The document discusses Januet XR, a new extended-release formulation combining sitagliptin and metformin for the treatment of type 2 diabetes. Januet XR provides glycemic control through the complementary mechanisms of action of sitagliptin and metformin. Studies showed Januet XR has similar pharmacokinetic properties to immediate-release sitagliptin and provides effective reduction in blood sugar levels with once-daily dosing. Its extended-release formulation aims to improve adherence by reducing dosing frequency compared to the individual components.
5. 5
Effect of DPP-4 inhibitors in monotherapy with comparable baseline
Treatment duration: * 18 weeks; † 24 weeks; ‡ 26 weeks. Morning dosing.
Source: US prescribing information (linagliptin, saxagliptin, sitagliptin and alogliptin); EU summary of product characteristics
(saxagliptin, vildagliptin).
Vildagliptin†
50 mg BID
8.6%
Saxagliptin†,§
5 mg OD
>=7%-<=10%
Linagliptin*
5 mg OD
8.1%
Vildagliptin†
50 mg BID
8.4%
Sitagliptin*
100 mg OD
8%
Sitagliptin†
100 mg OD
8%
Saxagliptin†
5 mg OD
8%
Linagliptin†
5 mg OD
8.0%
-0.6
-0.7
-0.4
-0.6 -0.6
-0.8
-0.5
-0.7
Placebo-corrected, adjusted mean change from baseline HbA1c
6. None of the Major Oral Monotherapies Are Able to
Address All 3 Core Defects in Type 2 Diabetes
Oral Monotherapies
Lowers hepatic
glucose production
SUs Glinides TZDs
Improves insulin
resistance
Improves insulin
secretion
DPP-4 InhibitorsMetformin
MechanismsofAction
7. Januet combines two OHAs
with complementary
mechanisms of action
>7 years in market
~60 million prescriptions all
over the world
FDA and EMA approval
www.accessdata.fda.gov/scripts/cder; www.ema.europa.eu/ema/index.jsp
10. Januet XR tablet consists of an XR metformin core tablet
Metformin XR core is coated with an immediate-release layer
of Sitagliptin
Sitagliptin layer is coated with a soluble polymeric film
MSD data on file
11. The extended release formulation allows slow and
controlled release of metformin into the GI tract
12. Januet
(50/500)
Januet XR (50/500)
3777 ~= 3666 AUC 0-∞
(nM•hr)
304 ~= 273 Cmax (nM)
3.5 ~= 4 Tmax (hr)
MSD data on file
Plasma Pharmacokinetic Parameters of
Sitagliptin
Januet XR group: n=11 healthy adult subjects
Januet group: n=12 healthy adult subjects
The AUC0-∞ and Cmax for sitagliptin after administration of a single tablet
of Januet XR or a single tablet of Januet were similar
In the field of pharmacokinetics, the area under the curve
(AUC) is the area under the curve (mathematically known
as definite integral) in a plot of concentration of drug in
blood plasma against time. This is useful when trying to
determine whether two formulations of the same dose (for
example a capsule and a tablet) release the same dose of
drug to the body.
Cmax is a term used in pharmacokinetics refers to the
maximum (or peak) serum concentration that a drug
achieves in a specified compartment or test area of the
body after the drug has been administrated and prior to
the administration of a second dose.
Tmax is the term used in pharmacokinetics to describe the
time at which the Cmax is observed.
13. Januet (50/500) Januet XR (50/500)
9454 ~= 9148 AUC 0-∞
(ng•hr/ml)
1010 < 709 Cmax (ng/ml)
4.0 > 8.0 Tmax (hr)
Plasma Pharmacokinetic Parameters of
Metformin
MSD data on file
Januet XR group: n=11 healthy adult subjects
Januet group: n=12 healthy adult subjects
The mean Cmax value of metformin is 30% lower and the median Tmax value
occurs 4 hours later in Januet XR compared with Januet
14. Efficacy- Metformin XR Provided Effective reduction in HbA1c
Met-XR 1500mg qd
Met-XR 2000mg qd
Met-XR 1500mg bid
Met-IR 1500mg bid
Met-XR 1500mg bid
Met-IR 1500mg bid
Met-XR 2000mg qd
Met-XR 1500mg qd
24w endpoint
Shwartz et al., Diabetes Care, 2006; Shwartz et al., Expert Opin Drug Metab Toxicol, 2008
15.
16. Age
Perception and duration of disease
Psychological factors
Safety
Dosing regime: Once daily vs. twice/three times
a day
Tolerability
Polytherapy
Cost
17. Adapted from Paes et al., Diabetes Carer 1997
98.7
83.1
65.8
0
20
40
60
80
100
1 2 3
Compliance(%)
פעםביום פעמיים
ביום
שלושפעמים
ביום
Adherence:
Once Daily is Better Than Twice Daily
18. Age
Perception and duration of disease
Psychological factors
Safety
Dosing regime: Once daily vs. twice/three times
a day
Tolerability
Polytherapy
Cost
19. Frequency of GI AEs During the First Year of treatment within the
SAME population
Blonde et al., Curr Med Res Opin, 2004
20. Age
Perception and duration of disease
Psychological factors
Safety
Dosing regime: Once daily vs. twice/three times
a day
Tolerability
Polytherapy
Cost
22. N= 129 patients with
T2DM and ESRD who
were on dialysis
therapy
Arjona Ferreira et al., Am J Kidney Dis. , 2013
23. Met DPP4i SGLT2i GLP1RA TZD AGI SU/ GLN Insulin
Hypo Neutral Neutral Neutral Neutral Neutral Neutral Moderate-
severe/
mild
Moderate-
severe
Weight Slight loss Neutral Loss Loss Gain Neutral Gain Gain
Renal/
GU
Contraindicated
stage 3B, 4,5
Dose
adjustme
nt maybe
required
Infections Exenatide BID
contraindicate
d CrCl<30
May
worsen
fluid
retention
Neutral More hypo
risk
More hypo
risk & fluid
retention
GI AE Moderate Neutral Neutral Moderate Neutral Moderate Neutral Neutral
CHF Neutral Neutral Neutral Neutral Moderate Neutral Neutral Neutral
CVD Benefit Neutral Increased
LDL
Neutral Neutral Neutral Neutral
Bone Neutral Neutral Neutral Neutral Moderate
bone
mass loss
Neutral Neutral Neutral
Profiles of antidiabetic agents
Few AE or possible benefits Use with precaution Likelihood of adverse events
Adapted from Garber et al. AACe comprehensive diabetes management algorithm 2013.
+/-
n
e
u
t
r
a
l
24. The primary goal:
To Achieve Glycemic Control
Improved Toleability Improved Pill Burden
Improved HbA1C
The proportion of patients that achieved the HbA1C<7 goal was largest in the group that received fixed dose combination therapy
The proportions of patients with an HbA1c <7% at week 104 were 60, 45, 45, 28 and 32% for the higher dose coadministration,
lower dose co-administration, higher dose metformin, lower dose metformin and sitagliptin groups,
respectively.
JANUET XR is a fixed-dose combination (FDC) product that contains sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in combination with an extended release formulation of the biguanide metformin (metformin XR), which provides for convenient once-daily dosing.
Approval of JANUET XR is based on bioequivalence studies and clinical studies evaluating the efficacy and safety of combination therapy with sitagliptin and metformin as separate tablets.
Tablet Design:
JANUET XR tablets consist of an extended-release metformin core tablet coated with an immediate-release layer of sitagliptin and are formulated to gradually release metformin to the upper gastrointestinal (GI) tract . The sitagliptin layer is coated with a soluble polymeric film.
The tablet absorb water from the stomach. This process results with a slow and controlled release of metformin into the GI tract, while the tablet stays in the stomach. A slow and controlled release results with absorption of most of the metformin into the bloodstream.
Comparisons for the Plasma Pharmacokinetic Parameters of Sitagliptin after Administration of a Single Januet XR 50 mg/500 mg
or administration of a Single Januet 50 mg/500 mg Tablet in Healthy Adult Subjects.
The AUC0-∞ and Cmax for sitagliptin after administration of a single Januet XR 50 mg/500 mg tablet and administration of a single Januet 50 mg/500 mg tablet are similar.
Comparisons for the Plasma Pharmacokinetic Parameters of Metformin after administration of a Single Januet XR 50 mg/500 mg
Tablet or Administration of a Januet 50 mg/500 mg Tablet in Healthy Adult Subjects.
The AUC0-∞ for metformin after administration of a single Januet XR 50 mg/500 mg tablet and administration
of a single Januet 50 mg/500 mg tablet are similar. After administration of a single Januet XR 50 mg/500 mg tablet, the mean Cmax value for metformin is 30% lower and the median Tmax value occurs 4 hours later compared
with corresponding values after administration of a single Januet 50 mg/500 mg tablet, which is consistent with the expected modified-release characteristics for metformin associated with the Januet XR formulation.
Significant (P <0.001) reductions in mean A1C concentrations were observed by week 12 in all treatment groups. A1C
levels continued to decline until week 20 and were maintained for the duration of the study (left). The mean changes in
A1C concentrations from baseline to end point in all extended-release metformin groups were noninferior to those in the
immediate-release metformin group.
The reduction in HbA 1c in the Metformin XR 2000 mg q.d. group was greater than for the other groups, indicating greater efficacy at higher doses, which may be related to the linearity of the dose proportionality data for Metformin XR.
Adherence is influenced by many factors. Here we will show how Januet XR can improve adherence in two forms:
Improved dosing regime
Improved tolerability
היעילות בהורדת A1C צפויה להיות זהה, אך מכיוון שההיענות לטיפול גבוהה יותר, זה עשוי להוביל לאיזון גליקמי טוב יותר, וליותר חולים שיגיעו למטרה.
היענות החולה לטיפול יורדת ככל שמספר הנטילות של התרופה עולה. במחקר שבוצע בחולי סוכרת בהולנד (כ-90 חולים) נצפתה היענות של כ-2/3 בלבד במטופלים תחת משטר נטילה של 3 פעמים ביום- כלומר כשליש מהכדורים לא נצרכו. בקרב מטופלים תחת משטר נטילה של פעם ביום ההיענות היתה כמעט מלאה.
Frequency of gastrointestinal adverse events reported in ≥ 1% of 205 patients taking immediate-release metformin (metformin-IR) before switching to metformin-XR. For this analysis, only those symptoms reported in the first year of therapy with immediate-release metformin were compared to the symptoms reported during the year following a switch to metformin-XR.
There was a statistically significant reduction in GI AE in patients switched to metformin XR.
ג'אנואט XR זמין במספר מינונים משולבים:
טבליה המשלבת 50 מ"ג סיטהגליפטין עם 1000 מ"ג מטפורמין בשחרור מושהה.
טבליה המשלבת 50 מ"ג סיטהגליפטין עם 500 מ"ג מטפורמין בשחרור מושהה.
טבליה המשלבת 1000 מ"ג סיטהגליפטין עם 1000 מ"ג מטפורמין בשחרור מושהה.
חולים המקבלים 2000 מ"ג מטפורמין ליום יוכלו לקחת 2 טבליות של 50/1000, ביחד, פעם ביום
חולים המקבלים 1500 מ"ג מטפורמין ליום יוכלו לקחת טבליה אחת של 50/1000 וטבליה אחת של 50/500, ביחד, פעם ביום
חולים המקבלים 1000 מ"ג מטפורמין ליום יוכלו לקחת טבליה אחת של 100/1000, פעם ביום
יש לקחת 2 טבליות בבת אחת במינונים הגבוהים, מפאת גודל הכדור.
שימו לב יש 60 טבליות באריזה או 30 (במינון הנמוך ).
ליעילות מירבית , יש לקחת ג'נואט XR עם האוכל (כלומר לא בצום, לא בבוקר).