|indication=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
|hasBlackBoxWarning=Yes
|hasBlackBoxWarning=Yes
|adverseReactions=<!--Black Box Warning-->
|adverseReactions=Abdominal pain , Loss of appetite, Nausea, Vomiting,
|blackBoxWarningTitle=WARNING: SEVERE HYPOGLYCEMIA
|blackBoxWarningBody=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.
* Content
|fdaLIADAdult=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.
SYMLIN is supplied as a sterile injection in the following dosage forms:
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
<!--Non–Guideline-Supported Use (Adult)-->
<!--Non–Guideline-Supported Use (Adult)-->
|offLabelAdultNoGuideSupport======Condition1=====
|offLabelAdultNoGuideSupport=
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
Line 69:
Line 27:
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
|fdaLIADPed======Condition1=====
|fdaLIADPed=
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
Line 82:
Line 34:
<!--Guideline-Supported Use (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
|offLabelPedGuideSupport======Condition1=====
|offLabelPedGuideSupport=
* Developed by:
* Class of Recommendation:
* Strength of Evidence:
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Non–Guideline-Supported Use (Pediatric)-->
<!--Non–Guideline-Supported Use (Pediatric)-->
|offLabelPedNoGuideSupport======Condition1=====
|offLabelPedNoGuideSupport=
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Contraindications-->
<!--Contraindications-->
|contraindications=* Condition1
|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=* 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.
* 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:
<!--Warnings-->
have failed to achieve adequate glycemic control despite individualized insulin management.
|warnings=* Description
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:
====Precautions====
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.
* Description
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)].
<!--Adverse Reactions-->
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.
<!--Clinical Trials Experience-->
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.
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
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)].
=====Cardiovascular=====
5.7 Allergy
Local Allergy
|clinicalTrials=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.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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
=====Digestive=====
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.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|postmarketing=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
|drugInteractions=* 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)].
=====Endocrine=====
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.
|FDAPregCat=C
|useInPregnancyFDA=* 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.
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=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.
|useInPed=Safety and effectiveness of SYMLIN in pediatric patients have not been established.
|useInGeri=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.
|useInGender=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).
|useInRace=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.
|useInRenalImpair=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
|useInHepaticImpair=SYMLIN use has not been studied in patients with hepatic impairment
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
=====Hematologic and Lymphatic=====
<!--Administration and Monitoring-->
|administration=* Subcutaneous
|monitoring=* Monitor glucoses frequently and individualize subsequent insulin dose adjustments.
* Monitor blood glucoses frequently, including pre- and post-meals and at bedtime, particularly when initiating SYMLIN or increasing the SYMLIN dose.
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
<!--Overdosage-->
|overdose=* 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.
|drugBox=<!--Mechanism of Action-->
|mechAction=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).
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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.
=====Metabolic and Nutritional=====
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.
=====Musculoskeletal=====
|structure=*
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
<!--Pharmacodynamics-->
|PD=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.
=====Neurologic=====
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
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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.
|PK=Absorption
=====Respiratory=====
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
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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
=====Skin and Hypersensitivy Reactions=====
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
=====Special Senses=====
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.
=====Urogenital=====
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)].
=====Miscellaneous=====
Gender
No study has been conducted to evaluate the effect of gender on pramlintide pharmacokinetics.
Race/Ethnicity
<!--Postmarketing Experience-->
No study has been conducted to evaluate the effect of ethnicity on pramlintide pharmacokinetics.
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
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)].
=====Cardiovascular=====
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
=====Digestive=====
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.
|nonClinToxic=* 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
=====Endocrine=====
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.
=====Hematologic and Lymphatic=====
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.
|clinicalStudies=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.
=====Metabolic and Nutritional=====
Table 6 summarizes the 6-month results for those patients assigned to the 30 or 60 mcg dose of SYMLIN or placebo.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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.
=====Musculoskeletal=====
Table 7 summarizes the 6-month results for the dose-titration study.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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.
=====Neurologic=====
Table 8 summarizes the 6-month results for each trial for those patients assigned to the 120 mcg dose of SYMLIN and placebo.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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.
|howSupplied=** 16.1 How Supplied
=====Respiratory=====
SYMLIN Injection is available in the following package sizes:
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.
=====Miscellaneous=====
<!--Drug Interactions-->
|drugInteractions=* Drug
:* Description
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
<!--Administration and Monitoring-->
|administration=* Oral
* Intravenous
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description
<!--IV Compatibility-->
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|overdose====Acute Overdose===
====Signs and Symptoms====
* Description
====Management====
* Description
===Chronic Overdose===
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
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|fdaPatientInfo=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.
<!--Pharmacokinetics-->
17.2 Never Share a SymlinPen Between Patients
|PK=There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.
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.
<!--Nonclinical Toxicology-->
17.3 Never Mix SYMLIN and Insulin
|nonClinToxic=There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
Inform patients that SYMLIN and insulin should always be administered as separate injections and never be mixed.
<!--Clinical Studies-->
Show patients how to administer SYMLIN using the pen-injector. Advise patients to use a new needle for each injection.
|clinicalStudies=There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.
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<!--Precautions with Alcohol-->
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.
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
<!--Brand Names-->
<!--Brand Names-->
|brandNames=* ®<ref>{{Cite web | title = | url = }}</ref>
|brandNames=*SYMLINPEN ®<ref>{{Cite web | title = SYMLINPEN- pramlintide acetate injection | url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2262f20-bedb-43d9-b274-6ce275b0a69e}}</ref>
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Black Box Warning
WARNING: SEVERE HYPOGLYCEMIA
See full prescribing information for complete Boxed Warning.
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.
Overview
Pramlintide is a antidiabetic that is FDA approved for the treatment of 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. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Abdominal pain , Loss of appetite, Nausea, Vomiting,
Hypersensitivity reaction, Dizziness, Headache.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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.
SYMLIN is supplied as a sterile injection in the following dosage forms:
See full prescribing information for complete Boxed Warning.
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.
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.
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
Adverse Reactions
Clinical Trials Experience
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.
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.
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.
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
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.
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.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pramlintide in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Pramlintide during labor and delivery.
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.
Pediatric Use
Safety and effectiveness of SYMLIN in pediatric patients have not been established.
Geriatic 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.
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
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.
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
Hepatic Impairment
SYMLIN use has not been studied in patients with hepatic impairment
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pramlintide in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Pramlintide in patients who are immunocompromised.
Administration and Monitoring
Administration
Subcutaneous
Monitoring
Monitor glucoses frequently and individualize subsequent insulin dose adjustments.
Monitor blood glucoses frequently, including pre- and post-meals and at bedtime, particularly when initiating SYMLIN or increasing the SYMLIN dose.
IV Compatibility
There is limited information regarding IV Compatibility of Pramlintide in the drug label.
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.
Pharmacology
There is limited information regarding Pramlintide Pharmacology in the drug label.
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).
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.
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
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 (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.
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.
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.
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.
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.
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
16.1 How Supplied
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
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.
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.
Precautions with Alcohol
Alcohol-Pramlintide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
