Instructions for use Sumatriptan

In May 2022, the US Food and Drug Administration (FDA) approved Aimovig (international nonproprietary name: erenumab), the first fully human antibody for the treatment of migraine. This medicine, developed jointly by the pharmaceutical companies Novartis and Amgen, has a fundamentally different mechanism of action than the drugs traditionally used to treat migraine. Will Aimovig be able to significantly reduce symptoms and improve the quality of life of migraine sufferers? Let's try to figure it out.

pharmachologic effect

Serotonin 5-HT1 receptor agonist. A drug with antimigraine activity.

Pharmacokinetics

After oral administration, it is quickly absorbed. 70% of the maximum plasma concentration is achieved after 45 minutes. Cmax in blood plasma is 54 ng/ml. Bioavailability - 14% (due to first-pass metabolism and incomplete absorption). Plasma protein binding is 14-21%.

Metabolized by oxidation with the participation of monoaminoxylase (mainly isoenzyme A) with the formation of metabolites, the main of which are the indoleacetic analogue of sumatriptan, which does not have pharmacological activity against 5-HT1-serotonin receptors, and its glucuronide. It is excreted by the kidneys, mainly in the form of metabolites.

Pharmacodynamics

Sumatriptan is a specific selective agonist of 5-HT1-serotonin receptors, localized primarily in the blood vessels of the brain and their stimulation leads to a narrowing of these vessels. Does not affect other subtypes of 5-HT-serotonin receptors (5-HT2-7). Activates the sensitivity of trigeminal nerve receptors. The therapeutic effect usually occurs 30 minutes after administration.

"Aimovig" and competitors

It must be said that Novartis and Amgen already have serious competitors in the field of targeted anti-migraine therapy: Eli Lilly released Emgality, and Teva Pharmaceutical released Ajovy. These drugs are humanized monoclonal antibodies that target the ligand rather than the CGRP receptor, and in this way they differ from Aimovig, being inferior to the latter at least in tolerability. When using Ajovy, 43–45% of patients experienced pain, redness and itching at the injection site, when using Emgality, 18% of patients experienced such symptoms, and Aimovig caused such reactions only in 5–6% of cases. At the same time, Aimovig is also more convenient to use, since of the three listed drugs, only it comes in the form of an auto-injector - a device that resembles an insulin syringe pen - which needs to be used only once a month. The listed advantages, coupled with the fact that Aimovig became the first targeted drug for the treatment of migraine and immediately filled an empty niche in the market, will most likely provide it with a bright financial future: according to experts, its market share in 2024 will be $2 billion, while the predicted shares of competitors are approximately half as much [20].

The success of Aimovig, apparently, cannot be hampered even by the extremely high price ($575 per month according to the Amgen price list - however, in the United States, the drug is covered by insurance for many patients), which, by the way, some experts consider unreasonable [11]. The company is conducting research on Aimovig in Russia, but when the drug will appear on the market, how much it will cost and who will pay for it is still unknown.

Contraindications to the use of Sumatriptan

• hemiplegic, basilar or ophthalmoplegic forms of migraine;
• IHD or the presence of symptoms suggesting its presence;
• history of myocardial infarction;
• pharmacologically uncontrolled arterial hypertension;
• occlusive diseases of peripheral vessels;
• stroke or transient cerebrovascular accident (including history);
• severe dysfunction of the liver and kidneys;
• simultaneous use with ergotamine or its derivatives and within 24 hours after their administration;
• use while taking monoamine oxidase inhibitors or earlier than 2 weeks after discontinuation of these drugs;
• age under 18 and over 65 years (efficacy and safety have not been established);
• pregnancy;
• breastfeeding (breastfeeding is possible no earlier than 24 hours after taking the drug;
• congenital galactosemia, glucose/galactose malabsorption syndrome, congenital lactose deficiency;
• hypersensitivity to any of the components of the drug.

With caution: epilepsy (including any conditions with a reduced epileptic threshold), pharmacologically controlled arterial hypertension, impaired liver or kidney function, hypersensitivity to sulfonamides (administration of sumatriptan can cause allergic reactions, the severity of which varies from skin manifestations to anaphylaxis) .

Targeted therapy for migraine: a solution to the problem?

Since migraine is a chronic disease and the effectiveness and safety of the drugs used for prevention is poor, there is clearly an unmet need in this area; however, there are few new drugs specifically developed for this indication [14].

Amgen and Novartis can boast of a breakthrough today, having received approval in May 2022 for the use of the targeted drug Aimovig erenumab antibodies ) for the prevention of migraine in adult patients [20]. This is the first fully human antibody to be commercialized whose preventive effect is due to binding and blocking the CGRP receptor, which is considered critically important in the development of migraine (Fig. 3).

Figure 3. Aimovig specifically binds to the CGRP receptor, preventing CGRP from binding to it. The binding of CGRP to its receptor in a molecular complex (shown on the left) results in the transmission of pain signals associated with migraine. In people with migraine, CGRP levels are elevated during a painful attack and return to normal levels when the migraine pain subsides.

About Aimovig® (erenumab) in migraine prevention

Aimovig was approved after three series of clinical trials, the results of which, although slightly different, were similar in one thing: the drug showed a significant reduction in the number of days with attacks and the total duration of migraine pain. Moreover, in phase III trials, in 50% of patients taking 140 mg of Aimovig, the number of painful days decreased by half compared to placebo, and the safety and tolerability of the drug turned out to be quite similar to placebo [21], [22]. . These results are very encouraging, and it is clear that although Aimovig is not a panacea, its use will definitely change the lives of patients suffering from frequent and severe migraines for the better.

Antibody purification using continuous countercurrent chromatography

Biotechnologically derived antibodies can be purified using the chromatography equipment of this material's partner, Cytiva. This is done in continuous counter-current chromatography (PCC) mode on an ÄKTA pcc . In combination with the minimal dimensions of the system, continuous chromatography technology ensures the most efficient use of the chromatographic sorbent (resin). This method is particularly suitable for the purification of unstable molecules, as the rapid process ensures the stability of the target product. The ÄKTA pcc system is based on the well-established and widely used ÄKTA chromatography system platform by scientists around the world. Key features of the ÄKTA pcc system:

• Flow rate: 0.5–75 ml/min.
• Maximum operating pressure: 20 bar.
• Supports three and four column PCC configuration (3C and 4C PCC).
• Integrated UV detectors: one tunable wavelength (three values) and three fixed wavelength (280 nm).
• Monitors for tracking pH and conductivity readings.
• Interactive visualization that continuously shows column status and process progress.
• Trend lines that allow you to immediately begin analyzing the information received about the process.

ÄKTA chromatography systems can be used in conjunction with AxiChrom columns, although they are also suitable for larger scale protein purifications. A wide range of column sizes of the same type (Figure 4) allows protein purification to be scaled up with minimal parameter changes.

Figure 4. AxiChrom is a family of pilot-scale to industrial-scale protein purification columns with i.d. diameters of 50–1600 mm. AxiChrom columns successfully combine standardization and customization and are compatible with a variety of advanced media, such as MabSelect SuRe™ antibody purification resin.

Cytiva's research has confirmed the similarity between the protein purified in the laboratory and in production. In this case, the volume of the drug was scaled by 294 times (Fig. 5).

Figure 5. Comparison of chromatograms obtained using ÄKTA pcc on HiTrap columns (a) and AxiChrom 50 columns (b)

Material provided by our partner - Cytiva

Side effects

The frequency of adverse reactions listed below was determined according to the following: very often - more than 1/10; often - from more than 1/100 to less than 1/10; sometimes - from more than 1/1000 to less than 1/100; rarely - from more than 1/10,000 to less than 1/1000; very rarely - from less than 1/10,000, including isolated cases.

From the nervous system: often - dizziness, drowsiness, sensory disturbances, including parasthesia and decreased sensitivity.

From the cardiovascular system: often - a transient increase in blood pressure (observed soon after taking the drug), "hot flashes".

From the respiratory system and organs of the cell group: often - dyspnea, mild, transient irritation of the mucous membrane or a burning sensation in the nasal cavity or throat, nosebleeds.

From the gastrointestinal tract: often - nausea, vomiting.

From the musculoskeletal system and connective tissue: often - a feeling of heaviness (usually transient, can be intense and occur in any part of the body, including the chest and throat).

General and local reactions: often - pain, a feeling of cold or heat, a feeling of pressure or tightness (usually transient, can be intense and occur in any part of the body, including the chest and throat), weakness, fatigue (usually mild or moderate, transitory).

Laboratory indicators: very rarely - minor deviations in liver test results.

Post-marketing surveillance

From the immune system: very rarely - hypersensitivity reactions, including skin manifestations, as well as anaphylaxis.

From the nervous system: very rarely - seizures (in some cases observed in patients with a history of seizures or with concomitant conditions predisposing to seizures; in some patients no risk factors were identified), tremor, dystonia, nystagmus, scotoma.

On the part of the visual organs: very rarely - flickering, diplopia, decreased visual acuity, blindness (usually transient). However, visual disturbances can be caused by the migraine attack itself.

From the cardiovascular system: very rarely - bradycardia, tachycardia, flutter, arrhythmias, transient changes on the ECG, coronary vasospasm, angina pectoris, myocardial infarction, hypotension, Raynaud's syndrome.

From the gastrointestinal tract: very rarely - ischemic colitis, dysphagia, feeling of discomfort in the abdomen.

Literature

1. Three generations of drugs;
2. Search for drug targets;
3. Sanoeva M.Zh. and Saidvaliev F.S. (2016). Migraine - yesterday, today, tomorrow. A modern view of the problem. "International Neurological Journal". 8, 72–78;
4. How a migraine happens. Johns Hopkins Medicine;
5. Migraine headaches. (2018). WebMD;
6. Paul L. Durham. (2006). Calcitonin Gene-Related Peptide (CGRP) and Migraine. Headache
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   46 , S3-S8;
7. What to know about the new anti CGRP migraine treatment options. (2018). American Migraine Foundation;
8. Silberstein S. D. (2016). Migraine. MSD Directory;
9. Migraine triggers: your personal checklist. (2019). WebMD;
10. Rusakova E. (2018). The FDA has approved the drug to prevent migraines. N+1;
11. Kolata G. (2018). The FDA approves the first drug designed to prevent migraines. The New York Times;
12. Theo Vos, Amanuel Alemu Abajobir, Kalkidan Hassen Abate, Cristiana Abbafati, Kaja M Abbas, et. al.. (2017). Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet
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    390 , 1211-1259;
13. Francesca Puledda, Kevin Shields. (2018). Non-Pharmacological Approaches for Migraine. Neurotherapeutics
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    15 , 336-345;
14. Doodipala Samba Reddy. (2013). The pathophysiological and pharmacological basis of current drug treatment of migraine headache. Expert Review of Clinical Pharmacology
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    6 , 271-288;
15. Ogbru A. and Ogbru O. Prescription migraine medications. RxList;
16. Boyce S., Ali Z., Hill R. G. (2001). New developments in analgesia. Drug Discovery World;
17. Azimova Yu.E. (2017). Triptans: an era of specific treatment for migraine. "Nervous diseases". 1, 10–14;
18. Ameri M. and Lewis H. (2018). The evolution of transdermal drug delivery and treating migraine. Drug Discovery World;
19. Migraine medications. (2013). TMedWeb;
20. Dmitriev R. (2019). "Aimovig" will turn chronic migraine into episodic. "Mosmedpreparaty";
21. Aimovig (erenumab) for the treatment of episodic migraine. Clinical Trials Arena;
22. Khoruzhaya A. (2018). A new anti-migraine drug goes on sale. "Neuronews";
23. Targeted therapy is a targeted strike against the disease.

Drug interactions

When administered simultaneously with ergotamine and ergotamine-containing drugs, prolonged vasospasm is possible.

Possible interaction between sumatriptan and MAO inhibitors (decreased metabolism of sumatriptan, increased its concentration).

With the simultaneous use of sumatriptan and drugs from the group of selective serotonin reuptake inhibitors, the development of weakness, hyperreflexia and impaired coordination of movements is possible.

There was no interaction of sumatriptan with propranolol, flunirizine, pizotifen and ethanol.

Modern medicines

A special project about modern medicines, the history of their creation, development methods and development trends.

The special project partner, Cytiva, was formed as a result of the sale of the GE Healthcare Biopharma division to Danaher Corporation. Cytiva is a global provider of technologies and services that advance and accelerate the development and manufacturing of therapeutics. The company has a rich heritage dating back hundreds of years. Cytiva's clients conduct life-saving activities ranging from basic biological research to the development of innovative vaccines, biologics and novel cell and gene therapies. The company's mission is to provide the tools and services they need to do things better, faster and safer, leading to better outcomes for patients.

The first two articles of our special project “Modern Medicines” were devoted to general issues of how the drug industry developed [1] and how scientists search for new drug targets [2]. This article opens a number of news materials about interesting modern medicines.

Sumatriptan dosage

Inside, the tablet should be swallowed whole with water. Treatment should be started as early as possible when a migraine attack occurs. The recommended dose is 50 mg, if necessary - 100 mg.

If migraine symptoms do not disappear or decrease after taking the first dose, then the drug should not be used again to relieve the same attack.

To relieve subsequent attacks (if symptoms decrease or disappear and then recur), you can take a second dose within the next 24 hours, provided that the interval between doses is at least 2 hours.

The maximum daily dose is 300 mg.