Rosiglitazone

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Structural formula
Structural formulas of the enantiomers of the drug rosiglitazone
1: 1 mixture of ( S ) -rosiglitazone (left) and ( R ) -rosiglitazone (right)
General
Non-proprietary name Rosiglitazone
other names
  • ( RS ) -5 - ({4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl} methyl) -2,4-thiazolidinedione
  • (±) -5 - ({4- [2- (Methyl-2-pyridinylamino) ethoxy] phenyl} methyl) -2,4-thiazolidinedione
  • rac -5 - ({4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl} methyl) -2,4-thiazolidinedione
Molecular formula
  • C 18 H 19 N 3 O 3 S (rosiglitazone)
  • C 18 H 19 N 3 O 3 S · C 4 H 4 O 4 (rosiglitazone maleate)
External identifiers / databases
CAS number
  • 122320-73-4 (rosiglitazone)
  • 155141-29-0 (rosiglitazone maleate )
EC number 924-121-1
ECHA InfoCard 100.108.114
PubChem 77999
ChemSpider 70383
DrugBank DB00412
Wikidata Q424771
Drug information
ATC code

A10 BG02

Drug class

Insulin sensitizer

Mechanism of action

oral antidiabetic drug

properties
Molar mass
  • 357.43 g · mol -1 (rosiglitazone)
  • 473.50 g · mol -1 (rosiglitazone maleate)
Melting point
  • 153–155 ° C (rosiglitazone)
  • 122–123 ° C (rosiglitazone maleate)
solubility
  • soluble in methanol (rosiglitazone)
  • soluble in ethanol (rosiglitazone maleate)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Rosiglitazon is an antidiabetic from the group of insulin sensitizers for the treatment of type 2 diabetes mellitus . The principle of action is to increase the sensitivity of the tissue to insulin. The body's own insulin is consequently able to lower increased blood sugar levels more effectively.

Since November 2010, by order of the Federal Institute for Drugs and Medical Devices (BfArM), the marketability of drugs with the active ingredient rosiglitazone has been suspended in Germany . Their risk-benefit ratio had been classified by the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency as generally unfavorable (cardiovascular risks, frequent heart attacks). However, recent studies show that the original concerns may be unfounded, according to a review, rosiglitazone (trade name Avandia ) does not increase the risk of heart attacks. The raw data were more or less consciously manipulated in the original study, which was also not blinded. However, there is currently little economic interest in re-marketing the drug because the patent has already expired.

Rosiglitazone does not seem to be superior to conventional antidiabetic drugs at higher costs.

Pharmacological information

Effects

Corresponding to the mechanism of action of the insulin sensitizer, rosiglitazone activates the PPAR receptor ( peroxisome proliferator-activated receptors ) of type γ in the cell nucleus after oral ingestion . This receptor is involved in the regulation of various mechanisms in carbohydrate and fat metabolism. Activation increases the sensitivity of the cells of the liver, muscles and adipose tissue to insulin (lowering of insulin resistance ). The effect of supplied insulin is also increased. Fatty acids and glucose are increasingly absorbed into the cells and converted into metabolism. In the liver, the formation of new glucose is also reduced.

In addition to its metabolic effects, rosiglitazone also has anti-inflammatory properties. It lowers the concentration of NF-κB (nuclear factor κB) and increases the concentration of IκB (inhibitory kappa-B) in inflammatory cells. On the basis of animal experiments, a therapeutic effect in Alzheimer's disease and Alzheimer's dementia was also discussed.

Pharmacokinetics

The maximum level in the blood is reached after about an hour due to the rapid absorption from the intestine. The bioavailability is 99%. The plasma protein binding is almost 100%. The degradation takes place via the cytochrome P450 system of the liver, the metabolites are not active. 70% of these are excreted via the kidneys ( renal ) and 30% via the stool. The plasma half-life is three to four hours; it can be longer in liver disease. A dose adjustment in renal insufficiency is not necessary.

Clinical information

application areas

Rosiglitazone is indicated for the treatment of type 2 diabetes mellitus. Rosiglitazone is used either alone or in combination with other drugs.

Monotherapy
Monotherapy with rosiglitazone is indicated in adults whose blood sugar can not be adequately controlled through diet and exercise and for whom metformin is unsuitable.
Dual combination therapy
Simultaneous administration together with either metformin or a drug from the group of sulfonylureas is indicated if administration of these drugs alone is insufficiently effective.
Triple combination therapy
Simultaneous administration together with metformin and a sulphonylurea is indicated in adults in whom the blood sugar cannot be adequately controlled with dual combination therapy.

Side effects

The most common undesirable effects are edema , anemia , weight gain and increased cholesterol levels in the blood ( hypercholesterolaemia ). These occur significantly more frequently in combination with insulin than under single medication with rosiglitazone. In combination with insulin or a sulfonylurea also are very common dose-related hypoglycaemia ( hypoglycemia ) on. Furthermore, there may be increased appetite and body weight, constipation ( constipation ) and liver damage with an increase in transaminases , but only very rarely with manifest liver inflammation ( hepatitis ). Inflammation of the pancreas ( pancreatitis ), anaphylactic reactions , angioedema , urticaria , rash and itching of the skin or macular edema of the eye rarely occur . Particularly in combination with insulin, the heart muscle can suffer from a lack of oxygen .

In May 2005 the BfArM published that studies found an increased risk of bone fractures in women; the product information was supplemented and the medical profession was informed by red hand letter .

In a review of 42 studies published in the New England Journal of Medicine in June 2007 , a 43% increased risk of heart attack was observed. The manufacturer of the drug and the European Medicines Agency questioned the validity of the meta-study. An independent control of the study data now confirms the doubt that rosiglitazone does not represent an increased risk of heart attacks. The FDA has therefore already relaxed the requirements for prescribing rosiglitazone.

Because of the alleged increased risk of cardiovascular disease when taking rosiglitazone preparations, the European Medicines Agency (EMA) finally recommended in September 2010 that the approval in Europe be revoked. The German Federal Institute for Drugs and Medical Devices (BfArM) complied with this recommendation, so that rosiglitazone has no longer been available in Germany since November 2010.

According to a former employee of the Food and Drug Administration (FDA), Avandia manufacturer GlaxoSmithKline PLC has withheld data about the risk. A panel of experts from the same authority has expressed a majority of concerns about "Avandia", but also a majority of them are in favor of keeping the drug on the market under certain conditions.

Interactions

Rosiglitazone is primarily metabolised by the cytochrome P450 isoenzymes CYP2C8 and CYP2C9 . Therefore, the simultaneous use of drugs that affect CYP2C8 such as rifampicin , trimethoprim or gemfibrozil can lead to fluctuations in the drug level. Interactions with phenytoin , carbamazepine , phenobarbital and St. John's wort cannot be ruled out. The pharmacokinetics of the coumarin derivatives warfarin and acenocumarol , which are also broken down by CYP2C9, are unaffected. The effect of methotrexate can also be enhanced . Moderate alcohol consumption while taking it does not affect the effect.

Contraindications

Rosiglitazone is contraindicated in cases of known hypersensitivity to rosiglitazone, heart failure and liver dysfunction. The combination with insulin is also not indicated due to the greatly increased rate of side effects.

No data are available for use under the age of ten. Use is not recommended. Rosiglitazone crosses the placenta , so it must not be used during pregnancy and breastfeeding , even if no data are available on its toxicity in humans.

Chemical and pharmaceutical information

Rosiglitazone is chiral . The commercial preparations contain the drug as a racemate (1: 1 mixture of enantiomers).

Rosiglitazone can be used orally and is formulated as a film-coated tablet . The film-coated tablets contain the medicinal substance as the salt of maleic acid (rosiglitazone maleate ). Rosiglitazone requires a prescription.

See also

Pioglitazone

Individual evidence

  1. ↑ a b c d The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 1427.
  2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  3. ↑ DAZ online, Drugs Commission: BfArM orders sales to be discontinued ( memento of the original from September 28, 2010 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. , September 23, 2010. @1@ 2Template: Webachiv / IABot / www.deutsche-apotheker-zeitung.de
  4. ↑ Suspension of the marketing of medicinal products containing rosiglitazone (Avandia®, Avandamet® and Avaglim®) in the European Union (PDF; 243 kB), Rote-Hand-Brief dated September 23, 2010.
  5. ↑ Avandia: FDA should relax application restrictions
  6. ↑ a b c T. Koch, UP Masche: Rosiglitazon. In: pharma criticism. Volume 21, No. 9, 2000.
  7. ↑ a b c d e f g Avandia : Product information texts (PDF; 849 kB), as of July 2010.
  8. ↑ P. Mohanty, A. Aljada, H. Ghanim, D. Hofmeyer, D. Tripathy, T. Syed, W. Al-Haddad, S. Dhindsa, P. Dandona: Evidence for a potent antiinflammatory effect of rosiglitazone. In: J Clin Endocrinol Metab . 89 (6), Jun 2004, pp. 2728-2735. PMID 15181049 .
  9. ↑ G. Landreth: PPARgamma agonists as new therapeutic agents for the treatment of Alzheimer's disease. In: Neurol. 199 (2), Jun 2006, pp. 245-248. PMID 16733054 .
  10. ↑ Glitazone (rosiglitazone, pioglitazone): Increased risk of fractures in women. on the website of the Federal Institute for Drugs and Medical Devices
  11. ↑ Steven E. Nissen, Kathy Wolski: Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. In: N Engl J Med. Vol. 356, No. June 24, 2007. PMID 17517853 .
  12. ↑ Stefan Schmitt: Heart attack risk - study causes dispute over blockbuster drug. In: Spiegel online. May 25, 2007.
  13. ↑ FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines.
  14. ↑ European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim. European Medicines Agency press release, 23 September 2010.
  15. ↑ Alicia Mundy: Grassley Says Glaxo Withheld Drug Data. In: The Wall Street Journal. July 12, 2010.
  16. ↑ The Avandia Saga Continues. Editorial. In: The New York Times . July 14, 2010.

Trade names

All trade names are trademarked by the British pharmaceutical company GlaxoSmithKline :

Monopreparations

Avandia

Combination preparations