<?xml version="1.0" encoding="UTF-8"?><section ID="S12">
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<code code="34090-1" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL PHARMACOLOGY SECTION"/>
<title>12 CLINICAL PHARMACOLOGY</title>
<effectiveTime value="20191218"/>
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<section ID="S12.1">
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<code code="43679-0" codeSystem="2.16.840.1.113883.6.1" displayName="MECHANISM OF ACTION SECTION"/>
<title>12.1 Mechanism of Action</title>
<text>
<paragraph>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).</paragraph>
<table width="100%">
<col width="100%"/>
<tbody>
<tr>
<td valign="top">
<paragraph>Figure 1: Secretion Profile of Amylin and Insulin in Healthy Adults</paragraph>
</td>
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<tr>
<td align="center" valign="top">
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<paragraph>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.</paragraph>
<paragraph>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.</paragraph>
<paragraph>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.</paragraph>
</text>
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<text>Figure 1</text>
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<code code="43681-6" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACODYNAMICS SECTION"/>
<title>12.2 Pharmacodynamics</title>
<text>
<paragraph>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.</paragraph>
</text>
<effectiveTime value="20191218"/>
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<title>Reduction in Postprandial Glucose Concentrations</title>
<text>
<paragraph>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<content styleCode="italics">
<linkHtml href="#S2"> Dosage and Administration (2)</linkHtml>
</content>].</paragraph>
<table width="100%">
<col width="100%"/>
<tbody>
<tr>
<td valign="top">
<paragraph>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</paragraph>
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<td align="center" valign="top">
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<paragraph>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.</paragraph>
</text>
<effectiveTime value="20191218"/>
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<text>Figure 2</text>
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<reference value="image-03.jpg"/>
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<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Reduced Food Intake</title>
<text>
<paragraph>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.</paragraph>
</text>
<effectiveTime value="20141212"/>
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<code code="43682-4" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACOKINETICS SECTION"/>
<title>12.3 Pharmacokinetics</title>
<effectiveTime value="20191218"/>
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<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Absorption</title>
<text>
<paragraph>The absolute bioavailability of pramlintide following a single subcutaneous dose of SYMLIN is approximately 30% to 40%. Subcutaneous administration of different doses of SYMLIN into the abdominal area or thigh of healthy individuals showed a linear, dose-dependent increase in maximum plasma concentrations (C<sub>max</sub>) and overall exposure (AUC) (Table 5).</paragraph>
<table ID="_Reftable5" width="100%">
<caption>Table 5: Mean Pharmacokinetic Parameters Following Administration of Single Subcutaneous Doses of SYMLIN</caption>
<col width="21%"/>
<col width="16%"/>
<col width="11%"/>
<col width="8%"/>
<col width="16%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Subcutaneous Dose</content>
<br/>
<content styleCode="bold">(mcg)</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">AUC <sub>(0-∞)</sub>
</content>
<br/>
<content styleCode="bold">(pmol*min/L)</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">C<sub>max</sub>
</content>
<br/>
<content styleCode="bold">(pmol/L)</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">T<sub>max</sub>
</content>
<br/>
<content styleCode="bold">(min)</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Elimination t<sub>½</sub>
</content>
<br/>
<content styleCode="bold">(min)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>30</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3750</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>39</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>21</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>55</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>60</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>6778</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>79</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>49</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>90</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8507</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>102</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>51</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>120</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>11970</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>147</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>21</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>48</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>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.</paragraph>
<paragraph>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.</paragraph>
</text>
<effectiveTime value="20191218"/>
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<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Distribution</title>
<text>
<paragraph>SYMLIN does not extensively bind to red blood cells or albumin (approximately 40% of the drug is unbound in plasma).</paragraph>
</text>
<effectiveTime value="20141212"/>
</section>
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<component>
<section ID="ID_baca4d93-8753-4c59-b6bd-6b4dce39a73e">
<id root="baca4d93-8753-4c59-b6bd-6b4dce39a73e"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Metabolism and Elimination</title>
<text>
<paragraph>In healthy individuals, the half-life of pramlintide is approximately 48 minutes. The primary metabolite, Des-lys<sup>1</sup> pramlintide (2-37 pramlintide), is biologically active <content styleCode="italics">in vitro</content>. Overall exposure (AUC) to pramlintide is relatively constant with repeat dosing of SYMLIN, indicating no bioaccumulation.</paragraph>
</text>
<effectiveTime value="20141212"/>
</section>
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<section ID="ID_76afdb86-578a-4787-aaad-2d90c96f0db9">
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<title>Specific Populations</title>
<effectiveTime value="20191218"/>
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<section ID="ID_66077429-ff3b-4dbb-b667-355d6d8c1f1c">
<id root="66077429-ff3b-4dbb-b667-355d6d8c1f1c"/>
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<title>
<content styleCode="bold">Renal Impairment</content>
</title>
<text>
<paragraph>No studies have been conducted in patients with end-stage renal disease. In a single-dose pharmacokinetic study in patients with type 1 diabetes, 60 mcg of SYMLIN was administered to 4 patients with normal renal function (Cl<sub>Cr</sub> >90 mL/min), 9 patients with mild renal impairment (Cl<sub>Cr</sub> 60-89 mL/min), 5 patients with moderate renal impairment (Cl<sub>Cr</sub> 30-59 mL/min) and 3 patients with severe renal impairment (Cl<sub>Cr</sub> 15-29 mL/min). No statistically significant differences were noted in total (AUC<sub>0-∞</sub>) and peak (C<sub>max</sub>) 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.</paragraph>
</text>
<effectiveTime value="20141212"/>
</section>
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<section ID="ID_e84130a8-5f65-4126-8011-b8857ebb7dfe">
<id root="e84130a8-5f65-4126-8011-b8857ebb7dfe"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Hepatic Impairment</content>
</title>
<text>
<paragraph>Pharmacokinetic studies have not been conducted in patients with hepatic impairment.</paragraph>
</text>
<effectiveTime value="20141212"/>
</section>
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<section ID="ID_27801cf0-0d32-4115-9ae9-32af61af9cdc">
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<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Geriatric</content>
</title>
<text>
<paragraph>Pharmacokinetic studies have not been conducted in the geriatric population [see<content styleCode="italics">
<linkHtml href="#_RefS8.5"> Use in Specific Populations (8.5)</linkHtml>
</content>].</paragraph>
</text>
<effectiveTime value="20191218"/>
</section>
</component>
<component>
<section ID="ID_8b7695ca-a0ad-448d-9957-6870e1523908">
<id root="8b7695ca-a0ad-448d-9957-6870e1523908"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Pediatric</content>
</title>
<text>
<paragraph>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<content styleCode="italics">
<linkHtml href="#S5.1"> Warnings and Precautions (5.1</linkHtml>,<linkHtml href="#S5.2"> 5.2)</linkHtml>
</content>].</paragraph>
</text>
<effectiveTime value="20141212"/>
</section>
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<component>
<section ID="ID_d7ef4c18-72f4-4df6-975f-3f8563c96f91">
<id root="d7ef4c18-72f4-4df6-975f-3f8563c96f91"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Gender</content>
</title>
<text>
<paragraph>No study has been conducted to evaluate the effect of gender on pramlintide pharmacokinetics.</paragraph>
</text>
<effectiveTime value="20141212"/>
</section>
</component>
<component>
<section ID="ID_0bd357c8-ea80-4334-a958-93cd5cd862cb">
<id root="0bd357c8-ea80-4334-a958-93cd5cd862cb"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Race/Ethnicity</content>
</title>
<text>
<paragraph>No study has been conducted to evaluate the effect of ethnicity on pramlintide pharmacokinetics.</paragraph>
</text>
<effectiveTime value="20141212"/>
</section>
</component>
</section>
</component>
<component>
<section ID="ID_a3b98d0a-e7c4-4da2-9de0-412b5fffc189">
<id root="a3b98d0a-e7c4-4da2-9de0-412b5fffc189"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Drug Interactions</title>
<effectiveTime value="20141212"/>
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<section ID="ID_1f887f28-304e-48eb-85d9-9418a55155ed">
<id root="1f887f28-304e-48eb-85d9-9418a55155ed"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Effect of Pre-Mixing SYMLIN with Insulin</content>
</title>
<text>
<paragraph>Pharmacokinetic profiles of pramlintide and insulins after coadministration of 30 mcg SYMLIN with different insulins (regular, NPH, and 70/30 premixed formulations of recombinant human insulin) as one subcutaneous injection, premixed in one syringe, were compared to those observed after the coadministration of SYMLIN and different insulins given as separate subcutaneous injections. The effects of premixing on pramlintide pharmacokinetics varied across the different insulin products with a maximum decrease of 40% in pramlintide C<sub>max</sub> and a maximum increase of 36% in pramlintide AUC<sub>0-∞</sub>. Similarly, effects of premixing on insulin pharmacokinetics varied across different insulin products with a maximum increase of 15% in insulin C<sub>max</sub> and up to a 20% increase in insulin AUC<sub>0-600min</sub>. Always administer SYMLIN and insulin as separate injections and never mix [see <content styleCode="italics">
<linkHtml href="#S5.3">Warnings and Precautions (5.4)</linkHtml>
</content>]<content styleCode="italics">.</content>
</paragraph>
</text>
<effectiveTime value="20141212"/>
</section>
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<component>
<section ID="ID_2a523c24-3474-45be-b025-65dfc0033896">
<id root="2a523c24-3474-45be-b025-65dfc0033896"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Acetaminophen</content>
</title>
<text>
<paragraph>When 1000 mg acetaminophen was given within 0, 1, and 2 hours after a 120 mcg SYMLIN injection in patients with type 2 diabetes (n=24), acetaminophen C<sub>max</sub> decreased by 29%, 23%, and 20%, respectively compared to placebo. The time to maximum plasma concentration or T<sub>max</sub> increased by 72, 48, and 48 minutes, respectively. SYMLIN did not significantly affect acetaminophen T<sub>max</sub> or C<sub>max</sub> 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.</paragraph>
</text>
<effectiveTime value="20141212"/>
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<component>
<section ID="ID_10b6a17b-f33a-4b25-ae38-96e3e5e7efb3">
<id root="10b6a17b-f33a-4b25-ae38-96e3e5e7efb3"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Oral Contraceptives</content>
</title>
<text>
<paragraph>When a single dose of a combination oral contraceptive product, containing 30 mcg ethinyl estradiol and 300 mcg norgestrel, was administered 15 minutes after SYMLIN injection (90 mcg dose) in healthy female subjects, there was no statistically significant change in the C<sub>max</sub> and AUC of ethinyl estradiol. However, the norgestrel C<sub>max</sub> was reduced by about 30% and T<sub>max</sub> was delayed by 45 minutes; there was no effect on norgestrel AUC. The clinical relevance of this change is unknown.</paragraph>
</text>
<effectiveTime value="20141212"/>
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<component>
<section ID="ID_95a9fa12-bbb7-4acd-8564-2150ded69c3c">
<id root="95a9fa12-bbb7-4acd-8564-2150ded69c3c"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Ampicillin</content>
</title>
<text>
<paragraph>The effect of concomitant administration of SYMLIN and ampicillin was evaluated in healthy volunteers. The administration of a single oral 500 mg dose of ampicillin 15 minutes after a single dose of SYMLIN (90 mcg) did not alter the C<sub>max</sub> or AUC for ampicillin. However, the T<sub>max</sub> for ampicillin was delayed by approximately 60 minutes.</paragraph>
</text>
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</section>
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</section>
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</section>
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