Commentary
HOW LONG CAN A VIAL OF INSULIN BE USED AFTER IT IS STARTED: WHERE ARE WE 10 YEARS LATER? Martin M. Grajower, MD, FACP, FACE
ABSTRACT In August 2003, I wrote a commentary entitled “How Long Can a Vial of Insulin be Used After It Is Started.” The commentary included comments from each of the 3 insulin manufacturers, as well as the American Diabetes Association. Anyone reading the article quickly realized that there was little agreement among the insulin manufacturers and just as little clarity to this question. Over the ensuing 10 years, there has been little or no effort made by either the Food and Drug Administration (FDA) or the insulin manufacturers to clarify this issue of insulin storage after a bottle is started. Current package inserts list varying times from 28 to 42 days, while the latest recommendation from the American Diabetes Association gives a uniform 1-month time limit. I would therefore propose that insulin manufacturers begin putting on every insulin vial and pen, in addition to the expiration date, the amount of time that particular insulin should be used after it is started. In addition there should be a box for the patient to write the starting date directly onto the vial or pen. This would eliminate the need for uniformity of recommendations; all the patient would have to do is read the instructions written on the insulin vial or pen.
Submitted for publication October 20, 2013 Accepted for publication October 24, 2013 From the Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York. Address correspondence to Dr. Martin M. Grajower, 3736 Henry Hudson Parkway; Riverdale, NY 10463. Email: [email protected] Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on November 18, 2013. DOI:10.4158/EP13427.CO To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
188 ENDOCRINE PRACTICE Vol 20 No. 2 February 2014
In August 2003, I wrote a commentary entitled “How Long Can a Vial of Insulin be Used After It Is Started” (1). The commentary included comments from each of the 3 insulin manufacturers, as well as the American Diabetes Association (ADA). Anyone reading the article quickly realized that there was little agreement among the insulin manufacturers and just as little clarity to this question. As pointed out in a subsequent letter to the editor by Dr. Mark Molitch (2), the comments from the 3 insulin manufacturers were “totally unsatisfactory and self-serving.” The recommendations for how long an opened vial of insulin can be used are inconsistent and not necessarily based on definitive studies. While insulin manufacturers need to prove to regulatory governmental agencies that their insulin is stable up to 28 to 30 days, they do not necessarily have data to show that the insulin is less potent or unsafe after that time. There are certainly many times when a diabetic patient will discard a significant amount of insulin on a monthly basis. When questioned why they don’t just manufacturer smaller vials for such patients, they point out that the costs of obtaining governmental approval and establishing separate manufacturing facilities for these smaller vials would raise the cost of insulin for everyone to benefit a minority of patients (3). The latest recommendation from the American Diabetes Association regarding storage of insulin is the following (4): Vials of insulin not in use should be refrigerated. Extreme temperatures (86°F, 30°C) and excess agitation should be avoided to prevent loss of potency, clumping, frosting, or precipitation. Specific storage guidelines provided by the manufacturer should be followed. Insulin in use may be kept at room temperature to limit local irritation at the injection site, which may occur when cold insulin is used. The patient should always have available a spare bottle of each type of insulin used. Although an expiration date is stamped on each vial of insulin, a loss in potency may occur after the bottle has been in
Insulin Vial Use Duration, Endocr Pract. 2014;20(No. 2) 189
use for >1 month, especially if it was stored at room temperature (bold added by me). The person administering insulin should inspect the bottle before each use for changes (i.e., clumping, frosting, precipitation, or change in clarity or color) that may signify a loss in potency. Visual examination should reveal rapid- and short-acting insulins as well as insulin glargine to be clear and all other insulin types to be uniformly cloudy. The person with diabetes should always try to relate any unexplained increase in blood glucose to possible reductions in insulin potency. If uncertain about the potency of a vial of insulin, the individual should replace the vial in question with another of the same type. The manufacturers of insulin still do not agree with the 1-month duration of use after puncturing the vial. Table 1 shows information from current package inserts of various insulins. The ADA guidelines reference throwing out insulin vials after 1 month. The manufacturers list 28 days. That leaves a 2- to 3-day window where the obsessive-compulsive patient with diabetes, or even just the intelligent patient trying to be as accurate as possible, does not quite know what to do. Will the few days make a difference in the control of the glucose levels? If you consider this inconsequential, think of it this way. If a patient changes vials every 28 days as listed in the package insert, the patient would need 13 vials per year. If the patient changes vials every month as recommended by the ADA guidelines, the
patient would need only 12 vials per year. That translates to using “expired” insulin slightly more than 8% of the year (31/365 days). Let’s look at this difference of 1 vial a year another way. Take the cost of 1 vial per year multiplied by how many patients are using that insulin (more expensive for analog insulins). That will certainly add up to a substantial savings for the 12-vial users versus the 13-vial users. Conversely, the 13-vial users are going to add a substantial cost over the course of the year. Regarding Levemir, the package insert reads as follows: “Punctured vials: After initial use, the punctured vials should be stored in a refrigerator but not in a freezer. If refrigeration is not possible, the vial that you are currently using can be kept at room temperature up to 42 days, as long as it is kept below 30°C (86°F). Throw away unrefrigerated vials after 42 days from the first use, even if they still contain insulin.” What conclusion do I then draw regarding punctured vials that are refrigerated after 42 days; can the insulin still be used? Furthermore, a recent article showed that Levemir loses its potency by the 35th day after a vial is started when left at room temperature (5). Furthermore, the manufacturers are not in agreement whether the recommendation to discard the vial after 28 days is based on a loss of potency, concern about sterility, or concern about clumping of the insulin from either excessive agitation or significant changes in temperature over the course of the month (1). This last concern is only
Table 1 Current Insulin Package Insert Information Manufacturer
Insulin (brand name)
Discard after
How to store opened vial
Sanofi-Aventis
Glulisine (Apidra)
28 days
Refrigerated or room temperature
Sanofi-Aventis
Glargine (Lantus)
28 days
Refrigerated or room temperature
Novo Nordisk
Detemir (Levemir)
42 days
Refrigerated or room temperature
Novo Nordisk
Aspart (NovoLog)
28 days
Refrigerated or room temperature
Novo Nordisk
NovoLog MIX 70/30
28 days
Refrigerated preferred, room temperature acceptable
Eli Lilly
Lispro protamine/lispro (Humalog 50/50)
28 days
Refrigerated or room temperature
Eli Lilly
lispro (Humalog)
28 days
Refrigerated or room temperature
Eli Lilly
NPH (Humulin N)
Expiration date on vial
Refrigerated preferred, room temperature acceptable
Eli Lilly
Regular (Humulin R)
Expiration date on vial
Refrigerated preferred, room temperature acceptable
Abbreviation: NPH = neutral protamine Hagedorn
190 Insulin Vial Use Duration, Endocr Pract. 2014;20(No. 2)
relevant to insulins that exist in suspension (e.g., protamine insulin) but not those that are in solution (e.g., insulin lispro and regular insulin). Pharmacists presumably calculate the number of vials that they issue for a 1- or 3- month refill based on the patient’s total daily insulin use. In the case of detemir, should the pharmacist follow the package insert (42 days) or the ADA guidelines (1 month) in dispensing the requisite number of vials? It seems to me that there is little or no effort being made by either the Food and Drug Administration (FDA) or the insulin manufacturers to clarify this issue of insulin storage after a bottle is started. With the increasing numbers of patients with diabetes and the increasing focus on cost-containment in medicine in general, we should be doing what we can to avoid unnecessary discarding of unused insulin. I would therefore propose that insulin manufacturers begin putting on every insulin vial and pen, in addition to the expiration date, the amount of time that particular insulin should be used after it is started. There should also be a box for the patient to write the starting date directly onto the vial or pen. This would eliminate the need
for uniformity of recommendations; all the patient would have to do is read the instructions written on the insulin vial or pen. DISCLOSURE
The author has no multiplicity of interest to disclose.
REFERENCES 1. Grajower MM, Fraser CG, Holcombe JH, et al. How long should insulin be used once a vial is started? Diabetes Care. 2003;26:2665-2669. 2. Molitch ME. How long should insulin be used once a vial is started? Response to Grajower et al. (letter) Diabetes Care. 2004;27:1240-1241. 3. Holcombe JH, Daugherty ML, De Felippis MR. How long should insulin be used once a vial is started? Response to Molitch (letter). Diabetes Care. 2004;27:1241-1242. 4. American Diabetes Association. Position Statement: Insulin Administration. Diabetes Care. 2004;27 Suppl 1: S106-9. 5. Silva MA, Chuong M, Kerr S, Cabrera A. Stability of two long-acting insulin formulations after 28 days. J Pharm Prac Research. 2013;43:37-40.
HOW LONG CAN A VIAL OF INSULIN BE USED AFTER IT IS STARTED: WHERE ARE WE 10 YEARS LATER? Martin M. Grajower, MD, FACP, FACE
ABSTRACT In August 2003, I wrote a commentary entitled “How Long Can a Vial of Insulin be Used After It Is Started.” The commentary included comments from each of the 3 insulin manufacturers, as well as the American Diabetes Association. Anyone reading the article quickly realized that there was little agreement among the insulin manufacturers and just as little clarity to this question. Over the ensuing 10 years, there has been little or no effort made by either the Food and Drug Administration (FDA) or the insulin manufacturers to clarify this issue of insulin storage after a bottle is started. Current package inserts list varying times from 28 to 42 days, while the latest recommendation from the American Diabetes Association gives a uniform 1-month time limit. I would therefore propose that insulin manufacturers begin putting on every insulin vial and pen, in addition to the expiration date, the amount of time that particular insulin should be used after it is started. In addition there should be a box for the patient to write the starting date directly onto the vial or pen. This would eliminate the need for uniformity of recommendations; all the patient would have to do is read the instructions written on the insulin vial or pen.
Submitted for publication October 20, 2013 Accepted for publication October 24, 2013 From the Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York. Address correspondence to Dr. Martin M. Grajower, 3736 Henry Hudson Parkway; Riverdale, NY 10463. Email: [email protected] Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on November 18, 2013. DOI:10.4158/EP13427.CO To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
188 ENDOCRINE PRACTICE Vol 20 No. 2 February 2014
In August 2003, I wrote a commentary entitled “How Long Can a Vial of Insulin be Used After It Is Started” (1). The commentary included comments from each of the 3 insulin manufacturers, as well as the American Diabetes Association (ADA). Anyone reading the article quickly realized that there was little agreement among the insulin manufacturers and just as little clarity to this question. As pointed out in a subsequent letter to the editor by Dr. Mark Molitch (2), the comments from the 3 insulin manufacturers were “totally unsatisfactory and self-serving.” The recommendations for how long an opened vial of insulin can be used are inconsistent and not necessarily based on definitive studies. While insulin manufacturers need to prove to regulatory governmental agencies that their insulin is stable up to 28 to 30 days, they do not necessarily have data to show that the insulin is less potent or unsafe after that time. There are certainly many times when a diabetic patient will discard a significant amount of insulin on a monthly basis. When questioned why they don’t just manufacturer smaller vials for such patients, they point out that the costs of obtaining governmental approval and establishing separate manufacturing facilities for these smaller vials would raise the cost of insulin for everyone to benefit a minority of patients (3). The latest recommendation from the American Diabetes Association regarding storage of insulin is the following (4): Vials of insulin not in use should be refrigerated. Extreme temperatures (86°F, 30°C) and excess agitation should be avoided to prevent loss of potency, clumping, frosting, or precipitation. Specific storage guidelines provided by the manufacturer should be followed. Insulin in use may be kept at room temperature to limit local irritation at the injection site, which may occur when cold insulin is used. The patient should always have available a spare bottle of each type of insulin used. Although an expiration date is stamped on each vial of insulin, a loss in potency may occur after the bottle has been in
Insulin Vial Use Duration, Endocr Pract. 2014;20(No. 2) 189
use for >1 month, especially if it was stored at room temperature (bold added by me). The person administering insulin should inspect the bottle before each use for changes (i.e., clumping, frosting, precipitation, or change in clarity or color) that may signify a loss in potency. Visual examination should reveal rapid- and short-acting insulins as well as insulin glargine to be clear and all other insulin types to be uniformly cloudy. The person with diabetes should always try to relate any unexplained increase in blood glucose to possible reductions in insulin potency. If uncertain about the potency of a vial of insulin, the individual should replace the vial in question with another of the same type. The manufacturers of insulin still do not agree with the 1-month duration of use after puncturing the vial. Table 1 shows information from current package inserts of various insulins. The ADA guidelines reference throwing out insulin vials after 1 month. The manufacturers list 28 days. That leaves a 2- to 3-day window where the obsessive-compulsive patient with diabetes, or even just the intelligent patient trying to be as accurate as possible, does not quite know what to do. Will the few days make a difference in the control of the glucose levels? If you consider this inconsequential, think of it this way. If a patient changes vials every 28 days as listed in the package insert, the patient would need 13 vials per year. If the patient changes vials every month as recommended by the ADA guidelines, the
patient would need only 12 vials per year. That translates to using “expired” insulin slightly more than 8% of the year (31/365 days). Let’s look at this difference of 1 vial a year another way. Take the cost of 1 vial per year multiplied by how many patients are using that insulin (more expensive for analog insulins). That will certainly add up to a substantial savings for the 12-vial users versus the 13-vial users. Conversely, the 13-vial users are going to add a substantial cost over the course of the year. Regarding Levemir, the package insert reads as follows: “Punctured vials: After initial use, the punctured vials should be stored in a refrigerator but not in a freezer. If refrigeration is not possible, the vial that you are currently using can be kept at room temperature up to 42 days, as long as it is kept below 30°C (86°F). Throw away unrefrigerated vials after 42 days from the first use, even if they still contain insulin.” What conclusion do I then draw regarding punctured vials that are refrigerated after 42 days; can the insulin still be used? Furthermore, a recent article showed that Levemir loses its potency by the 35th day after a vial is started when left at room temperature (5). Furthermore, the manufacturers are not in agreement whether the recommendation to discard the vial after 28 days is based on a loss of potency, concern about sterility, or concern about clumping of the insulin from either excessive agitation or significant changes in temperature over the course of the month (1). This last concern is only
Table 1 Current Insulin Package Insert Information Manufacturer
Insulin (brand name)
Discard after
How to store opened vial
Sanofi-Aventis
Glulisine (Apidra)
28 days
Refrigerated or room temperature
Sanofi-Aventis
Glargine (Lantus)
28 days
Refrigerated or room temperature
Novo Nordisk
Detemir (Levemir)
42 days
Refrigerated or room temperature
Novo Nordisk
Aspart (NovoLog)
28 days
Refrigerated or room temperature
Novo Nordisk
NovoLog MIX 70/30
28 days
Refrigerated preferred, room temperature acceptable
Eli Lilly
Lispro protamine/lispro (Humalog 50/50)
28 days
Refrigerated or room temperature
Eli Lilly
lispro (Humalog)
28 days
Refrigerated or room temperature
Eli Lilly
NPH (Humulin N)
Expiration date on vial
Refrigerated preferred, room temperature acceptable
Eli Lilly
Regular (Humulin R)
Expiration date on vial
Refrigerated preferred, room temperature acceptable
Abbreviation: NPH = neutral protamine Hagedorn
190 Insulin Vial Use Duration, Endocr Pract. 2014;20(No. 2)
relevant to insulins that exist in suspension (e.g., protamine insulin) but not those that are in solution (e.g., insulin lispro and regular insulin). Pharmacists presumably calculate the number of vials that they issue for a 1- or 3- month refill based on the patient’s total daily insulin use. In the case of detemir, should the pharmacist follow the package insert (42 days) or the ADA guidelines (1 month) in dispensing the requisite number of vials? It seems to me that there is little or no effort being made by either the Food and Drug Administration (FDA) or the insulin manufacturers to clarify this issue of insulin storage after a bottle is started. With the increasing numbers of patients with diabetes and the increasing focus on cost-containment in medicine in general, we should be doing what we can to avoid unnecessary discarding of unused insulin. I would therefore propose that insulin manufacturers begin putting on every insulin vial and pen, in addition to the expiration date, the amount of time that particular insulin should be used after it is started. There should also be a box for the patient to write the starting date directly onto the vial or pen. This would eliminate the need
for uniformity of recommendations; all the patient would have to do is read the instructions written on the insulin vial or pen. DISCLOSURE
The author has no multiplicity of interest to disclose.
REFERENCES 1. Grajower MM, Fraser CG, Holcombe JH, et al. How long should insulin be used once a vial is started? Diabetes Care. 2003;26:2665-2669. 2. Molitch ME. How long should insulin be used once a vial is started? Response to Grajower et al. (letter) Diabetes Care. 2004;27:1240-1241. 3. Holcombe JH, Daugherty ML, De Felippis MR. How long should insulin be used once a vial is started? Response to Molitch (letter). Diabetes Care. 2004;27:1241-1242. 4. American Diabetes Association. Position Statement: Insulin Administration. Diabetes Care. 2004;27 Suppl 1: S106-9. 5. Silva MA, Chuong M, Kerr S, Cabrera A. Stability of two long-acting insulin formulations after 28 days. J Pharm Prac Research. 2013;43:37-40.
