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PRAMLINTIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pramlintide is a synthetic analog of human amylin, a hormone synthesized by pancreatic beta cells that helps to control glucose during the postprandial period.

Specific Substances

    1) Pramlintida
    2) Tripro-amylin
    3) AC-137
    4) AC-0137
    5) 25, 28, 29 tripro-amylin
    6) CAS 196078-30-5 (pramlintide acetate)
    7) NORMYLIN

Available Forms Sources

    A) FORMS
    1) Pramlintide is available as sterile solution for subcutaneous injection. The disposable multidose SymlinPen(R) pen-injector contains 1000 mcg/mL of pramlintide (as acetate) (Prod Info SYMLINPEN(R) subcutaneous injection, 2008). Symlin(R) vials contain 600 mcg/mL of pramlintide (as acetate) (Prod Info SYMLIN(R) subcutaneous injection, 2008).
    B) USES
    1) Pramlintide is indicated as adjunctive therapy for Type 1 diabetic patients who use mealtime insulin therapy and are not achieving adequate glycemic control (Prod Info SYMLIN(R) subcutaneous injection, 2008).
    2) Pramlintide is also indicated as adjunctive therapy for Type 2 diabetic patients who use mealtime insulin therapy, with or without concurrent administration of metformin and/or a sulfonylurea agent, and who are not achieving adequate glycemic control (Prod Info SYMLIN(R) subcutaneous injection, 2008).

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: Pramlintide is used to treat type 1 or type 2 diabetes, as an adjunct treatment in patients who are using mealtime insulin but have failed to achieve desired glucose control with optimal insulin therapy.
    B) PHARMACOLOGY: Pramlintide, an antidiabetic drug, is a stable, non-aggregating analogue of endogenous amylin. It is responsible for the modulation of gastric emptying, prevention of the postprandial glucagon secretion, and satiety which leads to decreased caloric intake and potential weight loss.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The most frequently reported adverse effects following therapeutic administration of pramlintide include nausea, vomiting, anorexia, and headache. Other adverse effects include abdominal pain, diarrhea, dizziness, lightheadedness, tachycardia, and a dermal reaction, consisting of erythema, edema, and pruritus. Pramlintide as a sole therapy (without concurrent administration of insulin) does NOT cause hypoglycemia.
    2) DRUG INTERACTION: Concomitant administration of pramlintide with one or more antidiabetic agents (eg, insulin, sulfonylureas) increases the risk of hypoglycemia. Severe hypoglycemia associated with pramlintide will generally occur within 2 to 3 hours after pramlintide administration.
    E) WITH POISONING/EXPOSURE
    1) Pramlintide overdose information is limited. Severe nausea, vomiting, diarrhea, vasodilatation, and dizziness were reported in healthy volunteers following administration of single 10-mg doses. Hypoglycemia is not expected after administration of pramlintide alone, but may develop if pramlintide is administered with insulin or other hypoglycemic agents.
    0.2.20) REPRODUCTIVE
    A) Pramlintide is classified as FDA pregnancy category C.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, there is no information regarding the carcinogenicity of pramlintide in humans.

Laboratory Monitoring

    A) Serum pramlintide concentrations are not clinically useful in managing overdose.
    B) Monitor vital signs in symptomatic patients.
    C) In patients with hypoglycemia or concomitant exposure to other hypoglycemic agents, monitor blood glucose every hour for 3 to 4 hours; longer in patients following concomitant overdose with intermediate or long acting insulin or oral hypoglycemics.
    D) Monitor serum electrolytes in patients with significant nausea, vomiting and diarrhea following exposure.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. HYPOGLYCEMIA: Hypoglycemia is not expected after administration of pramlintide alone, but may develop if pramlintide is administered with insulin or other hypoglycemic agents. In patients with pramlintide overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours. DIET: If the patient is awake and alert, offer carbohydrates. If hypoglycemia persists or becomes severe, treat hypoglycemia with IV dextrose boluses as needed. May need to repeat in patients with profound hypoglycemia. A dextrose infusion may be needed in patients in whom recurrent hypoglycemia develops, despite feeding and dextrose boluses. Titrate carefully to reduce the potential for reactive hypoglycemia. NOT RECOMMENDED: Prophylactic dextrose administration is not recommended in patients who do not become hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. HYPOGLYCEMIA: Hypoglycemia is not expected after administration of pramlintide alone, but may develop if pramlintide is administered with insulin or other hypoglycemic agents. In patients with pramlintide overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours. Treat hypoglycemia with IV dextrose boluses as needed. May need to repeat in patients with profound hypoglycemia. A dextrose infusion may be needed in patients in whom recurrent hypoglycemia develops, despite feeding and dextrose boluses. Titrate carefully to reduce the potential for reactive hypoglycemia.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not necessary as pramlintide is administered subcutaneously.
    D) AIRWAY MANAGEMENT
    1) Generally, airway management is not necessary as CNS depression from these agents should resolve with dextrose administration. Endotracheal intubation should be performed in patients with excessive drowsiness and the inability to protect their own airway that do not respond to IV dextrose.
    E) ANTIDOTE
    1) None.
    F) HYPOGLYCEMIA
    1) Pramlintide alone does not cause hypoglycemia; however, concomitant administration of pramlintide and other anti-diabetic agents (i.e. insulin, sulfonylureas) may increase the risk of hypoglycemia. DEXTROSE: Give dextrose if symptomatic or BS less than 60 mg/dL. DOSE: ADULT: 0.5 to 1 g/kg of D50W (50% dextrose) IV push; ADOLESCENT: 0.5 to 1 g/kg (1 to 2 mL/kg) of 50% dextrose IV push; INFANT and CHILD: 0.5 to 1 g/kg (2 to 4 mL/kg) of 25% dextrose IV push. Follow with an infusion of 10% dextrose; titrate to a BS of 100 mg/dL. DIET: When the patient is awake and alert, supplement IV glucose with carbohydrate intake.
    G) HEMODIALYSIS
    1) Hemodialysis is likely not to be of value because of the large volume of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: All children with inadvertent injections should be sent to a healthcare facility for evaluation and treatment. Adults with a deliberate overdose should be sent to a healthcare facility for evaluation and treatment. Diabetic adults with an inadvertent injection of an extra dose who are asymptomatic can be monitored at home. Asymptomatic nondiabetic adults with an inadvertent injection of an extra dose can be monitored at home.
    2) OBSERVATION CRITERIA: The patient with an inadvertent overdose of pramlintide can be observed in the Emergency Department and discharged if hypoglycemia resolves after feeding and a few hours of observation.
    3) ADMISSION CRITERIA: Patients who develop hypoglycemia should be admitted for a minimum of 24 hours for frequent blood glucose monitoring. They should only be discharged when free of symptoms and are able to maintain euglycemia without supplemental dextrose for 8 hours.
    4) CONSULT CRITERIA: Consult a medical toxicologist or a poison center for assistance with medical management in patients with severe overdose or in whom the diagnosis is unclear.
    I) PITFALLS
    1) Patients who develop hypoglycemia should not be discharged until they have been able to maintain euglycemia for at least 8 hours without supplemental dextrose.
    J) PHARMACOKINETICS
    1) Based on a single subcutaneous dose, the absolute bioavailability is approximately 30% to 40%. Protein binding: not extensively bound, 40% unbound. Vd: 56 L at steady state. Pramlintide is primarily metabolized by the kidneys. Elimination half-life: About 48 minutes.
    K) DIFFERENTIAL DIAGNOSIS
    1) Exposure to other hypoglycemic agents such as insulin or sulfonylureas. The differential diagnosis of hypoglycemia is otherwise very broad and includes sepsis, liver failure, malnutrition, neoplasm, adrenal insufficiency, insulinoma and others.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Severe nausea, vomiting, diarrhea, vasodilatation and dizziness were reported in healthy volunteers following the administration of single 10-mg pramlintide doses.
    B) THERAPEUTIC DOSES: ADULT: TYPE 1 DIABETES: Initial dose is 15 mcg SubQ, with titration at 15 mcg increments to a maintenance dose of 30 or 60 mcg as tolerated. TYPE 2 DIABETES: Initial dose is 60 mcg SubQ with an increase to 120 mcg as tolerated. PEDIATRIC: The safety and efficacy of pramlintide in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Pramlintide is used to treat type 1 or type 2 diabetes, as an adjunct treatment in patients who are using mealtime insulin but have failed to achieve desired glucose control with optimal insulin therapy.
    B) PHARMACOLOGY: Pramlintide, an antidiabetic drug, is a stable, non-aggregating analogue of endogenous amylin. It is responsible for the modulation of gastric emptying, prevention of the postprandial glucagon secretion, and satiety which leads to decreased caloric intake and potential weight loss.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The most frequently reported adverse effects following therapeutic administration of pramlintide include nausea, vomiting, anorexia, and headache. Other adverse effects include abdominal pain, diarrhea, dizziness, lightheadedness, tachycardia, and a dermal reaction, consisting of erythema, edema, and pruritus. Pramlintide as a sole therapy (without concurrent administration of insulin) does NOT cause hypoglycemia.
    2) DRUG INTERACTION: Concomitant administration of pramlintide with one or more antidiabetic agents (eg, insulin, sulfonylureas) increases the risk of hypoglycemia. Severe hypoglycemia associated with pramlintide will generally occur within 2 to 3 hours after pramlintide administration.
    E) WITH POISONING/EXPOSURE
    1) Pramlintide overdose information is limited. Severe nausea, vomiting, diarrhea, vasodilatation, and dizziness were reported in healthy volunteers following administration of single 10-mg doses. Hypoglycemia is not expected after administration of pramlintide alone, but may develop if pramlintide is administered with insulin or other hypoglycemic agents.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia was reported in 4 of 6 patients, 3 of 6 patients, and 4 of 6 patients who received 30 mcg doses, 100 mcg doses, and 300 mcg doses of pramlintide intravenously, respectively (Colburn et al, 1996).
    B) VASODILATATION
    1) WITH POISONING/EXPOSURE
    a) Vasodilatation was reported in healthy volunteers following single 10-mg doses of pramlintide (83 times the maximum recommended dose of 120 mcg) (Prod Info SYMLIN(R) subcutaneous injection, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches may be a frequent occurrence following therapeutic administration of pramlintide (Prod Info SYMLIN(R) subcutaneous injection, 2014; Colburn et al, 1996).
    b) INCIDENCE: During a randomized placebo-controlled pramlintide efficacy trial, headaches occurred in 15% (n=171) and 17% (n=166) of patients who were given pramlintide 90 mcg or 120 mcg twice daily, respectively, as compared with 8% (n=161) in the placebo group (Hollander et al, 2003).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness and lightheadedness were reported in several patients with pramlintide therapy (Prod Info SYMLIN(R) subcutaneous injection, 2014; Colburn et al, 1996).
    2) WITH POISONING/EXPOSURE
    a) Dizziness occurred in 3 healthy volunteers following administration of single 10-mg doses of pramlintide (83 times the maximum recommended dose of 120 mcg) (Prod Info SYMLIN(R) subcutaneous injection, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Mild to moderate nausea has been frequently reported following pramlintide administration. In the majority of patients, the incidence of nausea was higher at the beginning of pramlintide therapy and gradually decreased as therapy continued (Prod Info SYMLIN(R) subcutaneous injection, 2014; Levetan et al, 2003; Hollander et al, 2003; Hollander et al, 2003a; Whitehouse et al, 2002; Thompson et al, 1998).
    b) INCIDENCE: During a randomized placebo-controlled pramlintide efficacy trial, the incidence of nausea was 23.6% in the pramlintide-treated patients as compared with 9.4% in the placebo group. The majority of nausea cases (greater than 95%) were mild to moderate in intensity and primarily occurred during the first 4 weeks of treatment (Hollander et al, 2004).
    c) INCIDENCE: During a randomized, placebo-controlled, dose escalation trial for weight loss with optimal dosing of 240 mcg, the incidence of nausea was 38% (59/137 patients). A majority of these were mild and only 1 patient withdrew from the study due to nausea (Aronne et al, 2007).
    2) WITH POISONING/EXPOSURE
    a) Severe nausea and vomiting were reported in 3 healthy volunteers following administration of single 10-mg doses of pramlintide (83 times the maximum recommended dose of 120 mcg) (Prod Info SYMLIN(R) subcutaneous injection, 2014; Anon, 1999).
    B) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia occurred in several patients on pramlintide therapy (Prod Info SYMLIN(R) subcutaneous injection, 2014; Hollander et al, 2003a; Whitehouse et al, 2002; Anon, 1999; Nyholm et al, 1999)
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain may occur infrequently in patients receiving pramlintide therapy, with more pronounced symptoms at the beginning of therapy and subsiding as therapy is continued (Prod Info SYMLIN(R) subcutaneous injection, 2014; Nyholm et al, 1999).
    D) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea was reported in 3 healthy volunteers following administration of single 10-mg doses of pramlintide (83 times the maximum recommended dose of 120 mcg) (Prod Info SYMLIN(R) subcutaneous injection, 2014; Anon, 1999).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) A dermal reaction, consisting of erythema, edema, and pruritus, may occur at the site of injection following pramlintide administration (Prod Info SYMLIN(R) subcutaneous injection, 2014; Hollander et al, 2003a). The reactions will generally resolve within a few days to a few weeks.
    b) INCIDENCE: A randomized, placebo controlled, dose escalation trial for weight loss did not find a significant difference in the incidence of skin problems between the control (43%) and test groups (42%) (Aronne et al, 2007).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Pramlintide as a sole therapy (without concurrent administration of insulin) does NOT cause hypoglycemia (Prod Info SYMLIN(R) subcutaneous injection, 2014).
    b) Pramlintide has been associated with an increased risk of insulin-induced severe hypoglycemia, especially in patients with type 1 diabetes (Kruger & Gloster, 2004; Weyer et al, 2003; Nyholm et al, 1999), and usually occurred within 3 hours following pramlintide administration (Prod Info Symlin, 2005).
    c) INCIDENCE: Among type 1 diabetics, who were on insulin therapy, the incidence of severe hypoglycemia (patient-ascertained) was 16.8% and 10.8% in pramlintide- and placebo-treated patients, respectively, during the first 3 months of clinical studies (n=716 on pramlintide; n=538 on placebo). Overall, 7.3% and 3.3% of the pramlintide- and placebo-treated patients, respectively, received medical assistance for the hypoglycemic episodes. Among type 2 diabetics, who were on insulin therapy, the incidence of severe hypoglycemia (patient-ascertained) was 8.2% and 2.1% in pramlintide- and placebo-treated patients, respectively, during the first 3 months of clinical studies (n=292 on pramlintide; n=284 on placebo). Overall, 1.7% and 0.7% of the pramlintide- and placebo-treated patients, respectively, received medical assistance for the hypoglycemic episodes (Prod Info SYMLIN(R) subcutaneous injection, 2014).
    d) INCIDENCE: Among 507 type I diabetic patients, the incidence of severe hypoglycemia within the first 4 weeks of treatment with pramlintide was 4-fold higher than that of the control group (Ratner et al, 2004).

Reproductive

    3.20.1) SUMMARY
    A) Pramlintide is classified as FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS - Congenital abnormalities (neural tube defect, cleft palate, exencephaly) have occurred in the fetuses of rats who were given pramlintide 0.3 and 1 mg/kg/day during organogenesis (10 and 47 times the exposure from the maximum recommended human dose based on AUC, respectively) (Prod Info Symlin, 2005).
    2) RABBITS - Administration of pramlintide up to 0.3 mg/kg/day (9 times the maximum recommended human dose based on AUC) to pregnant rabbits had no adverse effects in embryofetal development (Prod Info Symlin, 2005).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Pramlintide is classified by the manufacturer as FDA pregnancy category C (Prod Info Symlin, 2005).
    B) PLACENTAL BARRIER
    1) Studies, involving a perfused human placenta, have indicated that pramlintide has a low potential in crossing the maternal/fetal placental barrier (Prod Info Symlin, 2005).
    C) ANIMAL STUDIES
    1) DYSTOCIA
    a) RATS - Dystocia occurred in 8 of 12 female rats who were given 3 mg/kg/day of pramlintide (82 times the exposure from the maximum recommended human dose based on body surface area) and was secondary to significant decreases in serum calcium levels (Prod Info Symlin, 2005).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether pramlintide is excreted in human breast milk (Prod Info Symlin, 2005).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) There were no significant fertility effects in male or female rats following administration of pramlintide. The highest dose of pramlintide (3 mg/kg/day) resulted in dystocia in female rats secondary to significant decreases in serum calcium levels.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS151126-32-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, there is no information regarding the carcinogenicity of pramlintide in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) MICE - There were no drug-induced tumors observed following a two-year carcinogenicity study in CD-1 mice, involving pramlintide doses of 0.2, 0.5, and 1.2 mg/kg/day (32, 67, and 159 times the exposure from the maximum recommended human dose based on AUC, respectively) (Prod Info Symlin, 2005).
    2) RATS - A two-year carcinogenicity study in Sprague-Dawley rats, involving pramlintide doses of 0.04, 0.2, and 0.5 mg/kg/day (3, 9, and 25 times the exposure from the maximum recommended human dose based on AUC, respectively) did not result in any tumors (Prod Info Symlin, 2005).

Genotoxicity

    A) Pramlintide was not mutagenic or clastogenic and did not increase chromosomal aberrations (Prod Info Symlin, 2005).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum pramlintide concentrations are not clinically useful in managing overdose.
    B) Monitor vital signs in symptomatic patients.
    C) In patients with hypoglycemia or concomitant exposure to other hypoglycemic agents, monitor blood glucose every hour for 3 to 4 hours; longer in patients following concomitant overdose with intermediate or long acting insulin or oral hypoglycemics.
    D) Monitor serum electrolytes in patients with significant nausea, vomiting and diarrhea following exposure.

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 who develop hypoglycemia should be admitted for a minimum of 24 hours for frequent blood glucose monitoring. They should only be discharged when free of symptoms and are able to maintain euglycemia without supplemental dextrose for 8 hours.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) All children with inadvertent injections should be sent to a healthcare facility for evaluation and treatment. Adults with a deliberate overdose should be sent to a healthcare facility for evaluation and treatment. Diabetic adults with an inadvertent injection of an extra dose who are asymptomatic can be monitored at home. Asymptomatic nondiabetic adults with an inadvertent injection of an extra dose can be monitored at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a medical toxicologist or a poison center for assistance with medical management in patients with severe overdose or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) The patient with an inadvertent overdose of pramlintide can be observed in the Emergency Department and discharged if hypoglycemia resolves after feeding and a few hours of observation.

Monitoring

    A) Serum pramlintide concentrations are not clinically useful in managing overdose.
    B) Monitor vital signs in symptomatic patients.
    C) In patients with hypoglycemia or concomitant exposure to other hypoglycemic agents, monitor blood glucose every hour for 3 to 4 hours; longer in patients following concomitant overdose with intermediate or long acting insulin or oral hypoglycemics.
    D) Monitor serum electrolytes in patients with significant nausea, vomiting and diarrhea following exposure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not necessary as pramlintide is administered subcutaneously.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Severe nausea, vomiting, diarrhea, vasodilatation and dizziness were reported in healthy volunteers following the administration of single 10-mg pramlintide doses.
    B) THERAPEUTIC DOSES: ADULT: TYPE 1 DIABETES: Initial dose is 15 mcg SubQ, with titration at 15 mcg increments to a maintenance dose of 30 or 60 mcg as tolerated. TYPE 2 DIABETES: Initial dose is 60 mcg SubQ with an increase to 120 mcg as tolerated. PEDIATRIC: The safety and efficacy of pramlintide in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) TYPE 1 DIABETES MELLITUS
    1) Reduce mealtime insulin by 50% and administer 15 mcg subQ prior to major meals; may be increased up to 60 mcg after 3 days (Prod Info SYMLIN(R) subcutaneous injection, 2014)
    B) TYPE 2 DIABETES MELLITUS
    1) Reduce mealtime insulin by 50% and administer 60 mcg subQ prior to major meals; may be increased to 120 mcg after 3 days (Prod Info SYMLIN(R) subcutaneous injection, 2014)
    7.2.2) PEDIATRIC
    A) The safety and efficacy of pramlintide administration in pediatric patients have not been established (Prod Info SYMLIN(R) subcutaneous injection, 2014).

Maximum Tolerated Exposure

    A) Severe nausea, vomiting, diarrhea, vasodilatation, and dizziness were reported in healthy volunteers following administration of single 10-mg doses (83 times the maximum recommended dose of 120 mcg) (Prod Info SYMLIN(R) subcutaneous injection, 2014).

Workplace Standards

    A) ACGIH TLV Values for CAS151126-32-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS151126-32-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS151126-32-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS151126-32-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Amylin is co-located with insulin in secretory granules and co-secreted with insulin by pancreatic beta cells in response to food intake. Amylin and insulin show similar fasting and postprandial patterns in healthy individuals (Prod Info Symlin, 2005).
    B) Amylin affects the rate of postprandial glucose appearance through a variety of mechanisms. Amylin slows gastric emptying (i.e. the rate at which food is released from the stomach to the small intestine) without altering the overall absorption of nutrients. In addition, amylin suppresses glucagon secretion (not normalized by insulin alone), which leads to suppression of endogenous glucose output from the liver. Amylin also regulates food intake due to centrally-mediated modulation of appetite (Prod Info Symlin, 2005).
    C) Pramlintide is a stable, non-aggregating analogue of endogenous amylin; it mimics the following effects of amylin (Prod Info Symlin, 2005; Samsom et al, 278; Kong et al, 1997; Moyses et al, 1996; Nyholm et al, 1996; Young et al, 1996; Kolterman et al, 1996):
    1) Modulation of gastric emptying
    2) Prevention of the postprandial rise in plasma glucagon
    3) Satiety leading to decreased caloric intake and potential weight loss

References

General Bibliography

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    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
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    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
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