——降糖新药SYMLIN PEN(pramlintide acetate)获美国FDA批准上市 2014年8月，美国FDA批准醋酸普兰林肽预填充笔型注射剂(pramlintide acetate，SymlinPen 60/SymlinPen 120)上市，用于进餐时控制血糖。本品向患者提供了方便和准确剂量的用药器具。采用进餐胰岛素的糖尿病患者，添加醋酸普兰林肽可增强对血糖的控制。 SymlinPen 60的特点是每剂可释出15、30 、45或60 μg固定剂量的药物。SymlinPen 120的特点是每剂可释出60或120 μg固定剂量的药物。 2种笔型注射器在首次使用后均可在不超过30 ℃的室温储藏。醋酸普兰林肽不可单独与基础胰岛素(非进餐胰岛素)联用。 醋酸普兰林肽是首个和迄今唯一用于糖尿病患者与进餐胰岛素联用的支链淀粉模拟物。 本品并不适用于所有糖尿病患者，当其与胰岛素联用时会增加胰岛素引起的严重低血糖，尤其是1型糖尿病患者常发生。醋酸普兰林肽注射后3小时内可出现药物引起的严重低血糖。应注意当驾车、操作重型机器或进行其它危险活动时出现严重低血糖会产生严重伤害。醋酸普兰林肽与胰岛素联用时最常见的其它不良反应是恶心等胃肠道不适。 完整处方资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4aea30ff-eb0d-45c1-b114-3127966328ff ----------------------------------------------------------- 注：本品美国上市包装，不同规格和不同价格，购者以咨询为准 ----------------------------------------------------------- SYMLIN PEN 120 2.7ML 2 PRAMLINTIDE ACETATE  ASTRA/ZENECA PHARMACEUT  66780-0121-02             SYMLIN PEN 60 1.5ML 2  PRAMLINTIDE ACETATE  ASTRA/ZENECA PHARMACEUT  66780-0115-02             SYMLIN PEN 120 2.7ML 2 PRAMLINTIDE ACETATE  ASTRA/ZENECA PHARMACEUT  00310-6627-02             SYMLIN PEN 60 1.5ML 2  PRAMLINTIDE ACETATE  ASTRA/ZENECA PHARMACEUT  00310-6615-02 ----------------------------------------------------------- HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SYMLIN safely and effectively. See full prescribing information for SYMLIN. SYMLIN ® (pramlintide acetate) injection for subcutaneous use Initial U.S. Approval: 2005 WARNING: SEVERE HYPOGLYCEMIASee full prescribing information for complete boxed warning. • SYMLIN use with insulin has been associated with an increased risk of severe hypoglycemia, particularly in patients with type 1 diabetes. • Hypoglycemia risk may be reduced by appropriate patient selection, careful patient instruction, and insulin dose reduction (5.1, 5.2). RECENT MAJOR CHANGES Warnings and Precautions (5.3) 8/2014 INDICATIONS AND USAGE SYMLIN is an amylin analog indicated for patients with type 1 or type 2 diabetes who use mealtime insulin and have failed to achieve desired glycemic control despite optimal insulin therapy. (1) 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). DOSAGE FORMS AND STRENGTHS • 1.5 mL SymlinPen ® 60 disposable multidose pen-injector, (1000 mcg/mL) for 15, 30, 45, and 60 mcg doses (3). • 2.7 mL SymlinPen ® 120 disposable multidose pen-injector, (1000 mcg/mL) for 60 and 120 mcg doses (3). CONTRAINDICATIONS • Prior serious hypersensitivity reaction to SYMLIN or its ingredients (4) • Hypoglycemia unawareness (4) • Confirmed gastroparesis (4) 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). ADVERSE REACTIONS • Most common adverse reactions (incidence ≥5% and higher incidence than placebo): nausea, vomiting, anorexia, headache (6.1). To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.  See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 8/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 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. 2 DOSAGE AND ADMINISTRATION 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)]. 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. 2.3 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. 2.4 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. 2.5 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. 2.6 Preparation and Handling SYMLIN should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and the container permit. 3 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).  4 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. 5 WARNINGS AND PRECAUTIONS 5.1 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. 5.2 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. 5.3 Never Share a SymlinPen Between Patients SymlinPen should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.4 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)]. 5.5 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)]. 5.6 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)]. 5.7 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. 6 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. 6.1 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. 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 Examples of inflicted injury included among others, abrasions, bruises, burns, fractures, lacerations, and muscle strains. 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 (2)]. Severe Hypoglycemia Coadministration of SYMLIN with mealtime insulin increases the risk of severe hypoglycemia, particularly in patients with type 1 diabetes [seeBoxed 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. 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  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. 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. Table 4: Incidence and Event Rate of Severe Hypoglycemia in Six-Month, Placebo-Controlled Trials in Patients with Type 2 Diabetes Using Insulin 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. † 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 6.2 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  7 DRUG INTERACTIONS 7.1 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)]. 7.2 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)]. 7.3 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)]. 7.4 Drugs Affecting Glucose Metabolism The following are examples of medications that may increase the susceptibility to hypoglycemia when administered with SYMLIN: oral anti-diabetic products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, propoxyphene, salicylates, somatostatin analogs, and sulfonamide antibiotics. SYMLIN and these drugs should be coadministered with caution. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C No adequate and well-controlled studies have been conducted in pregnant women. Studies in perfused human placenta indicate that SYMLIN has low potential to cross the maternal/fetal placental barrier. Embryofetal toxicity studies with SYMLIN have been performed in rats and rabbits. Increases in congenital abnormalities (neural tube defect, cleft palate, exencephaly) were observed in fetuses of rats treated during organogenesis with 0.3 and 1.0 mg/kg/day (10 and 47 times the exposure resulting from the human dose of 360 mcg/day based on area under the plasma concentration curve [AUC], respectively). Administration of doses up to 0.3 mg/kg/day SYMLIN (9 times the human dose of 360 mcg/day based on AUC) to pregnant rabbits had no adverse effects in embryo fetal development; however, animal reproduction studies are not always predictive of human response. SYMLIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus 8.3 Nursing Mothers It is unknown whether SYMLIN is excreted in human milk. Many drugs, including peptides, are excreted in human milk. Therefore, SYMLIN should be administered to nursing women only if it is determined by the healthcare professional that the potential benefit outweighs the potential risk to the infant. 8.4 Pediatric Use Safety and effectiveness of SYMLIN in pediatric patients have not been established. 8.5 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. 8.6 Renal Impairment The dosing requirements for SYMLIN are not altered in patients with mild (creatinine clearance [ClCr] 60-89 mL/min), moderate (ClCr 30-59 mL/min) or severe renal impairment (ClCr 15-29 mL/min). SYMLIN has not been studied in patients with end-stage renal disease [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment SYMLIN use has not been studied in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 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). 8.9 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. 10 OVERDOSAGE Single 10 mg doses of SYMLIN (83 times the maximum recommended dose of 120 mcg for patients with type 2 diabetes) were administered to 3 healthy volunteers. All 3 individuals reported severe nausea associated with vomiting, diarrhea, vasodilatation, and dizziness. No hypoglycemia was reported. Pramlintide has a short half-life (approximately 48 minutes in healthy individuals). Initiate supportive measures in the case of overdose. 11 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 C171H267N51O53S2• × C2H4O2 (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. 12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 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. 12.3 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 (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. 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-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 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 (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. 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 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 (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 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. 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 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. 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 Cmax or AUC for ampicillin. However, the Tmax for ampicillin was delayed by approximately 60 minutes. 13 NONCLINICAL TOXICOLOGY 13.1 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 SYMLIN (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 SYMLIN (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 SYMLIN was not mutagenic in the Ames test and did not increase chromosomal aberration in the human lymphocytes assay. SYMLIN 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 SYMLIN (8, 17, and 82 times the exposure resulting from the human dose of 360 mcg/day of mcg based on body surface area) 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 significant decreases in serum calcium levels. 14 CLINICAL STUDIES A total of 2333 patients with type 1 diabetes and 1852 patients with type 2 diabetes received SYMLIN in controlled clinical trials. 14.1 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 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. Statistically significant reduction compared to placebo (p-value <0.05).  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/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  SD: standard deviation; LSM: least squares mean; SE: standard error; U: Units. Statistically significant reduction compared to placebo (p-value <0.05).  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. 14.2 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/m2 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. 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  SD: standard deviation; LSM: least squares mean; SE: standard error; U: Units. Statistically significant reduction compared to placebo (p-value <0.05).  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. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How SuppliedSYMLIN 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) 16.2 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. Table 9: Storage Conditions 17 PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide. 17.1 Risk of Hypoglycemia Discuss the risk and consequences of hypoglycemia and approaches to minimize its occurrence. Inform patients about the importance of self-management practices including glucose monitoring and timing of dosing. In addition, reinforce the importance of adherence to meal planning, physical activity, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. 17.2 Never Share a SymlinPen Between Patients Advise patients that they should never share a SymlinPen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens. 17.3 Never Mix SYMLIN and Insulin Inform patients that SYMLIN and insulin should always be administered as separate injections and never be mixed. Show patients how to administer SYMLIN using the pen-injector. Advise patients to use a new needle for each injection. 17.4 Instructions Inform patients of the potential risks and advantages of SYMLIN therapy. Advise women with diabetes to inform their healthcare professional if they are pregnant or contemplating pregnancy. Instruct patients on the proper injection technique and proper storage of SYMLIN. Instruct patients on handling of special situations such as intercurrent conditions (illness or stress), an inadequate or omitted insulin dose, inadvertent administration of increased insulin or SYMLIN dose, inadequate food intake or missed meals. Refer patients to the SYMLIN Medication Guide and Patient Instructions for Use for additional information.