Efficacy and safety of a conversion from the original tacrolimus and mycophenolate mofetil to the generics Tacpan^® and Mowel^® after liver transplantation

Figures & data

Figure 1 Study design.

Notes: After screening 375 liver-transplant patients for their immunosuppression 25 patients were switched to the generics Tacpan^® (TAP) and Mowel^® (MOW) for 6 months. Five patients dropped out due to mild adverse events. At the end of the study patients were free to continue TAP/MOW (eight patients) or to switch back to the original preparations (12 patients).
Abbreviations: TAC, tacrolimus; MMF, mycophenolate mofetil.

Table 1 Patient demographics

Patient demographics	TAP/MOW	TAC/MMF
Sex	Male =16	Male =16
	Female =4	Female =4
Age, median (range)	60.5 (48–70) years	61 (47–74) years
Time after LT, median (range)	58 (24–150) months	67.5 (24–170) months
Original tacrolimus	Prograf ^® =18	Prograf ^® =11
	Advagraf ^® =5	Advagraf ^® =9
Body mass index (BMI)	27.91 (22.53–38.82)	27.14 (19.84–38.27)
Primary disease	Alcoholic liver disease =5	Alcoholic liver disease =3
	Alcoholic liver disease + HCC =3	Alcoholic liver disease + HCC =3
	Hepatitis B =2	Hepatitis B =5
	Hepatitis B + HCC =2	Hepatitis C =2
	Hepatitis C + HCC =4	Hepatitis B + HCC =2
	Cryptogenic cirrhosis =l	Hepatitis C + HCC =3
	Primary biliary cholangiopathy =l	HCC =1
	Secondary sclerosing cholangitis =l	Familial amyloidosis =l
	Polycystic liver disease =l
Re-transplantation	2 patients	2 patients
Diabetes mellitus	7 patients	12 patients
Chronic kidney disease	Stage 1=2	Stage 1=4
	Stage 2=2	Stage 2=8
	Stage 3=2

Abbreviations: HCC, hepatocellular carcinoma; TAP, Tacpan^®; MOW, Mowel^®; TAC, tacrolimus; MMF, mycophenolate mofetil; LT, liver transplantation.

Figure 2 Matched-pair analysis of tacrolimus trough level/dose ratio.

Notes: No relevant difference was found between the generics (Tacpan^® [TAP] and Mowel^® [MOW]) and the original drugs (Prograf ^® or Advagraf ^® [TAC] and CellCept^® [MMF]) at the beginning (D 0: day 0) and at the end of the study 6 months later. The trough level/dose ratio was stable in both groups. P-values: paired Wilcoxon-test.
Abbreviations: TAC, tacrolimus; MMF, mycophenolate mofetil.

Figure 3 Change in tacrolimus trough level.

Notes: Tacrolimus trough levels were stable in both generic (Tacpan^® [TAP] and Mowel^® [MOW]) (A) and original (Prograf ^® or Advagraf ^® [TAC] and CellCept^® [MMF]) (B) groups. The majority of patients was within the range of intended trough levels (3–7 ng/mL) during the study. Trough levels are shown for each patient at different time points. The intra-individual comparison of tacrolimus trough levels at the beginning and at the end of the study showed a slight increase in both groups (in median +13.89% in the TAP/MOW and +5.86% in the TAC/MMF group) without statistical relevance (P=0.79, paired Wilcoxon-test).
Abbreviations: TAC, tacrolimus; MMF, mycophenolate mofetil.

Table 2 Tacrolimus dose and dose adjustment (generic group)

Patient number	Dose D 0	Dose 3 months	Dose 6 months	Dose adjustment
1	3 mg	3 mg	3 mg	None
3	2 mg	2 mg	2 mg	None
4	4 mg	4 mg	4 mg	None
5	2.5 mg	2.5 mg	2.5 mg	None
7	1.5 mg	1.5 mg	1.5 mg	None
8	1 mg	1 mg	0.75 mg	Reduction
9	5 mg	5 mg	2 mg	Reduction
11	1.25 mg	1.25 mg	1.25 mg	None
12	1 mg	1 mg	1 mg	None
13	1 mg	1 mg	1 mg	None
14	2 mg	3 mg	3 mg	Rise
16	4 mg	4 mg	4 mg	None
17	2 mg	2 mg	2 mg	None
18	2 mg	2 mg	2 mg	None
19	4 mg	4 mg	2 mg	Reduction
20	1 mg	1 mg	1.5 mg	Rise
21	2.5 mg	2.5 mg	2.5 mg	None
23	2 mg	2 mg	2 mg	None
24	2 mg	2 mg	2 mg	None
25	2 mg	2 mg	2 mg	None

Notes: Five patients in the generic group (Tacpan^® [TAP] and Mowel^® [MOW]) needed dose adjustments. The majority of dose adjustments were dose reductions (D 0: day 0). Dose adjustments are written in bold.

Table 3 Tacrolimus dose and dose adjustment (original group)

Patient number	Dose D 0	Dose 6 months	Dose adjustment
1b	4 mg	3 mg	Reduction
3b	0.5 mg	1 mg	Rise
4b	3 mg	3 mg	None
5b	3 mg	2.5 mg	Reduction
7b	2 mg	1 mg	Reduction
8b	3 mg	3 mg	None
9b	2 mg	2 mg	None
11b	1 mg/1.5 mg	1 mg/1.5 mg	None
12b	1.5 mg	1 mg	Reduction
13b	2.5 mg	2.5 mg	None
14b	3 mg	3 mg	None
16b	10 mg	6 mg	Reduction
17b	2 mg	2 mg	None
18b	2 mg	2 mg	None
19b	6 mg	6 mg	None
20b	1.5 mg	1.5 mg	None
21b	2 mg	2 mg	None
23b	3 mg	3 mg	None
24b	2 mg	2 mg	None
25b 2 mg		2 mg	None

Notes: Six patients in the original group (Prograf ^® or Advagraf ^® [TAC] and CellCept^® [MMF]) needed dose adjustments. The majority of dose adjustments were dose reductions (D 0: day 0). Dose adjustments are written in bold.

Abbreviations: TAC, tacrolimus; MMF, mycophenolate mofetil.

Table 4 Matched-pair analysis of blood parameters

	TAP/MOW D 0	TAC/MMF D 0	TAP/MOW End of study (month 6)	TAC/MMF End of study (month 6)	P-value (Friedman analysis)
Na^+ (mmol/L)	140 (137–145)	138.5 (134–142)	141 (136–146)	140 (136–144)	0.092
K^+ (mmol/L)	4.25 (3.5–5.7)	4.35 (3.7–5.7)	4.3 (3.8–5)	4.4 (3.6–5.8)	0.289
Ca^++ (mmol/L)	2.38 (2.25–2.61)	2.35 (2.2–2.35)	2.41 (2.2–2.58)	2.4 (2.13–2.56)	0.195
AST (U/L)	27.5 (17–61)	25.5 (18–129)	29.5 (18–56)	29 (16–34)	0.90
ALT (U/L)	20 (9–111)	22 (13–120)	24.5 (6–81)	24.5 (11–122)	0.74
AP (U/L)	81.5 (35–204)	78 (35–130)	82.5 (41–220)	72.5 (42–136)	0.884
γ-GT (U/L)	35 (9–154)	29.5 (13–134)	32.5 (10–206)	31.5 (12–167)	0.684
Bilirubin (mg/dL)	0.75 (0.31–3.86)	0.68 (0.26–2.19)	0.76 (0.24–2.58)	0.81 (0.37–2.15)	0.753
Creatinine (mg/dL)	1.24 (0.76–2.15)	1.4 (0.6–2.25)	1.17 (0.78–2.77)	1.36 (0.67–2.18)	0.467
Urea (mg/dL)	19 (9–34)	24 (9–47)	19.5 (13–48)	27 (9–51)	0.694
HbA1c (%)	5.55 (4.9–7.5)	6.5 (4.4–11.4)	5.85 (5–7.3)	6.55 (4.4–7.7)	0.21
Uric acid (mg/dL)	6.4 (2.9–9.5)	6.85 (3.3–9.1)	6.8 (3.9–9.9)	6.5 (3–11.3)	0.819
CRP (mg/L)	1.6 (0.23–23)	2.45 (0.36–32)	1.5 (0.2–18)	2.55 (0.33–50)	0.241
Quick (%)	104 (43–125)	104.5 (61–120)	105 (73–131)	104 (89–125)	0.849
Leucocytes (/nL)	6.17 (2.39–9.56)	5.66 (2.2–9.8)	6.45 (1.8–9.78)	6.29 (2.3–14.4)	0.44
Thrombocytes (/nL)	175 (97–341)	203.5 (104–339)	188 (94–395)	104 (43–125)	0.962
Hemoglobin (g/dL)	14.85 (9.6–17.4)	13.95 (10.8–16.8)	14.8 (9.5–17.8)	14 (10.3–15.6)	0.071

Notes: No relevant difference in blood values between the generic (Tacpan^® [TAP] and Mowel^® [MOW]) and the original (Prograf ^® or Advagraf ^® [TAC] and CellCept^® [MMF]) group at the beginning (D 0: day 0) and at the end of the study after 6 months (Friedman analysis). The data is presented as median (range).

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; AP, alkaline phosphatase; γ-GT, gamma glutamyltransferase; HbA_1c, glycosylated haemoglobin fraction; CRP, C-reactive protein; TAC, tacrolimus; MMF, mycophenolate mofetil.

Table 5 Side effects

Symptom	Frequency	WHO
GI
Nausea	20%	Grade 1
Gastric pain	8%	Grade 1
Diarrhea	25%	Grade 1
Obstipation	20%	Grade 1
Meteorism	8%	Grade l
Reflux	4%	Grade 1
Neurological
Vertigo	20%	Grade 1
Headache	8%	Grade 1
Paresthesia	4%	Grade 1
Insomnia	4%	Grade 1
Petulance	4%	Grade 1
Dysgeusia	4%	Grade 1
Dermatological
Pruritus	15%	Grade 2
Erythema	8%	Grade 1
Oral aphthae	4%	Grade 1
Oral blisters	15%	Grade 1
Xerostomia	4%	Grade 1
Dry nasal mucosa	4%	Grade 1
Unpleasant body odor	4%	Grade 1
Minimal hair loss	4%	Grade 1
Infections
Temperature <38°C	4%	Grade 1
Temperature 38°C–40°C	4%	Grade 2
Pneumonia	4%	Grade 2
Respiratory infection	8%	Grade 1
Pharynx infection	4%	Grade 1
Cardiocirculatory
Blood pressure increase	4%	Grade 1
Other
Reduced general condition	4%	Grade 1
Serious adverse events
Acute rejection	0%	–

Note: WHO grading of side effects and frequency after switching from originals to generics.

Abbreviations: GI, gastrointestinal; WHO, World Health Organization.

Figure 4 Intra-individual analysis of costs.

Notes: The use of Tacpan^® (TAP) saves in median 21.8% per day in comparison to Prograf ^® or Advagraf ^® (TAC) (P<0.001) (A). With Mowel^® (MOW) a cost reduction of 29.3% per day was achieved in comparison to CellCept^® (MMF) (P<0.001) (B). The combination of TAP and MOW saves 4.38 €/day in comparison to TAC and MMF (P<0.001) (C). P-values: paired Wilcoxon-test.
Abbreviations: TAC, tacrolimus; MMF, mycophenolate mofetil; d, day.