Heng Li An

Uses

Heng Li An is used for the treatment of acute migraine with or without aura in adults.

Heng Li An is also used to associated treatment for these conditions: Cluster Headache, Migraine

How Heng Li An works

Migraines are complex physiological events characterized by unilateral throbbing headaches combined with photophobia and other aversions to sensory input. Migraine attacks are generally divided into phases: the premonitory phase, which typically involves irritability, fatigue, yawning, and stiff neck; the headache phase, which lasts for between four and 72 hours; and the postdrome phase, which lasts for up to a day following resolution of pain and whose symptoms are similar to those of the premonitory phase. In addition, neurological deficits, collectively termed migraine aura, may precede the headache phase.

The underlying pathophysiology of migraines is a matter of active research but involves both neurological and vascular components. The head pain associated with migraine is thought to be a consequence of activation of the nociceptive nerves comprising the trigeminocervical complex (TCC). Terminals of nociceptive nerves that innervate the dura matter release vasoactive peptides, such as calcitonin gene-related peptide (CGRP), resulting in cranial vasodilation. Finally, when present, migraine aura appears to correlate with a transient wave(s) of cortical depolarization, termed cortical spreading depression (CSD).

Triptans, including zolmitriptan, are proposed to act in three ways. The main mechanism is through modulation of nociceptive nerve signalling in the central nervous system through 5-HT_1B/1D receptors throughout the TCC and associated areas of the brain. In addition, triptans can enhance vasoconstriction, both through direct 5-HT_1B-mediated dilation of cranial blood vessels, as well as through 5-HT_1D-mediated suppression of CGRP release.

Although triptans are classically described solely in terms of their effects on 5-HT_1B/1D receptors, they also act as 5-HT_1F agonists as well. This 5-HT subtype is also found throughout the TCC, but is not present appreciably in cerebral vasculature; the significance of triptan-mediated 5-HT_1F activation is currently not well described. Additionally, CSD that initiates in the ipsilateral parietal region may exert its effects in a manner that relies on 5-HT_1B/1D receptor activation, suggesting that triptans may have some effect on CSD-mediated symptoms.

Dosage

Heng Li An dosage

The recommended dose of Heng Li An to treat a migraine attack is 2.5 mg. If symptoms persist or return within 24 hours, a second dose has been shown to be effective, but it should not be taken within 2 hours of the initial dose. If a patient does not achieve satisfactory relief with 2.5 mg doses, subsequent attacks can be treated with 5 mg initial doses of Heng Li An. In those patients who respond, significant efficacy is apparent within 1 hour of dosing. Heng Li An is equally effective whenever the tablets are taken during a migraine attack, although it is advisable that Heng Li An tablets are taken as early as possible after the onset of migraine headache.Heng Li An is not indicated for prophylaxis of migraine. In the event of recurrent attacks, it is recommended that the total intake of Heng Li An in a 24 hour period should not exceed 10 mg.

Side Effects

Heng Li An is generally well tolerated. Adverse reactions are typically mild/moderate, transient, not serious and resolve spontaneously without additional treatment. Possible adverse reactions tend to occur within 4 hours of administration and are not more frequent following repeated dosing. The following adverse reactions have been the most commonly reported: nausea, dizziness, somnolence, warm sensation, asthenia and dry mouth. Abnormalities or disturbances of sensation have been reported, heaviness, tightness or pressure may occur in the throat, neck, limbs and chest (with no evidence of ischaemic changes on ECG) as may myalgia, muscle weakness, paraesthesia and dysesthesia.

Toxicity

Toxicity information regarding zolmitriptan is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as cardiovascular symptoms due to excessive vasoconstriction and activation of serotonergic receptors. Patients receiving a single 50 mg oral dose of zolmitriptan often experienced sedation. Symptomatic and supportive measures are recommended.

Precaution

Heng Li An should only be used where a clear diagnosis of migraine has been established. Care should be taken to exclude other potentially serious neurological conditions. There are no data on the use of Heng Li An in haemiplegic or basilar migraine. Heng Li An should not be given to patients with Wolff Parkinson White syndrome or arrhythmias associated with other accessory cardiac condition pathways. This class of compounds (5HT1D agonists) has been associated with coronary vasospasm; as a result, patients with ischaemic heart disease were excluded from clinical trials. Heng Li An is therefore, not recommended in this patient group. In patients in whom unrecognised coronary artery disease is likely, cardiovascular evaluation prior to commencement of treatment with 5HT1D agonists is recommended. As with other 5HT1D agonists, atypical sensations over the pericardium have been reported after the administration of Heng Li An, but in clinical trials these have not been associated with arrhythmias or ischaemic changes on ECG. Heng Li An may cause mild, transient increases in blood pressure (which may be more pronounced in the elderly), however this has not been associated with clinical sequelae in the clinical trial programme.

Interaction

From studies there is no evidence that concomitant use of migraine prophylactic medications (for example b blockers, oral dihydroergotamine, Pizotifen) has any effect on the efficacy or unwanted effects of Heng Li An. The pharmacokinetics and tolerability of Heng Li An oral tablets were unaffected by acute symptomatic treatments such as Paracetamol, Metoclopramide and Ergotamine. Concomitant administration of other 5HT1B/1D agonists within 12 hours of Heng Li An treatment should be avoided. Data from healthy subjects suggest that there are no pharmacokinetic or clinically significant interactions between Heng Li An and Ergotamine, however, the increased risk of coronary vasospasm is a theoretical possibility.Therefore, it is advised to wait at least 24 hours following the use of Ergotamine containing preparations before administering Zolmit. Conversely it is advised to wait at least six hours following use of Heng Li An before administering any Ergotamine preparation. A maximum intake of 5 mg Heng Li An nasal spray in 24 hours is recommended in patients taking an MAO inhibitor, general P450 inhibitor. Fluoxetine does not affect the pharmacokinetic parameters of Heng Li An. Therapeutic doses of the selective serotonin reuptake inhibitors (SSRIs), Fluoxetine, Sertraline, Paroxetine and Citalopram do not inhibit CYP1A2.

Food Interaction

• Take with or without food. Food does not significantly impact the oral bioavalibility of zolmitriptan.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Heng Li An Cholesterol interaction

[Major] The group of drugs known as 5-hydroxytryptamine1 receptor (5-HT1) agonists can cause vasospastic reactions, including coronary vasospasm, peripheral vascular ischemia, and colonic ischemia.

Rarely, serious adverse cardiac events including acute myocardial infarction, arrhythmia, cardiac arrest, and death have been reported within a few hours following the administration of 5-HT1 agonists, in some cases even in patients with no prior history or findings of coronary artery disease (CAD).

Significant elevation in blood pressure, including hypertensive crisis, has also been reported on rare occasions in patients with and without a history of hypertension, as have transient increases in blood pressure and peripheral vascular resistance.

In general, patients with potentially unrecognized CAD as predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, tobacco use, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) should not be administered 5-HT1 agonists unless a cardiovascular evaluation provides satisfactory clinical evidence indicating the lack of CAD, ischemic heart disease, or other significant underlying cardiovascular disease.

As a precaution, the manufacturers recommend that the first dose be administered under medical surveillance in such patients, and that electrocardiographic monitoring be considered during the interval immediately following administration to help detect any asymptomatic cardiac ischemia that may occur.

Periodic cardiovascular evaluations should be performed during intermittent, long-term use.

Heng Li An Drug Interaction

Major: duloxetine, cyclobenzaprine, escitalopram, ondansetron, sertralineModerate: lisdexamfetamineUnknown: erenumab, diphenhydramine, galcanezumab, omega-3 polyunsaturated fatty acids, fluticasone nasal, pregabalin, albuterol, topiramate, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, alprazolam, cetirizine

Heng Li An Disease Interaction

Major: CAD risk factors, cardiovascular disease, liver diseaseModerate: renal dysfunction

Volume of Distribution

Heng Li An has a volume of distribution between 7 and 8.4 L/kg.

Elimination Route

Heng Li An tablets have a mean absolute oral bioavailability of approximately 40%, with food having no effect on the rate or extent of absorption. The dosing kinetics are linear over a range of 2.5 to 50 mg with 75% of the eventual C_max being attained within 1 hour of dosing. The median T_max for the tablet form is 1.5 hours, while for the orally disintegrating tablet form, it is 3 hours. The AUC across studies was in the range of 84.4-173.8 ng/mL*h while the C_max was between 16 and 25.2 ng/mL.

Heng Li An administered as a nasal spray is detected in the plasma within 2-5 minutes, compared to 10-15 minutes for the tablet form; the faster kinetics likely reflect fast absorption across the nasal mucosa. The bioavailability compared to the tablet is 102%, and plasma zolmitriptan concentration is maintained for 4-6 hours after intranasal delivery.

The active N-desmethyl metabolite of zolmitriptan has a mean plasma concentration that is roughly two-thirds of zolmitriptan, regardless of dosage route or concentration.

Half Life

Heng Li An has a mean elimination half-life of approximately three hours, while its active N-desmethyl metabolite has a slightly longer (approximately 3.5 hours) half-life.

Clearance

Heng Li An has a clearance of 31.5 mL/min/kg for oral tablets and 25.9 mL/min/kg for nasal administration; one-sixth of the clearance is renal.

Elimination Route

Heng Li An is primarily excreted in urine (approximately 65%) and feces (approximately 30%). Within urine, the most common form is the indole acetic acid metabolite (31%), followed by the N-oxide (7%), and N-desmethyl (4%) metabolites; the majority of zolmitriptan recovered in feces remains unchanged.

Pregnancy & Breastfeeding use

Pregnancy: Heng Li An should be used in pregnancy only if the benefits to the mother justify potential risk to the foetus.Lactation: Studies have shown that Heng Li An passes into the milk of lactating animals. No data exist in lactating women. Therefore, caution should be exercised when administering Heng Li An to lactating women.

Contraindication

Heng Li An is contraindicated in patients with :

• Known hypersensitivity to any component of the product
• Uncontrolled hypertension
• Ischaemic heart disease
• Coronary vasospasm/Prinzmetal’s angina
• A history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA)

Special Warning

Use in children: Safety and efficacy of Heng Li An in paediatric patients have not been established.Use in patients aged over 65 years: Safety and efficacy of Heng Li An in individuals aged over 65 years have not been systematically evaluated.Patients with hepatic impairment: The dose of Heng Li An should be reduced in patients with moderate to severe hepatic impairment, maximum dose of 5 mg in 24 hours is recommended. Patients with renal impairment: No dosage adjustment is required.

Storage Condition

Keep out of the reach of children. Store at a cool and dry place. Protect from light and moisture.

Innovators Monograph

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