How to Switch Between Insulin Products

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PHARMACIST’S LETTER / PRESCRIBER’S LETTER

October 2009 ~ Volume 25 ~ Number 251005

How to Switch Between Insulin Products

Switching insulins should always be done with prescriber approval and close monitoring. Advise patients to closely monitor blood glucose levels after switching insulins. If switching between human insulin brands (e.g., Humulin R to Novolin R, Humulin N to Novolin N, or Humulin R/N or Novolin R/N to “store brand” R/N), keep the number of units each day the same. However, because these brands are not AB rated you may need to contact the prescriber for approval to switch between brands. See our Comparison of Insulins chart for meal timing, onset, peak, duration of action, and other information. Also see our algorithm Initiation and Adjustment of Insulin Regimens for Type 2 Diabetes.

Clinical Scenario Recommendation/Comments

NPH to Long-acting

NPH to insulin detemir (Levemir) • Convert unit-per-unit.¹

• Some patients on basal-bolus insulin may require more Levemir than NPH.¹

• Give Levemir once daily, or divided twice daily if necessary for control.¹

• Do not mix Levemir with other insulins¹

NPH to insulin glargine (Lantus) • NPH once daily: convert unit-per-unit and give once daily.²

• NPH twice daily: reduce daily dose by 20% and give once daily²

• Do not mix Lantus with other insulins.² Long-acting to NPH

Insulin detemir (Levemir) to NPH • Convert unit-per-unit.³

• NPH at bedtime (for type 2 patients when combined with oral antidiabetes meds).¹⁶ OR

• NPH twice daily (e.g., 50:50 or 2/3 in AM and 1/3 before dinner or at bedtime).^3-5

Insulin glargine (Lantus) to NPH • Convert unit-per-unit.³

• NPH at bedtime (for type 2 patients when combined with oral antidiabetes meds).¹⁶ OR

• NPH twice daily (e.g., 50:50 or 2/3 in AM and 1/3 before dinner or at bedtime).^3-5

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More. . .

Clinical Scenario Recommendation/Comments

Long-acting to long-acting

Insulin detemir (Levemir) to insulin glargine (Lantus) • Convert unit-per-unit.^6,17

• Give once daily, or divided twice daily if necessary for control.¹⁵

• A lower daily dose may be needed.¹⁴

• Do not mix Lantus with other insulins.² Insulin glargine (Lantus) to insulin detemir (Levemir) • Convert unit-per-unit.^1,6,17

• Give once daily, or divided twice daily if necessary for control.¹

• A higher daily dose may be needed, especially if divided twice daily.¹⁴

• Do not mix Levemir with other insulins.¹ Regular to rapid-acting

Regular human insulin (Humulin, Novolin) to rapid-acting insulin analog (insulin aspart [Novolog], insulin glulisine [Apidra], insulin lispro [Humalog])

• Convert unit-per-unit.^3,7,8,9

• Rapid-acting insulin analogs have a faster onset of action and a shorter duration of action than human regular insulin. Give rapid acting insulin analogs about 10 minutes before meals or with meals. See Comparison of Insulins for specifics of meal timing.¹⁰

Rapid-acting to regular

Insulin aspart (Novolog), insulin glulisine (Apidra), or insulin lispro (Humalog) to regular human insulin (Humulin, Novolin)

• Convert unit-per-unit.^3,7,8,9

• Rapid-acting insulin analogs have a faster onset of action and a shorter duration of action than human regular insulin. Give regular insulin about 30 minutes before meals.See Comparison of Insulins for specifics of meal timing.¹⁰

Rapid-acting to rapid-acting

Insulin aspart (Novolog), insulin glulisine (Apidra) or insulin lispro (Humalog) to Insulin aspart (Novolog), insulin glulisine (Apidra) or insulin lispro (Humalog)

• Convert unit-per-unit.^3,7,8,9,11

• Give rapid-acting insulin analogs about 10 minutes before meals or with meals. See Comparison of Insulins for specifics of meal timing.¹⁰

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Clinical Scenario Recommendation/Comments Premixed to premixed

Premixed NPH/regular insulin (Humulin 70/30, Novolin 70/30) to Premixed protamine/rapid-acting analog (insulin lispro protamine/insulin lispro [Humalog Mix 75/25], insulin aspart protamine/insulin aspart [Novolog Mix70/30])

• Convert unit-per-unit.^3,12,13

• Premixed insulin analogs have a faster onset of action but similar duration of action compared to human premixed insulin. Give insulin analogs about 10 minutes before meals or with meals.See Comparison of Insulins for specifics of meal timing.¹⁰

Premixed protamine/rapid-acting analog (insulin lispro protamine/insulin lispro [Humalog Mix 75/25], insulin aspart protamine/insulin aspart [Novolog Mix70/30]) to premixed NPH/regular insulin (Humulin 70/30, Novolin 70/30)

• Convert unit-per-unit.^3,12,13

• Premixed insulin analogs have a faster onset of action but similar duration of action compared to human premixed insulin. Give human premixed insulins (Humulin 70/30, Novolin 70/30) about 30 minutes before meals.See Comparison of Insulins for specifics of meal timing.¹⁰

Premixed NPH/regular insulin (Humulin 50/50) to insulin lispro/insulin lispro protamine (Humalog Mix 50/50)

• Convert unit-per-unit.¹

• Give Humalog 50/50 about 10 minutes before meals or with meals.See Comparison of Insulins for specifics of meal timing.¹⁰

• Humulin 50/50 insulin is being discontinued due to declining usage. Humulin 50/50 insulin is expected to be unavailable as of April 2010 (see http://www.humalog.com/pdf/humulin-

discontinued.pdf).

Users of this document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and Internet links in this article were current as of the date of publication.

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Project Leader in preparation of this Detail- Document: Melanie Cupp, Pharm.D., BCPS

References

1. Product information for Levemir. Novo Nordisk Inc.

Princeton, NJ 08540. May 2007.

2. Product information for Lantus. Sanofi-Aventis U.S.

LLC. Bridgewater, NJ 08807. March 2007.

3. U.S. Food and Drug Administration. Information regarding insulin storage and switching between products in an emergency.

http://www.fda.gov/Drugs/EmergencyPreparedness/u cm085213.htm. (Accessed September 7, 2009).

4. Carlise BA, Kroon LA, Koda-Kimble MA. Diabetes mellitus. In: Koda-Kimble MA, Young LY, Kradjan WA, Guglielmo BJ, editors. Applied therapeutics:

the clinical use of drugs. 8^th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

5. American College of Physicians Diabetes Care Guide.

http://diabetes.acponline.org/custom_resources/ACP _DiabetesCareGuide_Ch08.pdf?dbp. (Accessed September 9, 2009).

6. Hall DL, Drab SR, Havrilla PL. Advances in diabetes therapy: rapid and long-acting insulin analogs. Drug Topics continuing education. September 28, 2006.

http://drugtopics.modernmedicine.com/drugtopics/dat a/articlestandard/drugtopics/402006/376897/article.p df. (Accessed September 7, 2009).

7. Product information for Humalog. Eli Lilly and Company. Indianapolis, IN 46285. March 2009.

8. Product information for Apidra. Sanofi-Aventis U.S.

LLC. Bridgewater, NJ 08807. February 2009.

9. Product information for Novolog. Novo Nordisk Inc.

Princeton, NJ 08540. July 2009.

10. Comparison of insulins. Pharmacist's Letter/Prescriber's Letter 2006;22(9):220910.

11. United States Department of Veterans Affairs.

Pharmacy Benefits Management Services.

Recommendations for converting from insulin lispro to insulin aspart. January 2005.

http://www.pbm.va.gov/Clinical%20Guidance/Therap eutic%20Interchange%20Guidance/Insulin%20lispro

%20to%20Insulin%20aspart%20conversion.pdf.

(Accessed September 7, 2009).

12. Product information for Novolog Mix 70/30. Novo Nordisk Inc. Princeton, NJ 08540. March 2008.

13. Product information for Humalog Mix 75/25. Eli Lilly and Company. Indianapolis, IN 46285. March 2009.

14. Rosenstock J, Davies M, Home PD, et al. A randomized, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naïve people with type 2 diabetes.

Diabetologia 2008;51:408-16.

15. DeVries JH, Nattrass M, Pieber TR. Refining basal insulin therapy: what have we learned in the age of analogues? Diabetes Metab Res Rev 2007;23:441- 54.

16. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203.

17. King AB. Once-daily insulin detemir is comparable to once-daily insulin glargine in providing glycaemic control over 24 h in patients with type 2 diabetes: a double-blind, randomized, crossover study. Diabetes Obes Metab 2009;11:69-71.

Cite this Detail-Document as follows: How to switch between insulin products. Pharmacist’s Letter/Prescriber’s Letter 2009;25(10):251005.

Evidence and Advice You Can Trust…

Subscribers to Pharmacist’s Letter and Prescriber’s Letter can get Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com or www.prescribersletter.com

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PHARMACIST’S LETTER / PRESCRIBER’S LETTER

November 2008 ~ Volume 24 ~ Number 241101

Oral medications controlling

postprandial glucose, but high fasting glucose. Good for timid insulin users.

Premixed insulin daily or BID (doses harder to adjust since fixed combination)

Failure to control blood sugar*

Add rapid-acting insulin before meals where postprandial hyperglycemia occurs OR premixed insulin daily or BID

Failure to control blood sugar*

Start/intensify insulin therapy

Initiation and Adjustment of Insulin Regimens for Type 2 Diabetes

^1,2,3

Note: Insulin therapy should be individualized according to blood sugar values, A1c, diet, medications, lifestyle, etc.

Diagnosis of Type 2 Diabetes A1c > 7% (eAG > 154 mg/dL)

Assess current therapy

Lifestyle change Monotherapy usually with metformin

Metformin Add sulfonylurea if A1c < 8.5%, add insulin if A1c > 8.5%

Combination oral therapy** Failure to control blood sugar*

Motivated patient

Willing to frequently monitor High fasting, high postprandial glucose blood sugars

Basal insulin with rapid-acting Basal insulin (intermediate

mealtime insulin (~4 doses/day) or long-acting) once daily

Once daily basal insulin with rapid-acting mealtime insulin mealtime insulin

• Example of initial insulin regimen

o 10 units NPH or 0.2 units/kg at bedtime o 10 units glargine or 0.2 units/kg once daily o 10 units detemir or 0.2 units/kg once daily o 10 units premixed insulin once or twice daily

(prebreakfast and/or predinner)

• Twice daily provides better glucose control in most patients

• Pioglitazone or exenatide + metformin in select patients**³

• Rosiglitazone NOT recommended³

• Consider insulin as initial therapy in severe hyperglycemia (plasma glucose levels >250 mg/dL), random glucose levels consistently >300 mg/dL, or an A1c >10%)

• Failure to control blood sugar*=A1c>7%, eAG>154 mg/dL

Types of Insulin

Rapid-acting insulin: lispro (Humalog), aspart (NovoLog), glulisine (Apidra)

Regular short-acting insulin:

Humulin R, Novolin R

Intermediate-acting (basal) insulin:

NPH (Humulin N, Novolin N) Long-acting (basal) insulin:

glargine (Lantus), detemir (Levemir) Premixed insulin:

Rapid acting: NovoLog Mix 70/30, Humalog Mix75/25 or 50/50 Short-acting: Humulin 70/30 or 50/50 Novolin 70/30

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Users of this document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and Internet links in this article were current as of the date of publication.

Project Leader in preparation of this Detail- Document: Neeta Bahal O’Mara, Pharm.D., BCPS

References

1. Hirsch IB, Bergenstal RM, Parkin CG, et al. A real- world approach to insulin therapy in primary care practice. Clin Diabetes 2005;23:78-86.

2. Nathan DM, Buse JB, Davidson MB, et al.

Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29:1963-72.

3. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203.

Cite this Detail-Document as follows: Insulin use in patients with type 2 diabetes. Pharmacist’s Letter/Prescriber’s Letter 2008;24(11):241101.

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Technician Training Tutorial:

Dispensing Insulin and Other Injectable Diabetes Meds

Insulin is a hormone secreted from the pancreas. It helps the body use glucose as an energy source.

Insulin acts like a “key” that allows glucose to enter the body’s tissues to be used as energy. People with diabetes either don’t produce insulin (type 1), or don’t produce enough insulin at the right times to meet the body’s needs (type 2). Without the right amounts of insulin, glucose builds up in the blood and other organs to cause tissue damage or death. Although some patients’ diabetes can be managed with oral medications, many patients will eventually require injections of insulin. There are many types of insulin available to meet patients’ individual needs.

There are also other injectable drugs used to treat diabetes besides insulin. They include exenatide (Byetta), exenatide extended-release (Bydureon-U.S. only), and liraglutide. (Victoza). These meds help increase the body’s own natural secretion of insulin. Pramlintide (Symlin-U.S. only) is another injectable diabetes med. It helps reduce blood glucose in a different way than increasing insulin levels.

Insulins are high-risk medications that are frequently implicated in serious medication errors.

Examples of how these errors can happen with insulin include confusion between insulin products or dosage forms, and use of dangerous abbreviations such as “u” for units on prescriptions for insulin. “U”

can be mistaken for a four, or a zero, resulting in a ten-fold overdose. You must be vigilant when dispensing insulins and other injectable diabetes meds, and question any part of an order or prescription that seems inappropriate. This Technician Training Tutorial focuses on dispensing insulin and other injectable products for patients with diabetes.

Mrs. Johnson presents an Rx for Humulin R, one vial, to be used as directed. You notice that the abbreviation “ud” meaning “use as directed” could easily be mistaken for “4 days” or “40.”

You also see that the “R” following is sloppily written and could therefore be misread as “N.”

This could lead to incorrect interpretation of the prescription as being written for Humulin N instead of Humulin R.

What information should you ask when a patient drops off an Rx for insulin or another injectable diabetes med?

Patients with newly diagnosed diabetes, or patients with long-standing diabetes starting on insulin or another injectable med, may have a lot of anxiety about injections. These patients often have many questions. The pharmacist may need to spend some extra time counseling such patients. It will help the pharmacist if you ask patients some basic questions to clarify their educational needs. For example,

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“have you ever used insulin or an injectable medication before?” You may also want to ask if the patient knows how much of the medication to use, especially if the prescription is written “use as directed.”

(Insurers frown on a sig of “use as directed” and the pharmacist may need to clarify this with the exact directions for use with the prescriber.) The pharmacist will also want to know if the patient has any questions about checking their blood sugar (i.e., glucose). Inquire if the patient needs any other diabetes supplies (e.g., alcohol swabs, syringes, glucose meter strips, lancets, sharps container).

You know that Mrs. Johnson has not purchased insulin at your pharmacy before. You ask her if she knows how much to take and her response is “I think so.” Based on this answer, you ask her if she would like to speak to the pharmacist and she says, “yes.”

What should be considered when entering an insulin prescription or a prescription for another injectable diabetes med into the computer?

Choose the correct product in the computer and enter dosing instructions completely. Choose the correct pen, refill cartridge, or vial, as indicated on the prescription. Watch out for mix-ups between look-alike, sound-alike drug names such as Byetta and Bydureon. Byetta is dosed twice daily. Bydureon is dosed once per week.

Insulin prescriptions may have especially complex instructions. Pay special attention when entering dosing instructions for insulin prescriptions into the computer. Make sure the prescription label reads exactly as it is written on the prescription. Additional label space may be required for detailed instructions.

A prescriber might write the prescription instructions for insulin as “use as directed,” allowing changes to be communicated directly to the patient. (Once again, insurers frown on this practice, and the pharmacist may need to clarify instructions for use with the prescriber.) Patients may be instructed by the prescriber on how to vary the dose of their short- or rapid-acting insulin depending on what they will be eating at each meal. This is sometimes called “carb counting.” You will also see prescriptions written for “SS” or

“sliding scale” insulin. This is common in the hospital or nursing home setting. A sliding scale means the dose of insulin varies depending on the patient’s blood sugar.

Enter accurate quantity to be dispensed. One vial of insulin contains 10 mL of insulin. Prescription quantities for liquids are usually entered as the number of mLs instead of the number of vials or packages dispensed for reimbursement purposes. In this case, entering the quantity dispensed as “1” for the number of insulin vials dispensed may cause inadequate reimbursement since this may be communicated as

“1 mL” being dispensed, instead of the full 10 mL contained in one vial. For pens that come in multi- packs such as Victoza, make sure to enter the total number of mL in the whole box or carton instead of the number of pens or the number of mL in one pen. For example, a two-pack of pens that contain 3 mL of drug each will require a dispense quantity of 6 mL.

Enter accurate days’ supply. When specific dosing instructions are included, a days’ supply value can be calculated.

Example:

For a patient using 100 units of insulin per day, how long would one vial of insulin 100 units/mL last?

100 units/mL x 10 mL/vial = x x = 1000 units/vial

1000 units/vial ÷ 100 units/day = x x = 10 days

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When specific dosing instructions are NOT provided on the prescription, you’ll need to ask the patient how they have been advised to dose the medication so that you can determine how long the medication should last. An incorrect days’ supply entered on dispensing can cause future third party problems.

Insurance companies will often reject a claim with a “refill too soon” message if a claim is transmitted before the previous prescription’s days’ supply has passed. For example, if an Rx is entered as being for a 30-day supply, the insurance will not pay for a refill of that medication if the patient runs out in just 14 days.

For Mrs. Johnson’s prescription you enter the quantity dispensed as 10 mL. You do not know how much insulin she will be using each day, so you ask. Mrs. Johnson says that she expects to use about 40 units each day. You enter a days’ supply of 25 days (1000 units/vial ÷ 40 units/day

= 25 days).

What should be considered when selecting insulin or another injectable diabetes product from the fridge?

Insulins differ from each other in regard to source (e.g., human, human insulin analog, pork [Canada only]) and duration of action (e.g., rapid-, short-, intermediate-, or long-acting). Human insulin does not actually come from humans; it is genetically engineered, but it is identical to the insulin produced by the human pancreas. Human insulin analogs are human insulin that has been modified to make the insulin act more quickly for use around mealtimes (e.g., Humalog, Apidra) or last longer (e.g., Levemir, Lantus).

Mixtures of short- and longer-acting insulins are also available to reduce the number of injections for patients requiring both shorter- and longer-acting insulins. For example, Humulin 70/30 is 70% NPH (an intermediate-acting insulin) and 30% regular insulin (a short-acting insulin). It’s a good idea to use separate bins or shelf alerts to distinguish among products that look similar. For example, Lantus and Apidra vials are both manufactured by Sanofi-Aventis and have similar packaging that has contributed to mix-ups with these products.

Insulin most commonly comes in a concentration of 100 units per mL. This strength is referred to as U- 100. Vials contain 10 mL, or 1000 units (100 units/mL x 10 mL/vial = 1000 units). A 500 unit per mL Humulin R (referred to as U-500) is available by prescription in the U.S. for people requiring large doses.

If this very concentrated insulin is available in your pharmacy, it should be kept in a special place in the fridge to avoid mix-ups. Mistakenly dispensing 500 units per mL Humulin R in place of the 100 units per mL strength could result in a five-fold overdose. The patient’s blood sugar could plummet, which could be fatal. Another uncommon insulin is pork insulin (Canada only).

Some insulins are available as pre-filled pens, or as cartridges to be used with a reusable pen. Exenatide (Byetta), liraglutide, and pramlintide also come as pre-filled pens. With pens, patients just “dial up” the dose they need and inject it. For more details about all the insulins and the other injectable meds for diabetes, including formulations, storage, administration devices, cost, etc., see our chart, Comparison of Insulins (Detail-Documents #260304 [U.S. subscribers] or #220217 [Canadian subscribers]).

To fill Mrs. Johnson’s Rx, you choose Humulin R, which is regular human insulin. When you remove the insulin from the refrigerator, you take care not to confuse Humulin R with Humulin

N (an intermediate-acting insulin), Humalog (a rapid-acting analog), or a Humulin or Humalog

mixture. You also make sure you have U-100 and not the higher strength U-500.

Humulin and Humalog mix-ups are common. Levemir and Lantus can also be confused. Lantus has even been confused with Humalog even though they look and sound different. Many of the pens look similar and their names sound alike. For example in the U.S., NovoLog Mix 70/30 FlexPen looks and sounds similar to NovoLog FlexPen and Levemir FlexPen. They are all blue and have a black dial.

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What should be considered when labeling insulin and other injectable diabetes meds?

When labeling insulin and other injectable diabetes meds, take care not to cover the name of the product, storage information, expiration date, and NDC code (DIN in Canada) that may be printed on the box. If more than one vial or pen is needed to fill a prescription, print duplicate labels.

A label with a “use by” date is helpful for the patient, since these meds are usually good for around a month (often less than this for pens) once they are dispensed and stored at room temperature. For patients who get a supply of multiple vials or pens to last for a few months, a “refrigerate” label is helpful to remind them to keep the med in the fridge until they start using it. Our PL Chart, Comparison of Insulins (Detail-Documents #260304 [U.S. subscribers] or #220217 [Canadian subscribers]) has information on room temperature stabilities.

It’s important to note that most insulins and other injectable meds that come in pens should not be placed back in the refrigerator once they are in use. At this point, they should only be stored at room temperature. Storing them in the fridge can actually cause the pen to malfunction. (Symlin and Victoza are two exceptions.)

Although Humulin R requires refrigeration while stored in the pharmacy, it can be kept at room temperature for up to 28 days once in use. You place a label indicating this on Mrs. Johnson’s Rx. When the pharmacist counsels Mrs. Johnson, he also gives her information regarding correct storage.

What are some workflow considerations that apply to insulin and other injectable diabetes meds?

Once the prescription is ready, it should be stored in the refrigerator until it’s picked up by the patient.

Workflow for storage and retrieval of refrigerated prescriptions such as insulin varies among pharmacies.

Many pharmacies place an empty bag, label, and receipt in an alphabetized bin near the cash register, but store medication in a “patient pickup” bin in the refrigerator. With this method, prescription bags are easily located in the normal pharmacy storage area, while insulin is safely stored in the fridge. Make sure to use a “refrigerate” sticker or another reminder notation on the receipt and bag with this method to ensure that the insulin is retrieved from the refrigerator when the patient pays for the prescription. Other pharmacies using barcode systems may have a separate storage area in the refrigerator for labeled and bagged prescriptions that are ready to be picked up. Use our Technician Training Tutorial: Handling Refrigerated Drugs and Vaccines for more information.

What should be considered when dispensing insulin syringes and pen needles?

In some locations, insulin syringes require a prescription, or can only be dispensed along with insulin, either by law or by store policy. A prescription is required for third-party coverage. Be sure to enter the insulin prescription in the computer before dispensing syringes or other diabetes supplies. Some third- party payors reject coverage for diabetes supplies until the insulin prescription has been entered because the computer does not detect an “active” insulin prescription to justify the diabetes supplies.

Insulin syringes are marked in units, not in mLs like most other syringes. Insulin syringes are designed to be used with insulin vials containing insulin at a concentration of 100 units per mL. Insulin syringes differ in the total amount of insulin they can hold (e.g., 100 units [1 mL], 50 units [0.5 mL], 30 units [0.3 mL]). Insulin syringes come with a needle attached. The “gauge” of the needle tells you how fine, or thin, the needle is. The larger the gauge, the thinner the needle. For example, 31 gauge needles are thinner than 28 gauge needles. Thinner needles may be more comfortable for the patient, they also get bent more easily. Needles also differ in regard to the length. Common needle lengths are ½ inch (12.7 mm), 5/16 inch (8 mm), and 3/16 inch (5 mm). Some patients prefer shorter needles for comfort.

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But shorter needles may not be long enough for overweight patients. Patients should not change needle lengths without discussing it with their prescriber.

Unlike insulin syringes, insulin pens and other injectable diabetes meds require needles. When dispensing an insulin pen, be sure to choose the correct pen needle for the specific pen. Pen needles come in different sizes. If you are unsure of which brand name or needle type a patient’s pen requires, check with the pharmacist. Process the pens and pen needles as two separate prescriptions. Even though pen needles are OTC, most insurances will cover them as long as the patient has a prescription for them.

Mrs. Johnson returns the next day with the following prescription, which she forgot to bring in before: Lantus 15 units at bedtime, dispense a one-month supply, with three refills. Lantus is insulin glargine, a long-acting insulin. You know that it’s not unusual for a patient to use more than one insulin product at a time.

How do you calculate how much insulin to dispense? How is this entered into the computer?

Mrs. Johnson will need 15 units per day for 30 days. You calculate that she will need 450 units for a 30-day supply (15 units/day x 30 days = 450 units). You know that each 10 mL insulin vial contains 1000 units of insulin (100 units/mL x 10 mL/vial = 1000 units/vial), so you dispense one vial of Lantus for a one-month supply. However, since Lantus vials must be discarded after 28 days once they are in use, you enter a 28-day supply into the computer.

Keep insulin storage and stability in mind when entering days’ supply for insulin prescriptions. In the above example, Mrs. Johnson will only use approximately one-half of one Lantus vial in 30 days at her current dose of 15 units daily. When entering the days’ supply amount for this prescription, it would seem logical that one vial is enough insulin for two months. However, any in-use Lantus vials should be discarded after 28 days. As such, this prescription should be entered into the computer as being for one 10 mL vial and a 28-day supply.

Also be alert for patients requiring multiple vials for a one-month supply of insulin. For example, if this prescription had been for 40 units at bedtime, two vials (20 mL) would be dispensed (40 units/day x 30 days = 1200 units, requiring two vials). Also consider the patient’s third-party coverage. In some cases, the patient will pay less if they get a 90-day supply all at one time. For Mrs. Johnson, a 90-day supply of Lantus would be three vials, taking the 28-day expiration for an “in use” vial into account. The pharmacist would instruct Mrs. Johnson to keep the unused vials in the refrigerator until she needs them.

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Dispensing pens and refill cartridges can be tricky. For example, Lantus cartridges for the Lantus OptiClik (U.S. only) pen contain 3 mL (300 units) of Lantus each. Each box contains five cartridges, for a total of 15 mL (1500 units) of insulin.

3 mL/cartridge x 5 cartridges/box = x x = 15 mL/box

Check with your pharmacist about the best way to enter the quantity for an insulin pen cartridge prescription. In most cases, the quantity in this example would be entered as “15 mL” when dispensing a carton of five cartridges, reflecting the total volume dispensed in mL (as calculated above). It is best not to “break” a carton or box of insulin cartridges for inventory reasons. So if Mrs. Johnson’s prescription were for the pen cartridges, it would be best to dispense 15 mL, which would be about a three-month supply, if possible.

100 units/mL x 15 mL/box = x x = 1500 units/box

1500 units/box ÷ 15 units/day = x x = 100 days/box

Can insulin be dispensed without a prescription?

Some insulins are nonprescription. Humulin R is one example. Other insulins, such as Lantus, require a prescription in the U.S. For third-party coverage, a prescription is necessary, even for OTC insulins.

Cite this document as follows: PL Technician Training Tutorial, Dispensing Insulin and Other Injectable Diabetes Meds. Pharmacist’s Letter/Pharmacy Technician’s Letter. March 2012.

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Detail-Document #241101

−This Detail-Document accompanies the related article published in−

PHARMACIST’S LETTER / PRESCRIBER’S LETTER

November 2008 ~ Volume 24 ~ Number 241101

Insulin Use in Patients with Type 2 Diabetes

Introduction

With the ever increasing incidence of diabetes, more and more patients are using medications for hyperglycemia. Effective therapy is vital.

Achieving specific goals for glucose control has been shown to reduce the morbidity and mortality of diabetes. Insulin is the oldest and most effective agent to lower blood sugar. When used appropriately, insulin can decrease A1c level to normal or near-normal. This document reviews the use of insulin in the treatment of type 2 diabetes.

Management of Type 2 Diabetes

Lifestyle intervention is the mainstay of any diabetes therapy regimen. However, many patients subsequently require pharmacologic interventions. Choosing an antihyperglycemic agent is based on the effectiveness in lowering blood sugar, safety, tolerability, and cost.

Treatment should be tailored to the individual patient and take into account anticipated long- term benefits, acceptable level of side effects, and likelihood of compliance. Most commonly, metformin is the preferred initial oral agent. For a review on the treatment of type 2 diabetes, see our Stepwise Approach to Selecting Treatments for Type 2 Diabetes.

One of the most important factors in deciding which class of medications or specific agent to initiate therapy is the magnitude of A1c level.

When A1c levels are high (i.e., greater than 8.5%), agents which have the potential to significantly lower blood sugar in a rapid manner are necessary. Conversely, when the A1c is closer to target (i.e., A1c less than 7.5%) agents with less glucose lowering effect and a slower onset of action are acceptable.^1,2

It is important to keep in mind, however, that diabetes is a progressive disease and worsening glycemia due to beta-cell function deterioration will occur over time. In the United Kingdom

Prospective Diabetes Study, more than one-half of patients who were randomized to receive a sulfonylurea subsequently required insulin over the next six years.^3,4

When to Initiate Insulin

Insulin therapy is usually tried after lifestyle modification and other antihyperglycemic agents, usually oral, have failed.^1,2 Most patients who are unable to achieve glycemic goals with one or more oral agents are candidates for insulin therapy. For most patients with diabetes, the American Diabetes Association recommends targeting an A1c less than 7% (estimated average glucose of 154 mg/dL or 8.5 mmol/L) and the Canadian Diabetes Association recommends 7%

or lower.^5,6 The American Association of Clinical Endocrinologists recommends a goal of 6.5%

(estimated average glucose 140 mg/dL [7.8 mmol/L]) or lower, which is considered closer to an A1c in a patient without diabetes.⁷In patients who continue to experience hyperglycemia despite one or two oral agents, insulin should be considered. The addition of a third oral agent is usually more expensive, less effective, and less well tolerated compared with adding or intensifying insulin.^1,2

However, in the case of severe hyperglycemia (plasma glucose levels greater than 250 mg/dL), random glucose levels consistently greater than 300 mg/dL, or an A1c greater than 10%, insulin, along with lifestyle modification may be warranted as initial therapy. In addition, the patient with type 2 diabetes who experiences ketonuria or symptoms of diabetes such as polyuria, polydipsia, and weight loss, may also require insulin as initial therapy of type 2 diabetes.^1,2 In these situations, insulin is able to rapidly control blood sugar. After the symptoms of hyperglycemia dissipate, oral agents can be tried, and insulin may be discontinued if oral agents are sufficient to control blood glucose.

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More. . .

How to Initiate and Adjust Insulin Therapy

Initial insulin therapy should be tailored to the patient. Initial insulin therapy in patients with type 2 diabetes is aimed at increasing the supply of basal insulin.^1,2,8 This is usually accomplished with the use of an intermediate-acting (i.e., NPH) or long-acting (i.e., glargine [Lantus], detemir [Levemir]) basal insulin dose or with a commercially available “premixed” insulin combination containing either a rapid-acting (i.e., Novolog Mix 70/30, Humalog Mix 75/25 or 50/50) or short-acting insulin (Humulin 70/30 or 50/50, Novolin 70/30).

A common starting dose of insulin in patients with type 2 diabetes is 0.15 to 0.2 units per kg of body weight per day. However, for ease of administration, others suggest starting with an insulin dose of 10 units/day, either as a single dose of basal insulin or as in one or two divided premixed insulin doses.^1,2 For example, in a patient starting basal insulin, a reasonable dose would be 10 units of NPH at bedtime or 10 units of glargine or detemir, injected at the same time everyday. Doses are then titrated slowly based on response. For instance, the dose can by titrated by 2 units every 3 days until the fasting blood glucose is in the range of 70 to 130 mg/dL. If the fasting glucose is >180 mg/dL the dose can be increased by 4 units every 3 days. However, if hypoglycemia occurs or fasting glucose is less than 70 mg/dL the bedtime dose should be reduced by 4 units or 10% if the dose is more than 60 units.² It is important to remember that since many patients with type 2 diabetes demonstrate some insulin resistance, significantly higher doses may be necessary.

In patients who continue to experience hyperglycemia (i.e., A1c greater than 7%) on single basal insulin once or twice daily, the basal insulin should be replaced with premixed insulin containing either rapid-acting insulin (i.e., Novolog Mix, Humalog Mix) or a short-acting insulin (Humulin 70/30, 50/50 or Novolin 70/30).

A number of studies have shown that twice daily mixed insulin regimens give better glucose control and lower A1c levels than once daily mixed insulin regimens.^1,2 Twice daily regimens are also more effective when postprandial hyperglycemia occurs with a once daily regimen (basal only or once daily mixed insulin regimens).^1,2However, twice daily mixed regimens are associated with

causing more hypoglycemia then once daily basal insulin.

In patients who are receiving once or twice daily premixed insulin regimens (i.e., Novolog Mix, Humalog Mix, Humulin 70/30 or 50/50, or Novolin 70/30), the following titration guidelines have been suggested:¹

Majority of fasting blood sugar readings over past week

Dosage change*

Less than 80 mg/dL Subtract 2 units 80 to 109 mg/dL No change 110 to 139 mg/dL Add 2 units 140 to 179 mg/dL Add 4 units 180 mg/dL or greater Add 6 units

*Prebreakfast doses are adjusted based on the predinner reading and predinner doses are adjusted based on the prebreakfast values.

Timely adjustment of insulin doses is vital for successful therapy. Patients should be asked to monitor prebreakfast and/or predinner glucose levels and report them to their healthcare provider.

After initiating insulin, doses should be adjusted weekly until blood glucose levels are controlled.^1,2 In patients who are not at goal A1c level after three to six months of an insulin regimen, changes to the regimen should be made. For example, in a patient receiving once daily basal insulin, the total daily dose of basal insulin should be divided in two, and the dose should be given as a premixed preparation before breakfast and dinner (same total daily premixed dose as prior total daily basal insulin dose). In a patient who fails to meet glycemic goals on a single daily premixed dose of insulin, the total daily dose should be divided in two, and again, half should be given before breakfast and dinner. In patients who are already receiving twice daily premixed insulin, multiple daily dose insulin may be necessary. This consists of replacing premixed insulin with an initial basal dose (80% of one-half of the total daily dose) plus rapid-acting mealtime doses.

Mealtime doses are calculated by multiplying one- half of the total daily dose of insulin by the percent of total daily calories ingested at that meal.¹ For example, if a patient was receiving 40 units of premixed insulin a day (20 units twice daily), the basal dose would be 40 divided by 2 times 80%, or 16 units of basal insulin once a day plus the remaining 20 units of insulin given in divided doses as rapid-acting insulin before meals,

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depending on the size of the meal (i.e., percent of total daily calories). Once blood glucose concentrations are relatively stable on a consistent dose of insulin, A1c should be checked every three months.

Combining Insulin with Oral Agents

Insulin can be combined with some oral antihyperglycemic agents. For example it is rational to combine insulin with metformin.

Benefits of the combination of metformin plus insulin include improved glycemic control, less weight gain, and fewer episodes of hypoglycemia.³ While mechanistically, it makes sense to combine insulin with a thiazolidinedione (an insulin sensitizer), the risk of plasma volume expansion, peripheral edema, and subsequent heart failure limits the use of this combination.

(Note: The ADA is no longer recommending the use of rosiglitazone [Avandia] due to its potential cardiac risk.¹¹) In addition, the prescribing information for both rosiglitazone (Avandia) and pioglitazone (Actos) contain warnings about congestive heart failure.^9,10 Sulfonylureas should be stopped when insulin is started because they are not considered to be synergistic.¹¹ Finally, neither exenatide (Byetta) nor sitagliptin (Januvia) should be combined with insulin because there is no proof that the combination of these agents with insulin results in better glucose control or lower insulin doses.

Conclusion

The incidence of type 2 diabetes continues to grow. Because of the morbidity and mortality associated with the disease, aggressive therapy is required to rapidly achieve and maintain glycemic levels as close to normal as possible. Insulin is one of the most effective agents to control blood sugar. In most patients, insulin should be initiated after failure of metformin with or without a second oral agent [Evidence level A; high-quality RCTs].^2,11 Close monitoring and insulin dose titration is necessary to optimize therapy.

Users of this document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national

organizations. Information and Internet links in this article were current as of the date of publication.

Levels of Evidence

In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish.

Level Definition A High-quality randomized controlled trial (RCT)

High-quality meta-analysis (quantitative systematic review)

B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT

Clinical cohort study Case-control study Historical control Epidemiologic study

C Consensus Expert opinion

D Anecdotal evidence In vitro or animal study

Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this Detail- Document: Neeta Bahal O’Mara, Pharm.D., BCPS

References

1. Hirsch IB, Bergenstal RM, Parkin CG, et al. A real- world approach to insulin therapy in primary care practice. Clin Diabetes 2005;23:78-86.

2. Nathan DM, Buse JB, Davidson MB, et al.

Management of hyperglycemia in type 2 diabetes:

a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29:1963-72.

3. Nelson SE, Palumbo PJ. Addition of insulin to oral therapy in patients with type 2 diabetes. Am J Med Sci 2006;331:257-63.

4. Massi-Benedetti M, Orsini-Federici M. Treatment of type 2 diabetes with combined therapy. Diabetes Care 2008;31(Suppl 2):S131-5.

5. American Diabetes Association. Standards of medical care in diabetes - 2008. Diabetes Care 2008; 31(Suppl 1):S12-54.

6. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2003;27(Suppl 2):S1- S152.

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Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007;13(Suppl 1):1-68.

8. Edelman SV, Morello CM. Strategies for insulin therapy in type 2 diabetes. South Med J 2005;98:363-71.

9. Product information for rosiglitazone (Avandia).

GlaxoSmithKline. Research Triangle Park, NC 27709. July 2008.

10. Product information for pioglitazone (Actos).

Takeda Pharm. Deerfield, IL 60015. September 2007.

management of hyperglycemia in type 2 diabetes:

a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2008 (Dec);31:1-11.

Cite this Detail-Document as follows: Insulin use in patients with type 2 diabetes. Pharmacist’s Letter/Prescriber’s Letter 2008;24(11):241101.

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PHARMACIST’S LETTER / PRESCRIBER’S LETTER

March 2010 ~ Volume 26 ~ Number 260304

Comparison of Insulins and Injectable Diabetes Meds

-Information for the non-insulin injectables Byetta, Symlin, and Victoza is located at the end of the chart- Rapid-acting (Information specific to U.S. products)

Brand (generic), Maker

Humalog (insulin lispro), Eli Lilly

NovoLog (insulin aspart), Novo Nordisk

Apidra (insulin glulisine), Sanofi-aventis

Availability Prescription only¹

Description Human insulin analog (rDNA origin)^2,4,6

Onset^d 15 to 30 minutes³ 10 to 20 minutes⁵ 25 minutes³

Peak^d 30 minutes to 2.5 hours³ 40 to 50 minutes⁵ 45 to 48 minutes³

Duration^d 3 to 6.5 hours³ 3 to 5 hours⁵ 4 to 5.3 hours³

Administration FDA-approved for SC injection and SC infusion.^2,4,6 NovoLog and Apidra approved for IV infusion in clinical settings.^4,6 Meal Timing Give SC injection within 15 minutes before or immediately

after meals.²

Give 5 to 10 minutes before meals.⁵ Give SC injection within 15 minutes before or within 20 minutes after starting a meal.⁶ Formulations 100 units/mL. 10 mL vial, 3 mL cartridge, disposable pen

and KwikPen, all latex-free⁵⁰

100 units/mL. 10 mL vial, 3 mL PenFill cartridge, 3 mL disposable FlexPen; all latex-free⁹

100 units/mL. 10 mL vial, 3 mL cartridge, 3 mL disposable SoloStar pen

Appearance Clear¹

Compatibility^a • Can mix with NPH (Humulin N). Draw insulin lispro into syringe first and inject immediately.²

• Mixture with NPH stable in vials for 28 days at room temperature and refrigeration. Prefilled syringes stable for 14 days refrigerated.⁵¹

• Can mix Humalog in vial with Lilly diluent to dilutions of 1:2 (U-50) or 1:10 (U-10). Diluted solutions stable for 28 days at 5°^{C (41}°F) and 14 days at 30°^{C (86}°^F).^2,c

• Can mix with NPH. Draw aspart into syringe first and inject immediately after mixing.⁴

• Can mix with Insulin Diluting Medium for NovoLog to dilutions of 1:2 (U-50) or 1:10 (U-10). Diluted solutions stable for 28 days at <30°^{C (86}°^F).^4,c

• Can mix with NPH. Draw insulin glulisine into syringe first and inject immediately.⁶

Stability of in- use products at room temp

Vial, cartridge, pens: 28 days²

External pump: 48 hours; 7 days for 3 mL cartridge in D- TRON or D-TRON plus. Discard pump insulin exposed to

>37^oC (98.6^oF).²

Vial, cartridge, pen: 28 days⁴

External pump: 6 days (reservoir), 3 days (infusion set/insertion site).⁴ Discard pump insulin exposed to >37°^{C (98.6}^o^F).⁴ Infusion bags: 24 hours⁴

Vial, cartridge, pen: 28 days⁶ External pump: 48 hours. Do not expose to >37^oC (98.6ºF).⁶ Infusion bags: 48 hours⁶ Cost^b $118.24/10 mL vial

$213.95/5 of 3 mL cartridge

$223.87/5 of 3 mL pen, $221.47/5 of 3 mL KwikPen

$111.20/10 mL vial (AWP)

$216.19/5 of 3mL PenFill cartridge

$235.74/5 of 3 mL FlexPen

$105.95/10 mL vial

$203.64/5 of 3 mL cartridges

$201.01/5 of 3 mL SoloStar

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More. . .

Short-acting (i.e., Regular insulin)

Brand, Maker Humulin R, Eli Lilly Novolin R, Novo Nordisk

Availability Non-prescription (except 500 units/mL Humulin R)¹

Description Human insulin (rDNA origin)¹

Onset 30 to 60 minutes³ (30 minutes U-500)⁵⁶ Around 30 minutes⁷

Peak 1 to 5 hours³ (1 to 3 hours U-500)⁵⁶ 2.5 to 5 hours⁷

Duration 4 to 12 hours⁸(longer with U-500; up to 24 hours)¹⁰ Around 8 hours⁷ Administration

(SC infusion is off-label, 100 units/mL)³

SC^8,10

IM, IV (unlabeled uses)³(500 unit/mL SC only)^54,55

SC; IM or IV infusion in clinical settings⁷

Meal timing Most commonly recommended 30 minutes before meals.¹¹

Formulations 100 units/mL: 10 mL vial, latex-free⁵⁰

500 units/mL: 20 mL vial, latex-free⁵⁰

100 units/mL: 10 mL vial, latex-free⁹

Appearance Clear and colorless^7.8

Compatibility^a • Can mix with NPH. Draw regular insulin into syringe first.³ Mixtures stable in syringe at room temp for 28 days but must consider possibility of microbial contamination; refrigeration recommended.^3,49

• Diluent available for Humulin R and Humulin R U-500^c Stability of in-use products at room temperature • Vial (100 units/mL): 28 days⁵¹

• Infusion bags: 24 hours³

• Vial: 42 days¹²

• Infusion bags: 24 hours^3,7

Cost^b $62.11/10 mL vial (U-100)

$284.22/20 mL vial (U-500)

$73.19/10mL vial

Intermediate-acting (i.e., NPH)

Brand, Maker Humulin N, Eli Lilly Novolin N, Novo Nordisk

Availability Non-prescription¹

Description Human (rDNA) isophane suspension¹

Onset 1 to 2 hours³ 90 minutes¹⁴

Peak 6 to 14 hours³ 4 to 12 hours¹⁴

Duration Up to 24 hours¹³ Up to 24 hours¹⁴

Administration SC³

Formulations 100 units/mL. 10 mL vial, 3 mL disposable pen,

both latex-free⁵⁰

100 units/mL. 10 mL vial, latex-free⁹

Appearance Cloudy¹

Compatibility^a • Can mix with aspart, glulisine, lispro, and regular insulins. See above for details.

• Diluent available for Humulin N^c Stability of in-use products at room temperature Vial: 28 days⁵¹

3 mL pen: 14 days¹

Vial: 42 days¹⁴

Cost^b $62.11/10 mL vial

$167.92/5 of 3 mL disposable pen

$73.19/10 mL vial

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Long-acting

Brand (generic), Maker Lantus (insulin glargine), Sanofi-aventis Levemir (insulin detemir), Novo Nordisk

Availability Prescription only^15,16

Description Human insulin analog (rDNA origin)¹

Onset 1.1 hour³ 1.1 to 2 hours³

Peak No significant peak¹⁵ Relatively flat¹⁶

Duration 10.8 to >24 hours (median 24 hours; sampling period 24 hours)¹⁵

Mean 5.7 to 23.2 hours (dose-dependent; binds to albumin; sampling period 24 hours)¹⁶

Administration • SC once daily at same time each day¹⁵

• Convert 1:1 from once daily NPH, but reduce Lantus by 20% dose if converting from twice daily NPH¹⁵

• No need to shake before administration.¹⁵

• Pain at injection site reported more commonly than with NPH (2.7% vs 0.7%)³

• SC once or twice daily. Give once-daily dose with evening meal or at bedtime. If twice daily dosing needed for glucose control, give evening dose with evening meal, at bedtime, or 12 hours after morning dose.¹⁶

• Convert 1:1 from another basal insulin.¹⁶

• Type 2 diabetes: Some patients may need higher doses of Levemir than NPH. Insulin-naïve patients with poor control on oral drugs: 0.1 to 0.2 units/kg once daily in evening or 10 units once or twice daily.¹⁶

Meal timing Not applicable See “Administration” above.

Formulations 100 units/mL. 10 mL vial, 3 mL cartridge for Opticlik, 3 mL disposable SoloStar pen

100 units/mL. 10 mL vial, 3 mL disposable FlexPen, both latex-free⁹

Appearance Clear, colorless¹⁵ Clear, colorless¹⁶

Compatibility^a • Do not mix with other insulins or dilute.¹⁵ Preliminary evidence shows mixing glargine with lispro or aspart did not adversely affect glycemic control.^17-19 The mixture was cloudy.^17,19

• Has acidic pH (about 4)³

• Do not mix with other insulins or dilute. Mixing with Levemir reduced levels of insulin aspart substantially.¹⁶

• Has neutral pH.¹⁶ Stability of in-use products at room

temperature

10 mL vial: 28 days¹⁵ 3 mL cartridge: 28 days¹⁵ SoloStar pen: 28 days¹⁵

10 mL vial: 42 days¹⁶ FlexPen: 42 days¹⁶

Cost^b $111.88/10 mL vial

$206.09/5 of 3 mL cartridges

$202.71/5 of 3 mL SoloStar pen

$110.49/10 mL vial

$199.27/5 of 3 mL FlexPens (AWP)