Indications and Usage (
|
07/2023 |
Dosage and Administration (
|
07/2023 |
Contraindications (
|
07/2023 |
Warnings and Precautions (
|
07/2023 |
Estimated Glomerular Filtration Rate
[eGFR (mL/min/1.73 m 2)] |
Recommended Dosage |
---|---|
eGFR 30 to less than 60 | The maximum recommended dosage is100 mg orally once daily. |
eGFR less than 30 |
|
Note: Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes. | |||
|
N=646 |
100 mg N=833 |
300 mg N=834 |
Urinary tract infections
|
3.8% | 5.9% | 4.4% |
Increased urination
|
0.7% | 5.1% | 4.6% |
Thirst
|
0.1% | 2.8% | 2.4% |
Constipation | 0.9% | 1.8% | 2.4% |
Nausea | 1.6% | 2.1% | 2.3% |
|
|
|
|
Female genital mycotic infections
|
2.8% | 10.6% | 11.6% |
Vulvovaginal pruritus | 0.0% | 1.6% | 3.2% |
|
|
|
|
Male genital mycotic infections
|
0.7% | 4.2% | 3.8% |
Placebo
N=1441 |
INVOKANA
100 mg N=1445 |
INVOKANA
300 mg N=1441 |
INVOKANA
(Pooled) N=2886 |
|
---|---|---|---|---|
Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. | ||||
Patients with an amputation, n (%) | 22 (1.5) | 50 (3.5) | 45 (3.1) | 95 (3.3) |
Total amputations | 33 | 83 | 79 | 162 |
Amputation incidence rate
(per 1000 patient-years) |
2.8 | 6.2 | 5.5 | 5.9 |
Hazard Ratio (95% CI) | -- | 2.24 (1.36, 3.69) | 2.01 (1.20, 3.34) | 2.12 (1.34, 3.38) |
Placebo
N=2903 |
INVOKANA
100 mg (with up-titration to 300 mg) N=2904 |
|
---|---|---|
Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. | ||
Patients with an amputation, n (%) | 25 (0.9) | 45 (1.5) |
Total amputations | 36 | 59 |
Amputation incidence rate
(per 1000 patient-years) |
4.2 | 7.5 |
Hazard Ratio (95% CI) | -- | 1.80 (1.10, 2.93) |
Baseline Characteristic | Comparator Group
% |
INVOKANA 100 mg
% |
INVOKANA 300 mg
% |
---|---|---|---|
Overall population | 1.5% | 2.3% | 3.4% |
75 years of age and older
|
2.6% | 4.9% | 8.7% |
eGFR less than 60 mL/min/1.73 m
2
|
2.5% | 4.7% | 8.1% |
Use of loop diuretic
|
4.7% | 3.2% | 8.8% |
(26 weeks) |
(N=192) |
(N=195) |
(N=197) |
Overall [N (%)] | 5 (2.6) | 7 (3.6) | 6 (3.0) |
(26 weeks) |
(N=183) |
(N=368) |
(N=367) |
Overall [N (%)] | 3 (1.6) | 16 (4.3) | 17 (4.6) |
Severe [N (%)]
|
0 (0) | 1 (0.3) | 1 (0.3) |
(52 weeks) |
(N=482) |
(N=483) |
(N=485) |
Overall [N (%)] | 165 (34.2) | 27 (5.6) | 24 (4.9) |
Severe [N (%)]
|
15 (3.1) | 2 (0.4) | 3 (0.6) |
(18 weeks) |
(N=69) |
(N=74) |
(N=72) |
Overall [N (%)] | 4 (5.8) | 3 (4.1) | 9 (12.5) |
(26 weeks) |
(N=156) |
(N=157) |
(N=156) |
Overall [N (%)] | 24 (15.4) | 43 (27.4) | 47 (30.1) |
Severe [N (%)]
|
1 (0.6) | 1 (0.6) | 0 |
(52 weeks) |
(N=378) |
(N=377) |
|
Overall [N (%)] | 154 (40.7) | 163 (43.2) | |
Severe [N (%)]
|
13 (3.4) | 15 (4.0) | |
(26 weeks) |
(N=115) |
(N=113) |
(N=114) |
Overall [N (%)] | 3 (2.6) | 3 (2.7) | 6 (5.3) |
(18 weeks) |
(N=565) |
(N=566) |
(N=587) |
Overall [N (%)] | 208 (36.8) | 279 (49.3) | 285 (48.6) |
Severe [N (%)]
|
14 (2.5) | 10 (1.8) | 16 (2.7) |
|
|
|
UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKANA. |
|
For patients with eGFR 60 mL/min/1.73 m
2or greater, if an inducer of UGTs is administered with INVOKANA, increase the dosage to 200 mg daily in patients currently tolerating INVOKANA 100 mg daily. The total daily dosage may be increased to 300 mg daily in patients currently tolerating INVOKANA 200 mg daily who require additional glycemic control.
For patients with eGFR less than 60 mL/min/1.73 m 2, if an inducer of UGTs is administered with INVOKANA, increase the dosage to 200 mg daily in patients currently tolerating INVOKANA 100 mg daily. Consider adding another antihyperglycemic agent in patients who require additional glycemic control |
|
Rifampin, phenytoin, phenobarbital, ritonavir |
|
|
|
The risk of hypoglycemia is increased when INVOKANA is used concomitantly with insulin secretagogues (e.g., sulfonylurea) or insulin. |
|
Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. |
|
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Canagliflozin increases digoxin exposure
|
|
Monitor patients taking INVOKANA with concomitant digoxin for a need to adjust the dosage of digoxin. |
|
|
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Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. |
|
Monitor serum lithium concentration more frequently during INVOKANA initiation and dosage changes. |
|
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SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. |
|
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. |
|
|
|
Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. |
|
Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. |
Co-Administered Drug | Dose of Co-Administered Drug
|
Dose of Canagliflozin
|
Geometric Mean Ratio
(Ratio With/Without Co-Administered Drug) No Effect = 1.0 |
|
---|---|---|---|---|
AUC
(90% CI) |
C
max
(90% CI) |
|||
QD = once daily; BID = twice daily | ||||
|
||||
Rifampin | 600 mg QD for 8 days | 300 mg | 0.49
(0.44; 0.54) |
0.72
(0.61; 0.84) |
|
||||
Cyclosporine | 400 mg | 300 mg QD for 8 days | 1.23
(1.19; 1.27) |
1.01
(0.91; 1.11) |
Ethinyl estradiol and levonorgestrel | 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel | 200 mg QD for 6 days | 0.91
(0.88; 0.94) |
0.92
(0.84; 0.99) |
Hydrochlorothiazide | 25 mg QD for 35 days | 300 mg QD for 7 days | 1.12
(1.08; 1.17) |
1.15
(1.06; 1.25) |
Metformin | 2,000 mg | 300 mg QD for 8 days | 1.10
(1.05; 1.15) |
1.05
(0.96; 1.16) |
Probenecid | 500 mg BID for 3 days | 300 mg QD for 17 days | 1.21
(1.16; 1.25) |
1.13
(1.00; 1.28) |
Co-Administered Drug | Dose of Co-Administered Drug
|
Dose of Canagliflozin
|
Geometric Mean Ratio
(Ratio With/Without Co-Administered Drug) No Effect = 1.0 |
||
---|---|---|---|---|---|
AUC
(90% CI) |
C
max
(90% CI) |
||||
QD = once daily; BID = twice daily; INR = International Normalized Ratio | |||||
|
|||||
Digoxin | 0.5 mg QD first day followed by 0.25 mg QD for 6 days | 300 mg QD for 7 days | Digoxin | 1.20
(1.12; 1.28) |
1.36
(1.21; 1.53) |
|
|||||
Acetaminophen | 1,000 mg | 300 mg BID for 25 days | Acetaminophen | 1.06
(0.98; 1.14) |
1.00
(0.92; 1.09) |
Ethinyl estradiol and levonorgestrel | 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel | 200 mg QD for 6 days | ethinyl estradiol | 1.07
(0.99; 1.15) |
1.22
(1.10; 1.35) |
Levonorgestrel | 1.06
(1.00; 1.13) |
1.22
(1.11; 1.35) |
|||
Glyburide | 1.25 mg | 200 mg QD for 6 days | Glyburide | 1.02
(0.98; 1.07) |
0.93
(0.85; 1.01) |
3-cis-hydroxy-glyburide | 1.01
(0.96; 1.07) |
0.99
(0.91; 1.08) |
|||
4-trans-hydroxy-glyburide | 1.03
(0.97; 1.09) |
0.96
(0.88; 1.04) |
|||
Hydrochlorothiazide | 25 mg QD for 35 days | 300 mg QD for 7 days | Hydrochlorothiazide | 0.99
(0.95; 1.04) |
0.94
(0.87; 1.01) |
Metformin | 2,000 mg | 300 mg QD for 8 days | Metformin | 1.20
(1.08; 1.34) |
1.06
(0.93; 1.20) |
Simvastatin | 40 mg | 300 mg QD for 7 days | Simvastatin | 1.12
(0.94; 1.33) |
1.09
(0.91; 1.31) |
simvastatin acid | 1.18
(1.03; 1.35) |
1.26
(1.10; 1.45) |
|||
Warfarin | 30 mg | 300 mg QD for 12 days | (R)-warfarin | 1.01
(0.96; 1.06) |
1.03
(0.94; 1.13) |
(S)-warfarin | 1.06
(1.00; 1.12) |
1.01
(0.90; 1.13) |
|||
INR | 1.00
(0.98; 1.03) |
1.05
(0.99; 1.12) |
Efficacy Parameter | Placebo
(N=192) |
INVOKANA
100 mg (N=195) |
INVOKANA
300 mg (N=197) |
---|---|---|---|
|
|||
Baseline (mean) | 7.97 | 8.06 | 8.01 |
Change from baseline (adjusted mean) | 0.14 | -0.77 | -1.03 |
Difference from placebo (adjusted mean) (95% CI)
|
-0.91
(-1.09; -0.73) |
-1.16
(-1.34; -0.99) |
|
|
21 | 45
|
62
|
|
|||
Baseline (mean) | 166 | 172 | 173 |
Change from baseline (adjusted mean) | 8 | -27 | -35 |
Difference from placebo (adjusted mean) (95% CI)
|
-36
(-42; -29) |
-43
(-50; -37) |
|
|
|||
Baseline (mean) | 229 | 250 | 254 |
Change from baseline (adjusted mean) | 5 | -43 | -59 |
Difference from placebo (adjusted mean) (95% CI)
|
-48
(-59.1; -37.0) |
-64
(-75.0; -52.9) |
|
|
|||
Baseline (mean) in kg | 87.5 | 85.9 | 86.9 |
% change from baseline (adjusted mean) | -0.6 | -2.8 | -3.9 |
Difference from placebo (adjusted mean) (95% CI)
|
-2.2
(-2.9; -1.6) |
-3.3
(-4.0; -2.6) |
Efficacy Parameter | Placebo + Metformin
(N=183) |
INVOKANA 100 mg + Metformin
(N=368) |
INVOKANA 300 mg + Metformin
(N=367) |
---|---|---|---|
|
|||
Baseline (mean) | 7.96 | 7.94 | 7.95 |
Change from baseline (adjusted mean) | -0.17 | -0.79 | -0.94 |
Difference from placebo (adjusted mean) (95% CI)
|
-0.62
(-0.76; -0.48) |
-0.77
(-0.91; -0.64) |
|
|
30 | 46
|
58
|
|
|||
Baseline (mean) | 164 | 169 | 173 |
Change from baseline (adjusted mean) | 2 | -27 | -38 |
Difference from placebo (adjusted mean) (95% CI)
|
-30
(-36; -24) |
-40
(-46; -34) |
|
|
|||
Baseline (mean) | 249 | 258 | 262 |
Change from baseline (adjusted mean) | -10 | -48 | -57 |
Difference from placebo (adjusted mean) (95% CI)
|
-38
(-49; -27) |
-47
(-58; -36) |
|
|
|||
Baseline (mean) in kg | 86.7 | 88.7 | 85.4 |
% change from baseline (adjusted mean) | -1.2 | -3.7 | -4.2 |
Difference from placebo (adjusted mean) (95% CI)
|
-2.5
(-3.1; -1.9) |
-2.9
(-3.5; -2.3) |
Efficacy Parameter | Metformin XR
(N=237) |
INVOKANA 100 mg
(N=237) |
INVOKANA 300 mg
(N=238) |
INVOKANA 100 mg + Metformin XR
(N=237) |
INVOKANA 300 mg + Metformin XR
(N=237) |
---|---|---|---|---|---|
|
|||||
Baseline (mean) | 8.81 | 8.78 | 8.77 | 8.83 | 8.90 |
Change from baseline (adjusted mean)
|
-1.30 | -1.37 | -1.42 | -1.77 | -1.78 |
Difference from canagliflozin 100 mg (adjusted mean) (95% CI)
|
-0.40
(-0.59, -0.21) |
||||
Difference from canagliflozin 300 mg (adjusted mean) (95% CI)
|
-0.36
(-0.56, -0.17) |
||||
Difference from metformin XR (adjusted mean) (95% CI)
|
-0.06
(-0.26, 0.13) |
-0.11
(-0.31, 0.08) |
-0.46
(-0.66, -0.27) |
-0.48
(-0.67, -0.28) |
|
|
38 | 34 | 39 | 47
|
51
|
Efficacy Parameter | INVOKANA 100 mg + Metformin
(N=483) |
INVOKANA 300 mg + Metformin
(N=485) |
Glimepiride (titrated) + Metformin
(N=482) |
---|---|---|---|
|
|||
Baseline (mean) | 7.78 | 7.79 | 7.83 |
Change from baseline (adjusted mean) | -0.82 | -0.93 | -0.81 |
Difference from glimepiride (adjusted mean) (95% CI)
|
-0.01
(-0.11; 0.09) |
-0.12
(-0.22; -0.02) |
|
|
54 | 60 | 56 |
|
|||
Baseline (mean) | 165 | 164 | 166 |
Change from baseline (adjusted mean) | -24 | -28 | -18 |
Difference from glimepiride (adjusted mean) (95% CI)
|
-6
(-10; -2) |
-9
(-13; -5) |
|
|
|||
Baseline (mean) in kg | 86.8 | 86.6 | 86.6 |
% change from baseline (adjusted mean) | -4.2 | -4.7 | 1.0 |
Difference from glimepiride (adjusted mean) (95% CI)
|
-5.2
(-5.7; -4.7) |
-5.7
(-6.2; -5.1) |
Figure 1: Mean HbA 1CChange at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population) |
---|
|
Efficacy Parameter | Placebo + Sulfonylurea
(N=45) |
INVOKANA 100 mg + Sulfonylurea
(N=42) |
INVOKANA 300 mg + Sulfonylurea
(N=40) |
---|---|---|---|
|
|||
Baseline (mean) | 8.49 | 8.29 | 8.28 |
Change from baseline (adjusted mean) | 0.04 | -0.70 | -0.79 |
Difference from placebo (adjusted mean) (95% CI)
|
-0.74
(-1.15; -0.33) |
-0.83
(-1.24; -0.41) |
Efficacy Parameter | Placebo + Metformin and Sulfonylurea
(N=156) |
INVOKANA 100 mg + Metformin and Sulfonylurea
(N=157) |
INVOKANA 300 mg + Metformin and Sulfonylurea
(N=156) |
---|---|---|---|
|
|||
Baseline (mean) | 8.12 | 8.13 | 8.13 |
Change from baseline (adjusted mean) | -0.13 | -0.85 | -1.06 |
Difference from placebo (adjusted mean) (95% CI)
|
-0.71
(-0.90; -0.52) |
-0.92
(-1.11; -0.73) |
|
|
18 | 43
|
57
|
|
|||
Baseline (mean) | 170 | 173 | 168 |
Change from baseline (adjusted mean) | 4 | -18 | -31 |
Difference from placebo (adjusted mean) (95% CI)
|
-22
(-31; -13) |
-35
(-44; -25) |
|
|
|||
Baseline (mean) in kg | 90.8 | 93.5 | 93.5 |
% change from baseline (adjusted mean) | -0.7 | -2.1 | -2.6 |
Difference from placebo (adjusted mean) (95% CI)
|
-1.4
(-2.1; -0.7) |
-2.0
(-2.7; -1.3) |
Efficacy Parameter | Placebo + Metformin and Sitagliptin
(N=108 |
INVOKANA + Metformin and Sitagliptin
(N=109 |
---|---|---|
|
||
Baseline (mean) | 8.40 | 8.50 |
Change from baseline (adjusted mean) | -0.03 | -0.83 |
Difference from placebo (adjusted mean) (95% CI)
|
-0.81
(-1.11; -0.51) |
|
|
9 | 28 |
|
||
Baseline (mean) | 180 | 185 |
Change from baseline (adjusted mean) | -3 | -28 |
Difference from placebo (adjusted mean) (95% CI) | -25
(-39; -11) |
Efficacy Parameter | INVOKANA 300 mg + Metformin and Sulfonylurea
(N=377) |
Sitagliptin 100 mg + Metformin and Sulfonylurea
(N=378) |
---|---|---|
|
||
Baseline (mean) | 8.12 | 8.13 |
Change from baseline (adjusted mean) | -1.03 | -0.66 |
Difference from sitagliptin (adjusted mean) (95% CI)
|
-0.37
(-0.50; -0.25) |
|
|
48 | 35 |
|
||
Baseline (mean) | 170 | 164 |
Change from baseline (adjusted mean) | -30 | -6 |
Difference from sitagliptin (adjusted mean) (95% CI)
|
-24
(-30; -18) |
|
|
||
Baseline (mean) in kg | 87.6 | 89.6 |
% change from baseline (adjusted mean) | -2.5 | 0.3 |
Difference from sitagliptin (adjusted mean) (95% CI)
|
-2.8
(-3.3; -2.2) |
Efficacy Parameter | Placebo + Metformin and Pioglitazone
(N=115) |
INVOKANA 100 mg + Metformin and Pioglitazone
(N=113) |
INVOKANA 300 mg + Metformin and Pioglitazone
(N=114) |
---|---|---|---|
|
|||
Baseline (mean) | 8.00 | 7.99 | 7.84 |
Change from baseline (adjusted mean) | -0.26 | -0.89 | -1.03 |
Difference from placebo (adjusted mean) (95% CI)
|
-0.62
(-0.81; -0.44) |
-0.76
(-0.95; -0.58) |
|
|
33 | 47
|
64
|
|
|||
Baseline (mean) | 164 | 169 | 164 |
Change from baseline (adjusted mean) | 3 | -27 | -33 |
Difference from placebo (adjusted mean) (95% CI)
|
-29
(-37; -22) |
-36
(-43; -28) |
|
|
|||
Baseline (mean) in kg | 94.0 | 94.2 | 94.4 |
% change from baseline (adjusted mean) | -0.1 | -2.8 | -3.8 |
Difference from placebo (adjusted mean) (95% CI)
|
-2.7
(-3.6; -1.8) |
-3.7
(-4.6; -2.8) |
Efficacy Parameter | Placebo + Insulin
(N=565) |
INVOKANA 100 mg + Insulin
(N=566) |
INVOKANA 300 mg + Insulin
(N=587) |
---|---|---|---|
|
|||
Baseline (mean) | 8.20 | 8.33 | 8.27 |
Change from baseline (adjusted mean) | 0.01 | -0.63 | -0.72 |
Difference from placebo (adjusted mean) (95% CI)
|
-0.65
(-0.73; -0.56) |
-0.73
(-0.82; -0.65) |
|
|
8 | 20
|
25
|
|
|||
Baseline | 169 | 170 | 168 |
Change from baseline (adjusted mean) | 4 | -19 | -25 |
Difference from placebo (adjusted mean) (97.5% CI)
|
-23
(-29; -16) |
-29
(-35; -23) |
|
|
|||
Baseline (mean) in kg | 97.7 | 96.9 | 96.7 |
% change from baseline (adjusted mean) | 0.1 | -1.8 | -2.3 |
Difference from placebo (adjusted mean) (97.5% CI)
|
-1.9
(-2.2; -1.6) |
-2.4
(-2.7; -2.1) |
Placebo
N=4347(%) |
Canagliflozin
N=5795 (%) |
Hazard ratio
(95% C.I.) |
|
---|---|---|---|
Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke
(time to first occurrence) |
426 (10.4) | 585 (9.2) | 0.86 (0.75, 0.97) |
Non-fatal myocardial infarction
|
159 (3.9) | 215 (3.4) | 0.85 (0.69, 1.05) |
Non-fatal Stroke
|
116 (2.8) | 158 (2.5) | 0.90 (0.71, 1.15) |
Cardiovascular Death
|
185 (4.6) | 268 (4.1) | 0.87 (0.72, 1.06) |
Placebo | canagliflozin | ||||
---|---|---|---|---|---|
Endpoint | N=2,199 (%) | Event Rate
|
N=2,202 (%) | Event Rate
|
HR
(95% CI) |
Intent-To-Treat Analysis Set (time to first occurrence) | |||||
The individual components do not represent a breakdown of the composite outcomes, but rather the total number of subjects experiencing an event during the course of the study. | |||||
Primary Composite Endpoint (ESKD, doubling of serum creatinine, renal death, or CV death) | 340 (15.5) | 6.1 | 245 (11.1) | 4.3 | 0.70
(0.59, 0.82) |
ESKD | 165 (7.5) | 2.9 | 116 (5.3) | 2.0 | 0.68
(0.54, 0.86) |
Doubling of serum creatinine | 188 (8.5) | 3.4 | 118 (5.4) | 2.1 | 0.60
(0.48, 0.76) |
Renal death | 5 (0.2) | 0.1 | 2 (0.1) | 0.0 | |
CV death | 140 (6.4) | 2.4 | 110 (5.0) | 1.9 | 0.78
(0.61, 1.00) |
CV death or hospitalization for heart failure | 253 (11.5) | 4.5 | 179 (8.1) | 3.1 | 0.69
(0.57, 0.83) |
CV death, non-fatal myocardial infarction or non-fatal stroke | 269 (12.2) | 4.9 | 217 (9.9) | 3.9 | 0.80
(0.67, 0.95) |
Non-fatal myocardial infarction | 87 (4.0) | 1.6 | 71 (3.2) | 1.3 | 0.81
(0.59, 1.10) |
Non-fatal stroke | 66 (3.0) | 1.2 | 53 (2.4) | 0.9 | 0.80
(0.56, 1.15) |
Hospitalization for heart failure | 141 (6.4) | 2.5 | 89 (4.0) | 1.6 | 0.61
(0.47, 0.80) |
ESKD, doubling of serum creatinine or renal death | 224 (10.2) | 4.0 | 153 (6.9) | 2.7 | 0.66
(0.53, 0.81) |
NDC 50458-140-30 | Bottle of 30 |
NDC 50458-140-90 | Bottle of 90 |
NDC 50458-140-50 | Bottle of 500 |
NDC 50458-141-30 | Bottle of 30 |
NDC 50458-141-90 | Bottle of 90 |
NDC 50458-141-50 | Bottle of 500 |
This Medication Guide has been approved by the U.S. Food and Drug Administration. | Revised: 07/2023 | ||||||
INVOKANA ®(in-vo-KAHN-uh) (canagliflozin) tablets, for oral use |
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