Status - approved; marketed

Organizations involved:

Novo Nordisk A/S – Manuf.; R&D; Tech.; Intl. mark.; Parent

Novo Nordisk Pharmaceuticals, Inc. – USA mark.

Washington Research Foundation (WRF) – Tech.

Genentech, Inc. – Tech.

University of Washington – Tech.

Cross ref.: See the Insulin Products entry (#630).

Description: Insulin aspart or NovoLog is an aqueous formulation of a recombinant insulin mutein (mutant or modified form) produced by transformed a transformed Saccharomyces cerevisiae (yeast) cell line. Proline, the amino acid at the 28 position of the insulin B-chain (B28 position) of human insulin has been substituted with aspartic acid (Asp) residue. In all other respects, Insulin aspart is structurally identical to human insulin. Insulin aspart has a molecular formula C256-H381N65-O79-S6, and a molecular weight of 5,825.5 (5.82 kDa).

The substitution of the aspartic acid at position B28 results in insulin aspart having a decreased tendency to form hexamers (crystals) in solution. Thus, insulin aspart is released into the circulation and absorbed more rapidly than regular human insulin. The replacement does not affect the molecule’s overall three-dimensional structure, the B28 position is not involved in direct interaction with the insulin receptor, and the substitution does not alter the molecule’s biological activity (units of insulin activity). Insulin aspart has the same potency (1 unit = 6 nmol) as regular human insulin, as determined by hypoglycemia assays.

NovoLog has faster absorption, faster onset of action, and shorter duration of action than regular insulin. The quick onset of the lowering of blood sugar levels after injection of NovoLog allows people with diabetes to conveniently inject themselves immediately before eating, offering increased flexibility to patients. Traditional regular human insulin requires patients to inject their insulin dosage 30 minutes before eating. Extensive clinical studies in diabetic and healthy subjects have shown that insulin aspart reaches plasma concentrations that are higher and occur earlier than those of regular human insulin, leading to faster onset and shorter duration of blood glucose lowering action.

NovoLog is packaged in 10 mL vials containing 100 Units of insulin per mL (U-100); and in 3 mL PenFill cartridges for subcutaneous administration with NovoPen Insulin Delivery Devices and NovoFine disposable needles. One unit of insulin aspart corresponds to 6 nanomolar, 0.035 mg salt-free anhydrous insulin aspart. Each milliliter (mL) of NovoLog contains 100 Units (U) of insulin aspart, plus excipients --16 mg glycerol, 1.50 mg phenol, 1.72 mg meta-cresol, 19.6 µg zinc (as zinc chloride), 1.25 mg disodium phosphate dihydrate, and 0.58 mg sodium chloride – in Water for Injection, USP. NovoLog has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium hydroxide 10% may be added to adjust pH. Shelf life is two years stored at 2-8˚C (refrigerated). The product may be stored at room temperature (<86˚C) for up to 28 days.

NovoLog Mix 70/30 and NovoLog Mix 70/30 FlexPen, combining 70% insulin aspart (Novolog) as a protamine complex suspension (longer-acting) and 30% uncomplexed insulin aspart injection, Inactive ingredients for the 10 mL vial are mannitol 36.4 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6 µg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL, and protamine sulfate 0.32 mg/mL. Inactive ingredients for the NovoLog Mix 70/30 FlexPen are glycerol 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6 µg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.877 mg/mL, and protamine sulfate 0.32 mg/mL. NovoLog Mix 70/30 has a pH of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.

NovoLog may also be administered by continuous subcutaneous insulin infusion using an external pump. Intravenous administration was approved in late 2005.

The NovoPen 3 insulin pen, approved for use with NovoLog, is all-in-one insulin delivery system with a hidden needle. A button is pressed to activate a spring mechanism that automatically inserts the needle under the skin. A dual-acting formulation of insulin aspart, NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection), was made available with FlexPen in Sept. 2002. In March 2003, the FlexPen for delivery of NovoLog was launched in the U.S. This 3 mL prefilled pen contains 300 units, can be used for 28 days without refrigeration, and provides doses in one-unit increments up to 60 units per injection. Compared to other insulin delivery devices that have to be manually loaded with insulin cartridges, prefilled pens are ready to use, eliminating the step of loading insulin into the device.

In March 2009, Novo Nordisk launched a redesigned FlexPen autoinjector in the U.S. This allows diabetes patients to use less force when pushing the button to inject their insulin and easily identify their insulin with prominent color branding. FlexPen is only available with Novo Nordisk insulin products, Levemir (insulin detemir [rDNA origin] injection), NovoLog (insulin aspart [rDNA origin] injection) and NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection, [rDNA origin]). Similar to the original FlexPen, the improved FlexPen allows users to set an appropriate dose, and does not allow a dose larger than the amount of insulin remaining in the pen. It also permits dose corrections without loss of insulin, and provides doses in one-unit increments up to 60 units per injection (each pen contains 300 units in total). The dose scale of the improved FlexPen automatically returns to zero after each injection to allow visual confirmation of dose delivery. Like the original FlexPen, once in use, FlexPen does not require refrigeration (below 86˚F) for up to 42 days if used with Levemir, for up to 28 days if used with NovoLog and for up to 14 days if used with NovoLog Mix 70/30..

Nomenclature: Insulin aspart, rDNA [BIO]; Insulin aspart [rDNA origin] [FDA]; insulin aspart [USAN INN]; NovoLog [TR]; NovoRapid [TR outside U.S.]; Insulin aspart [rDNA origin] [FDA]; 8B-L-aspartic acid-insulin (human) [CAS]; 116094-23-6 [CAS RN]; IAsp [SY]; insulin X14 [SY]; INA-X14 [SY]; B28-Asp-insulin, [SY]; B28 asp regular human insulin analog [SY]; NDC 00169-3303-12; NDC 00169-7501-11; NDC 0169-6339-10 [NDC]

Companies.: Novo Nordisk A/S developed and manufactures NovoLog products. Novo Nordisk Pharmaceuticals, Inc. markets NovoLog products in the U.S.

Manufacture: Yeast propagation, fermentation and recovery are performed at a Novo Nordisk facility in Kalundborg, Denmark. Purification, formulation, packaging and batch release are performed at a facility in Bagsvaerd, Denmark. NovoLog may also be manufactured at facilities in Clayton, NC.

In Oct. 2004, Novo Nordisk announced a $100 million expansion of these insulin manufacturing facilities. The first phase, to be completed in 2006, will double capacity. The second phase of the expansion will include two new FlexPen assembly and packaging lines.

Insulin aspart is reportedly manufactured via two intermediate products.

FDA class: Drug NDA

Approvals: Date = 20000607, NDA; first approval

Date = 20011101; NDA; approval of NovoLog Mix 70/30

Date = 20011227; NDA supplement; Indication = delivery by external pump for continuous subcutaneous insulin infusion

Date = 20040423; NDA supplement; Indication = approval of NovoLog use with 3 mL disposable prefilled InnoLet syringes

Date = 20051000; NDA supplement; Indication = approval of intravenous administration

Date = 20050915; NDA supplement; Indication = approval for use in children 6-18 years of age

Date = 20070130; NDA supplement; Indication = reclassification with a Pregnancy Category B rating (approval for use in pregnant women)

Date = 20070720; NDA supplement; Indication = change in formulation for NovoLog Mix 70/30 (70% insulin aspart protamine suspension/30% insulin aspart injection [rDNA origin]) used to fill NovoLog Mix 70/30 FlexPen prefilled syringes including replacement of mannitol with glycerol, an increased amount of sodium chloride, and batch size increase

Date = 20080314; NDA supplement; Indication = pediatric pump use

Date = 20080826; NDA (no. 021810; 505(b)(2) approval); Indication = approval of NovoLog Mix 50/50

Date = 20080903; NDA supplement; Indication = two different approvals for unspecified labeling revisions

Date = 20110202; NDA supplement; Indication = 510K clearance of V-Go, a fully disposable, non-electronic basal-bolus injector device, for the delivery of Novolog for the treatment of type 2 diabetes. V-Go is a once-daily, disposable, waterproof device that provides a continuous set basal rate and on-demand bolus dosing for meal-time coverage, via a rapid acting insulin analogue.

indications: [full text of "INDICATIONS AND USAGE” section of product insert]:

NovoLog is indicated for the treatment of adult patients with diabetes mellitus, for the control of hyperglycemia. Because NovoLog has a more rapid onset and a shorter duration of action than human regular insulin, NovoLog should normally be used in regimens together with an intermediate or long-acting insulin.

Status: The NDA was filed on Sept.15, 1998, received standard review, and was approved on June 8, 2000 (review time = ~20.8 months or 1.7 years). NovoLog was launched in the U.S. in Sept. 2001 (in cartridges and vials). The Dec. 2001 approval allows administration by external insulin pumps.

The European Union (EU) application was filed on Aug. 12, 1998 and approved on Sept. 7, 1999 for treatment of type I diabetes. On April 4, 2005, the EU granted supplemental approval to include treatment of diabetes in children 2 to 6 years of age. With this, Novo Nordisk became the first company in the European Union to offer both a long-acting insulin analog (Levemir; see related entry) and a rapid-acting insulin analog (NovoRapid) for children with diabetes.

NovoLog Mix 70/30 (70% insulin aspart [rDNA origin] protamine suspension and 30% insulin aspart [rDNA origin] injection) was launched in the U.S. on Sept. 30, 2002, including use with the new FlexPen injection system. NovoLog Mix 70/30 is typically dosed twice a day, immediately before breakfast and dinner.

The Jan. 2007 approval of a Pregnancy Category B rating for NovoLog indicates that adequate studies in pregnant women with Type 1 diabetes have demonstrated that NovoLog® does not increase risk to the unborn baby. Previously, NovoLog was classified as a Category C rating, which indicated that adverse effects on the fetus had been demonstrated in animal reproduction studies, and that adequate and well-controlled studies in pregnant women had not been conducted to demonstrate safety.

On July 31, 2006, NovoRapid was approved in the European Union for use in pregnant women, becoming “the first modern insulin that has a label stating it can be used in pregnancy in the EU.”

On Sept. 20, 2007, NovoRapid received supplemental European Union approval for treatment of diabetes in the elderly and in patients with renal or hepatic impairment. With this approval, NovoRapid has been established in the EU as safe to use by all people from two years of age with types 1 or 2 diabetes.

On      Aug. 26, 2008, NovoLog Mix 50/50 (50% insulin aspart [rDNA origin] protamine suspension and 50% insulin aspart [rDNA origin] injection) received FDA approval (full NDA). NovoLog Mix 50/50 received a 505(b)(2) approval, i.e., an abbreviated approval based largely on comparison with already-approved product(s).

In July 2010, Calibra Medical announced receiving 510(k) clearance from FDA for its Finesse insulin patch-pen for up to three-day use with Novo Nordisk's Novolog rapid acting insulin. Combining the mealtime therapy-adherence benefits of i nsulin pumps with the simplicity and affordability of syringes and pens, Calibra's novel bolus-only patch-pen is a small, adhesively attached, flat device that can be operated discretely through clothing to deliver mealtime, snack time, and correction bolus insulin in seconds.

Tech. transfer: Novo Nordisk has received various patents covering insulin aspart, its use, and formulations, including with protamine. The product insert (7/2012) cites 6,582,404, 6,004,297, and 6,235,004.

Novo Nordisk has received various patents covering insulin aspart, its use, and formulations, including with protamine. U.S. 5,618,913, “Insulin analogues,” April 8, 1997, claims rapid-acting human insulin analogs, including B28-Asp insulin. According to the FDA Orange Book, this patent has an expiration date of April 8, 2014 and covers NovoLog and NovoLog Mix 70/30. U.S. 5,866,538, “Insulin preparations containing NaCl,” Feb. 2, 1999, claims various insulin aspart formulations. According to the FDA Orange Book, this patent has an expiration date of Feb. 2, 2017 and covers NovoLog. Patent covering methods of use of NovoLog Mix 70/30 include 5,834,422 and 5,840,680, with expiration on Sept. 28, 2013, according the to Orange Book. Other NovoLog Mix 70/30 patents are 5,948,751, claiming insulin analogs including B28-Asp insulin, expiring on June 19, 2017; and 5,547,930, “AspB28 insulin crystals,” claiming insulin aspart protamine crystals, expiring on Sept. 28, 2013.

U.S. 5,618,913, “Insulin analogues,” April 8, 1997, claims rapid-acting human insulin analogs, including B28-Asp insulin.

Yeast expression system technology used for manufacture was developed by the University of Washington and Genentech, and has been nonexclusively licensed to Novo Nordisk by the Washington Research Foundation (WRF), the licensing agent for this family of yeast expression patents. The patents, particularly the more recent ones, broadly claim processes and materials for expression of proteins in yeast. Patents include U.S. 5,854,018 and 5,856,123, both continuations of 5,618,676, concerning recombinant production of proteins in yeast expression systems including Saccharomyces, Kluyveromyces, Pichia and Hansenula. All three U.S. patents will expire in 2014. The new patents are broader, as they claim processes and materials for expression of proteins in recombinant yeast systems generally.

Trials: In Jan. 2005, results from open-label study in 233 insulin-naive patients showed that Novolog Mix 70/30 was more effective than insulin glargine (Lantus from Sanofi Aventis). At the end of the 28-week treatment period, 66% of patients taking Novolog had HbA1c levels of < 7.0% vs. 40% taking insulin glargine. The average HbA1c value after 28-weeks was 6.9% for the Novolog group vs. 7.4% for the insulin glargine group (p=0.001). Mean HbA1c reduction was 2.79% for the NovoLog group vs. 2.36% for the insulin glargine group (p<0.01).

The Jan. 2007 Pregnancy Category B rating change was based on a review of the largest ever randomized controlled trial using an insulin analog in pregnant women with type 1 diabetes. The study, conducted at 63 sites in 18 countries, compared the safety and efficacy of NovoLog versus human regular insulin in the treatment of 322 pregnant women with type 1 diabetes. Changes in HbA1c and rates of maternal hypoglycemia were comparable with NovoLog compared to regular insulin. The study was not large enough to evaluate the risk of congenital malformations. Compared to regular insulin, NovoLog showed improved outcomes for both mother and child.

indications: NovoLog was originally approved for subcutaneous administration. Intravenous administration was approved in late 2005.

The time to maximum plasma concentration of insulin aspart is, on average, half of that for human or regular recombinant insulin. A mean maximum plasma concentration of 492 ± 256 pmol/L is reached 40 minutes after a subcutaneous dose of 0.15 U/kg in type I diabetes patients. The concentration returns to baseline in 4-6 hours, and is somewhat longer in Type II patients.

NovoLog has faster absorption, a faster onset, and shorter duration of action than regular human insulin, making it well suited for mealtime dosing to control postprandial glycemia (rise in blood sugar following food consumption). NovoLog is generally be given immediately before a meal (start meal within 5-10 minutes after injection). Like other fast-acting insulins, the product is often used in combination with intermediate-acting or long-acting insulins administered at least once daily. Presuming, the average individual insulin requirement is between 0.5 and 1.0 U/day, up to 50-70% of this requirement may be provided by NovoLog, and the remainder by intermediate- and long-acting insulins.

NovoLog Mix 70/30 has peak pharmacodynamic activity one hour after injection. NovoLog Mix 70/30 FlexPen is suited for those first starting or needing changes in standard insulin therapy. The dual action of NovoLog Mix 70/30 provides mealtime and basal insulin coverage, in most cases with just two daily administrations, before breakfast and dinner.

Market: The 2007 Average Wholesale Price (AWP) for NovoLog Penfil cartridges is $170.70 for five 3 mL, 100 U/mL; and $91.88 for one 100 U/mL 10 mL vial. The AWP for NovoLog FlexPen is $177.49 for five 3 mL, 100 U/mL prefilled syringes. The AWP for NovoLog Mix 70/30 is $177.49 for five 3 mL FlexPens.

Total NovoLog sales worldwide were $3.135 billion in 2013; $2.8 billion in 2012; $2.274 billion in 2011; $2.198 billion in 2010; $1.780 billion in 2009; $1.338 billion in in 2008; and $1.351 billion in 2007. Total 2006 worldwide sales for NovoLog and Levemir products combined were ~$1.908 billion.

Total sales of NovoMix 50/50 were: $1.816 billion in 2013 and $1.645 billion in 2012.

NovoLog competes, to some extent, with Humalog (insulin lispro) from Eli Lilly & Co., a rapid-acting insulin analog taken within 15 minutes of eating. There have been no head-to-head comparisons of the two drugs.