Lisdexamfetamine
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| Non-proprietary name | Lisdexamfetamine | ||||||||||||
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| Molecular formula | C 15 H 25 N 3 O | ||||||||||||
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indirect sympathomimetic |
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| Mechanism of action |
Norepinephrine / dopamine release |
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| Molar mass | 263.38 g mol −1 | ||||||||||||
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||
Lisdexamfetamine (LDX) is a synthetically produced prodrug from the group of amphetamines .
The substance is used as a drug to treat ADHD . In Germany, it is approved for children and adolescents aged 6 and over who have responded insufficiently to therapy with methylphenidate , and since February 2019 also as a first-line therapy for adults. In Switzerland, lisdexamfetamine is approved for children and adolescents as well as for adults up to 55 years of age, provided that therapy with methylphenidate has failed.
After two studies in the indication " depression (in adults)" were unsuccessful, the manufacturer Shire plc announced in February 2014 that it would no longer continue the clinical development program for lisdexamfetamine.
Mechanism of action
Lisdexamfetamine is a derivative of dexamfetamine ( D - amphetamine ). Its primary amino group is covalently linked to the carboxy group of the amino acid L - lysine via an amide bond . Lisdexamfetamine dimesylate, a salt of methanesulfonic acid, is used medicinally .
Lisdexamfetamine is a pharmacologically inactive prodrug and is rapidly absorbed in the gastrointestinal tract after ingestion . Only then does the cleavage into lysine and dexamfetamine, which is pharmacologically active, take place, especially on the erythrocytes . This prodrug effect extends the time (when taken after a high-fat meal) until the maximum concentration in the blood is reached: for D-amphetamine after LDX intake it is 3.5 hours, for amphetamine it is normally only 2 hours. The effect lasts between 8 and 11 hours, depending on the patient.
The mechanism of the therapeutic effects of amphetamines in ADHD is not fully understood. Presumably it is based on an increased release of noradrenaline and dopamine into the synaptic cleft . This release is mainly caused by a reversal of the working direction of the dopamine transporter (DAT). In contrast to the principle of reuptake inhibition (such as with methylphenidate), the transmitter level is increased independently of the activity of the nerve cell.
Pharmacokinetics
After a single oral dose, lisdexamfetamine dimesylate is rapidly absorbed. Peak levels occurred in children after about 1 hour. During the biotransformation, the main active metabolite dexamfetamine is initially formed - peak levels under fasting conditions approx. 3.5 hours (children) or 3.8 hours (adults) - and then other, likewise active metabolites ( norephedrine , 4-hydroxyamfetamine). Cytochrome P450 enzymes are not involved in the biotransformation, but are in part (CYP1A2, 2D6, 3A4) slightly inhibited. This can lead to interactions with other active substances that are metabolized via these metabolic pathways. After oral administration of radioactively labeled lisdexamfetmin to healthy volunteers, about 96% of the orally administered radioactivity was recovered in the urine within 120 hours. The half-life of dexamfetamine is approximately 11 hours.
Side effects
The most common side effects are the same as for other stimulants: decreased appetite, difficulty sleeping, dry mouth, headache, weight loss and upper abdominal pain.
Application restrictions
The restrictions on use are also comparable to those for other stimulants. There is a potential for abuse, but this should be less pronounced than that of the active dexamfetamine, since the amide is only broken down very slowly after intravenous administration.
rating
Early benefit assessment according to AMNOG
Since 2011, newly approved drugs with new active ingredients in Germany have had to undergo an " early benefit assessment " by the Federal Joint Committee (G-BA) based on Section 35a SGB V ( AMNOG ) if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . The drug manufacturer can only negotiate a price with the National Association of Statutory Health Insurance Funds if there is an additional benefit .
This also applies to lisdexamfetamine. In an initial assessment, the Institute for Quality and Efficiency in Health Care considers an additional benefit of lisdexamfetamine to be not proven compared to the appropriate comparator therapy ( Strattera , active ingredient atomoxetine ). The Medicines Commission of the German medical profession also sees no additional benefit from lisdexamfetamine dimesilate compared to the ACT. The G-BA followed the assessments and made the final decision on the extent of the additional benefit in November 2013, which concludes the early benefit assessment: “Appropriate comparator therapy for the treatment of attention deficit hyperactivity disorder (ADHD) in children from the age of six years An overall therapeutic strategy when the response to previously received treatment with methylphenidate is considered clinically inadequate is atomoxetine. Extent and probability of the additional benefit compared to atomoxetine: An additional benefit has not been proven. ”On June 1, 2014, the manufacturer Shire Germany and the National Association of Statutory Health Insurance Funds agreed on a reimbursement amount for the drug in Germany.
Cost comparison
According to the drug prescription report for 2014 and 2015, the costs for Elvanse per defined daily dose were significantly higher than for methylphenidate products, but lower than for atomoxetine (Strattera) .
In 2013, the pharmacritical drug telegram criticized the lack of meaningful data for the approved indication (use as part of an overall therapeutic strategy for the treatment of ADHD in the case of inadequate response to methylphenidate) and the safety advantages over dexamfetamine. The therapy costs with lisdexamfetamine are considerably more expensive than with retarded methylphenidate (Concerta) or dexamfetamine (Attentin) .
Legal position
Lisdexamfetamine has been listed in Appendix III of the Narcotics Act in Germany since July 17, 2013 and is therefore a marketable and prescription narcotic . Handling without permission or prescription is generally punishable.
Switzerland also controls the trade, handling and prescription of lisdexamfetamine under the Narcotics Act . The list of active ingredients a of the Federal Department of Home Affairs has recorded "Lisdexamphetamine" since October 1, 2014 with the trade number 7611764965442 and makes the substance subject to all control measures under narcotic law.
Finished medicinal products
Elvanse (D, A, CH), Elvanse Adult / Adults (D, A, UK), Vyvanse (USA)
Situation in Germany: the capsules (marketing authorization holder: Shire Pharmaceuticals Ireland Limited , part of Takeda Pharmaceutical ) are offered in different strengths from 20 to 70 milligrams (in 10 mg increments). Elvanse was approved in April 2013. The preparation Elvanse Adult for adult patients was approved in February 2019 , and it was launched on the market in May 2019.
Situation in Switzerland: Elvanse has been approved in Switzerland since March 2014. The pharmaceutical company Opopharma offers the capsules in different strengths from 20 to 70 milligrams.
Austria: Elvanse has been approved since April 2016, Elvanse adults since August 2017.
Individual evidence
- ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
- ↑ Elvanse®, capsules (Lisdexamphetamini dimesylas) - Swissmedic -. (No longer available online.) Archived from the original on March 29, 2017 ; Retrieved April 6, 2017 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice.
- ↑ HCI Solutions AG: Elvanse ®. In: compendium.ch. Retrieved April 6, 2017 .
- ↑ Shire Reports Top-line Results from Two Phase 3 Studies for Vyvanse® (lisdexamfetamine dimesylate) Capsules (CII) as an Adjunctive Treatment for Adults with Major Depressive Disorder . ( Memento of the original from February 22, 2014 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. PM Sire, Feb. 6, 2014; accessed on February 10, 2014.
- ↑ a b Otto Benkert u. a .: Compendium of Psychiatric Pharmacotherapy . Springer 2016. ISBN 978-3-662-50333-1 . P. 809f.
- ↑ Manfred Gerlach (Ed.): Neuro- / psychopharmaceuticals in children and adolescents: Basics and therapy . Springer 2016. ISBN 978-3-662-48624-5 . P. 298 f.
- ↑ David Sulzer et al. a .: Mechanisms of neurotransmitter release by amphetamines: a review . In: Progress in Neurobiology . tape 75 , no. 6 , 2005, p. 406-433 , doi : 10.1016 / j.pneurobio.2005.04.003 ( pharmacology.ucsd.edu ( Memento from June 30, 2010 in the Internet Archive ) [PDF]).
- ↑ Shire plc: Product Information Elvanse 20/30/40/50/60/70 mg hard capsules , as of October 2018.
- ↑ David W. Goodman: Lisdexamfetamine Dimesylate. The First Prodrug Stimulant . In: Psychiatry (Edgmont) . tape 4 , no. 8 , August 2007, p. 39-45 , PMID 20532026 .
- ↑ Michael Pennick: Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine . In: Neuropsychiatric Disease and Treatment . tape 6 , 2010, p. 317-327 , PMID 20628632 .
- ↑ Added benefit of lisdexamfetamine has not been proven . IQWiG, PM of September 2, 2013; Retrieved September 2, 2013.
- ↑ Statement of the AkdÄ on Lisdexamfetamine dimesylate (Elvanse®) (PDF) Template for the submission of a written statement on the benefit assessment according to § 35a SGB V; Retrieved October 9, 2013.
- ↑ Benefit assessment procedure for the active ingredient Lisdexamfetamine dimesylate , decision of the G-BA on the benefit assessment according to Section 35a SGB V; Retrieved December 6, 2013.
- ↑ Reimbursement amount for ADHD drug is available - No additional costs for statutory health insurance . Joint press release from Shire Deutschland GmbH and the National Association of Statutory Health Insurance Funds from June 2, 2014.
- ↑ Net costs for Elvanse in Germany: 3.10 euros (2014) and 2.73 euros (2015). From: Drug Ordinance Report 2015 . ( ISBN 978-3-662-47186-9 . Pp. 968f.) And Drug Ordinance Report 2016 . ( ISBN 978-3-662-50351-5 . P. 683 f.)
- ↑ New on the market: Lisdexamfetamine (Elvanse) for treatment-resistant ADHD? In: arznei-telegram , September 13, 2013.
- ↑ Cabinet adopts 27th Ordinance to Amend Narcotics (PDF) Federal Ministry of Health , press release of May 22, 2013.
- ↑ Ordinance of the EDI on the registers of narcotics, psychotropic substances, precursors and auxiliary chemicals (Narcotics Directory Ordinance, BetmVV-EDI) dated May 30, 2011 (as of November 30, 2018). Retrieved April 12, 2019 .
- ↑ Amendment of September 5, 2014 to the Ordinance on Narcotics List. (PDF; 120 kB) AS 2014 3011. In: Official collection. Federal Chancellery, Federal Department of Home Affairs, September 5, 2014, accessed on December 11, 2019 .
- ↑ Product information Elvanse Adult 30 mg / 50 mg / 70 mg hard capsules , Shire Pharmaceuticals Ireland Limited. Status: March 2019.
- ↑ Attack on Medikinet: Elvanse Comes Adult . apotheke adhoc, May 7, 2019.
- ↑ Elvanse®, capsules (Lisdexamphetamini dimesylas) . ( Memento of the original from March 29, 2017 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Swissmedic , accessed on March 28, 2017.
- ↑ Elvanse. In: compendium.ch. Retrieved March 28, 2017 .
