Pramlintide (Monograph)

Brand name: Symlin
Drug class: Amylinomimetics
Molecular formula: C₁₇₁H₂₆₇N₅₁O₅₃S₂•xC₂H₄O₂•yH₂O
CAS number: 196078-30-5

Introduction

Antidiabetic agent; synthetic analog of human amylin.

Uses for Pramlintide

Diabetes Mellitus

Treatment of type 1 diabetes mellitus as an adjunct to preprandial insulin therapy in patients without adequate glycemic control on insulin therapy.

Treatment of type 2 diabetes mellitus as an adjunct to preprandial insulin therapy with or without concomitant metformin and/or a sulfonylurea in patients without adequate glycemic control on insulin therapy alone or in combination with metformin and/or a sulfonylurea.

Therapy should only be considered in patients with type 1 or 2 diabetes mellitus who are receiving insulin and have failed to achieve adequate glycemic control despite individualized insulin management. (See Patient Selection under Cautions.)

Pramlintide Dosage and Administration

General

• Adjust dosage of pramlintide and preprandial insulin under medical supervision. Dosing of both insulin and pramlintide should be reviewed at least once weekly until target dose is achieved, drug is well tolerated, and blood glucose concentrations are stable.

• Monitor blood glucose frequently, including before and after meals and at bedtime.

Discontinuance of Therapy

• Discontinue therapy if any of the following occurs:

• Recurrent unexplained hypoglycemia that requires medical assistance.

• Persistent clinically important nausea.

• Non-compliance with self-monitoring of blood glucose.

• Noncompliance with insulin dose adjustments.

• Noncompliance with scheduled clinician visits or contacts.

Administration

Sub-Q Administration

Administer by sub-Q injection immediately before each major meal (≥250 kcal or ≥30 g of carbohydrate).

Administer into abdominal wall or thigh using a conventional U-100 syringe (preferably 0.3-mL size). Do not administer into the arm because of variable absorption.

Pramlintide dosage (mcg) must be converted to insulin unit equivalents for administration using a U-100 syringe. Withdraw the appropriate volume of drug from the vial; fill syringe to the unit mark that corresponds to the appropriate volume of solution to be administered. (See Table 1.)

Injection sites should be rotated and should be >2 inches away from insulin injection sites.

Do not mix pramlintide injection with any type of insulin; administer pramlintide and insulin as separate injections. (See Compatibility.)

Omit pramlintide dose if meal is skipped or provides <250 kcal or <30 g of carbohydrates.

Always use a new syringe and needle for each dose.

If a dose is missed, skip that dose; do not give an additional injection.

Dosage

Available as pramlintide acetate; dosage expressed in terms of pramlintide.

Dosage expressed in mcg; dosage must be converted to insulin unit equivalents if administered using a U-100 insulin syringe. (See Table 1.)

Prior to initiating therapy, reduce preprandial, rapid-acting, short-acting, or fixed-mix insulin dosages by 50%. (See Hypoglycemia under Cautions.)

Once maintenance dosage of pramlintide is attained and nausea (if experienced) has subsided, adjust dosage of preprandial insulin to achieve optimal glycemic control.

Adults

Diabetes Mellitus

Type 1 Diabetes Mellitus

Sub-Q

Initially, 15 mcg immediately before each major meal, up to 4 times daily.

Increase dosage in increments of 15 mcg to 30, 45, or 60 mcg, as tolerated, before each major meal, when no clinically important nausea has occurred for ≥3 days at the current dosage level.

If nausea persists at the 45- or 60-mcg dosage level, reduce dosage to 30 mcg before each major meal.

If the 30-mcg dosage is not tolerated, consider discontinuance of therapy.

If pramlintide is reinitiated following a discontinuance for any reason, use initial dosage and dosage titration schedule.

Type 2 Diabetes Mellitus

Sub-Q

Initially, 60 mcg immediately before each major meal, up to 3 times daily.

Increase dosage to 120 mcg before each major meal, when no clinically important nausea has occurred for 3–7 days.

If nausea persists at dosage of 120 mcg, reduce dosage to 60 mcg before each major meal.

If pramlintide is reinitiated following a discontinuance for any reason, use initial dosage and dosage titration schedule.

Prescribing Limits

Adults

Diabetes Mellitus

Type 1 Diabetes Mellitus

Sub-Q

Maximum daily dosage not established; however, in clinical studies, has been administered up to 4 times daily before each major meal.

Type 2 Diabetes Mellitus

Sub-Q

Maximum daily dosage not established; however, in clinical studies, has been administered up to 3 times daily before each major meal.

Special Populations

Hepatic Impairment

No dosage adjustment required.

Renal Impairment

No dosage adjustment required. (See Renal Impairment under Cautions.)

Geriatric Patients

Careful dosage selection recommended due to possible age-related increased sensitivity to hypoglycemia; careful patient selection for full understanding of insulin adjustments and glucose monitoring is recommended.

Cautions for Pramlintide

Contraindications

• Confirmed diagnosis of gastroparesis.

• Hypoglycemic unawareness.

• Poor compliance with current insulin regimen or with self-monitoring of blood glucose concentrations.

• HbA_1c >9%.

• Recurrent episodes of hypoglycemia requiring medical assistance during the previous 6 months.

• Concomitant therapy with drugs that stimulate GI motility.

• Pediatric patients.

• Known hypersensitivity to pramlintide, metacresol, or any other ingredient in the formulation.

Warnings/Precautions

Warnings

Patient Selection

Appropriate patient selection required for safe and effective use of pramlintide. (See Diabetes Mellitus under Uses and also see Contraindications under Cautions.)

Assess patient’s glycosylated hemoglobin (HbA_1c), current insulin regimen, recent blood glucose monitoring data, history of insulin-induced hypoglycemia, and body weight prior to initiating therapy.

Ongoing care under the guidance of a clinician skilled in the use of insulin and supported by a diabetes educator required.

Hypoglycemia

Possible severe hypoglycemia, potentially resulting in serious injuries, with concomitant pramlintide and insulin therapy, particularly in patients with type 1 diabetes. Usually occurs within 3 hours following pramlintide injection.

Appropriate patient selection, careful patient instruction, frequent premeal and postmeal glucose monitoring, and an initial 50% reduction in pre-meal doses of short-acting insulin are important to avoid insulin-induced severe hypoglycemia. (See Patient Selection under Cautions and also see Dosage under Dosage and Administration.)

Rapid reductions in serum glucose concentrations may precipitate symptoms of hypoglycemia (e.g., hunger, headache, sweating, tremor, irritability, difficulty concentrating, loss of consciousness, coma, seizure), regardless of glucose concentration.

Early symptoms of hypoglycemia may be altered or decreased in patients with long-standing diabetes mellitus or diabetic neuropathy or those receiving intensive antidiabetic drug (e.g., insulin) regimens or sympatholytic agents. (See Specific Drugs under Interactions.)

Concomitant use with certain drugs (e.g., oral antidiabetic agents, ACE inhibitors, disopyramide, fibric acid derivatives, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates, sulfonamides) may increase risk of hypoglycemia. (See Specific Drugs under Interactions.)

Does not alter the counterregulatory hormonal response to insulin-induced hypoglycemia and does not appear to alter perception of hypoglycemic symptoms at plasma glucose concentrations as low as 45 mg/dL.

Sensitivity Reactions

Hypersensitivity Reactions

Possible localized allergic reactions (e.g., pruritus, erythema, swelling) at injection site; usually resolve in a few days to a few weeks.

Systemic hypersensitivity reactions reported in 5% of patients; discontinuance of therapy has not been required.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether pramlintide is distributed into milk. Use only if potential benefit outweighs the risk to the infant.

Pediatric Use

Safety and efficacy not established in children ≤17 years of age.

Geriatric Use

Response in patients ≤84 years of age does not appear to differ from that in younger adults, but increased sensitivity cannot be ruled out. Manage both pramlintide and insulin regimens carefully to obviate an increased risk of severe hypoglycemia.

Hepatic Impairment

Pharmacokinetics not evaluated but impact of hepatic impairment should be minimal.

Renal Impairment

No increased exposure or decreased clearance in patients with moderate or severe renal impairment (Cl_Cr 21–50 mL/minute); not studied in those undergoing dialysis.

Common Adverse Effects

Hypoglycemia, nausea, headache, anorexia, inflicted injury, vomiting, abdominal pain, arthralgia, fatigue, allergic reaction, dizziness, cough, pharyngitis.

Drug Interactions

Orally Administered Drugs

Possible decreased rate of absorption of concomitantly administered oral drugs. Administer ≥1 hour prior to or 2 hours after pramlintide injection if rapid onset of a concomitantly orally administered drug is a critical determinant of effectiveness.

Specific Drugs

Pramlintide Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is 30–40%.

Distribution

Extent

Does not extensively bind to blood cells.

Not known whether distributed into human milk.

Plasma Protein Binding

Approximately 60%; does not extensively bind to albumin.

Elimination

Metabolism

Metabolized principally by the kidneys primarily to the active metabolite des-lys¹ pramlintide (2-37 pramlintide).

Half-life

Approximately 48 minutes.

Stability

Storage

Parenteral

Solution for Injection

With unopened vials, 2–8°C. Do not freeze and protect from light. Discard vial if frozen or overheated. Vials in use may be stored at 2–25°C. Discard unused solution after 28 days.

Compatibility

Parenteral

Drug Compatibility

Incompatible with insulin (all types).

Actions

• An amylinomimetic agent that has physiologic actions equivalent to those of human amylin (glucoregulatory hormone synthesized by pancreatic β-cells and released with insulin in response to a meal).

• Inhibits inappropriately high glucagon secretion during episodes of hyperglycemia (e.g., after a meal) in patients with type 1 or type 2 diabetes mellitus; does not impair normal glucagon response to hypoglycemia.

• Slows gastric emptying and reduces the rate of glucose absorption from a meal without altering the net absorption of ingested carbohydrate and other nutrients.

• Prevents the initial postprandial glucose excursions usually observed with insulin therapy alone.

• Reduces food intake and increases satiety, possibly resulting in weight loss.

Advice to Patients

• Importance of adhering to diet and exercise regimen. Importance of regular monitoring (preferably self-monitoring) of blood glucose and HbA_1c.

• Importance of providing patient a copy of manufacturer’s patient information.

• Inform patients of the potential risks and advantages of pramlintide therapy.

• Importance of appropriate management of hypoglycemia and hyperglycemia, and assessment for other diabetes complications. Risk of hypoglycemia in patients receiving concomitant insulin therapy. Provide instructions regarding management of hypoglycemia, including recognition of symptoms, predisposing conditions, and treatment.

• Risk of nausea, particularly upon initiation of therapy.

• Importance of patient informing clinician of recurrent hypoglycemia or nausea.

• Provide instructions regarding proper use and storage of the injection. Importance of advising patient that if a dose is missed, resume the treatment regimen as prescribed with the next scheduled dose.

• Importance of providing instruction on proper injection technique and of administering pramlintide using a U-100 insulin syringe (preferably a 0.3-mL size for optimal accuracy) filled to the unit mark that corresponds to the volume to be injected.

• Importance of not mixing pramlintide with insulin. Importance of administering pramlintide and insulin as separate injections given at least 2 inches apart.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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