Pramlintide Acetate Injection

SYMLIN is indicated as an adjunctive treatment in patients with type 1 or type 2 diabetes who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.

Included as part of the PRECAUTIONS section.

Mechanism Of Action

Pramlintide is an analog of human amylin. Amylin is colocated with insulin in secretory granules and cosecreted with insulin by pancreatic beta cells in response to food intake. Amylin and insulin show similar fasting and postprandial patterns in healthy individuals (Figure 1).

Figure 1: Secretion Profile of Amylin and Insulin in Healthy Adults

In patients with type 1 and type 2 diabetes, there is reduced secretion from pancreatic beta cells of both insulin and amylin in response to food.

Amylin affects the rate of postprandial glucose appearance through a variety of mechanisms, as determined by nonclinical studies. 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.

In human studies, pramlintide, acting as an amylin analog, slows gastric emptying, reduces the postprandial rise in plasma glucagon, and modulates satiety leading to decreased caloric intake.

Pharmacodynamics

In clinical studies in patients with type 1 diabetes and patients with type 2 diabetes using mealtime insulin, SYMLIN reduced mean postprandial glucose concentrations, reduced glucose fluctuations, and reduced food intake.

In a randomized, single-blind, placebo-controlled, crossover study, 19 subjects with type 2 diabetes using insulin lispro, 19 subjects with type 1 diabetes using regular human insulin, and 21 subjects with type 1 diabetes using insulin lispro underwent mixed-meal tests. SYMLIN administered subcutaneously immediately prior to a meal reduced plasma glucose concentrations following the meal when used with mealtime insulin (rapid-acting insulin analogs or regular human insulin) (Figure 2). When rapid-acting insulin analogs were used, plasma glucose concentrations tended to rise during the interval between 150 minutes following SYMLIN injection and the next meal [see DOSAGE AND ADMINISTRATION].

Figure 2: Postprandial Plasma Glucose Profiles in Patients with Type 1 Diabetes or Type 2 Diabetes Receiving SYMLIN and Insulin Compared to Those Receiving Insulin Alone

While SYMLIN reduces postprandial glucose, clinical studies employing a controlled hypoglycemic challenge have demonstrated that SYMLIN does not alter the counter-regulatory hormonal response to insulin-induced hypoglycemia. Likewise, in SYMLIN-treated patients, the perception of hypoglycemic symptoms was not altered with plasma glucose concentrations as low as 45 mg/dL. In a separate clinical trial pramlintide also reduced the 24-hour glucose fluctuations based upon 24-hour glucose monitoring.

A single, subcutaneous dose of 30 mcg of SYMLIN to patients with type 1 diabetes and 120 mcg of SYMLIN to patients with type 2 diabetes administered 1 hour prior to an unlimited buffet meal was associated with reductions in total caloric intake (placebo-subtracted mean changes of ~21% and 23%, respectively), which occurred without decreases in meal duration.

Pharmacokinetics

The absolute bioavailability of pramlintide following a single subcutaneous dose of SYMLIN is approximately 30% to 40%. Subcutaneous administration of different doses of SYMLIN into the abdominal area or thigh of healthy individuals showed a linear, dose-dependent increase in maximum plasma concentrations (Cmax) and overall exposure (AUC) (Table 5).

Table 5: Mean Pharmacokinetic Parameters Following Administration of Single Subcutaneous Doses of SYMLIN

Injection of SYMLIN into the arm in obese patients with type 1 or type 2 diabetes showed higher overall exposure (20%-36%) with greater variability (% CV for AUC: 73%-106%), compared with exposure after injection of SYMLIN into the abdominal area or thigh.

Relative bioavailability of pramlintide was not significantly different between obese and non-obese patients and based on BMI or skin fold thickness. Injections administered with 6.0-mm and 12.7-mm needles yielded similar bioavailability.

SYMLIN does not extensively bind to red blood cells or albumin (approximately 40% of the drug is unbound in plasma).

In healthy individuals, the half-life of pramlintide is approximately 48 minutes. The primary metabolite, Des-lys1 pramlintide (2-37 pramlintide), is biologically active in vitro. Overall exposure (AUC) to pramlintide is relatively constant with repeat dosing of SYMLIN, indicating no bioaccumulation.

Specific Populations

No studies have been conducted in patients with end-stage renal disease. In a single-dose pharmacokinetic study in patients with type 1 diabetes, 60 mcg of SYMLIN was administered to 4 patients with normal renal function (ClCr > 90 mL/min), 9 patients with mild renal impairment (ClCr 60-89 mL/min), 5 patients with moderate renal impairment (ClCr 30-59 mL/min) and 3 patients with severe renal impairment (ClCr 15-29 mL/min). No statistically significant differences were noted in total (AUC0-∞) and peak (Cmax) exposure of pramlintide for mild, moderate, and severe renal impairment categories in comparison to patients with normal renal function; although, inter-patient variability in pharmacokinetic parameters was high.

Pharmacokinetic studies have not been conducted in patients with hepatic impairment.

Pharmacokinetic studies have not been conducted in the geriatric population [see Use In Specific Populations].

The efficacy and safety of SYMLIN have not been established in the pediatric population. The use of SYMLIN is not recommended in pediatric patients due to the risk of severe hypoglycemia [see WARNINGS AND PRECAUTIONS].

No study has been conducted to evaluate the effect of gender on pramlintide pharmacokinetics.

No study has been conducted to evaluate the effect of ethnicity on pramlintide pharmacokinetics.

Drug Interactions

Pharmacokinetic profiles of pramlintide and insulins after coadministration of 30 mcg SYMLIN with different insulins (regular, NPH, and 70/30 premixed formulations of recombinant human insulin) as one subcutaneous injection, premixed in one syringe, were compared to those observed after the coadministration of SYMLIN and different insulins given as separate subcutaneous injections. The effects of premixing on pramlintide pharmacokinetics varied across the different insulin products with a maximum decrease of 40% in pramlintide Cmax and a maximum increase of 36% in pramlintide AUC0-∞. Similarly, effects of premixing on insulin pharmacokinetics varied across different insulin products with a maximum increase of 15% in insulin Cmax and up to a 20% increase in insulin AUC0-600min. Always administer SYMLIN and insulin as separate injections and never mix [see WARNINGS AND PRECAUTIONS].

When 1000 mg acetaminophen was given within 0, 1, and 2 hours after a 120 mcg SYMLIN injection in patients with type 2 diabetes (n=24), acetaminophen Cmax decreased by 29%, 23%, and 20%, respectively compared to placebo. The time to maximum plasma concentration or Tmax increased by 72, 48, and 48 minutes, respectively. SYMLIN did not significantly affect acetaminophen Tmax or Cmax when acetaminophen was administered 1 to 2 hours before SYMLIN injection. SYMLIN did not affect acetaminophen AUC regardless of the time of acetaminophen administration in relation to SYMLIN injection.

When a single dose of a combination oral contraceptive product, containing 30 mcg ethinyl estradiol and 300 mcg norgestrel, was administered 15 minutes after SYMLIN injection (90 mcg dose) in healthy female subjects, there was no statistically significant change in the Cmax and AUC of ethinyl estradiol. However, the norgestrel Cmax was reduced by about 30% and Tmax was delayed by 45 minutes; there was no effect on norgestrel AUC. The clinical relevance of this change is unknown.

The effect of concomitant administration of SYMLIN and ampicillin was evaluated in healthy volunteers. The administration of a single oral 500 mg dose of ampicillin 15 minutes after a single dose of SYMLIN (90 mcg) did not alter the Cmax or AUC for ampicillin. However, the Tmax for ampicillin was delayed by approximately 60 minutes.

Clinical Studies

A total of 2333 patients with type 1 diabetes and 1852 patients with type 2 diabetes received SYMLIN in controlled clinical trials.

Type 1 Diabetes

The efficacy and safety of SYMLIN were evaluated in 3 (26-52-week), randomized, double-blind, placebo-controlled trials in patients with type 1 diabetes. In these studies, insulin adjustments were minimized in order to isolate the SYMLIN effect with insulin adjustments allowed, at the investigator's discretion, when excessive hypoglycemia was encountered. Patients participating in these 3 trials had a mean age of 40 years, a mean duration of diabetes of 17 years, and a mean body mass index of 25.9 kg/m².

Table 6 summarizes the 6-month results for those patients assigned to the 30 or 60 mcg dose of SYMLIN or placebo.

Table 6: Mean (SE) Change in HbA1c and Insulin at 6 Months in the Double-Blind, Placebo-Controlled Studies in Patients with Type 1 Diabetes for the Intent-to-Treat Population

In the three studies, from a mean baseline body weight of 75.3 kg, 73.3 kg, and 76.6 kg, respectively, after randomization there were corresponding mean reductions of –0.8 kg, –1.6 kg, and –1.3 kg (60 mcg TID) and –0.8 kg (60 mcg QID) in the SYMLIN treatment group compared to mean increases of +0.8 kg, +0.4 kg, and +0.7 kg in the placebo treatment group.

A dose-titration study of SYMLIN was conducted in patients with type 1 diabetes who had a mean age of 41 years, a mean duration of diabetes of 20 years, and a mean body mass index of 28 kg/m². Patients with a mean baseline HbA1c of 8.1% (range 6.5%-10.7%) were randomized to receive either SYMLIN or placebo, both administered before major meals as add-on to insulin therapy. SYMLIN was initiated at a dose of 15 mcg and titrated upward at weekly intervals in 15 mcg increments to maintenance doses of 30 or 60 mcg, based on whether patients experienced nausea. Upon initiation of SYMLIN, the insulin dose (mostly the mealtime insulin) was reduced by 30% to 50% in order to minimize the occurrence of hypoglycemia. Once the maintenance dose of SYMLIN was reached, insulin dose adjustments were made according to standard clinical practice, based on pre-and post-meal blood glucose monitoring.

Table 7 summarizes the 6-month results for the dose-titration study.

Table 7: Mean (SE) Change in HbA1c and Insulin at 6 Months in the Dose-Titration Study in Patients with Type 1 Diabetes for Intent-to-Treat Population

In the dose titration study, from mean baseline body weight of 81.5 kg, after randomization there was a mean reduction of –1.33 kg in the SYMLIN treatment group compared to a mean increase of +1.25 kg in the placebo treatment group.

Type 2 Diabetes

The efficacy and safety of SYMLIN were evaluated in 2 (a 26-week and a 52-week) randomized, double-blind, placebo-controlled trials in patients with type 2 diabetes. These trials enrolled patients with inadequate glycemic control (HbA1c > 8%) on fixed dose insulin. In both trials, SYMLIN or placebo was added to existing insulin therapies. Concomitant use of a sulfonylurea and/or metformin was permitted. Insulin doses were to be kept as stable as possible throughout the treatment period to isolate the SYMLIN effect.

Patients participating in these 2 trials had a mean age of 57 years and a mean duration of diabetes of 13 years. Mean body mass index was 32.9 kg/m² for SYMLIN and 32.2 kg/m²for placebo.

Table 8 summarizes the 6-month results for each trial for those patients assigned to the 120 mcg dose of SYMLIN and placebo.

Table 8: Mean (SE) Change in HbA1c and Insulin at 6 Months in the Double-Blind, Placebo-Controlled Studies in Patients with Type 2 Diabetes for the Intent-to-Treat Population

In both studies, from a mean baseline body weight of 96.7 kg, and 85.6 kg, respectively, after randomization there were corresponding mean reductions of –1.4 kg, and –1.6 kg in the SYMLIN treatment group compared to mean increases of +0.3 kg, and +0.1 kg in the placebo treatment group.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial Experience

Adverse reactions (excluding hypoglycemia, which is discussed separately below) commonly associated with SYMLIN when coadministered with a fixed dose of insulin in the 26-to 52-week, placebo-controlled trials in patients with type 1 diabetes and patients with type 2 diabetes on mealtime insulin are presented in Table 1 and Table 2, respectively.

Table 1: Patients with Type 1 Diabetes: Common Adverse Reactions (Incidence ≥ 5% and Greater Incidence with SYMLIN Compared to Placebo) in 3 Pooled Placebo-Controlled Trials

Table 2: Patients with Type 2 Diabetes on Insulin: Common Adverse Reactions (Incidence ≥ 5% and Greater Incidence with SYMLIN Compared to Placebo) in 2 Pooled Placebo-Controlled Trials

Most adverse reactions were gastrointestinal in nature. The incidence of nausea is higher at the beginning of SYMLIN treatment and decreases with time in most patients. Gradual titration of the SYMLIN dose minimizes the incidence and severity of nausea [see DOSAGE AND ADMINISTRATION].

Coadministration of SYMLIN with mealtime insulin increases the risk of severe hypoglycemia, particularly in patients with type 1 diabetes [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Two definitions of severe hypoglycemia were used in the SYMLIN clinical trials. Patient-ascertained severe hypoglycemia was defined as an episode of hypoglycemia requiring the assistance of another individual (including help administering oral carbohydrate) or requiring the administration of glucagon, intravenous glucose, or other medical intervention. Medically-assisted severe hypoglycemia was defined as an episode of hypoglycemia that was classified as a serious event by the investigator or that required glucagon, intravenous glucose, hospitalization, paramedic assistance or an emergency room visit. The incidence of severe hypoglycemia during the SYMLIN clinical development program is summarized in Table 3 and Table 4.

Table 3: Incidence and Event Rate of Severe Hypoglycemia in Six-Month, Placebo-Controlled Trials and Dose Titration Trial in Patients with Type 1 Diabetes

Table 4: Incidence and Event Rate of Severe Hypoglycemia in Six-Month, Placebo-Controlled Trials in Patients with Type 2 Diabetes Using Insulin

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of SYMLIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Injection site reactions
• Pancreatitis

Read the entire FDA prescribing information for Symlin (Pramlintide Acetate Injection)