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Levemir

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Levemir
detemir by Novo Nordisk
long-acting analog
U100 Special-via albumin binding
Line new molecular entity
Also known as Detemir (generic)
Similar to Lantus, ultralente
Action in cats  
  • dose dependent peak times
  • onset ~3h,
  • flattish peak at 8 to 12h
  • duration 10-24h depending on dose
Action in dogs  
  • use 1/4 usual dose for dogs!
  • onset Xh (unknown),
  • peak Xh,
  • duration Xh See Fleeman-Rand protocol[1]
Use and Handling
Type clear
Shelf Life 24 months
When opened 6 weeks room temp.[2] (often more refrig.)
In pen 6 weeks room temp.[3] (often more refrig.)
Notes  
  • protect from light and heat
  • Do Not Freeze
  • do not refrigerate after opening
  • no need to roll before use
  • mixing with other insulins may change action of one or both
  • dilution effects unknown
  • Do not use intravenously[4]
  • Avoid intramuscular use[5]

Levemir is Novo Nordisk A/S's worldwide brand name for insulin detemir, a long-lasting insulin analog that lasts up to 24 hours in humans. Its chief benefits according to Novo are a "peakless" action, less weight gain[6] than other insulins, and less day-to-day variability[7] than NPH or Lantus insulins.

Levemir has been shown (by the manufacturer) to vary less day-to-day than NPH or Lantus.[8][9] It was also found to vary less between patients[10].

Warning: This press release from Novo Nordisk dated June 13, 2009, advises there is some stolen Levemir on the market[11]. From the press release, the items were stolen in North Carolina and some vials have surfaced at a medical center in Houston. The stolen lot numbers are:XZF0036, XZF0037, XZF0038. FDA also issued an advisory; there was an adverse event reported in connection with a vial from one of these lot numbers[12].

Veterinary useEdit

Note: For vets and prospective new users, please see these Cases of cats using Levemir. If dogs try it, they would likely have to use only 1/4 of the expected dose. See below for why.

Levemir is long-acting in cats (peak at 8-12 hours, duration of 10-20 hours varying by dosage). Administered twice daily, with the same dosage each time, with substantial overlap, it is usually able to keep an uncomplicated diabetic cat very tightly regulated, often in non-diabetic ranges all day. This is because its curve is so gentle that there's no need to wait for a high diabetic number before injecting more.

Levemir is very new to feline use, but it seems effective in the first 16 cats[13]. This Levemir protocol[14] was made by one experienced Levemir feline user and works well for others, including feline Lantus users.

A 2008 University of Illinois study compared Lantus and Levemir in healthy cats. The result that Levemir had less variability than Lantus wasn't surprising, since these are what the human studies show. However, what has been seen with some people is that Levemir has less duration than Lantus; the feline studies show that in some cats, it's the direct opposite, with Levemir winning the duration race. Lantus was also found to have a faster onset than Levemir in some cats[15].

Doctors' Rand and Fleeman's protocol for Levemir use in dogs is at this link[16].


Here's a full 24h glucose curve in the first known feline case, Jocularity.
Jock Levemir 24h
Jock's 24 hour Levemir curve, at 0.5 U/kg. Click to zoom.
Notice that Jock's dose (3.25U for 6.5kg) here is higher than those shown in the Novo experiments (0.5 U/kg), and that his peak is close to 11 hours. This is consistent with the shifting peak time shown in the 0.2, 0.3, and 0.4U/kg cases above. But it's consistent with human times, not the usually sped-up feline times. Possible explanation: The protein-binding time-delay action of Levemir is not dependent on the animal's metabolism, or at least not the same part of it that makes other insulins run faster in cats.

Notice that except for the rise at the beginning (typical, due to slow onset), the curve is nearly symmetrical, gradual on both sides, and lasts 21 hours before returning to previous level. This means it's very easy on the animal both at the beginning and end of its action, and it can easily be overlapped to the next dose without surprises or difficult calculations. In cases where a rise after shot time causes problems, it can be suppressed with a small simultaneous booster dose.[17]

Levemir will need different doses in different species! A dog dose is likely to be about 1/4 of a human dose, per kg weight. The reason is revealed in the EU testing documents.[18] Levemir was found to be only 25% as effective as expected in humans, and so the concentration was quadrupled in the marketed version.

But note: the 25% efficacy figure at 6nmol/unit in humans was not consistent between species, due to the albumin-binding side-chain physically interfering with insulin receptors, which vary in structure by species. Dogs and pigs found it 100% effective, but in mice and rabbits it was only 1/15 as effective per nmol. (Cats are not mentioned.) According to the tests, therefore, the marketed concentration of 24nmol/unit will seem about normal to humans, 4 times stronger than normal to dogs, and we're not sure about cats. The handful of cats using Levemir so far appear to react to it with the same efficacy as humans, that is, using comparable doses to other human insulins they've used.

Usage and HandlingEdit

Levemir comes in 3ml pen cartridges or prefilled 3ml insulin pens in Europe, 10ml vials and 3ml prefilled insulin pens in the United States, and all three forms in Canada. Cartridges, when available, are compatible with all Novo Nordisk insulin pens including the Novopen Junior[19] and Novopen 3 Demi[20], which both allow half-unit doses. Dosages finer than 1/2 unit increments must be dispensed by using a syringe with the cartridge, which is in this case quite easy. Pictorial at link below[21]

Do not reinsert a cartridge into a refillable pen, or use a disposable pen mechanism, after using it with a syringe, to avoid stress on the pen mechanism and likely destruction of the cartridge or pen.

Levemir's shelf life is 2 years. After first opening the product must be stored, officially for a maximum of 6 weeks, not above 30°C. It may be stored in a refrigerator (2°C - 8°C) not near a freezing compartment. Do not freeze. Protect from light[22]. The insulin is clear and does not need rolling or agitation.

Pens in use are recommended not to be refrigerated, but stored in a dark cool place below 30°C. (Experienced users have not found problems with refrigerating pens in use, though. Users report longer usage life when refrigerated, up to 6 months[23].) Pen cartridges used with a syringe may of course be refrigerated for longer life. Levemir appears to work fine when stored overnight in syringes for prepared dosing. Novo Nordisk themselves have not yet tested diluted Levemir, and so have no consistent answer about whether this is possible. The US web site recommends against it.

About mixing with other insulins they say: "If Levemir is mixed with other insulin preparations the profile of action of one or both individual components may change. Mixing Levemir with a rapid-acting insulin analogue like insulin aspart will reduce and delay the maximum effect of the rapid-acting insulin compared to that observed following separate injections."[24]

AvailabilityEdit

Levemir is quite new:

  • was approved for use in Europe in 2003,
  • by the US FDA in June 2005.
  • available in Canada since January 2006,
  • available in the US since March 28, 2006[25].

FlexPens may be used with syringes just as pen cartridges may.

Technical detailsEdit

Levemir is a clear solution created by genetically engineered yeast. It is analogous to human insulin, but includes a "fatty acyl side chain" that binds temporarily to albumin (found under the skin and in abundance in blood plasma)(98% albumin-bound[26]) and makes the molecule "cling" to the bigger albumin molecules for a while before releasing -- making the molecules slower to enter and exit the bloodstream, and slower to enter the cells.

At an ADA Symposium prior to Levemir's US approval in 2005, Novo Nordisk claimed that if NPH has a patient to patient variability of 60%, Lantus (insulin glargine) then has a 40% variability, and Levemir a 25% rate of variability. Unlike its long-acting rival Lantus, Levemir's time-delay action occurs in the bloodstream and at the target sites, not only at the subcutaneous injection site, and doesn't depend as much on the properties of the injection site or the suspension (which is Isophane, like NPH and other analog mixed insulins)[27][28].

Human insulin is altered to produce insulin detemir (Levemir) by omitting the amino acid Threonine at insulin B chain position #30 and attaching a C14 fatty acid chain to the amino acid at position #29, Lysine[29]. The combination of the omission of the threonine amino acid at position #30 on the B insulin chain and the addition of the fatty acid side chain at position B-#29 binds the insulin heavily to albumin[30].

http://www.rxlist.com/cgi/images/levemir1.gif
Alterations of human insulin producing insulin detemir (Levemir)


Felineinsulin analog
Feline insulin compared with bovine, canine/porcine, human, glargine (Lantus) and detemir (Levemir). Differences, alterations and additions shown for all 6 insulins.
We hopeAdded by We hope


Insulin hex di mon
Insulin hexamers (as injected) must break down into dimers and monomers (also shown) to be absorbed.
We hopeAdded by We hope
Also, the insulin now has more self association tendencies (remaining in hexamer form) than unaltered human insulin. Having the insulin stay in hexamer form longer before breaking down into dimers and monomers means slower absorption, which works out to slower onset, peak and longer duration.

The mean duration of action for Levemir ranges from 5.7 hours at lower dosages to 23.2 hours at the higher ones. For doses in the range of 0.2 to 0.4 U/kg, Levemir exerts more than 50% of its maximum effect from 3-4 hours to approximately 14 hours after being administered[31].

Injection sites should be rotated to avoid lipodystrophy, as with any insulin[32]. The good news is, according to Novo Nordisk, Levemir's stretched-out action in the bloodstream makes its absorption less dependent on injection site conditions (and on rotation) than Lantus. This claim is boosted by Novo's findings of lower day-to-day variability on Levemir compared to Lantus[33].
Levemir was tested against NPH/isophane insulin for EU approval[34] During the tests, (see page 6) Levemir at usual insulin concentrations (6nmol per unit) was found in humans to have only about 25% of the glucose-lowering action of the same dose of NPH[35], so the concentration was increased fourfold to 24 nmol/unit to compensate. The version being marketed has a concentration of 24 nmol/unit, 2400 nmol per mL. Note that this efficacy problem differs between species, see Veterinary use above.

Levemir's action profile, according to Novo's Trial NN304-1338, a randomised, double-blind, cross-over trial involving 12 subjects, looks like this:

LevemirProfile
Levemir action over 24 hours at 3 different dosage levels.

Insulin amino acid sequencesEdit


Amino Acid Sequence of Insulin Preparations[36]
Amino Acid Substitutions

 

  A-Chain Position  

B-Chain Position

Source
Species
A-8 A-10 A-21 B-28 B-29 B-30 B-31
B-32
Beef Ala Val Asn Pro Lys Ala N/A
Pork Thr Ilc Asn Pro Lys Ala N/A
Human Thr Ilc Asn Pro Lys Thr N/A
Aspart Thr Ilc Asn Aspartic Acid Lys Thr N/A
Lispro Thr Ilc Asn Lys Pro Thr N/A
Glulisine Thr Ilc Asn Pro Glu Thr N/A
Lantus (glargine) Thr Ilc Gly Pro Lys Thr Arg
Levemir(detemir) Thr Ilc Asn Pro Lys N/A Myristic Acid
Ala=Alanine Val=Valine Asn=Asparagine Pro-Proline Lys=Lysine Thr=Threonine Ilc=Isoleucine Glu-Glutamine Gly=Glycine



Insulin PharmacokineticsEdit

<center>Pharmacokinetics of Insulin Preparations in HUMANS[37]
Insulin Preparations
Onset (hr)
Peak (hr)
Duration (hr)
Rapid-Acting
R/Neutral
0.5 to 1
2.5 to 5
8 to 12
Lispro
0.25 to 0.5
0.5 to 1.5
2 to 5
Aspart
0.17 to 0.33
1 to 3
3 to 5
Glulisine
0.17 to 0.33
1 to 3
3 to 5
Intermediate-Acting
NPH
Isophane
1 to 1.5
6 to 14
16 to 24
Lente[38]
1 to 3
6 to 14
20+
70/30-30/70
0.5 to 1
2 to 12
24
50/50
0.5 to 1
2 to 12
24
Novolog 70/30 Mix
0.25
1 to 3
24
Humalog 75/25 Mix
0.25
0.5 to 1.5
24
Long-Acting
Ultralente[39]
6
14 to 18
18 to 24
PZI[40]
4 to 6
14 to 18
24 to 36
Glargine
1.1
N/A
24
Detemir
0.8 to 2
N/A
up to 24
These are human activity profiles. Other animals, particularly cats, will differ significantly. Note that Detemir in particular seems to work in cats and humans similarly, though this is not true for most other insulins.

Further ReadingEdit

Wikicat3


Wikidog3


Wikicat3Wikidog3

ReferencesEdit

  1. Rand-Fleeman Protocol for Levemir, NPH, Lente Insulins
  2. Pharmacy Update-US National Institutes of Health-2006
  3. Pharmacy Update-US National Institutes of Health-2006
  4. FDA-Levemir-Page 8-IV Use Can Result in Severe Hypoglycemia
  5. FDA-Levemir-Page 8-IM Administration Means Faster & More Extensive Absorption
  6. David Mendosa: Benefits of Levemir
  7. Levemir:Product Details
  8. Variability of Levemir (detemir) study
  9. Diagrams from Novo Nordisk showing improved day-to-day reliability over Lantus and NPH
  10. Novo--Less Variability--ADA Symposium
  11. Novo Warns Customers About Stolen Levemir
  12. FDA Issues Advisory Re: Levemir
  13. Case studies of cats on Levemir, on this wiki
  14. Kirsten and Tilly's Levemir/Lantus protocol
  15. Comparison of Lantus and Levemir in Healthy Cats 2008 ACVIM Oral Presentations-Page 30, Abstract #96
  16. University of Queensland--Dosing information on Levemir for dogs
  17. [[Case:Jock#Curves_for_Levemir_and_Insulatard_.28Novolin_N.29 Use of Levemir with boosters to suppress rise at shot time]
  18. EU approval testing for Levemir
  19. Novopen Junior--Levemir Cartridges
  20. Novopen 3 Demi--Levemir Cartridges
  21. Small Doses From a Cartridge--Using a Syringe Pictorial
  22. Electronic Medicines Compendium--EMC-UK
  23. Jock's Levemir lasts 6 months when refrigerated
  24. ChildrenWithDiabetes--Mixing Levemir With Other Insulins
  25. Novo Press Release--US Availability of Levemir
  26. Insulin Detemir
  27. The Mechanism of Protraction of Insulin Detemir Pharmaceutical Research 2004
  28. Is Insulin Detemir Able to Favor a Lower Variability in the Action of Injected Insulin in Diabetic Subjects? Diabetes & Metabolism-2005
  29. Rx List.com-Levemir
  30. UCSD Medical Center-Department of Pharmacy-Insulin Detemir-Page 2
  31. Peak & Duration Information
  32. Lipoatrophy can Happen With Any Subcutaneous Insulin-Endocrine Abstracts-2006
  33. Levemir vs. Lantus: Day-to-Day Variability
  34. . EMEA Scientific Discussion Levemir
  35. Comparison of Levemir & NPH at Normal Insulin Concentrations
  36. Pharmacy Times-Guide to Insulin Preparations
  37. Pharmacy Times-Guide to Insulin Preparations
  38. Endotext.com-Insulin Pharmacology
  39. Endotext.com-Insulin Pharmacology
  40. NetDoctor-UK Hypurin Protamine Zinc
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