JANUVIA (Page 5 of 7)

14.2 Combination Therapy

Add-on Combination Therapy with Metformin

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with metformin. Patients already on metformin HCl (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week single-blind placebo run-in period. Patients on metformin and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin HCl (at a dose of at least 1500 mg per day) in monotherapy. Patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

In combination with metformin, JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 7). Rescue glycemic therapy was used in 5% of patients treated with JANUVIA 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 7: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Add-on Combination Therapy with Metformin *
JANUVIA 100 mg + MetforminPlacebo + Metformin
*
Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.
Least squares means adjusted for prior antihyperglycemic therapy and baseline value.
p<0.001 compared to placebo + metformin.
A1C (%)N = 453N = 224
Baseline (mean)8.08.0
Change from baseline (adjusted mean )-0.7-0.0
Difference from placebo + metformin (adjusted mean ) (95% CI)-0.7 (-0.8, -0.5)
Patients (%) achieving A1C <7%213 (47%)41 (18%)
FPG (mg/dL) N = 454N = 226
Baseline (mean) 170174
Change from baseline (adjusted mean )-179
Difference from placebo + metformin (adjusted mean ) (95% CI)-25(-31, -20)
2-hour PPG (mg/dL)N = 387N = 182
Baseline (mean) 275272
Change from baseline (adjusted mean )-62-11
Difference from placebo + metformin (adjusted mean ) (95% CI)-51(-61, -41)

Initial Combination Therapy with Metformin

A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin as initial therapy in combination with metformin. Patients on an antihyperglycemic agent (N=541) discontinued the agent, and underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with placebo, 100 mg of JANUVIA once daily, 500 mg or 1000 mg of metformin HCl twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin HCl twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Initial therapy with the combination of JANUVIA and metformin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to JANUVIA alone (Table 8, Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: JANUVIA 100 mg once daily, -1.1%; metformin HCl 500 mg bid, -1.1%; metformin HCl 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin HCl 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin HCl 1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo.

Table 8: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin, Alone and in Combination as Initial Therapy *

Placebo

Sitagliptin

(JANUVIA)

100 mg QD

MetforminHCl500 mg bidMetforminHCl1000 mg bidSitagliptin50 mg bid +MetforminHCl500 mg bidSitagliptin50 mg bid +MetforminHCl1000 mg bid
*
Intent-to-treat population using last observation on study prior to glyburide (glibenclamide) rescue therapy.
Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
p<0.001 compared to placebo.
A1C (%)N = 165N = 175N = 178N = 177N = 183N = 178
Baseline (mean)8.78.98.98.78.88.8
Change from baseline (adjusted mean )0.2-0.7-0.8-1.1-1.4-1.9
Difference from placebo (adjusted mean ) (95% CI)-0.8(-1.1, -0.6)-1.0(-1.2, -0.8)-1.3(-1.5, -1.1)-1.6(-1.8, -1.3)-2.1(-2.3, -1.8)
Patients (%) achieving A1C <7%15 (9%)35 (20%)41 (23%)68 (38%)79 (43%)118 (66%)
% Patients receiving rescue medication3221171282
FPG (mg/dL) N = 169N = 178N = 179N = 179N = 183N = 180
Baseline (mean)196201205197204197
Change from baseline (adjusted mean )6-17-27-29-47-64
Difference from placebo (adjusted mean ) (95% CI)-23(-33, -14)-33(-43, -24)-35(-45, -26)-53(-62, -43)-70(-79, -60)
2-hour PPG (mg/dL) N = 129N = 136N = 141N = 138N = 147N = 152
Baseline (mean)277285293283292287
Change from baseline (adjusted mean )0-52-53-78-93-117
Difference from placebo (adjusted mean ) (95% CI)-52(-67, -37)-54(-69, -39)-78(-93, -63)-93(-107, -78)-117(-131, -102)
Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin, Alone and in Combination as Initial Therapy in Patients with Type 2 Diabetes *
*
All Patients Treated Population: least squares means adjusted for prior antihyperglycemic therapy and baseline value.
Image of Figure 1
(click image for full-size original)

Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the health care provider.

Active-Controlled Study vs Glipizide in Combination with Metformin

The efficacy of JANUVIA was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin HCl monotherapy (dose of ≥1500 mg per day) which included washout of medications other than metformin, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of JANUVIA 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.

After 52 weeks, JANUVIA and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 9). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of JANUVIA to glipizide may be limited to patients with baseline A1C comparable to those included in the study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%).

Table 9: Glycemic Parameters in a 52-Week Study Comparing JANUVIA to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Intent-to-Treat Population)*
JANUVIA 100 mg Glipizide
*
The intent-to-treat analysis used the patients’ last observation in the study prior to discontinuation.
Least squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.
A1C (%)N = 576N = 559
Baseline (mean)7.77.6
Change from baseline (adjusted mean )-0.5-0.6
FPG (mg/dL) N = 583N = 568
Baseline (mean) 166164
Change from baseline (adjusted mean )-8-8
Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a Study Comparing JANUVIA to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Per Protocol Population)*
*
The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had observations at baseline and at Week 52.
image of Figure 2
(click image for full-size original)

The incidence of hypoglycemia in the JANUVIA group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with JANUVIA exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs +1.1 kg).

Add-on Combination Therapy with Pioglitazone

A total of 353 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with pioglitazone. Patients on any oral antihyperglycemic agent in monotherapy (N=212) or on a PPARγ agent in combination therapy (N=106) or not on an antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg per day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.

In combination with pioglitazone, JANUVIA provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 10). Rescue therapy was used in 7% of patients treated with JANUVIA 100 mg and 14% of patients treated with placebo. There was no significant difference between JANUVIA and placebo in body weight change.

Table 10: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Add-on Combination Therapy with Pioglitazone *
JANUVIA 100 mg + PioglitazonePlacebo + Pioglitazone
*
Intent-to-treat population using last observation on study prior to metformin rescue therapy.
Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
p<0.001 compared to placebo + pioglitazone.
A1C (%)N = 163N = 174
Baseline (mean)8.18.0
Change from baseline (adjusted mean )-0.9-0.2
Difference from placebo + pioglitazone (adjusted mean ) (95% CI)-0.7(-0.9, -0.5)
Patients (%) achieving A1C <7%74 (45%)40 (23%)
FPG (mg/dL) N = 163N = 174
Baseline (mean) 168166
Change from baseline (adjusted mean )-171
Difference from placebo + pioglitazone (adjusted mean ) (95% CI)-18(-24, -11)

Initial Combination Therapy with Pioglitazone

A total of 520 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind study designed to assess the efficacy of JANUVIA as initial therapy in combination with pioglitazone. Patients not on antihyperglycemic agents at study entry (<4 weeks cumulative therapy over the past 2 years, and with no treatment over the prior 4 months) with inadequate glycemic control (A1C 8% to 12%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with 100 mg of JANUVIA in combination with 30 mg of pioglitazone once daily or 30 mg of pioglitazone once daily as monotherapy. There was no glycemic rescue therapy in this study.

Initial therapy with the combination of JANUVIA and pioglitazone provided significant improvements in A1C, FPG, and 2-hour PPG compared to pioglitazone monotherapy (Table 11). The improvement in A1C was generally consistent across subgroups defined by gender, age, race, baseline BMI, baseline A1C, or duration of disease. In this study, patients treated with JANUVIA in combination with pioglitazone had a mean increase in body weight of 1.1 kg compared to pioglitazone alone (3.0 kg vs. 1.9 kg). Lipid effects were generally neutral.

Table 11: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Combination with Pioglitazone as Initial Therapy *
JANUVIA 100 mg + Pioglitazone Pioglitazone
*
Intent-to-treat population using last observation on study.
Least squares means adjusted for baseline value.
p<0.001 compared to placebo + pioglitazone.
A1C (%) N = 251 N = 246
Baseline (mean)9.59.4
Change from baseline (adjusted mean )-2.4-1.5
Difference from pioglitazone (adjusted mean ) (95% CI)-0.9(-1.1, -0.7)
Patients (%) achieving A1C <7%151 (60%)68 (28%)
FPG (mg/dL) N = 256 N = 253
Baseline (mean) 203201
Change from baseline (adjusted mean )-63-40
Difference from pioglitazone (adjusted mean ) (95% CI)-23(-30, -15)
2-hour PPG (mg/dL) N = 216 N = 211
Baseline (mean) 283284
Change from baseline (adjusted mean )-114-69
Difference from pioglitazone (adjusted mean ) (95% CI)-45(-57, -32)

Add-on Combination Therapy with Metformin and Rosiglitazone

A total of 278 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with metformin and rosiglitazone. Patients on dual therapy with metformin HCl ≥1500 mg/day and rosiglitazone ≥4 mg/day or with metformin HCl ≥1500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin HCl ≥1500 mg/day and rosiglitazone ≥4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.

In combination with metformin and rosiglitazone, JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 12) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with JANUVIA and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with JANUVIA 100 mg and 40% of patients treated with placebo. There was no significant difference between JANUVIA and placebo in body weight change.

Table 12: Glycemic Parameters at Week 18 for JANUVIA in Add-on Combination Therapy with Metformin and Rosiglitazone *
JANUVIA 100 mg + Metformin + Rosiglitazone

Placebo +

Metformin + Rosiglitazone
*
Intent-to-treat population using last observation on study prior to glipizide (or other sulfonylurea) rescue therapy.
Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
p<0.001 compared to placebo + metformin + rosiglitazone.
A1C (%) N = 176 N = 93
Baseline (mean)8.88.7
Change from baseline (adjusted mean )-1.0-0.4
Difference from placebo + rosiglitazone + metformin (adjusted mean ) (95% CI)-0.7(-0.9, -0.4)
Patients (%) achieving A1C <7%39 (22%)9 (10%)
FPG (mg/dL) N = 179 N = 94
Baseline (mean) 181182
Change from baseline (adjusted mean )-30-11
Difference from placebo + rosiglitazone + metformin (adjusted mean ) (95% CI)-18(-26, -10)
2-hour PPG (mg/dL) N = 152 N = 80
Baseline (mean) 256248
Change from baseline (adjusted mean )-59-21
Difference from placebo + rosiglitazone + metformin (adjusted mean ) (95% CI)-39(-51, -26)

Add-on Combination Therapy with Glimepiride, with or without Metformin

A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with glimepiride, with or without metformin. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin HCl (≥1500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

In combination with glimepiride, with or without metformin, JANUVIA provided significant improvements in A1C and FPG compared to placebo (Table 13). In the entire study population (patients on JANUVIA in combination with glimepiride and patients on JANUVIA in combination with glimepiride and metformin), a mean reduction from baseline relative to placebo in A1C of -0.7% and in FPG of -20 mg/dL was seen. Rescue therapy was used in 12% of patients treated with JANUVIA 100 mg and 27% of patients treated with placebo. In this study, patients treated with JANUVIA had a mean increase in body weight of 1.1 kg vs. placebo (+0.8 kg vs. -0.4 kg). In addition, there was an increased rate of hypoglycemia. [See Warnings and Precautions (5.4); Adverse Reactions (6.1).]

Table 13: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA as Add-On Combination Therapy with Glimepiride, with or without Metformin *
JANUVIA 100 mg+ GlimepiridePlacebo + GlimepirideJANUVIA 100 mg+ Glimepiride+ MetforminPlacebo+ Glimepiride+ Metformin
*
Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.
Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
p<0.001 compared to placebo.
§
p<0.01 compared to placebo.
A1C (%)N = 102N = 103N = 115N = 105
Baseline (mean)8.48.58.38.3
Change from baseline (adjusted mean )-0.30.3-0.60.3
Difference from placebo (adjusted mean ) (95% CI)-0.6(-0.8, -0.3)-0.9(-1.1, -0.7)
Patients (%) achieving A1C <7%11 (11%)9 (9%)26 (23%)1 (1%)
FPG (mg/dL) N = 104N = 104N = 115N = 109
Baseline (mean) 183185179179
Change from baseline (adjusted mean )-118-813
Difference from placebo (adjusted mean ) (95% CI)-19§(-32, -7)-21(-32, -10)

Add-on Combination Therapy with Insulin (with or without Metformin)

A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA as add-on to insulin therapy (with or without metformin). The racial distribution in this study was approximately 70% white, 18% Asian, 7% black, and 5% other groups. Approximately 14% of the patients in this study were Hispanic. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin HCl (≥1500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.

The median daily insulin dose at baseline was 42 units in the patients treated with JANUVIA and 45 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the study. In combination with insulin (with or without metformin), JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 14). Both treatment groups had an adjusted mean increase in body weight of 0.1 kg from baseline to Week 24. There was an increased rate of hypoglycemia in patients treated with JANUVIA. [See Warnings and Precautions (5.4); Adverse Reactions (6.1).]

Table 14: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA as Add-on Combination Therapy with Insulin *

JANUVIA 100 mg

+ Insulin

(+/- Metformin)

Placebo +

Insulin

(+/- Metformin)
*
Intent-to-treat population using last observation on study prior to rescue therapy.
Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value.
Treatment by stratum interaction was not significant (p>0.10) for metformin stratum and for insulin stratum.
§
p<0.001 compared to placebo.
A1C (%) N = 305 N = 312
Baseline (mean)8.78.6
Change from baseline (adjusted mean )-0.6-0.1
Difference from placebo (adjusted mean , ) (95% CI)-0.6§ (-0.7, -0.4)
Patients (%) achieving A1C <7%39 (12.8%)16 (5.1%)
FPG (mg/dL) N = 310 N = 313
Baseline (mean) 176179
Change from baseline (adjusted mean )-18-4
Difference from placebo (adjusted mean ) (95% CI)-15§ (-23, -7)
2-hour PPG (mg/dL) N = 240 N = 257
Baseline (mean) 291292
Change from baseline (adjusted mean )-315
Difference from placebo (adjusted mean ) (95% CI)-36§ (-47, -25)

Maintenance of JANUVIA During Initiation and Titration of Insulin Glargine

A total of 746 patients with type 2 diabetes (mean baseline HbA1C 8.8%, disease duration 10.8 years) participated in a 30-week, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of continuing JANUVIA during the initiation and uptitration of insulin glargine. Patients who were on a stable dose of metformin HCl (≥1500 mg/day) in combination with a DPP-4 inhibitor and/or sulfonylurea but with inadequate glycemic control (A1C 7.5% to 11%) were enrolled in the study. Those on metformin and JANUVIA (100 mg/day) directly entered the double-blind treatment period; those on another DPP-4 inhibitor and/or on a sulfonylurea entered a 4-8 week run-in period in which they were maintained on metformin and switched to JANUVIA (100 mg); other DPP-4 inhibitors and sulfonylureas were discontinued. At randomization patients were randomized either to continue JANUVIA or to discontinue JANUVIA and switch to a matching placebo. On the day of randomization, insulin glargine was initiated at a dose of 10 units subcutaneously in the evening. Patients were instructed to uptitrate their insulin dose in the evening based on fasting blood glucose measurements to achieve a target of 72-100 mg/dL.

At 30 weeks, the mean reduction in A1C was greater in the sitagliptin group than in the placebo group (Table 15). At the end of the trial, 27.3% of patients in the sitagliptin group and 27.3% in the placebo group had a fasting plasma glucose (FPG) in the target range; there was no significant difference in insulin dose between arms.

Table 15: Change from Baseline in A1C and FPG at Week 30 in the Maintenance of JANUVIA During Initiation and Titration of Insulin Glargine Study
Sitagliptin 100 mg+Metformin+ Insulin GlarginePlacebo+Metformin+ Insulin Glargine
*
N is the number of randomized and treated patients.
Analysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputation to model washout of the treatment effect using placebo data for all subjects having missing Week 30 data.
p<0.001 compared to placebo.
A1C (%) N = 373 *N = 370 *
Baseline (mean)8.88.8
Week 30 (mean)6.97.3
Change from baseline (adjusted mean)-1.9-1.4
Difference from placebo (adjusted mean) (95% CI)-0.4 (-0.6, -0.3)
Patients (%) with A1C <7%202 (54.2%)131 (35.4%)
FPG (mg/dL) N = 373 *N = 370 *
Baseline (mean)199201
Week 30 (mean)118123
Change from baseline (adjusted mean)-81-76

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.