Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

INSULIN

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Insulin is a hormone that facilitates the penetration of glucose and amino acids through cell membranes of skeletal and heart muscle.

Specific Substances

    A) RAPID-ACTING INSULIN
    1) Lispro
    2) Aspart
    SHORT-ACTING (REGULAR) INSULIN
    1) Regular insulinCrystalline Zinc Insulin
    INTERMEDIATE-ACTING INSULIN (NPH)
    1) NPH insulinNeutral Protamine Hagedorn InsulinIsophane insulin
    2) Lente Insulin
    INTERMEDIATE- AND SHORT-ACTING MIXTURES
    1) Humulin 70/30
    2) Humalog Mix 75/25
    3) Humalog Mix 50/50
    4) Novolin 70/30
    5) Novolog Mix 70/30
    LONG-ACTING INSULIN
    1) Glargine insulin
    2) Ultralente insulin
    3) Insulin detemir
    INHALED INSULIN (SYNONYM)
    1) Exubera
    2) Afrezza
    General Terms
    1) Endopancrine (polypeptide hormone used for diabetes)
    2) Insular (polypeptide hormone used for diabetes)
    3) Insulyl (polypeptide hormone used for diabetes)
    4) Iszilin (polypeptide hormone used for diabetes)

    1.2.1) MOLECULAR FORMULA
    1) INSULIN ASPART: C256H381N65O79S6
    2) INSULIN DEGLUDEC: C274H411N65O81S6
    3) INSULIN DETEMIR: C267H402O76N64S6
    4) INSULIN GLARGINE: C267H404N72O78S6
    5) INSULIN GLULISINE: C258H384N64O78S6
    6) INSULIN HUMAN REGULAR: C257H383N65O77S6
    7) INSULIN LISPRO: C257H383N65O77S6

Available Forms Sources

    A) FORMS
    1) Some of the available insulin products are listed below:
    a) RAPID-ACTING INSULIN
    1) Humalog (Insulin lispro) - Injection Solution: 100 Units/mL
    2) NovoLog (Insulin aspart) - Injection Solution: 100 Units/mL
    3) NovoLogFlexPen (Insulin aspart) - Injection Solution: 100 Units/mL
    b) SHORT-ACTING INSULIN (REGULAR)
    1) Humulin R or Novolin R (regular insulin) - Injection Solution: 100, 500 Units/mL
    2) Humulin R or Novolin R (regular insulin) - Injection Solution: 100, 500 Units/mL
    c) INTERMEDIATE-ACTING INSULIN (NPH)
    1) Humulin N (NPH) - Injection Solution: 100 Units/mL
    2) Novolin N (NPH) - Injection Solution: 100 Units/mL
    3) Humulin N Pen (NPH) - Injection Solution: 100 Units/mL
    d) INTERMEDIATE AND SHORT-ACTING MIXTURES
    1) Humulin 70/30 (70 Units/mL NPH plus 30 Units/mL Regular)
    2) Humalog Mix 75/25 (75 Units/mL Lispro protamine suspension plus 25 Units/mL Lispro injection)
    3) Humalog Mix 50/50 (50 Units/mL Lispro protamine suspension plus 50 Units/mL Lispro injection)
    4) Novolin 70/30 (70 Units/mL NPH plus 30 Units/mL Regular)
    5) Novolin 70/30 FlexPen (70 Units/mL NPH plus 30 Units/mL Regular)
    6) Novolog Mix 70/30 (70 Units/mL Insulin Aspart protamine suspension plus 30 Units/mL Aspart injection)
    7) Novolog Mix 70/30 FlexPen (70 Units/mL Insulin Aspart protamine suspension plus 30 Units/mL Aspart injection)
    e) LONG-ACTING INSULIN
    1) Lantus (glargine) - Injection Solution: 100 Units/mL
    2) Levemir (detemir) - 100 Units/mL
    f) Insulin Inhaler (Exubera)
    2) Freezing suspended insulins may result in erratic concentrations for subsequent doses. This may result in either an overdose or underdose of the medication, depending on the fraction administered (Spencer & Kitabchi, 1983).
    B) USES
    1) Insulin is used to treat patients with Type 1 and Type 2 diabetes.
    2) ILLICIT - Insulin has been used as a performance-enhancing drug by body builders (Rich et al, 1998). It can often be obtained on the "black market" by users identified as anabolic androgenic steroid injectors to promote anabolic processes and inhibit catabolism (Rich et al, 1998).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Insulin is a hormone used primarily in the treatment of diabetes mellitus mainly type 1 and sometimes type 2. It is also used for the treatment of hyperglycemia and hyperkalemia. It may be used as a performance enhancing drug.
    B) PHARMACOLOGY: Insulin is a polypeptide hormone composed of 51 amino acids secreted by the beta cells of the pancreas. It stimulates the uptake of glucose by the cardiac muscle, skeletal muscle and the adipose tissue. It also stimulates glycogenesis, lipogenesis, and protein synthesis, while it inhibits lipolysis.
    C) TOXICOLOGY: In overdose, insulin can cause hypoglycemia; the onset and duration depend on the type and quantity of the injected preparation.
    D) EPIDEMIOLOGY: While hypoglycemia during therapeutic use is common, deliberate insulin overdose is rare.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Hypoglycemia is common during therapeutic use. Hypokalemia may occur from intracellular shifts of potassium. Lethargy, lassitude, yawning, and irritability may occur when the blood glucose level drops to about 50 mg/dL.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Insulin overdose produces hypoglycemia which may manifest as hunger, anxiety, fatigue, diaphoresis, nausea, palpitation, tachycardia, tremor and headache. As the brain becomes more deprived of glucose, blurred vision, inability to concentrate, weakness, altered behavior or coordination or somnolence may develop. Hypokalemia is a common finding in insulin overdose and hypomagnesemia and hypophosphatemia have been reported.
    2) SEVERE TOXICITY: Confusion, seizure and coma may develop. Focal neurological signs may also occur. Protracted, untreated hypoglycemia may cause permanent neurologic injury and death. Acute myocardial infarction and acute lung injury have been reported rarely after severe overdose. Cardiac dysrhythmias secondary to hypokalemia may occur when blood glucose levels drop below 40 mg/dL following an overdose.
    0.2.20) REPRODUCTIVE
    A) Insulin aspart, recombinant, insulin detemir, insulin lispro recombinant, and insulin human regular are classified as FDA pregnancy category B. Inhaled insulin, insulin aspart, recombinant/insulin aspart protamine, recombinant and insulin glargine, recombinant are classified as FDA pregnancy category C. Insulin glargine use in pregnancy is associated with a greater incidence of fetal femoral length less than 50th percentile and large for gestational age compared with a control group. The incidence of fetal adverse effects is similar with insulin glargine and NPH insulin use during pregnancy.

Laboratory Monitoring

    A) Serum or capillary glucose should be measured immediately then hourly, and when symptoms develop. Plasma glucose levels of 30 mg/dL or lower are common following large overdosage.
    B) Blood electrolytes should be checked, in particular, potassium, magnesium and phosphorus following a large overdose.
    C) An ECG should be obtained after a large overdose.
    D) Serum insulin concentrations can be used to confirm the overdose.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Patients with more than mild symptoms should be treated with intravenous dextrose bolus (25 g). This should be followed with oral carbohydrates or a dextrose infusion. Glucagon may be used for initial management when IV access is not available.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Blood glucose should be monitored hourly and whenever symptoms develop. The goal of therapy is to maintain the blood glucose between 120 to 200 mg/dL using a dextrose infusion and IV blouses for hypoglycemic episodes.
    C) DECONTAMINATION
    1) PREHOSPITAL: Decontamination is not needed after ingestion because insulin is degraded in the stomach.
    2) HOSPITAL: Surgical removal of SubQ injected insulin has been described after large overdoses, but there is no evidence that this improves outcomes, and it is not recommended.
    D) AIRWAY MANAGEMENT
    1) Airway protection is mandatory in a patient with an altered mental status who does not improve with dextrose administration.
    E) ANTIDOTE
    1) DEXTROSE: The mainstay of therapy is intravenous dextrose sufficient to produce euglycemia. Dextrose administration is guided by frequent measurement of blood glucose. ADULT: An IV bolus of 25 g of dextrose (50 mL of 50% dextrose in water) is usually an adequate initial dose. However, in profound hypoglycemia an additional dose may be required. PEDIATRIC: Dose: 0.5 to 1 g/kg of 25% dextrose (a 1:1 dilution of 50% dextrose and sterile water) while in the neonate the dose should be 0.5 to 1 g/kg of 10% dextrose (a 1:4 dilution of 50% dextrose and sterile water). Once a patient is alert, they should be fed. Patients with recurrent hypoglycemia should receive an IV infusion of dextrose 10% titrated to maintain a blood glucose of 100 to 200 mg/dL. If patients develop recurrent hypoglycemia despite 10% dextrose, or if volume loading is a concern, dextrose 20% can be given; however, it should be administered via a central venous catheter. Dextrose solution should be titrated and slowly discontinued once the patient starts to eat an adequate diet and hypoglycemic episodes have stopped.
    2) GLUCAGON: It can be used as a temporizing method to correct hypoglycemia; it may be given intravenously. Glucagon also has the advantage of being given SubQ or IM in the prehospital setting in patients who cannot be given carbohydrates because of depressed mental status and in whom IV access cannot be established. DOSE: Adult: Usual dose is 1 mg SubQ or IM; Pediatric (less than 20 kg): 0.5 mg IM or SubQ. Only effective if the patient has adequate liver glycogen stores.
    F) SEIZURE
    1) Correct hypoglycemia, IV benzodiazepines, barbiturates if seizures persist after hypoglycemia corrected.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Enhanced elimination is of no benefit following insulin exposure.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic adult with an inadvertent overdose of a short-acting insulin can be managed at home with telephone follow-up, if the patient has the ability to monitor his blood glucose at home, can tolerate oral intake, and if another responsible adult is present to monitor for signs of hypoglycemia.
    2) ADMISSION CRITERIA: Patients with intentional insulin overdose or recurrent hypoglycemia should be admitted to the ICU for close blood glucose monitoring and dextrose therapy.
    3) OBSERVATION CRITERIA: The patient with an inadvertent overdose of a short acting preparation (typically a much smaller amount of insulin is administered) can be observed in the Emergency Department and discharged if hypoglycemia resolves after feeding and a few hours of observation. Patients with recurrent hypoglycemia or long acting insulin exposure require inpatient admission for at least 24 hours.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) Children, alcoholics, and other patients with reduced glycogen stores develop hypoglycemia more readily and are less likely to respond to glucagon administration.
    2) Clinical manifestations of hypoglycemia may be less apparent in patients taking beta adrenergic blocking agents.
    3) Prolonged absorption from large subcutaneous injections of even short acting insulin can cause prolonged and recurrent hypoglycemia.
    4) Clinical manifestations of hypoglycemia can easily be mistaken for intoxication with ethanol or other substances of abuse.
    J) PHARMACOKINETICS
    1) The duration of action of therapeutic doses of insulin depend on the formulation. In large overdoses, the duration of action cannot be predicted by the insulin formulation, and even short-acting products may cause hypoglycemia for several days due to prolonged absorption.
    K) DIFFERENTIAL DIAGNOSIS
    1) Any condition that can cause hypoglycemia including sulfonylurea hypoglycemic overdose, starvation, alcoholism, insulinoma, or sepsis.

Range Of Toxicity

    A) TOXICITY: There is substantial intraindividual response to insulin. In general, therapeutic doses of insulin will cause hypoglycemia in a nondiabetic patient, while a patient with insulin resistance may not get hypoglycemic even with a modest overdoses. If prolonged hypoglycemia is avoided by early appropriate treatment, patients should recover with normal neurologic function despite large overdoses.
    B) Permanent brain damage has been reported following injections of 800 and 3200 units of insulin in diabetic patients. Recovery has occurred following up to 880 units of insulin lispro (short acting) with 3800 units of insulin glargine in an adult with diabetes mellitus.

Clinical Effects

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) At levels of 50 mg/dL, the majority of patients exhibit lethargy, lassitude, yawning, and irritability following therapeutic use.
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) Hypoglycemic coma may mimic coma secondary to other etiologies (head trauma, cerebrovascular accident, other drugs). Onset of coma may be delayed from 18 to 38 hours in patients overdosed on intermediate or extended insulin preparations (Tsujimoto et al, 2006; Kamijo et al, 2000; Vogl & Youngwirth, 1949; Munck & Quaade, 1963).
    b) CASE REPORT: A 56-year-old remained in fluctuating states of coma which resulted in permanent cognitive (language and short term memory loss) and physical impairment following profound hypoglycemia secondary to intentional insulin injection. Initial serum glucose was 0.4 mmol/L (normal range 3.6 to 6.1) (Cooper, 1994).
    c) CASE REPORT: A 21-year-old woman presented with coma and hypoglycemia 2.5 hours after intentionally injecting herself with 26 units of insulin glargine (twice her standard dose of 13 units) in a suicide attempt. The patient had mydriasis and her Glasgow coma scale score was 3. The patient became responsive following an intravenous bolus of 50 mL 50% glucose; however, despite a continuous infusion of 10% glucose, she continued to experience intermittent hypoglycemia 53 hours postexposure (Brvar et al, 2005).
    d) CASE REPORT: A 58-year-old man with Type 2 diabetes was found comatose after he injected himself with approximately 500 units of regular insulin. Coma resolved after treatment with intravenous glucose, but he developed hypoglycemic hemiplegia. Following treatment with glucose and argatroban, he recovered completely within 48 hours (Shirayama et al, 2004).
    C) SEQUELA
    1) WITH POISONING/EXPOSURE
    a) Irreversible neurologic sequelae are likely to occur when the duration of untreated hypoglycemia approaches 7 hours following overdose (Simon, 1983). Sequelae may include amnesia, dementia, and confusion.
    b) Marked mental impairment was reported in patients in whom therapy was delayed for 10 to 14 hours (Lindgren, 1960; Martin et al, 1977; Nicholson, 1965) however one patient with a delay of 13 hours recovered completely (Nicholson, 1965).
    c) CASE REPORT: An adult remained in a fluctuating coma for 10 days and had focal seizures for the first 40 hours following a suicide attempt with insulin; initial serum glucose was 0.4 mmol/L (normal 3.6 to 6.1). Permanent neurological deficits were apparent 4 to 8 months after exposure, with an EEG showing abnormal wave forms consistent with brain damage (Cooper, 1994).
    D) CEREBRAL EDEMA
    1) WITH POISONING/EXPOSURE
    a) Cerebral edema has been reported following acute exposure (Bourgeois & Dufourg, 1967; Bour et al, 1960).
    E) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Generalized seizures may accompany severe hypoglycemia following overdose (Kamijo et al, 2000; Colsky et al, 1985; Arem & Zoghbi, 1985; Cooper, 1994).
    F) HEMIPLEGIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 58-year-old man with Type 2 diabetes developed hemiplegia as a result of hypoglycemia after he intentionally injected himself with approximately 500 units of regular insulin. Neurological examination showed complete hemiparesis (motor strength 0/5) on the left and normal side motor function on his right side. An MRI 3 hours later showed an increased signal intensity in the pons, indicating that the patient's hemiplegia resulted from an acute brain injury. Following treatment with glucose and argatroban, he recovered completely within 48 hours, without focal neurological deficit (Shirayama et al, 2004)
    G) CEREBELLAR ATAXIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 51-year-old man with diabetes mellitus was found unconscious after injecting 80 units of insulin instead of his usual dose of 8 units. His initial blood glucose was 30 mg/dL. Upon transfer to a hospital, his neurologic exam was concerning for slurred speech and significant dysmetria in all 4 limbs. Although the patient had a medical history significant for polysubstance and alcohol abuse, a diagnosis of acute cerebellar ataxia secondary to hypoglycemia was made since a neurologic exam 1 month prior to presentation was normal. The patient's abnormalities continued for weeks but normalized by 3 months after the initial insulin overdose (Berz & Orlander, 2008).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) INCREASED APPETITE
    1) WITH THERAPEUTIC USE
    a) At blood glucose levels of 70 mg/dL, increased parasympathetic activity is observed, including hunger, nausea, and eructations following acute exposure or therapeutic use.
    2) WITH POISONING/EXPOSURE
    a) At blood glucose levels of 70 mg/dL, increased parasympathetic activity is observed, including hunger, nausea, and eructations following acute exposure.

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 48-year-old inadvertently received excessive amounts of carbohydrates and insulin for 48 hours following an attempted suicide using multiple drugs which included 1000 units of subcutaneously injected short-acting and 1000 units of subcutaneously injected long-acting insulin. On hospital day 3, the patient developed elevated liver enzymes (ASAT/ALAT 420/610 International Units/L (normal less than 32/36 International Units/L)) along with abdominal pain and nausea. The authors reported that the excessive amounts of carbohydrates and insulin administration led to acute steatosis; signs and symptoms resolved quickly following discontinuation of intravenous dextrose. Long-term sequelae were not reported (Jolliet et al, 2001).
    b) CASE REPORT: A 29-year-old man presented unconscious with severe hypoglycemia (plasma glucose: 26 mg/dL; normal range: 80 to 110 mg/dL) after the self-injection of 3600 units of insulin (1500 units of regular insulin, 600 units of neutral protamine Hagedorn (NPH) insulin, and 1500 units of 70/30 NPH/regular mixed insulin) subcutaneously. Laboratory results revealed hyperinsulinemia (934 microinternational units/mL; normal range: 2.6 to 24.9) and low C-peptide concentration (0.05 ng/mL; normal range: 0.9 to 4). He regained consciousness after receiving a dextrose infusion (20 g/hr) continuously for 48 hours. Despite dextrose infusion, he developed severe hypoglycemic attacks 14, 32, and 44 hours after presentation. On day 5, he developed severe elevated liver enzymes 15 to 20 times of normal range (aspartate aminotransferase: 0 to 40 International units(IU)/L; alanine aminotransferase: 0 to 43 IU/L). All other laboratory results, including bilirubin concentrations, prothrombin time, INR, and ultrasonographic evaluation of the liver were normal. On day 8, the patient recovered and was discharged to a psychiatric ward (Guclu et al, 2009).
    B) LARGE LIVER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 41-year-old man, with type II diabetes mellitus, developed hypoglycemic coma after injecting 180 units of insulin glargine subcutaneously. On admission his hepatic enzymes were within normal limits. Despite administration of a high calorie infusion with repeated glucose boluses, the patient's hypoglycemia persisted for 36 hours. Approximately 2 days after hospital admission, the patient experienced upper abdominal pain. Physical exam revealed hepatomegaly and repeat laboratory studies revealed elevated hepatic enzyme levels (AST 1064 units/L, ALT 1024 units/L, LDH 1751 units/L, total bilirubin 2.3 mg/dL). An abdominal CT scan confirmed hepatomegaly and a liver biopsy 6 days after the overdose showed hepatocytic glycogen deposition with edematous degeneration. He had received intravenous glucose in amounts ranging from 326 to 926 grams/day for the 5 days prior to the biopsy. Based on these findings, a diagnosis of rapid onset glycogen storage hepatomegaly was made, believed to be due to a combination of an overdose of insulin and administration of large doses of glucose to correct the subsequent hypoglycemia. With stabilization of the patient's glycemia, his clinical condition gradually improved. A repeat abdominal CT scan and liver biopsy, performed 10 to 20 days post-hospital admission, showed improvement of his hepatomegaly and hepatic glycogenosis, respectively (Tsujimoto et al, 2006).

Summary Of Exposure

    A) USES: Insulin is a hormone used primarily in the treatment of diabetes mellitus mainly type 1 and sometimes type 2. It is also used for the treatment of hyperglycemia and hyperkalemia. It may be used as a performance enhancing drug.
    B) PHARMACOLOGY: Insulin is a polypeptide hormone composed of 51 amino acids secreted by the beta cells of the pancreas. It stimulates the uptake of glucose by the cardiac muscle, skeletal muscle and the adipose tissue. It also stimulates glycogenesis, lipogenesis, and protein synthesis, while it inhibits lipolysis.
    C) TOXICOLOGY: In overdose, insulin can cause hypoglycemia; the onset and duration depend on the type and quantity of the injected preparation.
    D) EPIDEMIOLOGY: While hypoglycemia during therapeutic use is common, deliberate insulin overdose is rare.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Hypoglycemia is common during therapeutic use. Hypokalemia may occur from intracellular shifts of potassium. Lethargy, lassitude, yawning, and irritability may occur when the blood glucose level drops to about 50 mg/dL.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Insulin overdose produces hypoglycemia which may manifest as hunger, anxiety, fatigue, diaphoresis, nausea, palpitation, tachycardia, tremor and headache. As the brain becomes more deprived of glucose, blurred vision, inability to concentrate, weakness, altered behavior or coordination or somnolence may develop. Hypokalemia is a common finding in insulin overdose and hypomagnesemia and hypophosphatemia have been reported.
    2) SEVERE TOXICITY: Confusion, seizure and coma may develop. Focal neurological signs may also occur. Protracted, untreated hypoglycemia may cause permanent neurologic injury and death. Acute myocardial infarction and acute lung injury have been reported rarely after severe overdose. Cardiac dysrhythmias secondary to hypokalemia may occur when blood glucose levels drop below 40 mg/dL following an overdose.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTHERMIA has been reported following overdose (Bourgeois & Dufourg, 1967).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MYDRIASIS: Pupils may be nonreactive and dilated following overdose (Brvar et al, 2005; Lindgren, 1960; Nicholson, 1965).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) At blood levels below 40 mg/dL, increased adrenergic activity is predominant, manifested as tachycardia and palpitations following acute exposure.
    B) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypertension (BP 260/130) with cardiac dysrhythmias were initially observed in an adult found unconscious following a massive self administration of insulin estimated to be 1000 units (exact route and type of insulin remained unknown due to the patient's later denial of the event) (Cooper, 1994).
    C) ATRIAL FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) Atrial fibrillation has been reported in two insulin-dependent diabetics that experienced hypoglycemia during insulin therapy (Collier et al, 1987).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Cardiac dysrhythmias were reported in an adult following an attempted suicide with an estimated 1000 units of insulin (exact route and type of insulin remained uncertain due to the patient's later denial of the event) (Cooper, 1994).
    E) MYOCARDIAL INFARCTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 36-year-old woman without overt coronary risk factors presented comatose and tachycardic (170 BPM) nearly 9 hours after injecting 1500 units of insulin; blood glucose was 11 mg/dL. She was treated with intravenous dextrose. About 10 hours after ingestion she developed recurrent seizures and profound hypotension with ECG evidence of anterolateral myocardial infarction and elevated CK-MB ant troponin t. Subsequent coronary angiography was normal. It was suggested that temporary coronary arterial narrowing or coronary arterial vasospasm induced by severe hyperinsulinemia contributed to the pathogenesis of the myocardial infarction. She sustained permanent neurologic injury (Kamijo et al, 2000).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Diaphoresis and flushing occurred following overdose (Ragan et al, 1985).
    b) CASE REPORT: A 33-year-old woman intentionally injected herself with 300 units of insulin glargine and approximately 200 units of insulin in a suicide attempt. She developed hypoglycemia and experienced several episodes of diaphoresis and tremulousness (Tofade & Liles, 2004).
    B) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Cutaneous bullae, resembling "barbiturate burns", were reported on the site of application of a blood pressure cuff on a woman who overdosed on insulin and was found comatose (Raymond & Cohen, 1972).
    C) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Delayed type IV hypersensitivity, with redness and pruritus at injection sites, was reported in a patient with positive skin tests to bovine, porcine, and human semisynthetic insulin. The reaction peaked at around 24 hours and lasted 3 to 4 days (Wurzburger et al, 1987).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) INCREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) Muscle pain, cramping, spasm, and twitching may occur in skeletal muscles following acute exposure (Beardwood, 1934; Lindgren, 1960) Munch & Quaade, 1963).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) Profound hypoglycemia associated with coma and seizures may occur following overdose (Tsujimoto et al, 2006; Kamijo et al, 2000; Cooper, 1994; Abdollahi et al, 1998). Hypoglycemia may develop later than predicted from duration of action of various insulin preparations (Haskell & Stapczynski, 1983).
    b) Nondiabetic patients were found to be more likely to present with hypoglycemia and develop recurrent hypoglycemia despite oral intake and IV glucose infusion following intentional misuse (Haskell & Stapczynski, 1983; Abdollahi et al, 1998).
    c) CASE SERIES: Hypoglycemia lasted 12 to 96 hours in a series of 11 insulin overdoses in 8 patients (Arem & Zoghbi, 1985).
    d) CASE REPORTS
    1) A 39-year-old man with a history of poorly controlled diabetes mellitus, depression, asthma, obstructive sleep apnea, and morbid obesity developed hypoglycemia after intentionally injecting himself with 880 units of insulin lispro and 3800 units of insulin glargine subcutaneously over 10 different abdominal sites. He presented to the emergency department the day of the injections with a blood glucose (BG) level of 100 mg/dL. Paramedics recorded an initial BG level of 50 mg/dL and had administered 1 ampule of 50% dextrose. Upon examination his vital signs, neurologic status, and ECG were within normal limits. Laboratory analysis showed a plasma insulin level of 3712.6 microunits/mL (normal range 2.6 to 31.1 microunits/mL), hypokalemia, and slightly elevated liver enzymes. Treatment included continuous IV infusion of 10% dextrose at 100 mL/hr paired with hourly BG checks and an unrestricted diet. He was transferred to ICU where his BG levels remained low fluctuating between 50 and 80 mg/dL. Seven hours after initiating IV dextrose, the infusion was titrated up to 200 mL/hr. On day 3, after 58 hours of treatment, IV dextrose was changed to a 5% solution. On day 4, after 81 hours of infusion, the dextrose was discontinued. Additional dextrose was administered on 5 occasions during treatment when BG levels dropped below 70 mg/dL. At 108 hours after admission, his plasma insulin level was 30.4 microunits/mL. He stabilized 109 hours after presentation and was transferred to an inpatient psychiatric facility without complication (Mork et al, 2011).
    2) A 29-year-old man presented unconscious with severe hypoglycemia (plasma glucose: 26 mg/dL; normal range: 80 to 110 mg/dL) after the self-injection of 3600 units of insulin (1500 units of regular insulin, 600 units of neutral protamine Hagedorn (NPH) insulin, and 1500 units of 70/30 NPH/regular mixed insulin), subcutaneously. Laboratory results revealed hyperinsulinemia (934 microinternational units/mL; normal range: 2.6 to 24.9) and low C-peptide concentration (0.05 ng/mL; normal range: 0.9 to 4). He regained consciousness after receiving a dextrose infusion (20 g/hr) continuously for 48 hours. Despite dextrose infusion, he developed severe hypoglycemic attacks 14, 32, and 44 hours after presentation. On day 5, he developed severe elevated liver enzymes 15 to 20 times of normal range (aspartate aminotransferase: 0 to 40 International units(IU)/L; alanine aminotransferase: 0 to 43 IU/L). All other laboratory results, including bilirubin concentrations, prothrombin time, INR, and ultrasonographic evaluation of the liver were normal. On day 8, the patient recovered and was discharged to a psychiatric ward (Guclu et al, 2009).
    3) Hypoglycemia accompanied by coma, was reported in a 21-year-old woman 2.5 hours after intentionally injecting 26 units of insulin glargine (twice her standard dose of 13 units) into her leg in a suicide attempt. Despite continuous glucose administration, the patient continued to experience intermittent hypoglycemia 53 hours postexposure (Brvar et al, 2005).
    4) A 33-year-old woman intentionally injected herself with 300 units of insulin glargine and approximately 200 units of insulin in a suicide attempt. She developed hypoglycemia and experienced several episodes of diaphoresis and tremulousness. She self treated with oral carbohydrates for the first 15 hours, and required dextrose infusion for another 40 hours after the overdose (Tofade & Liles, 2004).
    5) A 22-year-old woman with type I diabetes intentionally injected 300 units of insulin glargine and 300 units insulin in a suicide attempt. She was found comatose approximately 4 hours post-injection with an unmeasurable blood glucose. At the hospital, hypoglycemic relapse continued for 30 hours after initial insulin overdose, and IV insulin infusion therapy could not be reintroduced until 59 hours after the insulin overdose. Subcutaneous insulin therapy was reintroduced 65 hours following the initial overdose (Fromont et al, 2007).
    6) A 25-year-old man with poorly controlled type 1 diabetes developed severe hypoglycemia after intentionally using high doses (300 units) of insulin aspart. Laboratory results revealed a venous blood glucose of 1.6 mmol/L (28 mg/dL) and a serum insulin level of 452.3 mU/L (fasting reference range 3 to 15 mU/L). It was determined that his continuous glucose monitoring (CGM) system failed to detect hypoglycemia accurately, reporting sensor glucose ranging between 5 to 6 mmol/L (90 to 108 mg/dL) with a mean absolute relative difference for the whole 7 days of CGM of 17.7% (52% for the first 9 hours post-insulin overdose) (El-Laboudi et al, 2015).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis related to human insulin use has been reported with insulin therapy (Wintermantel et al, 1988).
    B) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A systemic reaction, with wheezing and generalized urticaria was reported in a patient receiving human insulin (Gossain et al, 1985).

Reproductive

    3.20.1) SUMMARY
    A) Insulin aspart, recombinant, insulin detemir, insulin lispro recombinant, and insulin human regular are classified as FDA pregnancy category B. Inhaled insulin, insulin aspart, recombinant/insulin aspart protamine, recombinant and insulin glargine, recombinant are classified as FDA pregnancy category C. Insulin glargine use in pregnancy is associated with a greater incidence of fetal femoral length less than 50th percentile and large for gestational age compared with a control group. The incidence of fetal adverse effects is similar with insulin glargine and NPH insulin use during pregnancy.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) INHALED INSULIN
    a) In animal studies, no major malformations were observed in pregnant animals given subQ doses up to 14- to 21-fold the estimated human exposure level from gestation day 6 through 17 (organogenesis). Decreased epididymis and testes weights were observed when pregnant animals were administered subQ doses of 10, 30, and 100 mg/kg/day of carrier particles from gestation day 7 through lactation day 20 (weaning). In addition, impaired learning was observed in pups after pregnant animals were given subQ doses of 6 times human systemic exposure from gestation day 7 through lactation day 20 (weaning). Adverse maternal effects were observed in pregnant rabbits given subQ doses approximately equivalent to a human systemic exposure from gestation day 7 through 19 (organogenesis) (Prod Info AFREZZA(R) oral inhalation powder, 2014).
    2) INSULIN ASPART
    a) Visceral/skeletal abnormalities have been reported in animals administered up to approximately 32 times the human dose. Animals administered insulin aspart at approximately 8 times the human dose did not experience any significant fetal effects (Prod Info RYZODEG(R) 70/30 subcutaneous injection solution, 2015; Prod Info NovoLog(R) Mix 50/50 subcutaneous injection suspension, 2013; Prod Info NOVOLOG(R) MIX 70/30 subcutaneous injection, suspension, 2007).
    3) INSULIN ASPART/INSULIN DEGLUDEC
    a) In animal studies of insulin degludec/insulin aspart administered during organogenesis visceral/skeletal abnormalities occurred at approximately 8 times the human dose. This result was consistent with that of human insulin (Prod Info RYZODEG(R) 70/30 subcutaneous injection solution, 2015).
    4) INSULIN DEGLUDEC
    a) During animal studies, subQ administration of insulin degludec before mating and throughout pregnancy resulted in pre- and post-implantation loss and visceral/skeletal abnormalities at doses approximately 5 or 10 times the human exposure. These effects are likely due to maternal hypoglycemia (Prod Info RYZODEG(R) 70/30 subcutaneous injection solution, 2015; Prod Info TRESIBA(R) subcutaneous injection solution, 2015).
    5) INSULIN DETEMIR
    a) During animal studies, administration of insulin detemir at doses up to approximately 3 times the recommended human dose prior to mating, during mating, and throughout pregnancy resulted in litters with visceral anomalies. Animals administered insulin detemir at doses up to approximately 135 times the recommended human dose during organogenesis, resulted in an increased incidence of fetal gallbladder abnormalities including small, bilobed, bifurcated, and missing gallbladders (Prod Info LEVEMIR(R) subcutaneous injection solution, 2015).
    6) INSULIN GLARGINE, RECOMBINANT
    a) Effects did not differ from those observed with regular insulin following administration of insulin glargine in female animals prior to and during mating and throughout pregnancy at doses up to 7 times the recommended human dose. Fertility and embryonic development were not affected (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info LANTUS(R) subcutaneous injection solution, 2015).
    7) INSULIN GLULISINE
    a) Administration of insulin glulisine at subQ doses up to approximately half the average human dose caused skeletal defects in pups (Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2015).
    8) INSULIN LISPRO
    a) Fetal growth retardation including decreased fetal weight and an increased incidence of fetal runts resulted when female animals were administered subQ insulin lispro injections up to approximately 3 times the human dose 2 weeks prior to cohabitation through gestation day 19. Pregnant animals receiving insulin lispro doses of up to approximately 0.24 times the human dose on gestation days 7 through 19 did not result in any adverse effects on fetal viability, weight, or morphology at any dose (Prod Info Humalog(R) subcutaneous injection, intravenous injection, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) INSULIN GLARGINE, RECOMBINANT
    a) Use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info LANTUS(R) subcutaneous injection solution, 2015; Prod Info TOUJEO(R) subcutaneous injection, 2015).
    B) FETAL/NEONATAL ADVERSE EFFECTS
    1) INSULIN GLARGINE
    a) In a meta-analysis of 8 observational cohort studies (7 retrospective) of pregnant women with pregestational or gestational diabetes (n=702), no significant increased risk of adverse fetal and neonatal outcomes, including large size for gestational age, macrosomia, neonatal hypoglycemia, NICU admissions, shoulder dystocia, congenital anomalies, preterm delivery, perinatal mortality, hyperbilirubinemia, and respiratory distress, was found in patients treated with insulin glargine (n=331) compared with controls treated with NPH insulin (n=371). Relative risk (RR) rates within the insulin glargine group of infant birth weights higher than the 90th percentile (5 studies) and of birth weights over 4000 g (macrosomia in 3 studies) were RR of 1.02 (95% confidence interval (CI), 0.8 to 1.31) and RR of 1.28 (95% CI, 0.77 to 2.12), respectively. Relative risk rates of neonatal hypoglycemia (7 studies) and NICU admissions (6 studies) in the insulin glargine group were reported as RR of 0.94 (96% CI, 0.64 to 1.39) and RR of 0.89 (95% CI, 0.55 to 1.43), respectively. Relative risk rates in the insulin glargine group of shoulder dystocia (2 studies) and congenital anomalies (5 studies) were RR of 0.22 (95% CI, 0.04 to 1.29) and RR of 0.97 (95% CI, 0.47 to 1.99), respectively. Relative risk rates of preterm delivery (2 studies) and perinatal mortality (4 studies) in the insulin glargine group were RR of 0.75 (95% CI, 0.3 to 1.83) and RR of 0.97 (95% CI, 0.18 to 5.37), respectively. Lastly, relative risk rates of hyperbilirubinemia (6 studies) and respiratory distress (6 studies) were reported as RR of 0.95 (95% CI, 0.59 to 1.54) and RR of 1.53 (95% CI, 0.82 to 2.85), respectively. Heterogeneity in the analyses was only seen for mean difference in gestational age at birth (Pollex et al, 2011).
    b) In a retrospective review of insulin use during pregnancy, fetal and neonatal outcomes were similar in diabetic women receiving insulin glargine (n=27) or NPH insulin (n=25) in combination with a short-acting insulin analogue during pregnancy. Thirteen neonates in the insulin glargine group had first-trimester exposure. Overall, infants exposed to insulin glargine compared with NPH insulin had no significant differences in average birth weight (3294 +/- 189 g vs 3274 +/- 137 g), distribution of birth weights, umbilical artery cord gas values, nadir blood sugars (50.3 +/- 2.8 mg/dL vs 51.4 +/- 2.9 mg/dL), and neonatal ICU stay longer than 4 hours (7 vs 6). One infant exposed to insulin glargine had a 5-minute Apgar score less than 7 and 3 infants exposed to NPH insulin had a uterine artery pH less than 7.2 (Smith et al, 2009).
    c) A retrospective analysis of insulin use in pregnant diabetes patients showed an increased incidence of adverse neonatal effects with exposure to NPH insulin compared with insulin glargine. Of the patients studied, 52 received insulin glargine (pregestational, 37; gestational, 15) and 60 received NPH insulin (pregestational, 16; gestational, 44) in combination with a short-acting insulin regimen. Insulin glargine use in pregestational diabetic patients was associated with significantly fewer macrosomic infants (18.9% vs 50%; relative risk (RR), 0.38; 95% confidence interval (CI), 0.17 to 0.87; p=0.04), lower incidence of neonatal hyperbilirubinemia (8.3% vs 31.3%; RR, 0.27; 95% CI, 0.07 to 0.98; p=0.05), and significantly lower incidence of neonatal hypoglycemia (0% vs 25%; p=0.01) compared with NPH insulin use. There were no significant between-group differences in neonatal respiratory distress syndrome, neonatal ICU admission, or 1-minute or 5-minute Apgar scores among pregestational diabetes patients or in any neonatal adverse events among gestational diabetes patients (Fang et al, 2009).
    d) A retrospective analysis showed that pregnant diabetes patients who received insulin glargine (n=65) had similar rates of adverse neonatal effects compared with patients who received NPH insulin (n=49), both in combination with short-acting insulin. Neonates exposed to insulin glargine had no significant differences in respiratory distress syndrome (8% vs 10%), hypoglycemia (29% vs 25%), hyperbilirubinemia (44% vs 27%), patent ductus arteriosus (13% vs 13%), major anomalies (16% vs 15%), or neonatal intensive or intermediate care admission (97% vs 98%) compared with NPH insulin (Egerman et al, 2009).
    e) A retrospective analysis of insulin use during pregnancy in type 1 diabetes patients showed an increased incidence of fetal femoral length less than 50th percentile with exposure to insulin glargine or NPH insulin compared with no exposure. Of the diabetes patients studied, 15 received insulin glargine and 15 received NPH insulin in combination with a short-acting insulin regimen; 43 healthy women acted as a control group. Insulin glargine use was associated with a significantly higher frequency of fetal femoral length less than 50th percentile at the second trimester (26.7% vs 4.6%; p=0.033) and third trimester (26.7% vs 2.3%; p=0.013) compared with the control group, while no significantly increased incidence was noted with NPH use in the second or third trimesters compared with control. The prevalence of large for gestational age (weight greater than 90th percentile) was significantly greater in the glargine (46.7% vs 4.6%; p less than 0.001) and NPH (26.7% vs 4.6%; p=0.033) groups compared with the control group. There were no significant differences in head circumference, abdominal circumference, interventricular septal thickness, respiratory distress syndrome, 1-minute or 5-minute Apgar scores, or neonatal hypoglycemia, respiratory adaptation, hypocalcemia, or jaundice between the 2 treatment groups (Imbergamo et al, 2008).
    f) Postpregnancy insulin therapy with insulin glargine or NPH insulin resulted in similar rates of fetal adverse events, according to a retrospective review of 107 women with type 1 diabetes treated in 27 Italian centers. All women were receiving insulin glargine at the time pregnancy was identified, but 57.4% were switched to NPH insulin in the first trimester and 42.6% remained on insulin glargine throughout pregnancy. Of all deliveries, there were no significant differences in congenital malformations (4.7% vs 5.2%), neonatal ICU admissions (25.7% vs 21.5%), neonatal hypoglycemia (14.6% vs 17.2%), or hyperbilirubinemia (19.5% vs 22.2%) in infants exposed to insulin glargine compared with NPH insulin (Di Cianni et al, 2008).
    C) INSULIN DEGLUDEC
    1) Use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info TRESIBA(R) subcutaneous injection solution, 2015).
    D) INSULIN DETEMIR
    1) During a randomized, controlled clinical trial of pregnant women with type 1 diabetes, there was no increased risk of fetal abnormalities. In an open-label clinical study of women with type 1 diabetes who were between 8 and 12 weeks gestation or planning to become pregnant, no differences in pregnancy outcomes and fetal or neonate health were observed between patients receiving insulin detemir (n=152) once or twice daily and patients receiving NPH insulin (n=158) once or twice or thrice daily. Six serious adverse effects in 4 mothers with placental disorders (placenta previa, placenta previa hemorrhage, premature separation of placenta) and 1 serious antepartum hemorrhage were observed in the NPH insulin group, but none of these adverse effects were reported in the insulin detemir group. Early fetal deaths (abortions), also reported as abortion spontaneous, abortion missed, blighted ovum, cervical incompetence, and abortion incomplete, were reported in 6.6% of insulin detemir-treated patients and 5.1% of NPH-treated patients. Pre-eclampsia developed in 10.5% (16 cases) and 7% (11 cases) of patients in insulin detemir and NPH insulin groups, respectively. Hospitalization was required in 8 patients in insulin detemir group and 1 patient in the NPH insulin group. These cases were within the expected rates for pregnancy complicated by diabetes and causal relationship could not be established. All 9 patients delivered healthy infants (Prod Info LEVEMIR(R) subcutaneous injection solution, 2015).
    2) In a study of 16 pregnant women with either gestational diabetes mellitus (n=11) or type 2 diabetes (n=5) who received insulin detemir (dose range, 10 to 96 units; mean, 57.5 units), maternal insulin detemir levels were in the expected range for adults; however, insulin detemir was undetectable in fetal circulation, indicating that the drug does not cross the placenta in humans. The mean maternal plasma concentration of insulin detemir at delivery was 1015 picomoles (pmol)/L (range, 159 to 3804 pmol/L). None of the umbilical cord plasma samples had detectable levels of insulin detemir. The mean maternal endogenous insulin level was 101.6 pmol/L (range, 10.8 to 184.8 pmol/L) and mean umbilical concentration was 178 pmol/L (range, 8 to 789 pmol/L). None of the 16 infants born to the women studied had neonatal hypoglycemia (Suffecool et al, 2015).
    E) INSULIN GLULISINE
    1) Administration of insulin glulisine in animals at subQ doses up to half the average human dose caused death (Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2015).
    F) PREGNANCY CATEGORY
    1) The manufacturers have classified insulin aspart, recombinant, insulin detemir, insulin lispro recombinant and human insulin regular: pregnancy category B (Prod Info NOVOLOG(R) subcutaneous injection, 2008; Prod Info LEVEMIR(R) subcutaneous injection solution, 2015; Prod Info Humalog(R) subcutaneous injection, intravenous injection, 2015; Prod Info HUMULIN(R) R U-500 solution for subcutaneous injection, 2011).
    2) Insulin aspart, recombinant/insulin aspart protamine, recombinant, insulin aspart, recombinant/insulin degludec, insulin degludec, and insulin glulisine: pregnancy category C (Prod Info RYZODEG(R) 70/30 subcutaneous injection solution, 2015; Prod Info TRESIBA(R) subcutaneous injection solution, 2015; Prod Info AFREZZA(R) oral inhalation powder, 2014; Prod Info NovoLog(R) Mix 50/50 subcutaneous injection suspension, 2013; Prod Info NOVOLOG(R) MIX 70/30 subcutaneous injection, suspension, 2007; Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2015).
    3) Inhaled insulin: pregnancy category C (Prod Info AFREZZA(R) oral inhalation powder, 2014).
    4) Insulin is useful during pregnancy for both pregestational (IDDM and NIDDM) and gestational forms of diabetes because of the need for precise control of maternal glucose levels and the limited information regarding fetal effects of some of the oral hypoglycemics (Buchanan & Coustan, 1995; Cunningham et al, 1993). The congenital risk of insulin aspart (recombinant) on human fetuses has not been well studied. Careful monitoring of glucose control is necessary in pregnant women using insulin, as the background risk for adverse fetal outcomes is increased in pregnancies complicated by hyperglycemia and insulin requirements may be variable throughout the pregnancy. Insulin aspart (recombinant) is rapidly absorbed after subcutaneous injection, and has a shorter duration of action when compared to regular human insulin (Prod Info NOVOLOG(R) subcutaneous injection, 2008), which may be useful for maintaining glycemic control in the pregnant patient. As adequate and well-controlled studies have not been conducted, insulin aspart/insulin aspart protamine combination use during pregnancy is recommended only if the potential benefit justifies the potential risk to the fetus (Prod Info NOVOLOG(R) MIX 70/30 subcutaneous injection, suspension, 2007).
    5) Insulin glargine should only be used during pregnancy if the potential benefit outweighs the fetal risk (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info TOUJEO(R) subcutaneous injection, 2015). As insulin glargine has up to 24-hour duration of action, frequent and close monitoring of blood glucose level is essential (Prod Info LANTUS(R) subcutaneous injection solution, 2015a)
    G) ANIMAL STUDIES
    1) INHALED INSULIN
    a) In animal studies, increased pre- and post-implantation loss was observed in pregnant animals given a subQ dose of 100 mg/kg/day of carrier particles (vehicle without insulin) beginning 2 weeks prior to mating until gestation day 7. No major malformations were observed in pregnant animals given subQ doses up to 21-fold the estimated human exposure level from gestation day 6 through 17 (organogenesis). Decreased epididymis and testes weights were observed when pregnant animals were administered subQ doses of 10, 30, and 100 mg/kg/day of carrier particles from gestation day 7 through lactation day 20 (weaning). In addition, impaired learning was observed in pups after pregnant animals were given subQ doses of 6 times human systemic exposure from gestation day 7 through lactation day 20 (weaning). Adverse maternal effects were observed in pregnant animals given subQ doses approximately equivalent to a human systemic exposure from gestation day 7 through 19 (organogenesis) (Prod Info AFREZZA(R) oral inhalation powder, 2014).
    2) INSULIN ASPART
    a) Pre and postimplantation losses have been reported in animals administered insulin aspart at up to approximately 32 times the human dose. Animals administered insulin aspart up to 50 units/kg/day did not experience any significant fetal effects (Prod Info NovoLog(R) Mix 50/50 subcutaneous injection suspension, 2013; Prod Info NOVOLOG(R) MIX 70/30 subcutaneous injection, suspension, 2007).
    3) INSULIN DEGLUDEC
    a) During animal studies, subQ administration of insulin degludec before mating and throughout pregnancy resulted in pre and postimplantation loss and visceral/skeletal abnormalities at doses approximately 5 or 10 times the human exposure. These effects are likely due to maternal hypoglycemia (Prod Info TRESIBA(R) subcutaneous injection solution, 2015).
    4) INSULIN GLARGINE, RECOMBINANT
    a) Effects did not differ from those observed with regular insulin following administration of insulin glargine in female animals prior to and during mating and throughout pregnancy at doses up to 7 times the recommended human dose. Fertility and embryonic development were not affected (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info LANTUS(R) subcutaneous injection solution, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Insulin produced by the human body is known to be present in human breast milk, while exogenous insulin is degraded in the gastrointestinal tract. There have been no adverse reactions seen in infants exposed to insulin during lactation. In a human lactation study, enteral administration of human insulin did not result in hypoglycemia in 8 preterm infants between 26 and 30 weeks gestation (Prod Info HUMULIN(R) R U-500 solution for subcutaneous injection, 2011).
    2) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info AFREZZA(R) oral inhalation powder, 2014; Prod Info LEVEMIR(R) subcutaneous injection solution, 2012; Prod Info NovoLog(R) Mix 50/50 subcutaneous injection suspension, 2013; Prod Info NOVOLOG(R) MIX 70/30 subcutaneous injection, suspension, 2007; Prod Info Humalog(R) subcutaneous injection, intravenous injection, 2015). Breastfeeding infants of women who use insulin should be carefully monitored. Breastfeeding mothers should also monitor their blood sugar and discuss any necessary insulin adjustments with their medical practitioner.
    B) BREAST MILK
    1) It is not known if insulin degludec, insulin glargine or insulin glulisine is excreted in any significant amounts into human breast milk. Caution is advised when insulin glargine or insulin glulisine is administered to a nursing woman (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info LANTUS(R) subcutaneous injection solution, 2015; Prod Info TRESIBA(R) subcutaneous injection solution, 2015; Prod Info TOUJEO(R) subcutaneous injection, 2015). Treatment with these drugs is compatible with breastfeeding; however, insulin dose adjustments may be necessary in nursing women with diabetes (Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info TOUJEO(R) subcutaneous injection, 2015).
    C) ANIMAL STUDIES
    1) INHALED INSULIN
    a) It is unknown whether inhaled insulin is excreted into human milk. Animal studies have indicated that the carrier is excreted in breast milk at approximately 10% of maternal exposure levels. Because inhaled insulin has not been studied in lactating women, patients may want to cease breastfeeding or suspend using this drug while nursing (Prod Info AFREZZA(R) oral inhalation powder, 2014).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) INHALED INSULIN
    a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent in humans (Prod Info AFREZZA(R) oral inhalation powder, 2014).
    B) ANIMAL STUDIES
    1) INHALED INSULIN
    a) No adverse effects on fertility were observed in male animals given 14- to 21-fold the estimated human exposure, based on AUC. Increased pre and postimplantation loss was observed in pregnant animals given a subQ dose of 100 mg/kg/day of carrier particles (vehicle without insulin) beginning 2 weeks prior to mating until gestation day 7. No adverse effects were observed at a dose of 14- to 21-fold the estimated human exposure, based on AUC ) (Prod Info AFREZZA(R) oral inhalation powder, 2014).
    2) INSULIN DEGLUDEC
    a) In fertility and embryofetal studies, treatment with insulin degludec at doses approximately 5 times the human exposure had no effects on mating performance or fertility in male and female animals (Prod Info TRESIBA(R) subcutaneous injection solution, 2015).
    3) INSULIN GLARGINE, RECOMBINANT
    a) SubQ administration of recombinant insulin glargine in male and female animals at doses approximately 7 times the recommended human dose resulted in a reduction in rearing rate (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info LANTUS(R) subcutaneous injection solution, 2015).
    4) SUBQ INSULIN
    a) In animal studies, no effects on fertility were observed in animals administered about 32 times the human subQ dose of Novolog(R) Mix 50/50, about 10 times the recommended human subQ dose of Toujeo(R), about 2 times the average human dose of Apidra(R), about 3 times the human dose of insulin lispro, and about 3 times the human dose of insulin detemir (Prod Info TOUJEO(R) subcutaneous injection, 2015; Prod Info NovoLog(R) Mix 50/50 subcutaneous injection suspension, 2013; Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2015; Prod Info Humalog(R) subcutaneous injection, intravenous injection, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Hyperventilation may occur at blood glucose levels under 40 mg/dL. Apnea has been reported following a large overdose (Lindgren, 1960).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema has been reported following a suicide attempt (Vogl & Youngwirth, 1949). ARDS was described in 2 cases of insulin overdose (Arem & Zoghbi, 1985).
    b) CASE REPORT: A 16-year-old girl with type I diabetes developed severe, prolonged hypoglycemia, acute lung injury, and cerebral edema following a suicide attempt with insulin (initial blood glucose was 17 mg/dL, and she required infusion of 50% dextrose because of recurrent hypoglycemia). Chest x-ray showed bilateral infiltrates and a normal heart silhouette, and she was severely hypoxic on presentation (PaO2 47.2 mmHg; PaCO2 37 mmHg; pH 7.439; HCO3 24.1 mEq/L on 8 L/min oxygen by mask). Laboratory evaluation revealed stimulation of the sympathetic nervous system and pituitary-adreno-cortical axis. Two days after admission her brain stem reflexes were absent and her EEG was flat due to worsening cerebral edema. Approximately 4 months later, she died from complications related to infection and electrolyte imbalance (Uchida et al, 2004).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum or capillary glucose should be measured immediately then hourly, and when symptoms develop. Plasma glucose levels of 30 mg/dL or lower are common following large overdosage.
    B) Blood electrolytes should be checked, in particular, potassium, magnesium and phosphorus following a large overdose.
    C) An ECG should be obtained after a large overdose.
    D) Serum insulin concentrations can be used to confirm the overdose.
    4.1.2) SERUM/BLOOD
    A) Monitor blood glucose levels immediately on arrival then hourly, and when symptoms develop. Monitor for clinical manifestations of hypoglycemia (ie, mental status changes, tachycardia, diaphoresis). Rapid decreases in serum glucose may cause signs and symptoms even in the absence of numeric hypoglycemia.
    B) Monitor serum electrolytes in symptomatic patients. Hypokalemia, hypophosphatemia, and hypomagnesemia have been reported with excess insulin administration.
    C) Proinsulin levels, c-peptide and insulin levels and blood or urine sulfonylurea levels obtained while the patient is hypoglycemic can help distinguish patients with surreptitious sulfonylurea or insulin use from those with insulinoma or decreased glucose production (Bosse, 2002).
    1) CASE REPORT: In one case report, a significant insulin overdose was managed by frequent blood glucose monitoring and daily plasma insulin concentrations. A 39-year-old man with a history of poorly controlled diabetes mellitus and morbid obesity intentionally injected himself with 880 units of insulin lispro and 3800 units of insulin glargine subcutaneously over 10 different abdominal sites. His plasma insulin level at presentation on the day of the injections was 3712.6 microunits/mL (normal range 2.6 to 31.1 microunits/mL). With continuous IV dextrose infusions, his plasma insulin level 10 hours after presentation was 1582.1 microunits/mL, at 34 hours it was 724.8 microunits/mL, and by 108 hours after presentation it was 30.4 microunits/mL. He recovered without long-term complications (Mork et al, 2011).
    D) SULFONYLUREA INGESTION: High plasma insulin and c-peptide, proinsulin present and sulfonylureas may be detected in blood or urine.
    1) EXOGENOUS INSULIN USE: High plasma insulin, low c-peptide and absent proinsulin.
    2) INSULINOMA: High plasma insulin and c-peptide, proinsulin present and sulfonylureas not present in blood or urine
    3) DECREASED GLUCOSE PRODUCTION: Low plasma insulin and c-peptide, proinsulin present.
    4.1.3) URINE
    A) Urinary glucose and acetone determination are also diagnostic for diabetic ketoacidosis.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) An ECG should be obtained after a large overdose.

Methods

    A) OTHER
    1) Immediate differentiation between hypoglycemia and ketoacidosis is accomplished by the use of a bedside blood glucose testing strip or Ketostix(R) (plasma ketones).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with intentional insulin overdose or recurrent hypoglycemia should be admitted to the ICU for close blood glucose monitoring and dextrose therapy.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) An asymptomatic adult with an inadvertent overdose of a short-acting insulin can be managed at home with telephone follow-up, if the patient has the ability to monitor his blood glucose at home, can tolerate oral intake, and if another responsible adult is present to monitor for signs of hypoglycemia.
    1) In a retrospective chart review of a single poison center's cases of insulin exposure during an 11-year period, 652 cases were identified. Twenty types of insulin formulations were involved and 579 (88.9%) cases used a rapid onset/short duration type (eg, regular insulin). The majority of calls were from the caller's home (89%; n=580); 10.7% (n=70) came from a healthcare facility, and 0.3% (n=2) from Emergency Medical Services (EMS). Fifty-six (8.6%) patients developed symptoms. Forty (6.1%) of 229 patients (35.1%) who were referred to a healthcare facility, were admitted. Hypoglycemia developed in only 18 (45%) of these admitted patients. Most patients (n=397; 60.9%) were managed at home. Overall, it was determined that the development of hypoglycemia (odds ratio [OR] 5.94; p less than 0.001) and dose of insulin accidentally administered (OR 1.04; p less than 0.001) predicted poison center referral to a healthcare facility. However, the type and dose of insulin did not predict the development of symptoms (Glogan et al, 2013).
    2) In an observational case series of unintentional insulin overdose cases, managed by 3 poison centers during a 22-month period, 642 cases were identified. Most patients (77.3%) were managed on site and only 17.4% of patients were treated in an emergency department. Hypoglycemia (blood sugar less than 60 mg/dL) developed in 15.9% of patients; numerical hypoglycemia was observed in 6.9% of cases. Most patients (64.3%) used short-acting insulin with a median insulin dose of 40 Units. A dose error of 80 or more units was observed in 13.8% of cases. Overall, 74.1% of patients had no effects. Moderate and minor effects were observed in 8.4% and 7.3% of patients, respectively. Major effects were not observed in any patients. There was no difference in the frequency of hypoglycemia (clinical or numerical) between short and non-short duration insulin cases (15.7% vs 16.9%, n=65 vs 37, p=0.91), cases receiving more than 50 Units of insulin (14.9% vs 16.7%, n=29 vs 73, p=0.64), and between those managed on site and other management locations (14.4% vs 21.4%, n=71 vs 31, p=0.053). It was concluded that unintentional insulin overdoses can routinely be managed at home by poison centers and have a low rate of hypoglycemia and adverse outcomes (Beuhler et al, 2013).
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) The patient with an inadvertent overdose of a short acting preparation (typically a much smaller amount of insulin is administered) can be observed in the Emergency Department and discharged if hypoglycemia resolves after feeding and a few hours of observation. Patients with recurrent hypoglycemia or long acting insulin exposure require inpatient admission for at least 24 hours.

Monitoring

    A) Serum or capillary glucose should be measured immediately then hourly, and when symptoms develop. Plasma glucose levels of 30 mg/dL or lower are common following large overdosage.
    B) Blood electrolytes should be checked, in particular, potassium, magnesium and phosphorus following a large overdose.
    C) An ECG should be obtained after a large overdose.
    D) Serum insulin concentrations can be used to confirm the overdose.

Abstracts

Case Reports

    A) ADULT
    1) ACUTE EFFECTS
    a) FATALITIES: Curry reported 3 diabetic patients who injected themselves with massive doses of insulin and subsequently went into coma and died. A fourth patient who had received 80 units of insulin for 4 consecutive days recovered with IV and PO glucose therapy.
    b) HYPOGLYCEMIC COMA: Raymond & Cohen (1972) reported that a 44-year-old woman administered up to 800 units of insulin in an apparent suicide attempt. Blood sugar was 35 mg/dL and cutaneous bullae developed at sites of pressure secondary to hypoglycemic coma.
    c) CASE REPORT: A 33-year-old man self-administered the contents of 7 bottles of insulin over 48 hours in a suicide attempt. A finger stick blood sugar level was 30 mg/dL, blood pressure was 202/104 mmHg, and serum potassium was 3.5 mEq/L. The patient was somewhat anxious, but did not lose consciousness or suffer apparent long-term effects. Intravenous potassium replacement was required in the first 24 hours, and 2809 g of IV dextrose was administered over 110 hours (Roberge et al, 1993).
    2) ADVERSE EFFECTS
    a) Smith et al (1979) reported elevated early morning urine cortisol/creatinine ratios in 17 of 62 adult insulin-treated outpatients.
    1) Although symptoms of nocturnal hypoglycemia were generally absent, 2 patients described headache on waking and 1 had restlessness and sweating noted by his wife.
    2) Improvements in fasting blood glucose and glycosuria, and return of the cortisol/creatinine ratio to normal followed reduction in insulin dose. Chronic insulin over-treatment may be detected in asymptomatic patients by use of the urine cortisol-creatinine ratio.

Range Of Toxicity

Summary

    A) TOXICITY: There is substantial intraindividual response to insulin. In general, therapeutic doses of insulin will cause hypoglycemia in a nondiabetic patient, while a patient with insulin resistance may not get hypoglycemic even with a modest overdoses. If prolonged hypoglycemia is avoided by early appropriate treatment, patients should recover with normal neurologic function despite large overdoses.
    B) Permanent brain damage has been reported following injections of 800 and 3200 units of insulin in diabetic patients. Recovery has occurred following up to 880 units of insulin lispro (short acting) with 3800 units of insulin glargine in an adult with diabetes mellitus.

Therapeutic Dose

    7.2.1) ADULT
    A) INSULIN ASPART
    1) IV: 0.05 to 1 unit/mL (Prod Info NovoLog(R) subcutaneous injection solution, 2013).
    2) SUBQ: 0.5 to 1 unit/kg/day 5 to 10 minutes prior to a meal (Prod Info NovoLog(R) subcutaneous injection solution, 2013).
    B) INSULIN ASPART, RECOMBINANT/INSULIN DEGLUDEC
    1) INSULIN-NAIVE: Initial dose, one-third to one-half the total daily insulin dose (general rule for total daily dose, 0.2 to 0.4 units/kg) subQ. The remainder of total daily dose should be given as a short- or rapid-acting insulin divided between each daily meal (Prod Info RYZODEG(R) 70/30 subcutaneous injection solution, 2015).
    2) SWITCHING FROM ONCE OR TWICE DAILY PREMIX OR SELF-MIX INSULIN ALONE OR AS PART OF MULTIPLE DAILY INJECTION REGIMEN: Initiate with same unit dose and injection schedule as the premix or self-mix insulin. Continue the short-or rapid-acting insulin at the same dose for meals not covered by insulin degludec/insulin aspart (Prod Info RYZODEG(R) 70/30 subcutaneous injection solution, 2015).
    3) SWITCHING FROM A MULTIPLE DAILY INJECTIONS REGIMEN THAT INCLUDES A BASAL AND SHORT- OR RAPID-ACTING INSULIN AT MEALTIMES: Initiate once daily subQ with the main meal at the same unit dose as the basal insulin. Continue the short- or rapid-acting insulin at the same dose for meals not covered by insulin degludec/insulin aspart (Prod Info RYZODEG(R) 70/30 subcutaneous injection solution, 2015).
    C) INSULIN DEGLUDEC
    1) TREATMENT NAIVE AND TYPE 1 DIABETES: Approximately one-third to one-half of the total daily insulin dose. Administer the remainder of the total daily insulin dose as a short-acting insulin divided between daily meals (Prod Info TRESIBA(R) subcutaneous injection solution, 2015)
    2) TREATMENT NAIVE AND TYPE 2 DIABETES: 10 units once daily (Prod Info TRESIBA(R) subcutaneous injection solution, 2015)
    3) TREATMENT EXPERIENCED: Start with the same unit dose as the total daily long or intermediate-acting insulin unit dose (Prod Info TRESIBA(R) subcutaneous injection solution, 2015).
    D) INSULIN DETEMIR
    1) SUBQ: Initial dose: 10 units (or 0.1 to 0.2 units/kg) once daily for patients with type 2 diabetes or one-third of the total daily insulin requirements for patients with type 1 diabetes. Subsequent doses: adjust based on blood glucose measurements (Prod Info LEVEMIR(R) subcutaneous injection, 2012).
    E) INSULIN GLARGINE
    1) Basaglar(R), Lantus(R) and Toujeo(R) have different concentrations. Insulin glargine (Toujeo(R)) is provided as 300 units per mL; insulin glargine (Basaglar(R) and Lantus(R)) are provided as 100 units per mL (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info TOUJEO(R) subcutaneous injection, 2015; Prod Info LANTUS(R) subcutaneous injection solution, 2013).
    2) BASAGLAR(R)
    a) Type-1 diabetes: Approximately one-third of total daily insulin requirement administered subQ once daily at the same time every day. Use in combination with short- or rapid-acting premeal insulin (Prod Info BASAGLAR(R) subcutaneous injection, 2016)
    b) Type-2 diabetes: 0.2 units/kg or up to 10 units subQ once daily at the same time every day (Prod Info BASAGLAR(R) subcutaneous injection, 2016)
    c) Titration: Adjust dose according to blood glucose measurements, glycemic goal, and individual's metabolic needs (Prod Info BASAGLAR(R) subcutaneous injection, 2016)
    3) LANTUS(R)
    a) SUBQ: Initial dose, 10 units (or 0.2 units/kg) once daily or one-third of the total daily insulin requirements; subsequent doses, adjust based on blood glucose measurements (Prod Info LANTUS(R) subcutaneous injection solution, 2013).
    4) TOUJEO(R)
    a) TYPE 1 DIABETES: About 0.2 to 0.4 units/kg subQ once daily; adjusted according to blood glucose levels (Prod Info TOUJEO(R) subcutaneous injection, 2015)
    b) TYPE 2 DIABETES: About 0.2 units/kg subQ once daily; adjusted according to blood glucose levels (Prod Info TOUJEO(R) subcutaneous injection, 2015)
    F) INSULIN GLULISINE
    1) IV: 0.05 to 1 unit/mL (Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2014).
    2) SUBQ: 0.5 to 1 unit/kg/day approximately 15 minutes prior to a meal or 20 minutes after initiation of a meal (Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2014).
    G) INSULIN HUMAN
    1) INJECTION
    a) SUBQ: 0.5 to 1 unit/kg/day before meals (Prod Info Humulin(R) R subcutaneous injection, intravenous injection, 2013).
    2) INHALATION POWDER
    a) AFREZZA
    1) INSULIN-NAIVE, 4 units via oral inhalation at the beginning of each meal; adjust dose as clinically indicated (Prod Info AFREZZA(R) oral inhalation powder, 2014)
    2) TRANSITION FROM SUBQ MEALTIME INSULIN, round current mealtime insulin dose up to the nearest increment of 4 units and administer via oral inhalation at the beginning of each meal; adjust dose as clinically indicated (Prod Info AFREZZA(R) oral inhalation powder, 2014)
    3) TRANSITION FROM SUBQ PREMIXED INSULIN, divide total daily dose of premixed insulin in half; administer half as a basal insulin dose; divide other half between the 3 daily meals, round up to the nearest increment of 4 units, and administer via oral inhalation at the beginning of each meal; adjust dose as clinically indicated (Prod Info AFREZZA(R) oral inhalation powder, 2014)
    b) EXUBERA
    1) Typical dose is 1 mg/meal to 6 mg/meal, depending on body weight and blood glucose measurements (Prod Info EXUBERA(R) inhalation powder, 2008).
    H) INSULIN LISPRO
    1) INTRAVENOUS ROUTE
    a) Usual dose: Insulin lispro U-100 may be infused IV at a concentration of 0.1 to 1 unit/mL in NS-containing infusion systems (Prod Info HUMALOG(R) subcutaneous, intravenous injection, 2015).
    2) CONTINUOUS SUBQ INFUSION VIA INSULIN PUMP (U-100 ONLY)
    a) Individualize dose based on route of administration, metabolic requirements of patient, blood glucose monitoring results, and glycemic control goals (Prod Info HUMALOG(R) subcutaneous, intravenous injection, 2015).
    b) Administer using U-100 only, unmixed and undiluted, via continuous subQ infusion into subQ tissue (Prod Info HUMALOG(R) subcutaneous, intravenous injection, 2015).
    3) SUBQ INJECTION (U-100 OR U-200)
    a) Individualize dose based on route of administration, metabolic requirements of patient, blood glucose monitoring results, and glycemic control goals (Prod Info HUMALOG(R) subcutaneous, intravenous injection, 2015).
    b) Administer subQ injection within 15 minutes before a meal or immediately after a meal (Prod Info HUMALOG(R) subcutaneous, intravenous injection, 2015).
    I) INSULIN LISPRO/PROTAMINE
    1) SUBQ: 0.3 units/kg (Prod Info HUMALOG(R) Mix50/50(TM) subcutaneous injection suspension, 2013; Prod Info HUMALOG(R) Mix75/25(TM) subcutaneous injection suspension, 2013).
    7.2.2) PEDIATRIC
    A) INSULIN ASPART
    1) SUBQ: 2 years of age and older: 0.5 to 1 unit/kg/day 5 to 10 minutes prior to a meal (Prod Info NovoLog(R) subcutaneous injection solution, 2013)
    2) Safety and efficacy of insulin aspart in pediatric patients below the age of 2 years have not been established (Prod Info NovoLog(R) subcutaneous injection solution, 2013).
    B) INSULIN ASPART, RECOMBINANT/INSULIN DEGLUDEC
    1) Safety and efficacy have not been established in pediatric patients (Prod Info RYZODEG(R) 70/30 subcutaneous injection solution, 2015).
    C) INSULIN DEGLUDEC
    1) Safety and efficacy have not been established (Prod Info TRESIBA(R) subcutaneous injection solution, 2015)
    D) INSULIN DETEMIR
    1) SUBQ: 2 TO 17 YEARS OF AGE: Initial dose: One-third of the total daily insulin requirements. Subsequent doses: adjust based on blood glucose measurements (Prod Info LEVEMIR(R) subcutaneous injection, 2012).
    2) Safety and efficacy of insulin detemir in pediatric patients below the age of 2 years or those with type 2 diabetes have not been established (Prod Info LEVEMIR(R) subcutaneous injection, 2012).
    E) INSULIN GLARGINE
    1) BASAGLAR(R)
    a) 6 YEARS AND OLDER: Approximately one-third of total daily insulin requirement administered subQ once daily at the same time every day. Use in combination with short- or rapid-acting premeal insulin (Prod Info BASAGLAR(R) subcutaneous injection, 2016)
    b) UNDER 6 YEARS OF AGE: Safety and efficacy have not been established (Prod Info BASAGLAR(R) subcutaneous injection, 2016).
    c) Titration: Adjust dose according to blood glucose measurements, glycemic goal, and individual's metabolic needs (Prod Info BASAGLAR(R) subcutaneous injection, 2016)
    2) LANTUS(R)
    a) 6 TO 15 YEARS: Initial dose, one-third of the total daily insulin requirements; subsequent doses, adjust based on blood glucose measurements (Prod Info LANTUS(R) subcutaneous injection solution, 2013).
    b) 6 YEARS AND UNDER: Safety and efficacy have not been established (Prod Info LANTUS(R) subcutaneous injection solution, 2013).
    3) TOUJEO(R)
    a) Safety and efficacy in pediatric patients have not been established (Prod Info TOUJEO(R) subcutaneous injection, 2015).
    F) INSULIN GLULISINE
    1) SUBQ: 4 years of age and older: 0.5 to 1 unit/kg/day approximately 15 minutes prior to a meal or 20 minutes after initiation of a meal (Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2014)
    2) Safety and efficacy of insulin glulisine in pediatric patients below the age of 4 years or those with type 2 diabetes have not been established (Prod Info APIDRA(R) subcutaneous injection solution, intravenous injection solution, 2014).
    G) INSULIN HUMAN
    1) INJECTION
    a) SUBQ: Prepubertal children: 0.7 to 1 unit/kg/day (Prod Info Humulin(R) R subcutaneous injection, intravenous injection, 2013)
    2) INHALATION POWDER
    a) Safety and efficacy of insulin human inhalation powder have not been established in pediatric patients (Prod Info AFREZZA(R) oral inhalation powder, 2014; Prod Info EXUBERA(R) inhalation powder, 2008).
    H) INSULIN LISPRO
    1) Safety and efficacy of insulin lispro in pediatric patients below the age of 3 years or those with type 2 diabetes have not been established (Prod Info HUMALOG(R) subcutaneous injection, intravenous injection, 2013).
    2) CONTINUOUS SUBQ INFUSION VIA INSULIN PUMP (U-100 ONLY)
    a) Individualize dose based on route of administration, metabolic requirements of patient, blood glucose monitoring results, and glycemic control goals (Prod Info HUMALOG(R) subcutaneous, intravenous injection, 2015).
    b) Administer using U-100 only, unmixed and undiluted, via continuous subQ infusion into subQ tissue (Prod Info HUMALOG(R) subcutaneous, intravenous injection, 2015).
    3) SUBQ INJECTION (U-100 OR U-200)
    a) Individualize dose based on route of administration, metabolic requirements of patient, blood glucose monitoring results, and glycemic control goals (Prod Info HUMALOG(R) subcutaneous, intravenous injection, 2015).
    b) Administer subQ injection within 15 minutes before a meal or immediately after a meal (Prod Info HUMALOG(R) subcutaneous, intravenous injection, 2015).
    I) INSULIN LISPRO PROTAMINE
    1) Safety and efficacy of insulin lispro protamine have not been established in pediatric patients (Prod Info HUMALOG(R) Mix50/50(TM) subcutaneous injection suspension, 2013).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) Myocardial infarction resulting in death was reported in a 77-year-old man following 20 units of insulin used for the Hollander test (a measure of gastric acid response to hypoglycemia) (Read & Doherty, 1970).
    2) Death has been reported in a 43-year-old man who injected 400 units of NPH insulin and ingested 10 g of aprobarbital (Munck & Quaade, 1963). Death also occurred in a 32-year-old man who intentionally injected himself with 980 units of NPH insulin (Sturner & Putnam, 1972).

Maximum Tolerated Exposure

    A) SUMMARY
    1) THERAPEUTIC USE: Hypoglycemia can occur with therapeutic doses of insulin in diabetics due to the following: lack of dietary control, too much exercise, or in patients with brittle diabetes. Alcohol in combination with insulin is a common cause of hypoglycemia.
    2) NONDIABETIC: Insulin will cause hypoglycemia in virtually all nondiabetic patients and may produce severe cardiovascular effects in patients with preexisting cardiac disease.
    3) CHANGING INSULIN TYPES
    a) Severe hypoglycemic reactions can occur in patients switched from bovine to porcine insulin in the same doses.
    b) The decrease in proinsulin levels in the new insulin preparations (improved single peak and single component) may necessitate reiteration of some patients when they are switched from older insulin preparations (de Mowbray et al, 1966).
    4) INSULIN OVERDOSE
    a) DIABETIC: A 39-year-old man with a history of poorly controlled diabetes mellitus, depression, asthma, obstructive sleep apnea, and morbid obesity survived after intentionally injecting himself with 880 units of insulin lispro and 3800 units of insulin glargine subcutaneously over 10 different abdominal sites. After 4 days of IV dextrose infusions in the ICU, his glucose levels stabilized and he was discharged to an inpatient psychiatric facility without serious long-term complications (Mork et al, 2011).
    b) DIABETIC: Permanent brain damage has been reported following 3200 (Nicholson, 1965) and 800 (Raymond & Cohen, 1972) units of insulin in diabetic patients.
    c) DIABETIC: A 46-year-old woman with a history of poorly controlled type 2 diabetes mellitus, inadvertently received 100 units of insulin glargine intravenously instead of subcutaneously. She did not experience any adverse effects. Her blood glucose was 435 mg/dL before insulin glargine administration and gradually decreased to 158 mg/dL after about 2 hours. She did not receive any parenteral glucose (Thornton & Gutovitz, 2012).
    d) NONDIABETIC: A suicidal adult developed permanent brain damage from an estimated 1000 units of insulin (Cooper, 1994). The exact amount could not be determined due to the patient's ongoing denial of the event.
    e) A 36-year-old woman developed coma, seizures, hypotension, and myocardial infarction and sustained permanent neurologic injury after developing profound hypoglycemia after injecting 1500 units of insulin (Kamijo et al, 2000).
    f) CASE REPORT: A 29-year-old man presented unconscious with severe hypoglycemia (plasma glucose: 26 mg/dL; normal range: 80 to 110 mg/dL) after the self-injection of 3600 units of insulin (1500 units of regular insulin, 600 units of neutral protamine Hagedorn (NPH) insulin, and 1500 units of 70/30 NPH/regular mixed insulin) subcutaneously. He regained consciousness after receiving a dextrose infusion (20 g/hr) continuously for 48 hours. Despite the dextrose infusion, he developed severe hypoglycemic attacks 14, 32, and 44 hours after presentation. On day 5, he developed severe elevated liver enzymes 15 to 20 times of normal range. All other laboratory results, including bilirubin concentrations, prothrombin time, INR, and ultrasonographic evaluation of the liver were normal. On day 8, the patient recovered and was discharged to a psychiatric ward (Guclu et al, 2009).
    g) Survival has been reported in adults injecting as high as 3000 to 3200 units of insulin (Nicholson, 1965; Martin et al, 1977; Arem & Zoghbi, 1985).
    h) A 33-year-old obese man intentionally injected himself with the contents of 7 full insulin vials (7000 units) over 48 hours without serious long-term sequela (Roberge et al, 1993).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) PEAK LEVELS AFTER OVERDOSE: The peak serum free insulin concentration was about 1425 microunits/mL at 8 hours after subcutaneous injection of 2500 units of NPH insulin in a 23-year-old woman with diabetes mellitus (Samuels & Eckel, 1989).
    a) CASE REPORT: A 31-year-old woman with diabetes mellitus self-injected 2400 units of insulin mixture (70% NPH and 30% Regular). The peak value of serum insulin was 7390 microunits/mL and was drawn 5.5 hours after the initial insulin overdose. The half-life was determined to be 6.2 hours and the insulin mixture's elimination followed a linear decline (Shibutani & Ogawa, 2000).
    2) CASE REPORTS
    a) PLASMA INSULIN LEVEL: A 39-year-old man with a history of poorly controlled diabetes mellitus and morbid obesity intentionally injected himself with 880 units of insulin lispro and 3800 units of insulin glargine subcutaneously over 10 different abdominal sites. His plasma insulin concentration at presentation on the day of the injections was 3712.6 microunits/mL (normal range 2.6 to 31.1 microunits/mL). He was treated with continuous IV dextrose infusions, and his plasma insulin level 10 hours after presentation was 1582.1 microunits/mL, at 34 hours it was 724.8 microunits/mL, and by 108 hours after presentation it was 30.4 microunits/mL. He recovered without long-term complications (Mork et al, 2011).
    b) INITIAL SERUM INSULIN LEVEL: An adult found comatose, with other laboratory tests essentially normal, had a serum insulin level greater than 5000 Pmol/L (normal range; 20 to 180). It was later estimated that the patient took approximately 1000 units of insulin, but this could not be confirmed because of the patient's ongoing denial of the event (Cooper, 1994).
    c) A 36-year-old woman developed coma, seizures, hypotension, and myocardial infarction and sustained permanent neurologic injury after developing profound hypoglycemia after injecting 1500 units of insulin. Her serum insulin concentrations were 1722.7 microunits/mL on admission and 197.2 microunits/mL several hours later (Kamijo et al, 2000).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Insulin facilitates the penetration of glucose and amino acids through cell membranes of skeletal and heart muscle (to correct hyperglycemia of diabetes mellitus).
    B) Insulin is destroyed in the GI tract and is not effective when given orally.

Physicochemical

Physical Characteristics

    A) INSULIN ASPART is a sterile, clear, colorless, aqueous solution (Prod Info NOVOLOG(R) subcutaneous injection, 2008).
    B) INSULIN ASPART PROTAMINE/INSULIN ASPART 70%/30% is a sterile, uniform, white suspension (Prod Info NOVOLOG(R) MIX 70/30 subcutaneous injection, suspension, 2007).
    C) INSULIN DEGLUDEC is a sterile, clear, colorless aqueous solution (Prod Info TRESIBA(R) subcutaneous injection solution, 2015).
    D) INSULIN DETEMIR is a sterile, clear, colorless, neutral, aqueous solution (Prod Info LEVEMIR(R) subcutaneous injection, 2007).
    E) INSULIN GLARGINE is a sterile, clear, aqueous solution (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info LANTUS(R) subcutaneous injection solution, 2015).
    F) INSULIN GLULISINE is a sterile, clear, colorless, aqueous solution (Prod Info APIDRA(R) subcutaneous, intravenous injection, 2009).
    G) INSULIN HUMAN REGULAR is a sterile, clear, colorless, aqueous solution (Prod Info Novolin(R) R injection solution, 2010).
    H) INSULIN LISPRO is a sterile, clear, aqueous solution (Prod Info HUMALOG(R) subcutaneous injection, 2009).
    I) INSULIN LISPRO PROTAMINE/INSULIN LISPRO 50%/50% is a sterile suspension (Prod Info HUMALOG(R) MIX 50/50(TM) subcutaneous injection, 2007).
    J) INSULIN LISPRO PROTAMINE/INSULIN LISPRO 75%/25% is a sterile suspension (Prod Info HUMALOG(R) MIX 75/25(TM) injection, suspension, 2007).

Ph

    A) INSULIN ASPART: 7.2 to 7.6 (Prod Info NOVOLOG(R) subcutaneous injection, 2008)
    B) INSULIN ASPART PROTAMINE/INSULIN ASPART 70%/30%: 7.2 to 7.44 (Prod Info NOVOLOG(R) MIX 70/30 subcutaneous injection, suspension, 2007)
    C) INSULIN DEGLUDEC: approximately 7.6 (Prod Info TRESIBA(R) subcutaneous injection solution, 2015)
    D) INSULIN DETEMIR: approximately 7.4 (Prod Info LEVEMIR(R) subcutaneous injection, 2007)
    E) INSULIN GLARGINE: approximately 4 (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info LANTUS(R) subcutaneous injection solution, 2015)
    F) INSULIN GLULISINE: approximately 7.3 (Prod Info APIDRA(R) subcutaneous, intravenous injection, 2009)
    G) INSULIN HUMAN REGULAR: 7.4 (Prod Info Novolin(R) R injection solution, 2010)
    H) INSULIN LISPRO: 7 to 7.8 (Prod Info HUMALOG(R) subcutaneous injection, 2009)
    I) INSULIN LISPRO PROTAMINE/INSULIN LISPRO 50%/50%: 7 to 7.8 (Prod Info HUMALOG(R) MIX 50/50(TM) subcutaneous injection, 2007)
    J) INSULIN LISPRO PROTAMINE/INSULIN LISPRO 75%/25%: 7 to 7.8 (Prod Info HUMALOG(R) MIX 75/25(TM) injection, suspension, 2007)

Molecular Weight

    A) INSULIN ASPART: 5825.8 Daltons (Prod Info NOVOLOG(R) MIX 70/30 subcutaneous injection, suspension, 2007)
    B) INSULIN DEGLUDEC: 6103.97 (Prod Info TRESIBA(R) subcutaneous injection solution, 2015)
    C) INSULIN DETEMIR: 5916.9 (Prod Info LEVEMIR(R) subcutaneous injection, 2007)
    D) INSULIN GLARGINE: 6063 (Prod Info BASAGLAR(R) subcutaneous injection, 2015; Prod Info LANTUS(R) subcutaneous injection solution, 2015)
    E) INSULIN GLULISINE: 5823 (Prod Info APIDRA(R) subcutaneous, intravenous injection, 2009)
    F) INSULIN HUMAN REGULAR: 5808 Daltons (Prod Info Novolin(R) R injection solution, 2010)
    G) INSULIN LISPRO: 5808 (Prod Info HUMALOG(R) subcutaneous injection, 2009)

References

General Bibliography

    1) AACE Diabetes Mellitus Clinical Practice 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.
    2) Abdollahi M, Jalali N, & Sharifzadeh M: Attempted suicide by insulin injection treated with hypertonic glucose solution. Med J Islam Repub Iran 1998; 12:85-87.
    3) Anderson RJ: Clinical Use of Drugs in Renal Failure, CC Thomas, Springfield, IL, 1976, pp 191-193.
    4) Arem R & Zoghbi W: Insulin overdose in eight patients: insulin pharmacokinetics and review of the literature. Medicine 1985; 64:323-332.
    5) Beardwood JT: A case of attempted suicide with insulin. JAMA 1934; 102:765-766.
    6) Berson SA & Yallow RS: Insulin in blood and insulin antibody. Am J Med 1966; 40:676-690.
    7) Berz JP & Orlander JD: Prolonged cerebellar ataxia: an unusual complication of hypoglycemia. J Gen Intern Med 2008; 23(1):103-105.
    8) Beuhler MC , Spiller HA , & Aleguas A : Demographics and outcome of unintentional insulin overdoses managed by three poison centers. Clin Toxicol (Phila) 2013; 51(8):789-793.
    9) Bosse GM: Antidiabetic and Hypoglycemic Agents in Goldfrank's TOxicologic Emergencies 7th ed. Goldfrank LR, Flomengaum NE, Lewin NA et al eds, McGraw Hill, New York, NY, 2002.
    10) Bour H, Roman M, & Hecht Y: Coma hypoglycemique mortel par suicide a l'insuline. Sem Hop Paris 1960; 36:2446.
    11) Bourgeois M & Dufourg J: Suicide insuliniques. Ann Med Psych 1967; 125:133.
    12) Brvar M, Mozina M, & Bunc M: Poisoning with insulin glargine (letter). Clin Toxicol 2005; 43:219-220.
    13) Buchanan TA & Coustan DRBuchanan TA & Coustan DR: Diabetes mellitus. In : Burrow GN & Ferris TF (Eds): Medical Complications During Pregnancy, 4th. WB Saunders Company, Philadelphia, PA, 1995.
    14) Campbell IW & Ratcliffe JG: Suicidal insulin overdose managed by excision of insulin injection site. Br Med J 1982; 285:408-409.
    15) Canadian Diabetes Association: Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2008; 32(Suppl 1):1-215.
    16) Collier A, Matthews DM, & Young RJ: Transient atrial fibrillation precipitated by hypoglycaemia: two case reports. Postgrad Med J 1987; 63:895-897.
    17) Colsky LC, Campo AE, & Gonzalez-Blanco M: Insulin and the suicidal patient. West J Med 1985; 143:679.
    18) Cooper AJ: Attempted suicide using insulin by a non diabetic: A case study demonstrating the acute and chronic consequences of profound hypoglycemia. Can J Psychiatry 1994; 39:103-107.
    19) Cunningham FG, MacDonald PC, Leveno KF, et alCunningham FG, MacDonald PC, Leveno KF, et al (Eds): Williams Obstetrics, 19th. Appleton & Lange, Norwalk, CT, 1993.
    20) DeWitt DE & Hirsch IB : Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 2003; 289(17):2254-2264.
    21) Di Cianni G, Torlone E, Lencioni C, et al: Perinatal outcomes associated with the use of glargine during pregnancy. Diabet Med 2008; 25(8):993-996.
    22) Egerman RS, Ramsey RD, Kao LW, et al: Perinatal Outcomes in Pregnancies Managed with Antenatal Insulin Glargine. Am J Perinatol 2009; Epub:-.
    23) El-Laboudi AH, Misra S, Martineau M, et al: Intentional Large Insulin Overdose Captured on a Continuous Glucose Monitor: A Novel Case Report. J Diabetes Sci Technol 2015; 9(4):929-931.
    24) Fang YM, MacKeen D, Egan JF, et al: Insulin glargine compared with Neutral Protamine Hagedorn insulin in the treatment of pregnant diabetics. J Matern Fetal Neonatal Med 2009; 22(3):249-253.
    25) Fromont I, Benhaim D, Ottomani A, et al: Prolonged glucose requirements after intentional glargine and aspart overdose. Diabetes Metab 2007; 33(5):390-392.
    26) Glogan D, Levitan RD, Brooks DE, et al: Unintentional Use of Mistaken Insulin Products: A Retrospective Review of Poison Center Data. J Emerg Med 2013; Epub:Epub-.
    27) Guclu M, Ersoy C, & Imamoglu S: Suicide attempt of a physician with 3600 units of insulin and rapid onset acute hepatitis. Intern Med J 2009; 39(12):e5-e7.
    28) Haskell RJ & Stapczynski JS: Intravenous glucose for the treatment of intentional insulin overdoses (Abstract). Ann Emerg Med 1983; 12:260.
    29) Hirsch IB : Insulin analogues. N Engl J Med 2005; 352(2):174-183.
    30) Imbergamo MP, Amato MC, Sciortino G, et al: Use of glargine in pregnant women with type 1 diabetes mellitus: a case-control study. Clin Ther 2008; 30(8):1476-1484.
    31) Jolliet P, Leverve X, & Pichard C: Acute hepatic steatosis complicating massive insulin overdose and excessive glucose administration. Inten Care Med 2001; 27:313-316.
    32) Kamijo Y, Soma K, Aoyama N, et al: Myocardial infarction with acute insulin poisoning--a case report. Angiology 2000; 51(8):689-693.
    33) Levine DF & Bulstrode C: Managing suicidal insulin overdose. Br Med J 1982; 285:974-975.
    34) Lindgren L: Enormous dose of insulin with suicidal intent. Acta Med Scand 1960; 167:297-300.
    35) Martin FIR, Hansen N, & Warne GL: Attempted suicide by insulin overdose in insulin requiring diabetics. Med J Aust 1977; 1:58-60.
    36) Martin FIR, Stocks AE, & Pearson MJ: Significance of disappearance rate of injected insulin. Lancet 1967; 1:619.
    37) Matsumura M, Nakashima A, & Tofuku Y: Electrolyte disorders following massive insulin overdose in a patient with type 2 diabetes. Intern Med 2000; 39:55-57.
    38) McIntyre AS, Woolf VJ, & Burnham WR: Local excision of subcutaneous fat in the management of insulin overdose. Br J Surg 1986; 73:538.
    39) Mork TA, Killeen CT, Patel NK, et al: Massive insulin overdose managed by monitoring daily insulin levels. Am J Ther 2011; 18(5):e162-e166.
    40) Munck O & Quaade F: Suicide attempted with insulin. Dan Med Bull 1963; 10:139-141.
    41) Nicholson WA: Attempted suicide with insulin. Practitioner 1965; 195:790-793.
    42) Pollex E, Moretti ME, Koren G, et al: Safety of insulin glargine use in pregnancy: a systematic review and meta-analysis. Ann Pharmacother 2011; 45(1):9-16.
    43) Product Information: AFREZZA(R) oral inhalation powder, insulin human oral inhalation powder. MannKind Corporation(TM) (per manufacturer), Danbury, CT, 2014.
    44) Product Information: APIDRA(R) subcutaneous injection solution, intravenous injection solution, insulin glulisine rDNA origin subcutaneous injection solution, intravenous injection solution. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2014.
    45) Product Information: APIDRA(R) subcutaneous injection solution, intravenous injection solution, insulin glulisine rDNA origin subcutaneous injection solution, intravenous injection solution. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2015.
    46) Product Information: APIDRA(R) subcutaneous, intravenous injection, insulin glulisine (rDNA origin) subcutaneous, intravenous injection. Sanofi-Aventis U.S. LLC, Bridgewater, NJ, 2009.
    47) Product Information: BASAGLAR(R) subcutaneous injection, insulin glargine subcutaneous injection. Eli Lilly and Company (per manufacturer), Indianapolis, IN, 2015.
    48) Product Information: BASAGLAR(R) subcutaneous injection, insulin glargine subcutaneous injection. Lilly USA, LLC (per FDA), Indianapolis, IN, 2016.
    49) Product Information: EXUBERA(R) inhalation powder, insulin human [rDNA origin] inhalation powder. Pfizer Labs, New York, NY, 2008.
    50) Product Information: HUMALOG(R) MIX 50/50(TM) subcutaneous injection, insulin lispro protamine suspension and insulin lispro (rDNA) subcutaneous injection. Eli Lilly and Company, Indianapolis, IN, 2007.
    51) Product Information: HUMALOG(R) MIX 75/25(TM) injection, suspension, insulin lispro protamine injection, suspension. Eli Lilly and Company, Indianapolis, IN, 2007.
    52) Product Information: HUMALOG(R) Mix50/50(TM) subcutaneous injection suspension, insulin lispro protamine 50% insulin lispro 50% rDNA origin subcutaneous injection suspension. Lilly USA, LLC (per FDA), Indianapolis, IN, 2013.
    53) Product Information: HUMALOG(R) Mix75/25(TM) subcutaneous injection suspension, insulin lispro protamine 75% insulin lispro 25% rDNA origin subcutaneous injection suspension. Lilly USA, LLC (per FDA), Indianapolis, IN, 2013.
    54) Product Information: HUMALOG(R) subcutaneous injection, insulin lispro (rDNA origin) subcutaneous injection. Eli Lilly and Company, Indianapolis, IN, 2009.
    55) Product Information: HUMALOG(R) subcutaneous injection, intravenous injection, insulin lispro rDNA origin subcutaneous injection, intravenous injection. Lilly USA, LLC (per FDA), Indianapolis, IN, 2013.
    56) Product Information: HUMALOG(R) subcutaneous, intravenous injection, insulin lispro subcutaneous, intravenous injection. Eli Lilly and Company (per manufacturer), Indianapolis, IN, 2015.
    57) Product Information: HUMULIN(R) R U-500 solution for subcutaneous injection, insulin human (rDNA origin) regular U-500 solution for subcutaneous injection. Lilly USA, LLC, Indianapolis, IN, 2011.
    58) Product Information: Humalog(R) subcutaneous injection, intravenous injection, insulin lispro rDNA origin subcutaneous injection, intravenous injection. Lilly USA, LLC (per FDA), Indianapolis, IN, 2015.
    59) Product Information: Humulin(R) R subcutaneous injection, intravenous injection, regular insulin human rDNA origin subcutaneous injection, intravenous injection. Lilly USA, LLC (per FDA), Indianapolis, IN, 2013.
    60) Product Information: LANTUS(R) subcutaneous injection solution, insulin glargine rDNA origin subcutaneous injection solution. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2013.
    61) Product Information: LANTUS(R) subcutaneous injection solution, insulin glargine rDNA origin subcutaneous injection solution. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2015a.
    62) Product Information: LANTUS(R) subcutaneous injection solution, insulin glargine subcutaneous injection solution. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2015.
    63) Product Information: LEVEMIR(R) injection, insulin detemir injection. Novo Nordisk Inc, Princeton, NJ, 2005.
    64) Product Information: LEVEMIR(R) subcutaneous injection solution, insulin detemir rDNA origin subcutaneous injection solution. Novo Nordisk Inc. (per FDA), Plainsboro, NJ, 2015.
    65) Product Information: LEVEMIR(R) subcutaneous injection solution, insulin detemir rDNA origin subcutaneous injection solution. Novo Nordisk Inc. (per FDA), Princeton, NJ, 2012.
    66) Product Information: LEVEMIR(R) subcutaneous injection, insulin detemir (rDNA origin) subcutaneous injection. Novo Nordisk Inc. (per FDA), Princeton, NJ, 2012.
    67) Product Information: LEVEMIR(R) subcutaneous injection, insulin detemir [rDNA origin] subcutaneous injection. Novo Nordisk,Inc, Princeton, NJ, 2007.
    68) Product Information: NOVOLOG(R) MIX 70/30 subcutaneous injection, suspension, insulin aspart protamine subcutaneous injection, suspension. Novo Nordisk Inc, Princeton, NJ, 2007.
    69) Product Information: NOVOLOG(R) subcutaneous injection, insulin aspart (rDNA origin) subcutaneous injection. Novo Nordisk Inc, Princeton, NJ, 2008.
    70) Product Information: NovoLog(R) Mix 50/50 subcutaneous injection suspension, insulin aspart protamine 50% insulin aspart 50% rDNA origin subcutaneous injection suspension. Novo Nordisk Inc. (per FDA), Princeton, NJ, 2013.
    71) Product Information: NovoLog(R) Mix 70/30 subcutaneous injection, 70% insulin aspart protamine suspension and 30% insulin aspart injection, (rDNA origin) subcutaneous injection. Novo Nordisk A/S, Bagsvaerd, Denmark, 2010.
    72) Product Information: NovoLog(R) subcutaneous injection solution, insulin aspart rDNA origin subcutaneous injection solution. Novo Nordisk Inc. (per FDA), Plainsboro, NJ, 2013.
    73) Product Information: Novolin(R) R injection solution, regular, human insulin (rDNA origin) injection solution. Novo Nordisk Inc., Princeton, NJ, 2010.
    74) Product Information: RYZODEG(R) 70/30 subcutaneous injection solution, insulin degludec and insulin aspart subcutaneous injection solution. Novo Nordisk Inc. (per FDA), Plainsboro, NJ, 2015.
    75) Product Information: TOUJEO(R) subcutaneous injection, insulin glargine subcutaneous injection. sanofi-aventis (per manufacturer), Bridgewater, NJ, 2015.
    76) Product Information: TRESIBA(R) subcutaneous injection solution, insulin degludec subcutaneous injection solution. Novo Nordisk (per manufacturer), Plainsboro, NJ, 2015.
    77) Product Information: glucagon injection, glucagon injection. Eli Lilly and Company, Indianapolis, IN, 2005.
    78) Ragan PW, Chernow B, & Resnik HL: Suicide attempt by insulin overdose. J Clin Psychiatry 1985; 46:34.
    79) Raymond LW & Cohen AB: "Barbiturate blisters" in a case of severe hypoglycemic coma (letter). Lancet 1972; 2:764.
    80) Read RC & Doherty JE: Cardiovascular effects of induced insulin hypoglycemia in man during the Hollander test. Am J Surg 1970; 119:155-162.
    81) Rich JD, Dickinson BP, & Merriman NA: Insulin use by bodybuilders (letter). JAMA 1998; 279:1613.
    82) Roberge R, Martin TG, & Delbridge TR: Intentional massive insulin overdose: recognition and management. Ann Emerg Med 1993; 22:228-234.
    83) Samuels MH & Eckel RH: Massive insulin overdose: detailed studies of free insulin levels and glucose requirements. Clin Toxicol 1989; 27:157-168.
    84) Shapiro DJ, Blumenkrantz MJ, & Levin SR: Absorption and action of insulin added to peritoneal dialysate in dogs. Nephron 1979; 23:174-180.
    85) Shibutani Y & Ogawa C: Suicidal insulin overdose in a type 1 diabetic patient: relation of serum insulin concentrations to the duration of hypoglycemia. J Diabetes Complications 2000; 14(1):60-62.
    86) Shirayama H, Ohshiro Y, Kinjo Y, et al: Acute brain injury in hypoglycaemia-induced hemiplegia. Diabet Med 2004; 21(6):623-624.
    87) Simon R: Management of prolonged coma and determination of brain death. Symposium on poisonings and toxicological emergencies, San Francisco Bay Area Regional Poison Center, San Francisco, CA, 1983.
    88) Smith JG, Manuck TA, White J, et al: Insulin glargine versus neutral protamine Hagedorn insulin for treatment of diabetes in pregnancy. Am J Perinatol 2009; 26(1):57-62.
    89) Spencer J & Kitabchi A: Lethargy and vomiting after the insulin thawed. Hosp Pract 1983; 196.
    90) Sturner WQ & Putnam RS: Suicidal insulin poisoning with nine day survival: recovery in bile at autopsy by radioimmunoassay. J Forensic Sci 1972; 17:514-521.
    91) Suffecool K, Rosenn B, Niederkofler EE, et al: Insulin detemir does not cross the human placenta. Diabetes Care 2015; 38(2):e20-e21.
    92) Thornton S & Gutovitz S: Intravenous overdose of insulin glargine without prolonged hypoglycemic effects. J Emerg Med 2012; 43(3):435-437.
    93) Tofade TS & Liles EA: Intentional overdose with insulin glargine and insulin aspart. Pharmacotherapy 2004; 24(10):1412-1418.
    94) Tsujimoto T, Takano M, Nishiofuku M, et al: Rapid onset of glycogen storage hepatomegaly in a type-2 diabetic patient after a massive dose of long-acting insulin and large doses of glucose. Intern Med 2006; 45(7):469-473.
    95) US Food and Drug Administration: Insulin Preparations. US Food and Drug Administration. Rockville, MDAvailable from URL: http://www.fda.gov/fdac/features/2002/chrt_insulin.html.
    96) Uchida D, Ohigashi S, Hikita S, et al: Acute pulmonary edema caused by hypoglycemia due to insulin overdose. Internal Medicine 2004; 43:1056-1059.
    97) Vogl A & Youngwirth SH: The effects of a single dose of 2,000 units of protamine Zinc Insulin taken by a diabetic patient with suicidal intent. N Engl J Med 1949; 241:606-609.
    98) de Mowbray, Young BA, & Kellock TD: Risk of changing from ox to pig insulin. Lancet 1966; 2:910-911.