Dihydroergotamine is an ergot derivative available as a nasal spray and as an intravenous formulation for the treatment of migraine.

It is a vasoconstrictor and has efficacy similar to sumatriptan.

Dihydroergotamine Uses:

• Cluster headaches (injection):

  • Dihydroergotamine is used to quickly treat cluster headaches when they happen.

• Migraines (intranasal and injection):

  • Dihydroergotamine can be used to quickly treat migraine headaches that come on suddenly, with or without warning signs.

  • However, it's not meant to prevent migraines from happening, or to manage certain types of severe migraines.

• Off Label Use of Dihydroergotamine in Adults:

  • Dihydroergotamine is sometimes used in adults for reasons not officially approved.

  • This includes treating headaches caused by using too much medication, severe and unmanageable migraine headaches, low blood pressure when standing up, and pelvic pain caused by congestion.

Dihydroergotamine Dose in Adults:

Dihydroergotamine Dose in the treatment of Migraine and cluster headache: 

• Intramuscular  Subcutaneous:

  • If you're using dihydroergotamine through a shot into the muscle or under the skin:

  • Start with 1 milligram as soon as you notice the headache.
  • You can repeat this dose every hour, but don't go over 3 milligrams in a day.
  • Make sure not to exceed 6 milligrams in a week.

• Intravenous:

  • When using dihydroergotamine through an injection into a vein:

  • Start with 1 milligram as soon as the headache starts.
  • You can give this dose every hour, but don't go over 2 milligrams in a day.
  • Make sure not to exceed 6 milligrams in a week.

• Intranasal:

  • When using dihydroergotamine through the nose:

  • Start with 1 spray (0.5 milligrams) in each nostril.
  • Repeat this every 15 minutes, but don't exceed a total of four sprays (2 milligrams).

• It's important to note:

  • Research hasn't found extra benefits from using more than 2 milligrams for one migraine attack.
  • Safety hasn't been confirmed for using more than six sprays (3 milligrams) in a day or eight sprays (4 milligrams) in a week.
  • Dihydroergotamine isn't meant for regular, daily use.

Dihydroergotamine dose for medication-overuse headache or intractable migraine headache (status migrainosus) as an alternative agent:

Note:

• Here are some important points to remember:

• Dihydroergotamine can be used in hospitalized patients dealing with medication-overuse headaches when it's hard for them to stop the overused medication, along with other treatments to manage the headache and prevent future ones.
• Before giving dihydroergotamine, it's common to give metoclopramide to help with nausea.
• While using dihydroergotamine, patients might also receive metoclopramide for nausea, diphenoxylate with atropine if they have diarrhea, and benztropine if they experience akathisia or dystonic reactions (types of movement disorders).
• Some doctors might adjust these treatments and add other medications or different anti-nausea drugs based on the patient's needs.

• Repetitive dosing regimen (Raskin protocol):

  • Intravenous:

    • Start with 0.5 milligrams.
    • Adjust the next doses based on how the patient responds and tolerates the medication, ranging from 0.2 to 1 milligram.
    • Give doses every 8 hours for up to 7 days. Most patients find relief within 72 hours.
    • If the headache continues but there's no nausea after the first dose, another 0.5-milligram dose can be given after 1 hour.

• Continuous dosing regimen (Ford protocol):

  • Intravenous:

    • Prepare 3 milligrams of dihydroergotamine in 1 liter of normal saline (NS).
    • Administer it at a rate of 42 milliliters per hour for up to seven days.
    • Most patients experience relief from headaches within 72 hours.
    • If the patient experiences significant nausea, decrease the infusion rate to 21 to 30 milliliters per hour.

Dihydroergotamine Dose in Childrens:

Dihydroergotamine Dose in the treatment of Intractable Migraine lasting more than 72 hours (status migrainosus):

• For intravenous use, it's advised to give an anti-nausea medication like metoclopramide or prochlorperazine before administering dihydroergotamine.

• Here are the dosing recommendations for different age groups:

  Low-dose regimen:

• Improvement typically occurs after five doses.
• Some experts suggest giving one extra dose after the headache goes away.
• If there's no improvement after five doses, stop the therapy.

• Children 6 to under 10 years old:

• Give 1 milligram per dose every 6 hours.
• Administer up to eight doses for each episode or until the headache is gone.

• Children 10 to 12 years old:

• Give 1.5 milligrams per dose every 6 hours.
• Continue the therapy until the headache is gone, for a maximum of 8 doses per episode.

• Adolescents up to 16 years old:

• Administer 2 milligrams per dose every 6 hours.
• Give up to eight doses for each episode or until the headache is relieved.

• High-dose regimen:

• Improvement is typically seen after 5 doses. Some experts suggest giving one extra dose after the headache is gone.
• If there's no improvement after 5 doses, stop the therapy.
• Some experts recommend starting with a test dose (half the appropriate dose based on age and weight).
• If the test dose is tolerated, give the rest of the dose 30 minutes later.

Children 6 to 9 years old or Children 10 years and older weighing less than 25 kg:

• Administer 5 milligrams per dose every 8 hours.
• Continue the therapy until the headache is gone, for a maximum of 15 doses per episode.

Children 10 years and older weighing more than 25 kg and Adolescents:

• Give 1 milligram per dose every 8 hours.
• If there's improvement, continue the therapy until the headache is gone, for a maximum of 15 doses per episode.

Intranasal dihydroergotamine:

• Adolescents:

  • Start with 1 spray (0.5 milligrams) into each nostril, totaling 1 milligram.
  • Based on adult data, repeat the dose after 15 minutes, for a total of four sprays (2 milligrams).
  • The maximum daily dose is 6 sprays (3 milligrams) within a 24-hour period.
  • Note: Don't exceed 8 sprays (4 milligrams) per week.

Pregnancy Risk Factor X

• Dihydroergotamine can be used to help with contractions during childbirth.

• However, it's not recommended for use during pregnancy.

Use of dihydroergotamine during breastfeeding

• Ergot derivatives, like ergotamine, can lower prolactin levels and may pass into breast milk, causing side effects like vomiting and diarrhea in nursing infants.

• Dihydroergotamine might have similar effects but is less likely to be found in breast milk.

• Still, it's not recommended for nursing mothers.

Dose in Kidney Disease:

• For mild to moderate impairment:

• No dosage adjustments are mentioned in the labeling.
• Dihydroergotamine is contraindicated.
• For severe impairment:

Dose in Liver disease:

• For mild to moderate impairment:

• No dosage adjustments are recommended based on labeling.

As for side effects related to the nasal spray formulation, let's explore those.

For severe impairment:

Dihydroergotamine is contraindicated.

Common Side Effects of Dihydroergotamine:

• Respiratory:

  • Rhinitis

Less Common Side effects of Dihydroergotamine:

• Central nervous system:

  • Taste disorder
  • Dizziness
  • Drowsiness

• Endocrine & metabolic:

  • Hot flash

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Diarrhea

• Local:

  • Application site reaction

• Neuromuscular & skeletal:

  • Stiffness
  • Weakness

• Respiratory:

  • Pharyngitis

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Contraindications to Dihydroergotamine:

• Hypersensitivity to dihydroergotamine and any component of the formulation
• Uncontrolled hypertension, IHD or angina pectoris, history MI, silent ischemia or coronary artery vasospasm, including Prinzmetal angina, are all possible.
• Basilar or hemiplegic migraine
• Peripheral vascular disease
• Sepsis
• Grave hepatic and renal dysfunction
• Following vascular surgery
• Avoid using 5-hydroxytryptamine-1 (5HT1a) receptor agonists ( triptans), serotonin-agonists or ergots within 24 hours.
• Concurrent use central and peripheral vasoconstrictors
• Concurrent use potent inhibitors for CYP3A4 (includes protease inhibitors, azole Antifungals and some macrolide Antibiotics);
• Pregnancy
• Breastfeeding

Warnings and precautions

• Cardiac Valvular Fibrosis:

  • The fibrotic valve thickening caused by ergot alkaloids has been linked to a variety of conditions, including aortic, mitral and tricuspid. This condition is usually caused by long-term, persistent use.

• Cardiovascular effects

  • It may cause vasospastic reaction, which can be associated with muscle pains, numbness and coldness, and cyanosis. Myocardial and peripheral arterial ischemia have been reported.
  • Patients with impaired circulation may experience persistent vasospasm, which can lead to gangrene and even death.
  • Patients who have signs or symptoms that suggest angina after receiving CAD medication or a predisposition for variant angina should be evaluated.
  • Patients who have other symptoms, such as Raynaud syndrome or ischemic bowel syndrome, that suggest decreased arterial flow should also be evaluated.
  • A rare case of significant hypertension was reported in a patient with and without hypertension.
  • Rarely have adverse cardiac events been reported, including death, acute MI, or life-threatening arrhythmias.

• Cerebrovascular events

  • After the injection, stroke, subarachnoid hemorhage, and cerebral hemorhage have all been reported (some cases even fatal).

• Retroperitoneal and pleural fibrosis

  • Rare cases of retroperitoneal and pleural fibrosis have been reported.

• Cardiovascular disease

  • Patients with risk factors for CAD should not be treated until a cardiology evaluation has been completed.
  • If the evaluation is positive, the healthcare provider should administer 1st dose. Cardiovascular status should also be checked periodically.

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Dihydroergotamine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

  Risk Factor C (Monitor therapy).
  Antiemetics (5HT3 Antagonists).	Serotonin Activators' serotonergic actions could be enhanced by this. The serotonin syndrome might result from this.
  Antipsychotic Agents	If antipsychotic drugs are controlled with serotonin modulators, the negative/toxic effects may be more pronounced.Neuroleptic malignant syndrome may be more likely to develop if serotonin modulators increase dopamine blockade.Antipsychotic drugs may augment the serotonergic effects of serotonin modulators. The serotonin syndrome might result from this.
  Aprepitant	High likelihood that inhibitors will raise serum concentrations of CYP3A4 substrates
  Chloroprocaine	May intensify ergot derivatives' hypertensive effects.
  Clofazimine	High likelihood that inhibitors will raise serum concentrations of CYP3A4 substrates
  Moderate CYP3A4 inhibitors	Might decrease metabolism of CYP3A4 substrates (High Risk with Inhibitors).
  Duvelisib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Erdafitinib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Fosaprepitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Fosnetupitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Larotrectinib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Metaxalone	This may increase the serotonergic effects of Serotonin Activators. This could lead to serotonin syndrome.
  Methylphenidate	Can increase the toxic/adverse effects of Serotonin Modulators. In particular, there may be an increase in the risk of serotonin syndrome and serotonin toxicities.
  Metoclopramide	The adverse/toxic effects of Metoclopramide may be exacerbated by Serotonin Modulators. This could manifest as serotonin syndrome, neuroleptic malignant syndrome, or other symptoms.
  Netupitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Opioid Agonists	This may increase the serotonergic effects of Serotonin Activators. This could lead to serotonin syndrome.
  Palbociclib	High likelihood that inhibitors will raise serum concentrations of CYP3A4 substrates
  Reboxetine	May intensify ergot derivatives' hypertensive effects.
  Serotonin Modulators	This might make other serotonin activators more toxic or harmful.
  Simeprevir	High likelihood that inhibitors will raise serum concentrations of CYP3A4 substrates
  Tedizolid	This might make other serotonin activators more toxic or harmful.The serotonin syndrome may manifest. The exceptions are Tedizolid and Nicergoline.Serotonin Activators' serotonergic actions could be enhanced by this.The serotonin syndrome might result from this.Serotonin Modulators may enhance TraMADol's harmful/toxic effects.Seizures can get worse.
  TraMADol	Serotonin Activators' serotonergic actions could be enhanced by TraMADol. The serotonin syndrome might result from this.
  Risk Factor D (Consider therapy modifications)
  Anti-Parkinson Agents (Monoamine oxidase inhibitor)	Serotonin Activators' serotonergic actions could be enhanced by this. The serotonin syndrome might result from this. A serotonin modator can be used in conjunction with selegiline, rasagiline, or safinamide to monitor for serotonin syndrome/serotonin toxicemia symptoms and signs. Combining transdermal selegiline with serotonin moderators is not advised.
  Beta-Blockers	May increase the vasoconstricting effects of Ergot Derivatives.
  Strong CYP3A4 inhibitors	Could possibly reduce the metabolism of CYP3A4 substrates (High Risk with Inhibitors).
  Linezolid	This may increase the serotonergic effects of Serotonin Activators. This could lead to serotonin syndrome. Management: Serotonin syndrome/serotonin toxicemia can occur if serotonin modulators are stopped 2 weeks before linezolid is administered. Stop using serotonin modators immediately if you need to initiate linezolid immediately.
  Antibiotics with Macrolide	Could increase serum concentrations of Ergot Derivatives. Cabergoline, Clarithromycin and Fidaxomicin may interact. Refer to the specific monograph for more details. Azithromycin (Systemic); Fidaxomicin, Spiramycin are exceptions.
  Stiripentol	.High chance that inhibitors will raise serum levels of CYP3A4 substrates. Treatment: Steer clear of using stiripentol with CYP3A4 substrates that have a limited therapeutic index. This is done to prevent negative consequences and toxicity. Any CYP3A4 substrate that is administered in conjunction with stiripentol should be strictly monitored.
  Risk Factor X (Avoid the combination)
  Alpha-/Beta Agonists	Alpha-/BetaAgonists' hypertensive effects may be enhanced by Ergot Derivatives. Alpha-/Beta Agonists' vasoconstricting effects may be enhanced by Ergot Derivatives
  Alpha1-Agonists	Alpha1-Agonists' hypertensive effects may be enhanced by Ergot Derivatives. Alpha1-Agonists' vasoconstricting effects may be enhanced by using Ergot Derivatives.
  Antihepaciviral combination products	May increase serum concentrations of Ergot Derivatives.
  Clarithromycin	May increase serum Dihydroergotamine concentrations
  Cobicistat	May increase serum Dihydroergotamine concentrations
  Conivaptan	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Crizotinib	May increase serum Dihydroergotamine concentrations
  Dapoxetine	Can increase the toxic/adverse effects of Serotonin Activators.
  Enzalutamide	Could lower the serum concentrations of Dihydroergotamine.
  Fusidic Acid (Systemic).	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Idelalisib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Itraconazole	May increase serum Dihydroergotamine concentrations
  Ketoconazole Systemic	May increase serum Dihydroergotamine concentrations
  Letermovir	May increase serum concentrations of Ergot Derivatives.
  Lorcaserin	Could increase the toxic/adverse effects of Ergot Derivatives. Particularly, the combination of these drugs may increase your risk of developing valvular disease. Lorcaserin could increase the serotonergic effects of Ergot Derivatives. This could lead to serotonin syndrome.
  Methylene Blue	This may increase the serotonergic effects of Serotonin Activators. This could lead to serotonin syndrome.
  MiFEPRIStone	This may increase serum levels of Dihydroergotamine. Treatment: Do not take dihydroergotamine for Cushing's syndrome hyperglycemia. Although the interaction magnitude may be smaller with single doses of mifepristone used to terminate a pregnancy, clinically neither effect has been examined.
  Nitroglycerin	Ergot derivatives can decrease the vasodilatory effects of Nitroglycerin. This is especially important for patients with angina. The serum concentrations of Ergot Derivatives may be increased by Nitroglycerin.
  Posaconazole	May increase serum Dihydroergotamine concentrations
  Protease inhibitors	May increase serum concentrations of Ergot Derivatives.
  Roxithromycin	May increase serum concentrations of Ergot Derivatives.
  Serotonin 5-HT1D Receptor Agonists	The vasoconstricting effects of Serotonin 5-HT1D Receptor Aggonists may be enhanced by Ergot Derivatives. The vasoconstricting effects of Ergot Derivatives could be enhanced by Serotonin 5-HT1D Receptor Aggonists.
  Voriconazole	May increase serum Dihydroergotamine concentrations

Monitoring parameters:

• It's important to:

• Monitor the electrocardiogram (ECG) in patients with risk factors for heart diseases.
• Perform pulmonary function tests and echocardiography before starting treatment.

How to administer Dihydroergotamine?

For intranasal administration:

• Prime the nasal spray applicator with 4 pumps before using it.
• Avoid deep inhalation into the nose while spraying the drug or shortly after to allow proper absorption through the skin.
• Start treatment as soon as possible after a migraine symptom or sign appears. However, nasal sprays can be used at any stage of a migraine attack.

For intravenous administration:

• The Ford protocol involves continuous infusions, with dosing details specified for each indication.
• In the repetitive dosing (Raskin protocol), slowly administer the medication over 2 to 3 minutes.

Mechanism of action of dihydroergotamine:

• Dihydroergotamine works by activating serotonin 5-HT-1D receptors in the blood vessels of the brain, leading to vasoconstriction and inhibition of pro-inflammatory neuropeptide release in the trigeminal system.

• It binds strongly to serotonin 5-HT-1Da, 5-HT-1Dss, 5-HT-1A, and 5-HT-2A receptors, as well as noradrenaline receptors a2A and a2B, and dopamine D-2L and D-3 receptors. It also has oxytocic properties.

  Here are some pharmacokinetic details:

• Protein binding: 93%
• Metabolism: Mainly hepatic, producing one active compound, 8'-bhydroxydihydroergotamine.
• Bioavailability:
  • Intramuscular, intravenous: 100%
  • Intranasal: 40%
• Elimination half-life: 9-10 hours
• Time to peak serum concentration:
  • Intramuscular: 24 minutes
  • Intravenous: 1 - 2 minutes
  • Intranasal: 30-60 minutes
  • Subcutaneous: 15 to 45 minutes
• Excretion:
  • Primarily through feces
  • About 6% - 7% is excreted unchanged in urine.

International Brands of Dihydroergotamine:

• H.E. 45
• Migranal
• H.E
• Cervasal
• Dergott
• Detemes Retard
• Detms
• DH-Ergotamin
• DHT
• Diergo
• Diergospray
• Digalo
• Dihydergot
• Dihydergot Sandoz
• Dihydroergotamin ”Dak”
• Dihydroergotaminum Methansulfonicum
• Dihydroergotaminum Tartaricum
• Ditamin
• Ergotamina
• Ergovasan
• Ginik
• Hadermik/Migomik
• Ikaran
• Ikaran LP
• Migranal
• Migranil
• Neomigran
• Orstanorm
• Parsel
• Rayor
• Seglor
• Seglor Retard
• Tamik
• Tonopan
• Verladyn

Dihydroergotamine Brands Names in Pakistan:

No Brands Available in Pakistan.