional doses being administered at twenty-minute intervals if needed.
For children 9 to 12 years of age—Intravenous, 200 mcg (0.2 mg), with one or two additional doses being administered at twenty-minute intervals if needed.
For adolescents 12 to 16 years of age—Intravenous, 250 to 500 mcg (0.25 to 0.5 mg), with one or two additional doses being administered at twenty-minute intervals if needed.
Administration of an antiemetic (such as metoclopramide or a phenothiazine antiemetic) is recommended in conjunction with intravenous dihydroergotamine. Administering the antiemetic orally one hour prior to the first dose of dihydroergotamine, if feasible, may reduce the risk of severe side effects, including extrapyramidal reactions, that may be encountered after intravenous administration. {56}


Strength(s) usually available
U.S.—


1 mg per mL (Rx) [D.H.E. 45 (alcohol) (glycerin) (methanesulfonic acid) (and/or sodium hydroxide)]

Canada—


1 mg per mL (Rx) [Dihydroergotamine-Sandoz (alcohol)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Stability:
Do not use if solution is discolored.


ERGOTAMINE

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effects—Adrenergic blocking actions somewhat less pronounced, and vasoconstrictive actions more pronounced, than those of dihydroergotamine.

Other actions/effects—Much more potent as a uterine stimulant than dihydroergotamine.

Time to peak effect—Oral: Usually within 1 to 2 hours, but up to 5 hours in some patients.



Inhalation Dosage Forms

ERGOTAMINE TARTRATE INHALATION AEROSOL USP

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Oral inhalation, 360 mcg (0.36 mg—1 metered spray) at the start of the attack, repeated at intervals of at least five minutes as needed for full relief, up to a total of 2.16 mg (6 metered sprays) per day. {05} {06}


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Dosage has not been established. {05}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


360 mcg (0.36 mg) per metered spray (9 mg per mL) (Rx) [Medihaler Ergotamine]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a light-resistant container.

Auxiliary labeling:
   • Shake well.

Note: Include patient instructions when dispensing.
Explain administration technique.




Oral Dosage Forms

ERGOTAMINE TARTRATE TABLETS USP

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Oral, 1 or 2 tablets (1 or 2 mg of ergotamine) at the start of the attack, followed by an additional 1 or 2 tablets at intervals of at least thirty minutes, up to a total of 6 tablets (6 mg of ergotamine) per day. {10} If an additional dose was needed, and the initial dose was well tolerated, a higher initial dose may be administered at the start of subsequent attacks. The maximum recommended initial dose is 3 tablets (3 mg of ergotamine). {76}


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg (Rx) [Gynergen]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.


ERGOTAMINE TARTRATE TABLETS (SUBLINGUAL) USP

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Sublingual, 2 mg at the start of the attack, repeated at intervals of at least thirty minutes, if necessary, up to a total of 6 mg per day. {03} {04}


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Product of suitable strength not available.

Strength(s) usually available
U.S.—


2 mg (Rx) [Ergostat (lactose) (saccharin)]

Canada—


2 mg (Rx) [Ergomar (lactose)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.


ERGOTAMINE AND CAFFEINE

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effects—

Ergotamine: Adrenergic blocking actions somewhat less pronounced, and vasoconstrictive actions more pronounced, than those of dihydroergotamine.

Caffeine: Probably contributes to efficacy of the combination by enhancing ergotamine absorption.

Other actions/effects—

Ergotamine: Much more potent as a uterine stimulant than dihydroergotamine.

Caffeine: Has CNS stimulating effects; may inhibit sleep.

Time to peak effect—Ergotamine: Oral—Usually within 1 to 2 hours, but up to 5 hours in some patients.



Precautions:
Breast-feeding—Caffeine: Total daily intake by breast-feeding women should be limited, because accumulation and stimulant effects in the infant have been reported.

Drug interactions and/or related problems—Caffeine: Potential excessive stimulation if used concurrently with other CNS stimulants; potential hypertension and arrhythmias if used concurrently with MAO inhibitors.

Laboratory value alterations—Caffeine: May interfere with dipyridamole-assisted myocardial perfusion studies and serum urate determinations (Bittner method).

Medical considerations/contraindications—Caffeine: Caution also recommended in patients with anxiety disorders, insomnia, peptic ulceration, and severe cardiac disease.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ERGOTAMINE TARTRATE AND CAFFEINE TABLETS USP

Usual adult dose
Acute headache
Oral, 1 or 2 tablets (1 or 2 mg of ergotamine) at the start of the attack, followed by an additional 1 or 2 tablets (1 or 2 mg of ergotamine) at intervals of at least thirty minutes, up to a total of 6 tablets (6 mg of ergotamine) per day. If an additional dose was needed, and the initial dose was well tolerated, a higher initial dose may be administered at the start of subsequent attacks. The maximum recommended initial dose is 3 tablets (3 mg of ergotamine). {07} {08} {15} {19} {76}

[Cluster headache prophylaxis]1
Oral, 1 or 2 tablets (1 or 2 mg of ergotamine) one to three times a day, one or two hours prior to the time that attacks usually occur. Cluster headaches that occur only during the night may be prevented by a single dose, administered one or two hours before bedtime. {87} {94}


Usual adult prescribing limits
Acute migraine
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}


Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe])
Children 6 to 12 years of age: Oral, 1 tablet (1 mg of ergotamine) initially; may be repeated one or two times, if necessary, up to a total of 3 tablets (3 mg of ergotamine) per day. {08}


Usual pediatric prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Strength(s) usually available
U.S.—


1 mg of ergotamine tartrate and 100 mg of caffeine (Rx) [Cafergot] [Ercaf] [Ergo-Caff] [Gotamine] [Wigraine (propylparaben ) (sucrose) (sugar)][Generic]

Note: In Canada, Wigraine tablets contain belladonna alkaloids in addition to ergotamine tartrate and caffeine.


Canada—


1 mg of ergotamine tartrate and 100 mg of caffeine (Rx) [Cafergot (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.



Rectal Dosage Forms

ERGOTAMINE TARTRATE AND CAFFEINE SUPPOSITORIES USP

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Rectal, one-fourth {83} to 1 {07} {08} {83} suppository (500 mcg [0.5 mg] to 2 mg of ergotamine) initially, repeated at intervals of at least thirty minutes, if needed and tolerated, up to a total dose of 2 suppositories (4 mg of ergotamine) per day. {07} {08} Most patients respond well to an initial dose of one-half suppository (1 mg of ergotamine). {83} However, if a repeat dose was necessary, and the first dose did not cause undue nausea, the initial dose for subsequent attacks may be increased. Up to 11/2 suppositories (3 mg of ergotamine) may be administered as a single initial dose, {07} {08} if tolerated. {87} {94}


Note: One headache specialist recommends that the patient determine a dose that does not cause nausea (during a headache-free period) by inserting one-fourth of a suppository every 60 minutes, until nausea occurs or a maximum of 1 suppository has been used. The highest cumulative dose that does not cause nausea may then be used as the initial dose during an acute attack. For example, if nausea occurs after the third dose (a total of three-fourths of a suppository), the initial dose for that patient should be one-half suppository. {83} {94}


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe])
Children 6 to 12 years of age: Rectal, one-fourth to one-half suppository (500 mcg [0.5 mg] to 1 mg of ergotamine) at the start of an attack. {08} {94} It is recommended that no more than one-half suppository be administered per day. {91}


Usual pediatric prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Strength(s) usually available
U.S.—


2 mg of ergotamine tartrate and 100 mg of caffeine (Rx) [Cafergot] [Cafertine] [Cafetrate] [Migergot] [Wigraine][Generic]

Note: In Canada, Wigraine suppositories contain belladonna alkaloids in addition to ergotamine tartrate and caffeine.


Canada—


2 mg of ergotamine tartrate and 100 mg of caffeine (Rx) [Cafergot]

Packaging and storage:
Store at a temperature not above 25 °C (77 °F). Store in a tight container. Do not expose unwrapped suppositories to sunlight.

Auxiliary labeling:
   • For rectal use only.
   • Store in a cool place.


ERGOTAMINE, CAFFEINE, AND BELLADONNA ALKALOIDS

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effects—

Ergotamine: Adrenergic blocking actions somewhat less pronounced, and vasoconstrictive actions more pronounced, than those of dihydroergotamine.

Caffeine: Probably contributes to efficacy of the combination by enhancing ergotamine absorption.

Belladonna alkaloids: Provide an antiemetic effect.

Other actions/effects—

Ergotamine: Much more potent as a uterine stimulant than dihydroergotamine.

Caffeine: Has CNS stimulating effects; may inhibit sleep.

Belladonna alkaloids: Have anticholinergic activity.

Time to peak effect—Ergotamine: Oral—Usually within 1 to 2 hours, but up to 5 hours in some patients.



Precautions:
Breast-feeding—

Caffeine: Total daily intake by breast-feeding women should be limited, because accumulation and stimulant effects in the infant have been reported.

Belladonna alkaloids: May inhibit lactation.

Pediatrics—Belladonna alkaloids: Young children, especially with spastic paralysis or brain damage, are especially susceptible to toxic effects of anticholinergics.

Geriatrics—Belladonna alkaloids: Increased risk of excitement, agitation, drowsiness, or confusion; also, risk of precipitating undiagnosed glaucoma.

Drug interactions and/or related problems—Caffeine: Potential excessive stimulation if used concurrently with other CNS stimulants; potential hypertension and arrhythmias if used concurrently with MAO inhibitors.

Belladonna alkaloids: Potential additive anticholinergic effects if administered concurrently with other medications having similar activity.

Laboratory value alterations—

Caffeine: May interfere with dipyridamole-assisted myocardial perfusion studies and serum urate determinations (Bittner method).

Belladonna alkaloids: Interfere with gastric acid secretion tests.

Medical considerations/contraindications—

Caffeine: Caution also recommended in patients with anxiety disorders, insomnia, peptic ulceration, and severe cardiac disease.

Belladonna alkaloids: Caution also required in patients with conditions that may be adversely affected by anticholinergic effects.



Oral Dosage Forms

ERGOTAMINE TARTRATE, CAFFEINE, AND BELLADONNA ALKALOIDS TABLETS

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Oral, 1 or 2 tablets (1 or 2 mg of ergotamine) at the start of the attack, followed by an additional 1 or 2 tablets (1 or 2 mg of ergotamine) at intervals of at least thirty minutes, up to a total of 6 tablets (6 mg of ergotamine) per day. If an additional dose was needed, and the initial dose was well tolerated, a higher initial dose may be administered at the start of subsequent attacks. The maximum recommended initial dose is 3 tablets (3 mg of ergotamine). {12} {76}


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe])
Children 6 to 12 years of age: Oral, 1 tablet (1 mg of ergotamine) initially; may be repeated one or two times, if necessary, up to a total of 3 tablets (3 mg of ergotamine) per day. {76}


Usual pediatric prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg of ergotamine tartrate, 100 mg of caffeine, and 100 mcg (0.1 mg) of belladonna alkaloids (Rx) [Wigraine (scored)]

Note: In the U.S. Wigraine tablets contain only ergotamine tartrate and caffeine.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.



Rectal Dosage Forms

ERGOTAMINE TARTRATE, CAFFEINE, AND BELLADONNA ALKALOIDS SUPPOSITORIES

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Rectal, one-half {83} to 2 {12} {83} suppositories (500 mcg [0.5 mg] to 2 mg of ergotamine) initially, repeated at intervals of at least thirty minutes, if needed and tolerated, up to a total dose of 4 suppositories (4 mg of ergotamine) per day. {76} Most patients respond well to an initial dose of one suppository (1 mg of ergotamine). {83} However, if a repeat dose was necessary, and the first dose did not cause undue nausea, the initial dose for subsequent attacks may be increased. Up to 3 suppositories (3 mg of ergotamine) may be administered as a single initial dose, {76} if tolerated. {87} {94}


Note: One headache specialist recommends that the patient determine a dose that does not cause nausea (during a headache-free period) by inserting one-half of a suppository every 60 minutes, until nausea occurs or a maximum of 2 suppositories has been used. The highest cumulative dose that does not cause nausea may then be used as the initial dose during an acute attack. For example, if nausea occurs after the third dose (a total of 11/2 suppositories), the initial dose for that patient should be 1 suppository. {83}


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe]
Children 6 to 12 years of age: Rectal, one-half to one suppository (500 mcg [0.5 mg] to 1 mg of ergotamine) at the start of an attack. {94} It is recommended that no more than one suppository be administered per day. {91}


Usual pediatric prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg of ergotamine tartrate, 100 mg of caffeine, and 100 mcg (0.1 mg) of belladonna alkaloids. (Rx) [Wigraine]

Note: In the U.S., Wigraine suppositories contain only ergotamine tartrate and caffeine.


Packaging and storage:
Store below 25 °C (77 °F), in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • For rectal use only.
   • Store in a cool place.


ERGOTAMINE, CAFFEINE, BELLADONNA ALKALOIDS, AND PENTOBARBITAL

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effects—

Ergotamine: Adrenergic blocking actions somewhat less pronounced, and vasoconstrictive actions more pronounced, than those of dihydroergotamine.

Caffeine: Probably contributes to efficacy of the combination by enhancing ergotamine absorption.

Belladonna alkaloids: Provide an antiemetic effect.

Pentobarbital: Provides a sedative effect.

Other actions/effects—

Ergotamine: Much more potent as a uterine stimulant than dihydroergotamine.

Caffeine: Has CNS stimulating effects; may inhibit sleep.

Belladonna alkaloids: Have anticholinergic activity.

Pentobarbital: Has CNS depressant effects.

Time to peak effect—Ergotamine: Oral—Usually within 1 to 2 hours, but up to 5 hours in some patients.



Precautions:
Breast-feeding—

Caffeine: Total daily intake by breast-feeding women should be limited, because accumulation and stimulant effects in the infant have been reported.

Belladonna alkaloids: May inhibit lactation.

Pentobarbital: May be distributed into breast milk.

Pediatrics—

Belladonna alkaloids: Young children, especially with spastic paralysis or brain damage, are especially susceptible to toxic effects of anticholinergics.

Pentobarbital: May cause paradoxical excitement.

Geriatrics—

Belladonna alkaloids: Increased risk of excitement, agitation, drowsiness, or confusion; also, risk of precipitating undiagnosed glaucoma.

Pentobarbital: Risk of excitement, depression, and/or confusion.

Drug interactions and/or related problems—

Caffeine: Potential excessive stimulation if used concurrently with other CNS stimulants; potential hypertension and arrhythmias if used concurrently with MAO inhibitors.

Belladonna alkaloids: Potential additive anticholinergic effects if administered concurrently with other medications having similar activity.

Pentobarbital: Potential additive effects with other CNS depressants.

Laboratory value alterations—

Caffeine: Interference with dipyridamole-assisted myocardial perfusion studies and serum urate determinations (Bittner method).

Belladonna alkaloids: Interfere with gastric acid secretion tests.

Medical considerations/contraindications—

Caffeine: Caution also recommended in patients with anxiety disorders, insomnia, peptic ulceration, and severe cardiac disease.

Belladonna alkaloids: Caution also required in patients with conditions that may be adversely affected by anticholinergic effects.



Oral Dosage Forms

ERGOTAMINE TARTRATE, CAFFEINE, BELLADONNA ALKALOIDS, AND PENTOBARBITAL SODIUM TABLETS

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Oral, 1 or 2 tablets (1 or 2 mg of ergotamine) at the start of the attack, followed by an additional 1 or 2 tablets (1 or 2 mg of ergotamine) at intervals of at least thirty minutes, up to a total of 6 tablets (6 mg of ergotamine) per day. If an additional dose was needed, and the initial dose was well tolerated, a higher initial dose may be administered at the start of subsequent attacks. The maximum recommended initial dose is 3 tablets (3 mg of ergotamine). {09} {76}


Note: Geriatric and debilitated patients may react to usual doses of barbiturates with excitement, confusion, or mental depression. A reduction in dosage may be required in these patients.


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe])—Children 6 to 12 years of age: Oral, 1 tablet (1 mg of ergotamine) initially; may be repeated one or two times, if necessary, up to a total of 3 tablets (3 mg of ergotamine) per day. {76}

Usual pediatric prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg of ergotamine tartrate, 100 mg of caffeine, 125 mcg (0.125 mg) of belladonna alkaloids, and 30 mg of pentobarbital sodium (Rx) [Cafergot-PB (lactose) (tartrazine)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Rectal Dosage Forms

ERGOTAMINE TARTRATE, CAFFEINE, BELLADONNA ALKALOIDS, AND PENTOBARBITAL SUPPOSITORIES

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Rectal, one-fourth {83} to 1 {09} {83} suppository (500 mcg [0.5 mg] to 2 mg of ergotamine) initially, repeated at intervals of at least thirty minutes, if needed and tolerated, up to a total dose of 2 suppositories (4 mg of ergotamine) per day. {09} Most patients respond well to an initial dose of one-half suppository (1 mg of ergotamine). {83} However, if a repeat dose was necessary, and the first dose did not cause undue nausea, the initial dose for subsequent attacks may be increased. Up to 11/2 suppositories (3 mg of ergotamine) may be administered as a single initial dose, {76} if tolerated. {87}


Note: One headache specialist recommends that the patient determine a dose that does not cause nausea (during a headache-free period) by inserting one-fourth of a suppository every 60 minutes, until nausea occurs or a maximum of 1 suppository has been used. The highest cumulative dose that does not cause nausea may then be used as the initial dose during an acute attack. For example, if nausea occurs after the third dose (a total of three-fourths of a suppository), the initial dose for that patient should be one-half suppository. {83}
Geriatric and debilitated patients may react to usual doses of barbiturates with excitement, confusion, or mental depression. A reduction in dosage may be required in these patients.


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe])
Children 6 to 12 years of age: Rectal, one-fourth to one-half suppository (500 mcg [0.5 mg] to 1 mg of ergotamine) at the start of an attack. {08} It is recommended that no more than one-half suppository be administered per day. {91}


Usual pediatric prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


2 mg of ergotamine tartrate, 100 mg of caffeine, 250 mcg (0.25 mg) of belladonna alkaloids, and 60 mg of pentobarbital (Rx) [Cafergot-PB (lactose)]

Packaging and storage:
Store in a tight container at a temperature not exceeding 25 °C (77 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • For rectal use only.
   • Store in a cool place.
   • Avoid alcoholic beverages.
   • May cause drowsiness.


ERGOTAMINE, CAFFEINE, AND CYCLIZINE

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effects—

Ergotamine: Adrenergic blocking actions somewhat less pronounced, and vasoconstrictive actions more pronounced, than those of dihydroergotamine.

Caffeine: Probably contributes to efficacy of the combination by enhancing ergotamine absorption.

Cyclizine: Provides antiemetic and sedative effects.

Other actions/effects—

Ergotamine: Much more potent as a uterine stimulant than dihydroergotamine.

Caffeine: Has CNS stimulating effects; may inhibit sleep.

Cyclizine: Has antihistaminic, anticholinergic, and CNS depressant activities.

Time to peak effect—Ergotamine: Usually within 1 to 2 hours, but up to 5 hours in some patients.



Precautions:
Breast-feeding—

Caffeine: Total daily intake by breast-feeding women should be limited, because accumulation and stimulant effects in the infant have been reported.

Cyclizine: May inhibit lactation and may be distributed into breast milk.

Pediatrics—Cyclizine: May cause paradoxical excitement.

Geriatrics—Cyclizine: Increased sensitivity to anticholinergic side effects; increased risk of dizziness, sedation, and hypotension.

Drug interactions and/or related problems—

Caffeine: Potential excessive stimulation if used concurrently with other CNS stimulants; potential hypertension and arrhythmias if used concurrently with MAO inhibitors.

Cyclizine: Risk of additive anticholinergic and/or CNS effects if used concurrently with other medications having similar actions.

Laboratory value alterations—

Caffeine: May interfere with dipyridamole-assisted myocardial perfusion studies and serum urate determinations (Bittner method).

Cyclizine: Interferes with skin tests using allergen extracts.

Medical considerations/contraindications—

Caffeine: Caution also recommended in patients with anxiety disorders, insomnia, peptic ulceration, and severe cardiac disease.

Cyclizine: Caution also recommended in patients who may be adversely affected by anticholinergic effects.



Oral Dosage Forms

ERGOTAMINE TARTRATE, CAFFEINE, AND CYCLIZINE TABLETS

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Oral, one-half or 1 tablet (1 or 2 mg of ergotamine) at the start of the attack, followed by an additional one-half or 1 tablet (1 or 2 mg of ergotamine) at intervals of at least thirty minutes, up to a total of 3 tablets (6 mg of ergotamine) per day. {13} {76} If an additional dose was needed, and the initial dose was well tolerated, a higher initial dose may be administered at the start of subsequent attacks. The maximum recommended initial dose is 11/2 tablets (3 mg of ergotamine). {76}


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe])—Children 6 to 12 years of age: Oral, one-half tablet (1 mg of ergotamine) initially; may be repeated one or two times, if necessary, up to a total of 11/2 tablets (3 mg of ergotamine) per day. {76}

Usual pediatric prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


2 mg of ergotamine tartrate, 100 mg of caffeine, and 50 mg of cyclizine hydrochloride (Rx) [Megral (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


ERGOTAMINE, CAFFEINE, AND DIMENHYDRINATE

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effects—

Ergotamine: Adrenergic blocking actions somewhat less pronounced, and vasoconstrictive actions more pronounced, than those of dihydroergotamine.

Caffeine: Probably contributes to efficacy of the combination by enhancing ergotamine absorption.

Dimenhydrinate: Provides antiemetic and sedative effects.

Other actions/effects—

Ergotamine: Much more potent as a uterine stimulant than dihydroergotamine.

Caffeine: Has CNS stimulating effects; may inhibit sleep.

Dimenhydrinate: Has antihistaminic, anticholinergic, and CNS depressant activities.

Time to peak effect—Ergotamine: Usually 1 to 2 hours, but up to 5 hours in some patients.



Precautions:
Breast-feeding—

Caffeine: Total daily intake by breast-feeding women should be limited, because accumulation and stimulant effects in the infant have been reported.

Dimenhydrinate: May inhibit lactation and is distributed into breast milk.

Pediatrics—Dimenhydrinate: May cause paradoxical excitement.

Geriatrics—Dimenhydrinate: Increased sensitivity to anticholinergic side effects; increased risk of dizziness, sedation, and hypotension.

Drug interactions and/or related problems—

Caffeine: Potential excessive stimulation if used concurrently with other CNS stimulants; potential hypertension and arrhythmias if used concurrently with MAO inhibitors.

Dimenhydrinate: Risk of additive anticholinergic and/or CNS effects if used concurrently with other medications having similar actions.

Laboratory value alterations—Caffeine: May interfere with dipyridamole-assisted myocardial perfusion studies and serum urate determinations (Bittner method).

Dimenhydrinate: Interferes with skin tests using allergen extracts.

Medical considerations/contraindications—

Caffeine: Caution also recommended in patients with anxiety disorders, insomnia, peptic ulceration, and severe cardiac disease.

Dimenhydrinate: Caution also recommended in patients who may be adversely affected by anticholinergic effects.



Oral Dosage Forms

ERGOTAMINE TARTRATE, CAFFEINE, AND DIMENHYDRINATE CAPSULES

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Oral, 1 or 2 capsules (1 or 2 mg of ergotamine) at the start of the attack, followed by an additional 1 or 2 capsules (1 or 2 mg of ergotamine) at intervals of at least thirty minutes, up to a total of 6 capsules (6 mg of ergotamine) per day. If an additional dose was needed, and the initial dose was well tolerated, a higher initial dose may be administered at the start of subsequent attacks. The maximum recommended initial dose is 3 capsules (3 mg of ergotamine). {11} {76}


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe])
Children 6 to 12 years of age: Oral, 1 capsule (1 mg of ergotamine) initially; may be repeated one or two times, if necessary, up to a total of 3 capsules (3 mg of ergotamine) per day. {76}


Usual pediatric prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg of ergotamine tartrate, 100 mg of caffeine, and 50 mg of dimenhydrinate (Rx) [Gravergol]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


ERGOTAMINE, CAFFEINE, AND DIPHENHYDRAMINE

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effects—

Ergotamine: Adrenergic blocking actions somewhat less pronounced, and vasoconstrictive actions more pronounced, than those of dihydroergotamine.

Caffeine: Probably contributes to efficacy of the combination by enhancing ergotamine absorption.

Diphenhydramine: Provides antiemetic and sedative effects.

Other actions/effects—

Ergotamine: Much more potent as a uterine stimulant than dihydroergotamine.

Caffeine: Has CNS stimulating effects; may inhibit sleep.

Diphenhydramine: Has antihistaminic, anticholinergic, and CNS depressant activities.

Time to peak effect—Ergotamine: Usually within 1 to 2 hours, but up to 5 hours in some patients.



Precautions:
Breast-feeding—

Caffeine: Total daily intake by breast-feeding women should be limited, because accumulation and stimulant effects in the infant have been reported.

Diphenhydramine: May inhibit lactation.

Pediatrics—Diphenhydramine: May cause paradoxical excitement.

Geriatrics—Diphenhydramine: Increased susceptibility to anticholinergic side effects; increased risk of dizziness, sedation, and hypotension.

Drug interactions and/or related problems—

Caffeine: Potential excessive stimulation if used concurrently with other CNS stimulants; potential hypertension and arrhythmias if used concurrently with MAO inhibitors.

Diphenhydramine: Risk of additive anticholinergic and/or CNS effects if used concurrently with other medications having similar actions.

Laboratory value alterations—

Caffeine: May interfere with dipyridamole-assisted myocardial perfusion studies and serum urate determinations (Bittner method).

Diphenhydramine: Interferes with skin tests using allergen extracts.

Medical considerations/contraindications—

Caffeine: Caution also recommended in patients with anxiety disorders, insomnia, peptic ulceration, and severe cardiac disease.

Diphenhydramine: Caution also recommended in patients who may be adversely affected by anticholinergic effects.



Oral Dosage Forms

ERGOTAMINE TARTRATE, CAFFEINE, AND DIPHENHYDRAMINE CAPSULES

Usual adult dose
Vascular headache suppressant (migraine or cluster [acute])
Oral, 1 or 2 capsules (1 or 2 mg of ergotamine) at the start of the attack, followed by an additional 1 or 2 capsules (1 or 2 mg of ergotamine) at intervals of at least thirty minutes, up to a total of 6 capsules (6 mg of ergotamine) per day. {14} If an additional dose was needed, and the initial dose was well tolerated, a higher initial dose may be administered at the start of subsequent attacks. The maximum recommended initial dose is 3 capsules (3 mg of ergotamine). {76}


Usual adult prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Usual pediatric dose
Vascular headache suppressant (migraine [acute, severe])
Children 6 to 12 years of age: Oral, 1 capsule (1 mg of ergotamine) initially; may be repeated one or two times, if necessary, up to a total of 3 capsules (3 mg of ergotamine) per day. {76}


Usual pediatric prescribing limits
To reduce the risk of dependence on ergotamine, it is recommended that the medication be used no more often than two times a week, {87} preferably at least five days apart. {92}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg of ergotamine tartrate, 100 mg of caffeine, and 25 mg of diphenhydramine (Rx) [Ergodryl]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Revised: 09/08/1992



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