Symlinpen - Pramlintide Acetate injection prescribing information
WARNING: SEVERE HYPOGLYCEMIA
SYMLIN use with insulin increases the risk of severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia occurs, it is seen within 3 hours following a SYMLIN injection. Serious injuries may occur if severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities. Appropriate patient selection, careful patient instruction, and insulin dose reduction are critical elements for reducing this risk.
INDICATIONS AND USAGE
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.
DOSAGE AND ADMINISTRATION
- Upon initiation of SYMLIN, reduce mealtime insulin dose by 50%. Monitor glucoses frequently and individualize subsequent insulin dose adjustments (2.1) .
- Type 1 Diabetes: Start at 15 mcg subcutaneously before major meals. Increase in 15 mcg increments to a maximum premeal dose of 30 or 60 mcg; if not tolerated, reduce to 30 mcg, as tolerated (2.2) .
- Type 2 Diabetes: Start at 60 mcg subcutaneously before major meals then increase to 120 mcg before meals, as tolerated (2.2) .
- Wait at least 3 days between dose titrations to minimize nausea (2.1) .
Important Considerations Pertaining to SYMLIN and Insulin Dose Adjustments
SYMLIN dosage differs depending on whether the patient has type 1 or type 2 diabetes [see Dosage and Administration (2.2 , 2.3) ].
SYMLIN should be used only in patients who can fully understand and adhere to proper insulin adjustments and glucose monitoring.
Insulin and SYMLIN dose adjustments should be made only as directed by a healthcare professional skilled in the use of insulin.
When initiating SYMLIN, reduce mealtime insulin doses, including premixed insulins, by 50% to reduce the risk of hypoglycemia.
To reduce the risk of nausea, wait at least 3 days before titrating SYMLIN to the next dose increment.
Monitor blood glucoses frequently, including pre- and post-meals and at bedtime, particularly when initiating SYMLIN or increasing the SYMLIN dose. After the initial 50% reduction in mealtime insulin dose, individualize insulin dose adjustments based on glycemic control and tolerability (e.g., if nausea occurs it may affect the dose of insulin required). An increased frequency of mild-to-moderate hypoglycemia should be viewed as a warning sign of increased risk for severe hypoglycemia.
If SYMLIN therapy is discontinued for any reason (e.g., surgery or illnesses), the same initiation protocol should be followed when SYMLIN therapy is reinstituted [see Dosage and Administration (2.2) ].
Patients with Type 2 Diabetes Using Mealtime Insulin
Reduce mealtime insulin doses (including premixed insulins) by 50%, then initiate SYMLIN at 60 mcg subcutaneously, injecting immediately prior to each major meal.
Increase the SYMLIN dose from 60 to 120 mcg prior to each major meal when no clinically significant nausea has occurred for at least 3 days.
If significant nausea persists at the 120 mcg dose, the SYMLIN dose should be decreased to 60 mcg.
Patients with Type 1 Diabetes
Reduce mealtime insulin doses by 50%, then initiate SYMLIN at 15 mcg subcutaneously, injecting immediately prior to each major meal.
Increase the SYMLIN dose to the next increment (30, 45, or 60 mcg) when no clinically significant nausea has occurred for at least 3 days.
If significant nausea persists at the 45 or 60 mcg dose level, the SYMLIN dose should be decreased to 30 mcg. If the 30 mcg dose is not tolerated, discontinuation of SYMLIN therapy should be considered.
Administration
SYMLIN should be administered subcutaneously immediately prior to each major meal (≥250 kcal or containing ≥30 grams of carbohydrate).
SYMLIN should be at room temperature before injecting to reduce potential injection site reactions. Each SYMLIN dose should be administered subcutaneously into the abdomen or thigh. Administration into the arm is not recommended because of variable absorption. Injection sites should be rotated so that the same site is not used repeatedly. The injection site selected should also be distinct from the site chosen for any concomitant insulin injection.
SYMLIN and insulin should always be administered as separate injections.
SYMLIN should not be mixed with any type of insulin.
If a SYMLIN dose is missed, wait until the next scheduled dose and administer the usual amount.
Discontinuation of Therapy
SYMLIN therapy should be discontinued if there is:
- recurrent unexplained hypoglycemia that requires medical assistance.
- persistent clinically significant nausea.
- noncompliance with self-monitoring of blood glucose concentrations.
- noncompliance with insulin dose adjustments.
- noncompliance with scheduled healthcare provider contacts or recommended clinic visits.
Preparation and Handling
SYMLIN should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and the container permit.
DOSAGE FORMS AND STRENGTHS
SYMLIN is supplied as a sterile injection in the following dosage forms:
- 1.5 mL disposable multidose SymlinPen ® 60 pen-injector containing 1000 mcg/mL pramlintide (as acetate).
- 2.7 mL disposable multidose SymlinPen ® 120 pen-injector containing 1000 mcg/mL pramlintide (as acetate).
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
Available data from a small number of reports in the manufacturer’s safety database on SYMLIN use in pregnant women are not sufficient to determine a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy ( see Clinical Considerations ).
Ex-vivo studies using term perfused human, rabbit, and rat placentas indicate that SYMLIN has low potential to cross the maternal/fetal placental barrier. In animal reproduction studies, congenital abnormalities were observed in fetuses of pregnant rats but not in fetuses of pregnant rabbits exposed during organogenesis to pramlintide at 10 times the clinical dose of 360 mcg/day, based on exposure (see Data ).
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Animal Data
Developmental and reproductive toxicity studies with SYMLIN were performed in pregnant rats and rabbits. Increases in congenital abnormalities (neural tube defect, cleft palate, exencephaly) were observed in fetuses of pregnant rats administered pramlintide subcutaneously during organogenesis at 0.3 and 1 mg/kg/day (10 and 47 times the human dose of 360 mcg/day based on AUC, respectively), but not at 3mg/kg/day. Administration of pramlintide to pregnant rabbits during organogenesis resulted in maternal toxicity but did not increase fetal malformations at doses up to 0.3 mg/kg/day (9 times the human dose of 360 mcg/day based on AUC).
Lactation
Risk Summary
There is no data on the presence of pramlintide in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYMLIN and any potential adverse effects on the breastfed child from SYMLIN or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness of SYMLIN in pediatric patients have not been established.
Geriatric Use
SYMLIN has been studied in patients ranging in age from 15 to 84 years of age, including 769 patients ≥65 to 75 years of age and 87 patients ≥75 years of age. No consistent differences in the efficacy and safety of SYMLIN have been observed in older patients, but greater sensitivity in some older individuals cannot be ruled out. As is recommended for all patients, SYMLIN and insulin regimens should be carefully managed to minimize the risk of severe hypoglycemia.
Renal Impairment
The dosing requirements for SYMLIN are not altered in patients with mild (creatinine clearance [Cl Cr ] 60-89 mL/min), moderate (Cl Cr 30-59 mL/min) or severe renal impairment (Cl Cr 15-29 mL/min). SYMLIN has not been studied in patients with end-stage renal disease [see Clinical Pharmacology (12.3) ] .
Hepatic Impairment
SYMLIN use has not been studied in patients with hepatic impairment [see Clinical Pharmacology (12.3) ] .
Gender
No consistent differences in the efficacy and safety of SYMLIN have been observed between men and women in SYMLIN clinical trials (n=2799 for male and n=2085 for female).
Race/Ethnicity
No consistent differences in the efficacy and safety of SYMLIN have been observed among patients of differing race/ethnicity in SYMLIN clinical trials (n=4257 for Caucasian, n=229 for black, n=337 for Hispanic or Latino, and n=61 for Asian and one or more races) although the smaller sample sizes for non-Caucasians, particularly Asians, limit conclusions.
CONTRAINDICATIONS
SYMLIN is contraindicated in patients with any of the following:
- serious hypersensitivity reaction to SYMLIN or to any of its product components.
- hypoglycemia unawareness.
- confirmed gastroparesis.
WARNINGS AND PRECAUTIONS
- Severe hypoglycemia: Increased risk particularly for type 1 diabetes. Upon initiation of SYMLIN, reduce mealtime insulin dose by 50% and frequently monitor blood glucoses (5.2) .
- Never share a SymlinPen between patients, even if the needle is changed (5.3) .
- Do not mix SYMLIN and insulin: Mixing can alter the pharmacokinetics of both products. Administer as separate injections (5.4 , 7.1) .
- Slows gastric emptying: Administer concomitant oral medications at least 1 hour before or 2 hours after SYMLIN if rapid onset or threshold concentration is critical (5.6 , 7.2) .
Patient Selection
Proper patient selection is critical to the safe and effective use of SYMLIN. Before initiating SYMLIN, the patient's HbA1c, recent blood glucose monitoring data, history of insulin-induced hypoglycemia, current insulin regimen, and body weight should be reviewed. SYMLIN therapy should only be considered in patients with type 1 diabetes or patients with type 2 diabetes using mealtime insulin who fulfill the following criteria:
- have failed to achieve adequate glycemic control despite individualized insulin management.
- are receiving ongoing care under the guidance of a healthcare professional skilled in the use of insulin and supported by the services of diabetes educator(s).
Patients meeting any of the following criteria should NOT be considered for SYMLIN therapy:
- poor compliance with current insulin regimen.
- poor compliance with prescribed self blood glucose monitoring.
- have a HbA1c >9%.
- recurrent severe hypoglycemia requiring assistance during the past 6 months.
- presence of hypoglycemia unawareness.
- confirmed diagnosis of gastroparesis.
- require the use of drugs that stimulate gastrointestinal motility.
- pediatric patients.
SYMLIN should be prescribed with caution to persons with visual or dexterity impairment.
Hypoglycemia
SYMLIN alone does not cause hypoglycemia. However, SYMLIN is indicated to be coadministered with mealtime insulin therapy, and in this setting there is an increased risk of severe hypoglycemia, particularly in patients with type 1 diabetes. If severe hypoglycemia associated with SYMLIN occurs, it is usually seen within the first 2 to 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries or death may occur. Therefore, when introducing SYMLIN therapy, appropriate precautions need to be taken to avoid increasing the risk for severe hypoglycemia. These precautions include frequent monitoring of pre- and post-meal glucose combined with an initial 50% reduction in doses of mealtime insulin [see Dosage and Administration (2.1 , 2.2 ) ].
Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes; diabetic neuropathy; use of medications such as beta-blockers, clonidine, guanethidine, or reserpine; or intensified glycemic control.
The addition of any anti-diabetic medication, such as SYMLIN, to an existing regimen of one or more anti-diabetic medications (e.g., sulfonylurea), or other medications that can increase the risk of hypoglycemia may necessitate further insulin dose adjustments and particularly close monitoring of blood glucose.
Never Share a SymlinPen Between Patients
SymlinPen must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.
Never Mix SYMLIN and Insulin
Mixing SYMLIN and insulin can alter the pharmacokinetics of both products which may result in inadequate glucose control or hypoglycemia. Therefore, SYMLIN and insulin must always be administered as separate injections and should never be mixed [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].
Concomitantly Administered Oral Medications
SYMLIN slows gastric emptying, which may delay the absorption of concomitantly administered oral medications. Administer the concomitant oral medication at least 1 hour prior to SYMLIN injection or 2 hours after SYMLIN injection if the rapid onset or threshold concentration of the concomitant medication is a critical determinant of its effectiveness (such as with analgesics, antibiotics, and oral contraceptives) [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ].
Medications that Affect Gastrointestinal Motility
SYMLIN slows gastric emptying. SYMLIN is not recommended for patients taking other medications that alter gastrointestinal motility [see Drug Interactions (7.3) ].
Allergy
Local Allergy
Patients may experience erythema, edema, or pruritus at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than SYMLIN, such as irritants in a skin cleansing agent or improper injection technique.
ADVERSE REACTIONS
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)
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.
| Long-Term, Placebo-Controlled Studies | ||
|---|---|---|
| SYMLIN 30 or 60 mcg 3 Times Daily + Insulin | Placebo + Insulin | |
| (N=716) % | (N=538) % | |
Nausea | 48 | 17 |
Anorexia | 17 | 2 |
Inflicted Injury Examples of inflicted injury included among others, abrasions, bruises, burns, fractures, lacerations, and muscle strains. | 14 | 10 |
Vomiting | 11 | 7 |
Arthralgia | 7 | 5 |
Fatigue | 7 | 4 |
Allergic Reaction | 6 | 5 |
Dizziness | 5 | 4 |
| Long-Term, Placebo-Controlled Studies | ||
|---|---|---|
| SYMLIN 120 mcg 2 Times Daily + Insulin | Placebo + Insulin | |
| (N=292) % | (N=284) % | |
Nausea | 28 | 12 |
Headache | 13 | 7 |
Anorexia | 9 | 2 |
Vomiting | 8 | 4 |
Abdominal pain | 8 | 7 |
Fatigue | 7 | 4 |
Dizziness | 6 | 4 |
Cough | 6 | 4 |
Pharyngitis | 5 | 2 |
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 (2) ].
Severe Hypoglycemia
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 (5.1) ].
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.
| Long-Term, Placebo-Controlled Studies (No Insulin Dose-Reduction During Initiation) | Placebo-Controlled Dose Titration Study | |||||||
|---|---|---|---|---|---|---|---|---|
| SYMLIN + Insulin | Placebo + Insulin | SYMLIN + Insulin | Placebo + Insulin | |||||
| Severe Hypoglycemia | 0 to 3 Months (n=716) | >3 to 6 Months (n=576) | 0 to 3 Months (n=538) | >3 to 6 Months (n=470) | 0 to 3 Months (n=148) | >3 to 6 Months (n=133) | 0 to 3 Months (n=147) | >3 to 6 Months (n=138) |
Patient-Ascertained Patient-ascertained severe hypoglycemia: Requiring the assistance of another individual (including help ingesting oral carbohydrate) and/or requiring the administration of glucagon injection, intravenous glucose, or other medical intervention. | ||||||||
Event Rate (events/patient-year) | 1.55 | 0.82 | 1.33 | 1.06 | 0.69 | 0.49 | 0.28 | 0.3 |
Subject Incidence (%) | 16.8 | 11.1 | 10.8 | 8.7 | 13.5 | 10.5 | 6.1 | 5.8 |
Medically-Assisted Medically-assisted severe hypoglycemia: Requiring glucagon, intravenous glucose, hospitalization, paramedic assistance, emergency room visit, and/or assessed as a serious adverse event by the investigator. | ||||||||
Event Rate (events/patient-year) | 0.50 | 0.27 | 0.19 | 0.24 | 0.14 | 0.20 | 0.08 | 0.15 |
Subject Incidence (%) | 7.3 | 5.2 | 3.3 | 4.3 | 3.4 | 4.5 | 2.0 | 2.9 |
| Long-Term, Placebo-Controlled Studies (No Insulin Dose-Reduction During Initiation) | ||||
|---|---|---|---|---|
| SYMLIN + Insulin | Placebo + Insulin | |||
| Severe Hypoglycemia | 0 to 3 Months (n=292) | >3 to 6 Months (n=255) | 0 to 3 Months (n=284) | >3 to 6 Months (n=251) |
Patient-Ascertained Patient-ascertained severe hypoglycemia : Requiring the assistance of another individual (including help ingesting oral carbohydrate) and/or requiring the administration of glucagon injection, intravenous glucose, or other medical intervention. | ||||
Event Rate (events/patient-year) | 0.45 | 0.39 | 0.24 | 0.13 |
Subject Incidence (%) | 8.2 | 4.7 | 2.1 | 2.4 |
Medically-Assisted Medically-assisted severe hypoglycemia : Requiring glucagon, intravenous glucose, hospitalization, paramedic assistance, emergency room visit, and/or assessed as a serious adverse event by the investigator. | ||||
Event Rate (events/patient-year) | 0.09 | 0.02 | 0.06 | 0.07 |
Subject Incidence (%) | 1.7 | 0.4 | 0.7 | 1.2 |
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
DRUG INTERACTIONS
Insulin
The pharmacokinetic parameters of pramlintide are altered when SYMLIN is mixed in the same syringe with regular, NPH, and 70/30 premixed formulations of recombinant human insulin. SYMLIN and insulin must not be mixed and must be administered as separate injections [see Dosage and Administration (2.4) , Warnings and Precautions (5.4) , and Clinical Pharmacology (12.3) ].
Oral Medications
SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset or threshold concentration of a concomitant orally administered medication is a critical determinant of effectiveness (such as with analgesics, antibiotics, and oral contraceptives), the medication should be administered at least 1 hour prior to SYMLIN injection or 2 hours after SYMLIN injection [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ].
Drugs Affecting Gastrointestinal Motility
Due to its effects on gastric emptying, SYMLIN should not be considered for patients taking medications that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) or medications that slow the intestinal absorption of nutrients (e.g., alpha-glucosidase inhibitors). Patients using these medications have not been studied in SYMLIN clinical trials [see Warnings and Precautions (5.6) ].
Drugs Affecting Glucose Metabolism
The following are examples of medications that may increase the susceptibility to hypoglycemia when administered with SYMLIN: anti-diabetic products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics. SYMLIN and these drugs should be coadministered with caution.
DESCRIPTION
SYMLIN ® (pramlintide acetate) injection is an anti-diabetic medication for use in patients with diabetes treated with insulin. Pramlintide is a synthetic analog of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells that contributes to glucose control during the postprandial period. Pramlintide is provided as an acetate salt of the synthetic 37-amino acid polypeptide, which differs in amino acid sequence from human amylin by replacement with proline at positions 25 (alanine), 28 (serine), and 29 (serine).
The structural formula of pramlintide acetate is shown below:
Pramlintide acetate is a white powder that has a molecular formula of C 171 H 267 N 51 O 53 S 2 • × C 2 H 4 O 2 (3≤ × ≤8); the molecular weight is 3949.4. Pramlintide acetate is soluble in water.
SYMLIN is formulated as a clear, isotonic, sterile solution for subcutaneous administration. The disposable multidose SymlinPen ® pen-injector contains 1000 mcg/mL of pramlintide (as acetate). The formulation contains 2.25 mg/mL of metacresol as a preservative, D-mannitol as a tonicity modifier, acetic acid, sodium acetate as pH modifiers, and water for injection. SYMLIN has a pH of approximately 4.0.
CLINICAL PHARMACOLOGY
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.
Reduction in Postprandial Glucose Concentrations
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 (2) ].
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.
Reduced Food Intake
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
Absorption
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 (C max ) and overall exposure (AUC) (Table 5).
| Subcutaneous Dose (mcg) | AUC (0-∞) (pmol•min/L) | C max (pmol/L) | T max (min) | Elimination t ½ (min) |
|---|---|---|---|---|
30 | 3750 | 39 | 21 | 55 |
60 | 6778 | 79 | 20 | 49 |
90 | 8507 | 102 | 19 | 51 |
120 | 11970 | 147 | 21 | 48 |
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.
Distribution
SYMLIN does not extensively bind to red blood cells or albumin (approximately 40% of the drug is unbound in plasma).
Metabolism and Elimination
In healthy individuals, the half-life of pramlintide is approximately 48 minutes. The primary metabolite, Des-lys 1 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
Renal Impairment
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 (Cl Cr >90 mL/min), 9 patients with mild renal impairment (Cl Cr 60-89 mL/min), 5 patients with moderate renal impairment (Cl Cr 30-59 mL/min) and 3 patients with severe renal impairment (Cl Cr 15-29 mL/min). No statistically significant differences were noted in total (AUC 0-∞ ) and peak (C max ) 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.
Hepatic Impairment
Pharmacokinetic studies have not been conducted in patients with hepatic impairment.
Geriatric
Pharmacokinetic studies have not been conducted in the geriatric population [see Use in Specific Populations (8.5) ].
Pediatric
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 (5.1 , 5.2) ].
Gender
No study has been conducted to evaluate the effect of gender on pramlintide pharmacokinetics.
Race/Ethnicity
No study has been conducted to evaluate the effect of ethnicity on pramlintide pharmacokinetics.
Drug Interactions
Effect of Pre-Mixing SYMLIN with Insulin
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 C max and a maximum increase of 36% in pramlintide AUC 0-∞ . Similarly, effects of premixing on insulin pharmacokinetics varied across different insulin products with a maximum increase of 15% in insulin C max and up to a 20% increase in insulin AUC 0-600min . Always administer SYMLIN and insulin as separate injections and never mix [see Warnings and Precautions (5.4) ] .
Acetaminophen
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 C max decreased by 29%, 23%, and 20%, respectively compared to placebo. The time to maximum plasma concentration or T max increased by 72, 48, and 48 minutes, respectively. SYMLIN did not significantly affect acetaminophen T max or C max 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.
Oral Contraceptives
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 C max and AUC of ethinyl estradiol. However, the norgestrel C max was reduced by about 30% and T max was delayed by 45 minutes; there was no effect on norgestrel AUC. The clinical relevance of this change is unknown.
Ampicillin
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 C max or AUC for ampicillin. However, the T max for ampicillin was delayed by approximately 60 minutes.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
A two-year carcinogenicity study was conducted in CD-1 mice with doses of 0.2, 0.5, and 1.2 mg/kg/day of pramlintide (32, 67, and 159 times the exposure resulting from the human dose of 360 mcg/day based on area under the plasma concentration curve or AUC, respectively). No drug-induced tumors were observed. A two-year carcinogenicity study was conducted in Sprague-Dawley rats with doses of 0.04, 0.2, and 0.5 mg/kg/day of pramlintide (3, 9, and 25 times the exposure resulting from the human dose of 360 mcg/day based on AUC, respectively). No drug-induced tumors were observed in any organ.
Mutagenesis
Pramlintide was not mutagenic in the Ames test and did not increase chromosomal aberration in the human lymphocytes assay. Pramlintide was not clastogenic in the in vivo mouse micronucleus test or in the chromosomal aberration assay utilizing Chinese hamster ovary cells.
Impairment of Fertility
Administration of 0.3, 1, or 3 mg/kg/day of pramlintide (up to 140 times the human dose of 360 mcg/day based on exposure) prior to and during mating had no significant effects on fertility in male or female rats. The highest dose of 3 mg/kg/day resulted in dystocia in 8/12 female rats secondary to maternal toxicity and significant decreases in serum calcium levels.
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/m 2 .
Table 6 summarizes the 6-month results for those patients assigned to the 30 or 60 mcg dose of SYMLIN or placebo.
| Trial 1 | Trial 2 | Trial 3 | |||||
|---|---|---|---|---|---|---|---|
| Variable | SYMLIN (30/60 mcg) | Placebo | SYMLIN (60 mcg) | Placebo | SYMLIN (60 mcg TID) | SYMLIN (60 mcg QID) | Placebo |
| N=243 | N=237 | N=148 | N=147 | N=164 | N=161 | N=154 | |
Baseline HbA 1c (%) (SD) | 8.7 (1.33) | 8.9 (1.46) | 9.0 (1.12) | 9.1 (1.08) | 8.9 (1.1) | 8.9 (1.0) | 9.0 (1.1) |
LSM Change in HbA 1c at 6 Months Relative to Baseline (%) (SE) | –0.58 (0.07) Statistically significant reduction compared to placebo (p-value <0.05). | –0.25 (0.07) | –0.24 (0.09) | +0.08 (0.09) | –0.44 (0.07) | –0.44 (–0.07) | –0.19 (0.08) |
Placebo- Subtracted LSM change in HbA 1c at 6 Months (%) | –0.34 | NA | –0.32 | NA | –0.25 | –0.25 | NA |
Mean Insulin Doses at Baseline: Mealtime/Bolus (U) (SE) | NM | NM | 29.5 (1.4) | 28.5 (1.1) | 19.9 (1.2) | 19.8 (2.2) | 19.8 (1.3) |
Mean Change in Insulin Doses (U) at 6 Months: Mealtime/Bolus (SE) | NM | NM | –2.0 (0.5) | +0.3 (0.4) | +0.6 (0.8) | –0.8 (0.7) | +0.3 (1.4) |
Mean Insulin Doses at Baseline: Basal (U) (SE ) | NM | NM | 21.0 (1.1) | 21.0 (1.1) | 33.1 (1.7) | 33.7 (1.6) | 31.9 (1.8) |
Mean Change in Insulin Doses (U) at 6 Months: Basal (SE) | NM | NM | +0.2 (0.3) | –0.3 (0.4) | –0.1 (0.9) | –0.6 (0.7) | +0.6 (0.7) |
SD: standard deviation; LSM: least squares mean; SE: standard error; U: Units; NM: not measured; TID: 3 times a day; QID: 4 times a day. | |||||||
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.
SYMLIN Dose-Titration Study
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/m 2 . 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.
| Variable | SYMLIN (all doses) | Placebo |
|---|---|---|
| N=148 | N=147 | |
Mean Baseline HbA 1c (%), (SD) | 8.1 (0.8) | 8.1 (0.8) |
LSM Change in HbA 1c at Week 29 Relative to Baseline (%) | –0.47 (0.07) | –0.49 (0.07) |
Placebo-Subtracted LSM change in HbA 1c at 6 Months (%) (SE) | 0.03 (0.10) | NA |
Mean Insulin Doses at Baseline: Mealtime/Bolus (U) (SD) | 26.5 (14.2) | 28.4 (16.3) |
Mean Percent Change in Insulin Doses (U) at 6 Months: Mealtime/Bolus (SE) | –7.1 (0.9) Statistically significant reduction compared to placebo (p-value <0.05). | –2.4 (1.2) |
Mean Insulin Doses at Baseline: Basal (U) (SD ) | 29.4 (19.6) | 28.1 (17.5) |
Mean Change in Insulin Doses (U) at 6 Months: Basal (SE) | +1.4 (0.9) | +2.6 (1.2) |
SD: standard deviation; LSM: least squares mean; SE: standard error; U: Units. | ||
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/m 2 for SYMLIN and 32.2 kg/m 2 for placebo.
Table 8 summarizes the 6-month results for each trial for those patients assigned to the 120 mcg dose of SYMLIN and placebo.
| Trial 1 | Trial 2 | |||
|---|---|---|---|---|
| Variable | SYMLIN (120 mcg) | Placebo | SYMLIN (120 mcg) | Placebo |
| N=166 | N=161 | N=126 | N=123 | |
Baseline HbA 1c (%) (SD) | 9.0 (0.08) | 9.3 (0.10) | 9.3 (1.1) | 9.5 (1.4) |
LSM Change in HbA 1c at 6 Months Relative to Baseline (%) (SE) | –0.66 (0.08) dStatistically significant reduction compared to placebo (p-value <0.05). | –0.32 (0.09) | –0.36 (0.10) | –0.06 (0.10) |
Placebo-Subtracted LSM change in HbA 1c at 6 Months (%) | –0.34 | NA | –0.30 | NA |
Insulin Dose at Baseline: Mealtime/Bolus (U) (SE) | 20.7 (1.6) | 21.4 (1.5) | 22.2 (1.8) | 22.0 (1.6) |
Mean Change in Insulin Doses (U) at 6 Months: Mealtime/Bolus (SE) | –0.7 (0.5) | –0.3 (0.6) | –0.0 (0.8) | +1.6 (0.7) |
Insulin Dose at Baseline: Basal (U) (SE) | 48.0 (1.9) | 52.4 (2.1) | 33.2 (1.4) | 30.9 (1.6) |
Mean Change in Insulin Doses (U) at 6 Months: Basal (SE) | +0.01 (0.8) | +1.1 (1.0) | –1.2 (0.8) | +1.3 (0.7) |
SD: standard deviation; LSM: least squares mean; SE: standard error; U: Units. | ||||
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.
HOW SUPPLIED/STORAGE AND HANDLING
SYMLIN Injection is available in the following package sizes:
- SymlinPen ® 60 pen-injector, containing 1000 mcg/mL pramlintide (as acetate) Two 1.5 mL disposable multidose pen-injectors (NDC 0310-6615-02)
- SymlinPen ® 120 pen-injector, containing 1000 mcg/mL pramlintide (as acetate) Two 2.7 mL disposable multidose pen-injectors (NDC 0310-6627-02)
Storage and Handling
SYMLIN pen-injectors not in use: Refrigerate (2°C to 8°C; 36°F to 46°F), and protect from light. Do not freeze. Do not use if product has been frozen. Unused SYMLIN (opened or unopened) should not be used after the expiration (EXP) date printed on the carton and the label.
SYMLIN pen-injectors in use: After first use, refrigerate or keep at a temperature not greater than 86°F (30°C) for 30 days. Use within 30 days, whether or not refrigerated.
Storage conditions are summarized in Table 9.
| Dosage Form | Unopened (not in use) Refrigerated | Open (in use) Refrigerated or Temperature up to 86°F (30°C) |
|---|---|---|
1.5 mL pen-injector | Until Expiration Date | Use Within 30 Days |
2.7 mL pen-injector |
Instructions for Use
SymlinPen ® (SĬM-lĭnP ε n) 120
(pramlintide acetate) Pen-Injector
Read the Medication Guide and these Instructions for Use before you start using SYMLIN and each time you get a refill. There may be new information.
Do not share your SymlinPen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.
Important:
- Ask your healthcare provider about your dose of SYMLIN and how to inject SYMLIN the right way before you inject it for the first time.
- Use a new needle for each SYMLIN injection. Do not reuse or share your needles with other people. You may give other people a serious infection, or get a serious infection from them.
- This SymlinPen is not recommended for use by the blind or visually impaired without the assistance of a person trained in the proper use of this SymlinPen.
- Check SYMLIN before you use it. SYMLIN should be clear and colorless. Do not use SYMLIN if the liquid looks cloudy or colored or has lumps or particles in it.
- Your SymlinPen may look empty because SYMLIN is a clear and colorless liquid.
- Small bubbles will not hurt you or affect your dose of SYMLIN.
- Do not transfer SYMLIN from your SymlinPen into a syringe.
- Do not inject your dose of SYMLIN if you:
- have low blood sugar (hypoglycemia)
- do not plan to eat. Do not inject SYMLIN if you skip a meal. Wait until the next meal and take your usual dose of SYMLIN at that meal.
- plan to eat a meal with less than 250 calories or 30 grams of carbohydrate
- are sick and cannot eat your usual meal
- are having surgery or a medical test where you cannot eat
- If you take more than your prescribed dose of SYMLIN, you may get nauseous or vomit, and may not be able to eat the amount of food you usually eat. If you take more SYMLIN than your prescribed dose, pay careful attention to the amount of insulin you use because you may be at more risk for low blood sugar. Contact your healthcare provider for guidance.
Supplies you will need to give each injection of SYMLIN:
- SymlinPen ® 120 Pen-Injector (Pen) (See Figure A)
- a new SymlinPen compatible needle (See Figure B). Pen needles are not included. Use 29, 30, or 31 gauge disposable pen needles. Ask your healthcare provider which needle gauge and length is best for you.
- alcohol swab
- 1 sharps container for throwing away used SymlinPens and needles. See “Disposing of used SymlinPens and needles” at the end of these Instructions for Use.
(Figure A)
(Figure B)
Preparing your SymlinPen:
- Wash your hands with soap and water.
- Check the SymlinPen label before each use to make sure you have the right SymlinPen.
- Check the expiration date (EXP) on the SymlinPen label (See Figure A). Do not use the SymlinPen past the expiration date printed on the label.
- Check the liquid in your SymlinPen to make sure you have enough SYMLIN left in your SymlinPen to load your correct dose.
- The lines on the cartridge show about how much SYMLIN is left in your SymlinPen. When the top of the plunger is at the thickest line on the cartridge, your SymlinPen is almost empty (See Figure C).
(Figure C)
Attaching a Needle:
Step 1:
|  Figure D |
Step 2:
|  Figure E |
Step 3:
|  Figure F |
Step 4:
|  Figure G |
New Pen Setup - Priming your SymlinPen:
Note:
- Steps 5 through 7 are only required if you are using your SymlinPen for the first time. Do not repeat Step 1 through 4 before each dose.
- If you have already primed your SymlinPen, go to Step 8 for instructions about giving your scheduled dose.
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Selecting your routine dose:
Step 8:
|  Figure K |
Step 9:
|  Figure L |
Step 10:
|  Figure M  Figure N |
Giving your SYMLIN injection:
- Inject your SYMLIN exactly as your doctor has shown you.
- Change (rotate) injection sites for SYMLIN. Inject SYMLIN at a site that is more than 2 inches away from your insulin injection. Do not inject SYMLIN and insulin in the same site.
- To help reduce the chances of getting a reaction at the injection site, let SYMLIN come to room temperature before you inject it.
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Step 14:
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Step 15:
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Step 16:
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Step 17:
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After your injection:
- Put your used needles and SymlinPen in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.
- If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
- made of a heavy-duty plastic,
- can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
- upright and stable during use,
- leak-resistant, and
- properly labeled to warn of hazardous waste inside the container.
- When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and SymlinPen. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
- Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
- If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
How should I store my SymlinPen?
Unused SymlinPens:
- Keep SYMLIN in the refrigerator between 36°F to 46°F (2°C to 8°C), until you are ready to use it.
- Do not freeze. Do not use SYMLIN if it has been frozen.
- Keep unopened SYMLIN out of the light.
Used SymlinPens:
- Store SymlinPens in the refrigerator or at room temperature between 36°F to 86°F (2°C to 30°C) for up to 30 days.
- Throw away used SymlinPens after 30 days of use, even if a used SymlinPen still has medicine in it.
- Do not use SymlinPens (opened or unopened) after the expiration (EXP) date printed on the carton and the label.
General information about the safe and effective use of SymlinPens.
- If you drop your SymlinPen, you should prime it before you use it to make sure your SymlinPen works.
- Do not use your SymlinPen if any part looks broken or damaged.
- Keep SYMLIN and all medicines out of the reach of children.
- It is not known if SYMLIN is safe and effective in children.
If you are having problems using your SymlinPen, go to www.SYMLIN.com or call Information Support at 1-800-236-9933.
These Instructions for Use have been approved by the U.S. Food and Drug Administration.
SYMLIN and SymlinPen are registered trademarks of the AstraZeneca group of companies.
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Revised: March 2015
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 |
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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.
