Injector pen

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Two disposable injector pens containing insulin. Insulin pen.JPG
Two disposable injector pens containing insulin.

An injector pen (also called a medication pen) is a device used for injecting medication under the skin. First introduced in the 1980s, injector pens are designed to make injectable medication easier and more convenient to use, thus increasing patient adherence. The primary difference between injector pens and traditional vial and syringe administration is the easier use of an injector pen by people with low dexterity, poor vision, or who need portability to administer medicine on time. Injector pens also decrease the fear or adversity towards self-injection of medications, which increases the likelihood that a person takes the medication.

Contents

Injector pens are commonly used for medications that are injected repeatedly by a person over a relatively short period of time, especially insulin and insulin analogs used in the treatment of diabetes (called insulin pens). Many other medications are also available as injector pens, including other injectable medicines for diabetes, high cholesterol, migraine prevention, and other monoclonal antibodies. Studies have shown injector pens to be at least as effective as vial and syringe administration, and surveys have shown that a vast majority of people would prefer an injector pen over vial and syringe administration if one was available. After a slow uptake in the United States, injector pens have surpassed vial and syringe administration of insulin in type 2 diabetes.

Uses

The primary goal of injector pens is to increase patient adherence by making it easier and more convenient for people to use injectable therapy. This is especially problematic with injectable medications given the extra work associated with an injection, as well as the potential aversion to self-injecting medication. [1] [2]

Injector pens increase patient adherence by increasing the ease of self-administering injectable medication, as well as the portability of injection medication. [2] Furthermore, injector pens are easier to handle and use than vials and syringes, making them useful in people with low dexterity, cognitive or visual impairment, or those who worry about being able to properly use a vial and syringe. [2] For medications which do not follow standard dosage in all people, injector pens may be designed to enable easier and more accurate administration of an exact dose, whereas a vial and syringe requires the person to prepare the correct dose themselves. [2] Injector pens may also remove stigma or fear around the use of injection medication in public environments, such as insulin before a meal at a restaurant. [2]

Combination injector pens which include multiple medications used to treat a disease are designed to reduce the number of injections a person must use to administer their medications. [3] The reduction in number of injections required may decrease the risk of non-adherence due to forgetfulness or unwillingness to self-inject medication. [3]

Design

An insulin pen with labels as follows: A) tip; B) medication chamber; C) plunger; D) dose window; E) dose selection dial; F) plunger button Insulin pen (labeled).jpg
An insulin pen with labels as follows: A) tip; B) medication chamber; C) plunger; D) dose window; E) dose selection dial; F) plunger button
Example of a reusable injector pen used for insulin
Penmate.jpg
A reusable insulin pen assembled.
Penmate zerlegt.jpg
The same insulin pen disassembled, showing replaceable cartridge and reusable housing pieces.

An injector pen consists of a chamber or cartridge of medication, a tip to attach a needle, and a piston or plunger to inject the dose. [4] Some pens, including most insulin pens, include dials to adjust the dose of the injection before each administration. [2] Dials enable more accurate dose measuring than traditional vial and syringe administration, especially for low doses of insulin. [2] Injector pens which have dials to adjust dosages may also include a clicking sound or other method to confirm the dose adjustment. [2]

Some pens may include a cartridge filled with medication which can be replaced when empty to enable reuse of the pen itself, whereas other pens are designed to be disposed of after their prefilled chamber is depleted. [2] Injector pens designed for single use may also be autoinjectors, which do not require the user to press a plunger to inject the dose. [4]

Pen needles

Comparison of 4mm and 12.7mm pen needle sizes Pen Needle comparison.jpg
Comparison of 4mm and 12.7mm pen needle sizes

All injector pens other than those designed for single use require the use of single-use replaceable pen needles for each injection. These pen needles come in various lengths to accommodate varying depths of subcutaneous tissue under the top of the skin. [5] Pen needles are designed for single use subcutaneous injection of medication and are not designed to be reused for more than one administration. [6] The needles are generally manufactured with an outer protective plastic shell, which is used by a person to attach the needle to the pen, and an inner plastic shell protecting the needle itself. Instruction on how to properly attach and use needles is the responsibility of the doctor or pharmacist to ensure proper use. [2] [7]

Today, pen needles are manufactured at shorter needle lengths than required for typical vial and syringe administration, which decreases the pain associated with injection. [2] They are available in multiple lengths and gauge of needle, including 3.5mm, 4mm, 5mm, and 8mm lengths, and 31 through 34 gauge. [8] Over time, needles have also had bevels designed which decrease the force required to penetrate the skin, which decreases the pain associated with injection and may increase the acceptability of self-injection. [8] Furthermore, pen needles are designed for insertion at a 90-degree angle to the skin, as opposed to normal syringes which are designed to be injected at an angle. Pen needles generally do not require pinching of the skin for proper administration, unlike historically used syringes. [9] Pen needles should be disposed of properly after each use, preferably in a purpose-made sharps container, to prevent injury from accidental contact after use. [9]

Comparison to syringe

A standard insulin syringe with needle is smaller than an injector pen. Blausen 0580 Insulin Syringe&Pen.png
A standard insulin syringe with needle is smaller than an injector pen.

Injector pens are an alternative to the manufacture of medication for injection in vials containing either liquid or a powder to which a diluent such as sterile water is added. When a vial is used as a means of storage, the end-user must use a syringe to "draw up" or remove the medication from the vial to prepare it for administration. The end user must then perform a series of actions to insert the needle of the syringe under the skin, and depress the plunger on the syringe to inject the dose. This requires dexterity which may make it difficult to accurately or completely administer the appropriate doses of medications. [2] Injector pens remove some of the complications of syringes by allowing the pen to be "pushed" against the skin at a 90 degree angle (removing the need to inject at a proper angle as is the case with syringes), as well as by replacing a long, thin plunger of a syringe with a simple button which is depressed and held to inject the dose. [2]

Availability

Many insulin analogs and GLP-1 agonists for diabetes treatment are available as injector pens. [2] As with insulin vials, some insulin pens are made with higher concentrations including U-200, U-300, and U-500. Different concentration insulin products may not have the same pharmacokinetic properties as other strengths. [10] The higher concentrations are used to lessen the volume of the injection, and allow the same dose of insulin to be injected with less force. [10] In some cases, these medications may be combined into one pen to be administered daily, for example insulin degludec with liraglutide [6] and insulin glargine with lixisenatide. [11] Combination products are available in fixed-dose ratios and are generally dosed by units of insulin, which will administer a proportional amount of the GLP-1 agonist as well. [12]

Another class of medication commonly available as an injector pen is monoclonal antibodies. Due to the molecular size of monoclonal antibodies, they must be administered via injection. Examples of monoclonal antibodies available or studied as injector pens include adalimumab, [13] secukinumab, [14] and alirocumab. [15] CGRP antagonists which are monoclonal antibodies, used for the prevention of migraines, are also available as injector pens. [16] Other monoclonal antibodies designed for home use may also be manufactured as injector pens. [17] [18]

Some medications are formulated as injector pens to quicken the onset of action of the medication. This includes epinephrine, which when used to treat anaphylaxis must work as soon as possible. [19] Contrary to most other injector pens, epinephrine injector pens are designed to administer the medication via intramuscular injection. [19] Another medication formulated as an injector pen to ensure quick onset of action is glucagon for hypoglycemia. [20] Other medications normally administered orally are also available or have been studied as injector pens, either due to different pharmacokinetic properties when administered via injection, or for those who cannot take oral medications. This includes methotrexate for juvenile idiopathic arthritis [21] and sumatriptan for treatment of migraines. [22]

Effectiveness

Most injector pens are designed for subcutaneous injection just under the skin, but some are designed for injection into muscle. The desired injection site and the skin profile at the injection site will determine what needle length is appropriate for a person to use. [23] For products with included needles, such as epinephrine pens, different brands may have different included needle lengths, which must be taken into account. [19]

Multiple studies have shown that many people prefer the use of injector pens over other forms of injectable medication, such as vial and syringe. [2] Injector pens in general have also been shown to be at least as effective therapeutically as other injection methods. [2] One study of the use of injector pens for insulin administration found that the chance a person initiated on insulin continued therapy for at least 12 months was higher with insulin pens than with vial and syringe administration. [2] The same study found that the increase in adherence to therapy resulted in increased short-term pharmacy costs (i.e. for the pens/needles) but resulted in an overall decrease in healthcare costs related to diabetes. [2] Insulin pens have also been shown to provide a higher quality of life than traditional injection methods. [2] A 2011 systematic review which examined preference of insulin pens over vial and syringe administration found that in almost all studies and surveys a majority of people preferred insulin pens. [24]

The effectiveness of an injector pen can also depend on the technique used to inject. After fully pressing the plunger button to activate the pen, the button must continue to be held for about 10 seconds to ensure the dose is administered before removing the pen needle from the skin and finally releasing the button. [23] Failure to use the pen as instructed may result in medication leakage and administration of a lower dose than was intended. [23] Another administration problem which may impact effectiveness of an injector pen is lipohypertrophy of the subcutaneous tissue near the injection site. For this reason, it is recommended to rotate the injection site every administration. [23]

History

The first injector pen was introduced in 1985, by Novo Nordisk to administer insulin products. [25] After their introduction, insulin pens had a slow adoption in the United States, with only 2% of insulin being injected via pen in 1999. A major barrier to adoption in the United States was the increased up-front cost of insulin pens compared to traditional injections. [26] Pen adoption in the United States accelerated after studies showed that the higher up-front cost of insulin pens was offset by the increase in compliance, which decreased overall healthcare costs. [27] Historically, pen needles were manufactured in lengths up to 12.7mm. Over time, pen needles designed for insulin pens have become shorter, and a 4mm long needle is considered sufficient for most people to administer subcutaneously correctly. [23]

In 1989, an injector pen form of human growth hormone was licensed in New Zealand. [28] In the US, a pen form of octreotide was approved by the FDA in 2020, under the brand name Bynfezia. [29]

Related Research Articles

Intensive insulin therapy or flexible insulin therapy is a therapeutic regimen for diabetes mellitus treatment. This newer approach contrasts with conventional insulin therapy. Rather than minimize the number of insulin injections per day, the intensive approach favors flexible meal times with variable carbohydrate as well as flexible physical activities. The trade-off is the increase from 2 or 3 injections per day to 4 or more injections per day, which was considered "intensive" relative to the older approach. In North America in 2004, many endocrinologists prefer the term "flexible insulin therapy" (FIT) to "intensive therapy" and use it to refer to any method of replacing insulin that attempts to mimic the pattern of small continuous basal insulin secretion of a working pancreas combined with larger insulin secretions at mealtimes. The semantic distinction reflects changing treatment.

<span class="mw-page-title-main">Syringe</span> Medical injection device

A syringe is a simple reciprocating pump consisting of a plunger that fits tightly within a cylindrical tube called a barrel. The plunger can be linearly pulled and pushed along the inside of the tube, allowing the syringe to take in and expel liquid or gas through a discharge orifice at the front (open) end of the tube. The open end of the syringe may be fitted with a hypodermic needle, a nozzle or tubing to direct the flow into and out of the barrel. Syringes are frequently used in clinical medicine to administer injections, infuse intravenous therapy into the bloodstream, apply compounds such as glue or lubricant, and draw/measure liquids. There are also prefilled syringes.

<span class="mw-page-title-main">Autoinjector</span> Medical device designed to deliver a dose of a particular drug

An autoinjector is a medical device designed to deliver a dose of a particular drug. The injectors were initially designed to overcome the hesitation associated with self-administration of the needle-based drug delivery device.

<span class="mw-page-title-main">Hypodermic needle</span> Device to inject substances into the circulatory system

A hypodermic needle, one of a category of medical tools which enter the skin, called sharps, is a very thin, hollow tube with one sharp tip. It is commonly used with a syringe, a hand-operated device with a plunger, to inject substances into the body or extract fluids from the body. Large-bore hypodermic intervention is especially useful in catastrophic blood loss or treating shock.

<span class="mw-page-title-main">Route of administration</span> Path by which a drug, fluid, poison, or other substance is taken into the body

In pharmacology and toxicology, a route of administration is the way by which a drug, fluid, poison, or other substance is taken into the body.

<span class="mw-page-title-main">Subcutaneous administration</span> Insertion of medication under the skin

Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion.

<span class="mw-page-title-main">Intramuscular injection</span> Medical injection into a muscle

Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have larger and more numerous blood vessels than subcutaneous tissue, leading to faster absorption than subcutaneous or intradermal injections. Medication administered via intramuscular injection is not subject to the first-pass metabolism effect which affects oral medications.

<span class="mw-page-title-main">Sumatriptan</span> 5-HT receptor agonist medication used for migraines & cluster headaches

Sumatriptan, sold commonly under brand names Imitrex and Treximet among others, is a medication used to treat migraine headaches and cluster headaches. It is taken orally, intranasally, or by subcutaneous injection. Therapeutic effects generally occur within three hours.

<span class="mw-page-title-main">Injection (medicine)</span> Method of medication administration

An injection is the act of administering a liquid, especially a drug, into a person's body using a needle and a syringe. An injection is considered a form of parenteral drug administration; it does not involve absorption in the digestive tract. This allows the medication to be absorbed more rapidly and avoid the first pass effect. There are many types of injection, which are generally named after the body tissue the injection is administered into. This includes common injections such as subcutaneous, intramuscular, and intravenous injections, as well as less common injections such as intraperitoneal, intraosseous, intracardiac, intraarticular, and intracavernous injections.

<span class="mw-page-title-main">Jet injector</span> Needle-free medical injection syringe

A jet injector is a type of medical injecting syringe device used for a method of drug delivery known as jet injection. A narrow, high-pressure stream of liquid is made to penetrate the outermost layer of the skin to deliver medication to targeted underlying tissues of the epidermis or dermis, fat, or muscle.

<span class="mw-page-title-main">Diabetic hypoglycemia</span> Medical condition

Diabetic hypoglycemia is a low blood glucose level occurring in a person with diabetes mellitus. It is one of the most common types of hypoglycemia seen in emergency departments and hospitals. According to the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP), and based on a sample examined between 2004 and 2005, an estimated 55,819 cases involved insulin, and severe hypoglycemia is likely the single most common event.

<span class="mw-page-title-main">Infusion pump</span> Medical device

An infusion pump infuses fluids, medication or nutrients into a patient's circulatory system. It is generally used intravenously, although subcutaneous, arterial and epidural infusions are occasionally used.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin twice daily or once weekly.

<span class="mw-page-title-main">Drug injection</span> Method of introducing a drug

Drug injection is a method of introducing a drug into the bloodstream via a hollow hypodermic needle, which is pierced through the skin into the body. Intravenous therapy, a form of drug injection, is universally practiced in modernized medical care. As of 2004, there were 13.2 million people worldwide who self-administered injection drugs outside of medical supervision, of which 22% are from developed countries.

<span class="mw-page-title-main">Injection port</span> Medical device

An injection port is a medical device used for the administration of insulin or other physician approved medicine into the subcutaneous tissue. The device is similar to infusion sets used by insulin pumps, except it is configured to receive a syringe instead of a tubing system. An injection port is usually a disposable device applied by the patient and worn for period of 3–5 days. When giving shots via an injection port, the needle stays above the surface of the skin. Medication is delivered via a short soft cannula. An injection port can be used in conjunction with multiple daily injections of insulin by people with diabetes. It can also be used for the subcutaneous administration of any other physician prescribed medication.

<span class="mw-page-title-main">Insulin (medication)</span> Use of insulin protein and analogs as medical treatment

As a medication, insulin is any pharmaceutical preparation of the protein hormone insulin that is used to treat high blood glucose. Such conditions include type 1 diabetes, type 2 diabetes, gestational diabetes, and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. Insulin is also used along with glucose to treat hyperkalemia. Typically it is given by injection under the skin, but some forms may also be used by injection into a vein or muscle. There are various types of insulin, suitable for various time spans. The types are often all called insulin in the broad sense, although in a more precise sense, insulin is identical to the naturally occurring molecule whereas insulin analogues have slightly different molecules that allow for modified time of action. It is on the World Health Organization's List of Essential Medicines. In 2020, regular human insulin was the 307th most commonly prescribed medication in the United States, with more than 1 million prescriptions.

Injection site reactions (ISRs) are reactions that occur at the site of injection of a drug. They may be mild or severe and may or may not require medical intervention. Some reactions may appear immediately after injection, and some may be delayed. Such reactions can occur with subcutaneous, intramuscular, or intravenous administration.

<span class="mw-page-title-main">Intradermal injection</span> Medical injection into the dermis

Intradermal injection is a shallow or superficial injection of a substance into the dermis, which is located between the epidermis and the hypodermis. For certain substances, administration via an ID route can result in a faster systemic uptake compared with subcutaneous injections, leading to a stronger immune response to vaccinations, immunology and novel cancer treatments, and faster drug uptake. Additionally, since administration is closer to the surface of the skin, the body's reaction to substances is more easily visible. However, due to complexity of the procedure compared to subcutaneous injection and intramuscular injection, administration via ID is relatively rare, and is only used for tuberculosis and allergy tests, Monkeypox vaccination, and certain therapies.

<span class="mw-page-title-main">Depot injection</span> Long-acting medication preparation

A depot injection is a term for an injection formulation of a medication which releases slowly over time to permit less frequent administration of a medication. They are designed to increase medication adherence and consistency, especially in patients who commonly forget to take their medicine. Depot injections can be created by modifying the drug molecule itself, as in the case of prodrugs, or by modifying the way it is administered, as in the case of oil/lipid suspensions. Depot injections can have a duration of action of one month or greater and are available for many types of drugs, including antipsychotics and hormones.

<span class="mw-page-title-main">Tirzepatide</span> Anti-diabetic medication

Tirzepatide, sold under the brand name Mounjaro among others, is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered through subcutaneous injection.

References

  1. ↑ Guerci, Bruno; Chanan, Neha; Kaur, Simarjeet; Jasso-Mosqueda, Juan Guillermo; Lew, Elisheva (April 2019). "Lack of Treatment Persistence and Treatment Nonadherence as Barriers to Glycaemic Control in Patients with Type 2 Diabetes". Diabetes Therapy. 10 (2): 437–449. doi: 10.1007/s13300-019-0590-x . PMC   6437240 . PMID   30850934.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Cuddihy, Robert M.; Borgman, Sarah K. (2013). "Considerations for Diabetes: Treatment With Insulin Pen Devices". American Journal of Therapeutics. 20 (6): 694–702. doi:10.1097/MJT.0b013e318217a5e3. PMID   21768872. S2CID   34997991.
  3. 1 2 Nuffer, Wesley; Guesnier, Ashley; Trujillo, Jennifer M. (March 2018). "A review of the new GLP-1 receptor agonist/basal insulin fixed-ratio combination products". Therapeutic Advances in Endocrinology and Metabolism. 9 (3): 69–79. doi: 10.1177/2042018817752315 . PMC   5813858 . PMID   29492243.
  4. 1 2 Misra, Ambikanandan, ed. (2010). "11". Challenges in delivery of therapeutic genomics and proteomics. Oxford: Elsevier. pp. 586–587. doi:10.1016/B978-0-12-384964-9.00011-6. ISBN   978-0-12-384964-9.
  5. ↑ Leonardi, Luca; Viganò, Mara; Nicolucci, Antonio (August 2019). "Penetration force and cannula sliding profiles of different pen needles: the PICASSO study". Medical Devices: Evidence and Research. 12: 311–317. doi: 10.2147/MDER.S218983 . PMC   6717876 . PMID   31695523.
  6. 1 2 Baker, Danial E. (May 2017). "Insulin Degludec/Liraglutide". Hospital Pharmacy. 52 (5): 374–380. doi:10.1177/0018578717715383. PMC   5551637 . PMID   28804155.
  7. ↑ Wei, Erin T.; Koh, Eileen; Kelly, Mary S.; Wright, Lorena A.; Tylee, Tracy S. (March 2020). "Patient errors in use of injectable antidiabetic medications: A need for improved clinic-based education". Journal of the American Pharmacists Association. 60 (5): e76–e80. doi:10.1016/j.japh.2020.02.030. PMID   32229089. S2CID   214749788.
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  9. 1 2 Bahendeka, Silver; Kaushik, Ramaiya; Swai, Andrew Babu; Otieno, Fredrick; Bajaj, Sarita; Kalra, Sanjay; Bavuma, Charlotte M.; Karigire, Claudine (April 2019). "EADSG Guidelines: Insulin Storage and Optimisation of Injection Technique in Diabetes Management". Diabetes Therapy. 10 (2): 341–366. doi: 10.1007/s13300-019-0574-x . PMC   6437255 . PMID   30815830.
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  11. ↑ "Sanofi Receives FDA Approval of Soliqua 100/33, for the Treatment of Adults with Type 2 Diabetes". Sanofi. November 21, 2016. Archived from the original on July 18, 2017. Retrieved August 20, 2020.
  12. ↑ Aroda, Vanita R; González-Galvez, Guillermo; Grøn, Randi; Halladin, Natalie; Haluzík, Martin; Jermendy, György; Kok, Adri; Őrsy, Petra; Sabbah, Mohamed; Sesti, Giorgio; Silver, Robert (August 2019). "Durability of insulin degludec plus liraglutide versus insulin glargine U100 as initial injectable therapy in type 2 diabetes (DUAL VIII): a multicentre, open-label, phase 3b, randomised controlled trial". The Lancet Diabetes & Endocrinology. 7 (8): 596–605. doi:10.1016/S2213-8587(19)30184-6. PMID   31189519. S2CID   189815494.
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  15. ↑ Farnier, Michel; Jones, Peter; Severance, Randall; Averna, Maurizio; Steinhagen-Thiessen, Elisabeth; Colhoun, Helen M.; Du, Yunling; Hanotin, Corinne; Donahue, Stephen (January 2016). "Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial". Atherosclerosis. 244: 138–146. doi: 10.1016/j.atherosclerosis.2015.11.010 . hdl: 10447/183606 . PMID   26638010.
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  19. 1 2 3 Dreborg, Sten; Tsai, Gina; Kim, Harold (July 2019). "Implications of variation of epinephrine auto-injector needle length". Annals of Allergy, Asthma & Immunology. 123 (1): 89–94. doi:10.1016/j.anai.2019.04.027. PMID   31071440. S2CID   149445920.
  20. ↑ "Drugs@FDA". www.accessdata.fda.gov. FDA. Retrieved 20 August 2020.
  21. ↑ Roszkiewicz, Justyna; Swacha, Zbigniew; Smolewska, Elżbieta (December 2020). "Prefilled pen versus prefilled syringe: a pilot study evaluating two different methods of methotrexate subcutaneous injection in patients with JIA". Pediatric Rheumatology. 18 (1): 64. doi: 10.1186/s12969-020-00455-4 . PMC   7425569 . PMID   32787934.
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  24. ↑ Anderson, Barbara J.; Redondo, Maria J. (November 2011). "What Can We Learn from Patient-Reported Outcomes of Insulin Pen Devices?". Journal of Diabetes Science and Technology. 5 (6): 1563–1571. doi: 10.1177/193229681100500633 . PMC   3262728 . PMID   22226279.
  25. ↑ Rex, Jørn; Jensen, Klaus H; Lawton, Simon A (2006). "A Review of 20??Years??? Experience with the Novopen?? Family of Insulin Injection Devices". Clinical Drug Investigation. 26 (7): 367–401. doi:10.2165/00044011-200626070-00001. PMID   17163272. S2CID   20771626.
  26. ↑ Bohannon, Nancy J. V. (January 1999). "Insulin delivery using pen devices: Simple-to-use tools may help young and old alike". Postgraduate Medicine. 106 (5): 57–68. doi: 10.3810/pgm.1999.10.15.751 . PMID   10560468.
  27. ↑ Alemayehu, B; Speiser, J; Bloudek, L; Sarnes, E (July 2018). "Costs associated with long-acting insulin analogues in patients with diabetes". The American Journal of Managed Care. 24 (8 Spec No): SP265–SP272. PMID   30020738.
  28. ↑ Gluckman, P D; Cutfield, W S (1 June 1991). "Evaluation of a pen injector system for growth hormone treatment". Archives of Disease in Childhood. 66 (6): 686–688. doi: 10.1136/adc.66.6.686 . PMC   1793174 . PMID   2053787.
  29. ↑ "Drugs@FDA". www.accessdata.fda.gov. Food and Drug Administration. Retrieved 20 August 2020.
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