Immunosuppression with Generics in Liver and Kidney Transplantation: A Real-World Evidence Study

Figures & data

Table 1 Branded and Generic Version of Tacrolimus, Cyclosporine and Mycophenolate

Active Ingredient	Branded, Approval Date	Generic, Approval Date
Tacrolimus (TAC)	Prograf (immediate release formulation), 29th May 1998	Adoport (immediate release formulation), 3rd September 2012 (as Tacrolimus Sandoz) Tacni (immediate release formulation), 3rd May 2011
	Envarsus (immediate release formulation), 26th March 2015
	Advagraf (sustained release), 5th April 2008
Cyclosporine (CsA)	Sandimmun, 27th April 1991 Sandimmun Neoral, 31st August 1995	Ciqorin, 7th April 2014
Mycofenolate (MYC)	Cellcept (mycophenolate mofetil), 23rd June 1996	Myfenax (mycophenolate mofetil), 17th January 2011 Aurobindo (mycophenolate mofetil), 20th January 2011
		Accord (mycophenolate mofetil), 20th January 2011
		Sandoz (mycophenolate mofetil), 20th January 2011
		Tillomed (mycophenolate mofetil), 14th December 2018
	Myfortic (mycophenolic acid), 23rd June 2005	Acido Micofenolico Accord (mycophenolic acid), 29th August 2015

Figure 1 Study eligibility criteria by kidney and liver transplantation.

Figure 2 Generic and branded users of TAC, CsA and MYC by year in kidney and liver transplantation.

Table 2 Transplant, Recipient and Donor Characteristics According to Generic/Branded Version by Active Ingredient in Kidney and Liver Transplantation

A. Kidney
	Kidney
	Tac			CsA			MMF
	Generic	Branded	Pvalue	Generic	Branded	Pvaluev	Generic	Branded	p value
N, %	824	1530		300	327		983	1160
Region
Veneto	11.9%	44.2%	<0.0001	0.0%	10.4%	<0.0001	16.5%	34.6%	<0.0001
Lombardy	77.4%	18.8%		99.3%	84.4%		76.1%	26.3%
Latium	10.6%	27.6%		0.7%	5.2%		3.3%	32.9%
Sardinia	0.1%	9.5%		0.0%	0.0%		4.2%	6.2%
Sex (receipt)
M	64.3%	64.0%	0.872	67.3%	67.6%	0.947	64.6%	63.4%	0.553
F	35.7%	36.0%		32.7%	32.4%		35.4%	36.6%
Age (receipt)
<50	43.1%	33.7%	<0.0001	28.7%	35.5%	0.109	37.8%	38.7%	0.916
50–59	27.2%	29.1%		32.3%	26.0%		28.2%	27.9%
60+	29.7%	37.2%		39.0%	38.5%		34.0%	33.4%
BMI (receipt)
Underweight	9.1%	5.6%		4.7%	9.5%		6.4%	7.0%
Normal	51.9%	54.2%		54.7%	48.3%		53.1%	54.7%
Overweight/obese	39.0%	40.1%		40.7%	42.2%		40.5%	38.3%
Overweight
Obese
Year of discharge
2013–2015	27.2%	46.3%	<0.0001	5.3%	90.8%	<0.0001	37.3%	42.2%	0.007
2016–2017	39.6%	23.9%		50.7%	7.0%		28.9%	30.2%
2018–2019	33.3%	29.8%		44.0%	2.1%		33.8%	27.7%
Transplant hospitalization stay
<15 days	53.9%	51.8%	0.341	53.0%	53.5%	0.897	47.3%	51.8%	0.038
≥15 days	46.1%	48.2%		47.0%	46.5%		52.7%	48.2%
Donor
Living	12.6%	13.3%	0.657	0.3%	4.0%	0.002	12.7%	14.5%	0.236
Dead	87.4%	86.7%		99.7%	96.0%		87.3%	85.5%
Sex (donor)
M	54.7%	53.1%	0.459	53.0%	54.7%	0.662	54.8%	54.1%	0.748
F	45.3%	46.9%		47.0%	45.3%		45.2%	45.9%
Age (donor)
<50	32.2%	26.7%	0.007	26.3%	34.9%	0.037	28.7%	31.3%	0.397
50–59	24.4%	23.7%		27.7%	21.1%		26.1%	24.6%
60+	43.4%	49.6%		46.0%	44.0%		45.2%	44.1%
BMI (donor)
Underweight	4.5%	2.3%		2.3%	4.0%		2.2%	3.5%
Normal	45.0%	43.5%		55.3%	46.2%		46.3%	44.1%
Overweight/obese	50.5%	54.2%		42.3%	49.8%		51.5%	52.3%
Overweight	24.2%	25.4%		22.5%	23.3%		24.6%	25.1%
Obese	9.4%	9.7%		7.3%	10.0%		9.4%	9.3%
Presence of infections (donor)	12.6%	15.2%	0.076	10.3%	14.7%	0.069	12.6%	15.5%	0.033
Presence of neoplasms (donor)	2.9%	2.6%	0.703	4.7%	5.5%	0.559	4.2%	2.8%	0.090
Indications for transplant
Glomerular nephropathies	45.4%	41.8%	0.088	48.3%	42.8%	0.262	43.4%	41.6%	0.598
Cystic nephropathies	21.2%	20.3%		18.3%	17.7%		19.8%	21.4%
Other renal diseases	33.4%	37.9%		33.3%	39.4%		36.7%	37.0%
Cirrhosis	–	–	–	–	–	–	–	–	–
HCC	–	–		–	–		–	–
Other liver diseases	–	–		–	–		–	–
PRA (Panel-Reactive Antibody)
<80	96.4%	96.6%	0.760	97.7%	96.0%	0.242	97.3%	95.6%	0.042
80+	3.6%	3.4%		2.3%	4.0%		2.7%	4.4%
Score MELD (Model for End-stage Liver Disease)
0–24	–	–	–	–	–	–	–	–	–
25+	–	–		–	–		–	–
Charlson index
0–1	82.8%	81.1%	0.604	80.3%	82.3%	0.300	78.8%	81.1%	0.420
2	13.8%	15.3%		16.7%	13.1%		17.4%	15.5%
3+	3.4%	3.6%		3.0%	4.6%		3.8%	3.4%
Comorbidities/comedications
Cancer	6.7%	7.3%	0.561	5.7%	5.5%	0.930	6.3%	6.1%	0.859
Diabetes	20.0%	18.6%	0.398	19.3%	18.7%	0.829	19.9%	17.8%	0.216
Thyroid disease	11.8%	15.0%	0.032	9.7%	9.5%	0.937	10.2%	15.0%	0.001
Lipid metabolism disorders	3.8%	5.8%	0.031	6.0%	5.5%	0.790	4.8%	5.8%	0.307
Cardio-cerebrovascular diseases	22.2%	23.7%	0.426	25.7%	22.6%	0.374	22.8%	21.5%	0.462
Hypertension	89.8%	93.2%	0.004	92.7%	90.8%	0.404	91.1%	92.2%	0.360
Depression	4.7%	5.9%	0.243	4.3%	4.9%	0.739	4.8%	5.9%	0.269
Infections	11.0%	7.4%	0.003	13.3%	20.8%	0.013	13.2%	9.6%	0.008
Anticoagulants	12.5%	12.2%	0.845	5.3%	8.9%	0.087	10.7%	11.9%	0.377
Antiplatelet	32.2%	33.0%	0.676	28.7%	30.3%	0.659	28.3%	34.1%	0.004
Statins	41.0%	47.2%	0.004	49.7%	44.3%	0.182	43.4%	45.0%	0.468
B. Liver
	Liver
	Tac			CsA			MMF
	Generic	Branded	Pvalue	Generic	Branded	Pvalue	Generic	Branded	p value
N, %	525	993		47	176		333	329
Region
Veneto	18.9%	20.7%	<0.0001	0.0%	2.3%	0.2970 (warning)	12.6%	16.7%	<0.0001
Lombardy	64.0%	39.7%		100.0%	97.7%		52.0%	4.0%
Latium	13.7%	27.0%		0.0%	0.0%		31.8%	41.3%
Sardinia	3.4%	12.6%		0.0%	0.0%		3.6%	38.0%
Sex (receipt)
M	78.5%	81.0%	0.248	85.1%	78.4%	0.310	75.1%	83.3%	0.009
F	21.5%	19.0%		14.9%	21.6%		24.9%	16.7%
Age (receipt)
<50	18.5%	23.2%	0.088	8.5%	14.2%	0.067	21.6%	24.6%	0.096
50–59	43.4%	42.4%		48.9%	52.3%		39.3%	44.4%
60+	38.1%	34.4%		42.6%	27.8%		39.0%	31.0%
BMI (receipt)
Underweight	1.9%	2.1%		2.1%	2.8%		2.4%	1.8%
Normal	45.1%	43.0%		44.7%	45.5%		43.5%	41.6%
Overweight/obese	53.0%	54.9%		53.2%	51.7%		54.1%	56.5%
Overweight
Obese
Year of discharge
2013–2015	17.5%	45.2%	<0.0001	0.0%	90.9%	<0.0001	27.3%	43.8%	<0.0001
2016–2017	46.9%	27.2%		57.4%	6.3%		34.5%	33.4%
2018–2019	35.6%	27.6%		42.6%	2.8%		38.1%	22.8%
Transplant hospitalization stay
<15 days	20.2%	36.7%	<0.0001	38.3%	18.2%	0.003	15.6%	43.5%	<0.0001
≥15 days	79.8%	63.3%		61.7%	81.8%		84.4%	56.5%
Donor
Living	–	–	–	–	–	–	–	–	–
Dead	100.0%	100.0%		100.0%	100.0%		100.0%	100.0%
Sex (donor)
M	57.7%	56.9%	0.760	55.3%	59.1%	0.641	55.6%	54.4%	0.767
F	42.3%	43.1%		44.7%	40.9%		44.4%	45.6%
Age (donor)
<50	23.0%	25.9%	0.366	14.9%	23.3%	0.455	25.8%	29.2%	0.530
50–59	17.1%	17.9%		19.1%	18.2%		17.7%	18.5%
60+	59.8%	56.2%		66.0%	58.5%		56.5%	52.3%
BMI (donor)
Underweight	1.3%	2.2%		0.0%	1.7%		3.0%	2.1%
Normal	45.0%	42.3%		40.4%	38.6%		45.0%	44.1%
Overweight/obese	53.7%	55.5%		59.6%	59.7%		52.0%	53.8%
Overweight	25.9%	26.8%		26.7%	26.0%		25.9%	26.9%
Obese	9.0%	8.9%		10.7%	11.4%		8.3%	8.1%
Presence of infections (donor)	10.9%	14.9%	0.037	10.6%	10.8%	0.927	11.1%	20.4%	0.021
Presence of neoplasms (donor)	7.0%	5.9%	0.384	2.1%	5.1%	0.3762 (warning)	6.0%	6.4%	0.833
Indications for transplant
Glomerular nephropathies	–	–	–	–	–	–	–	–	–
Cystic nephropathies	–	–		–	–		–	–
Other renal diseases	–	–		–	–		–	–
Cirrhosis	25.3%	24.2%	0.868	9.3%	21.0%	0.0374 (warning)	27.1%	28.1%	0.789
HCC	35.4%	35.9%		53.3%	41.3%		33.6%	32.6%
Other liver diseases	4.3%	4.2%		0.0%	0.4%		5.1%	4.3%
PRA (Panel-Reactive Antibody)
<80	–	–	–	–	–	–	–	–	–
80+	–	–		–	–		–	–
Score MELD (Model for End-stage Liver Disease)
0–24	83.4%	80.7%	0.186	95.7%	88.6%	0.1465 (warning)	75.4%	76.9%	0.646
25+	16.6%	19.3%		4.3%	11.4%		24.6%	23.1%
Charlson index
0–1	34.1%	32.3%	0.028	14.9%	24.4%	0.362	32.4%	33.1%	0.981
2	51.2%	47.4%		57.4%	52.8%		46.8%	46.5%
3+	14.7%	20.2%		27.7%	22.7%		20.7%	20.4%
Comorbidities/comedications
Cancer	3.8%	4.9%	0.317	2.1%	2.8%	0.7883 (warning)	3.6%	4.9%	0.421
Diabetes	47.4%	39.2%	0.002	44.7%	47.7%	0.710	42.6%	33.7%	0.018
Thyroid disease	5.1%	5.3%	0.872	4.3%	6.8%	0.5199 (warning)	6.3%	7.6%	0.513
Lipid metabolism disorders	3.0%	4.9%	0.084	6.4%	1.1%	0.0309 (warning)	6.6%	6.4%	0.907
Cardio-cerebrovascular diseases	15.4%	15.1%	0.868	19.1%	15.9%	0.596	16.5%	15.5%	0.722
Hypertension	81.7%	81.4%	0.869	70.2%	78.4%	0.238	84.7%	87.5%	0.289
Depression	5.3%	5.9%	0.628	2.1%	8.5%	0.1312 (warning)	3.6%	6.4%	0.100
Infections	11.0%	9.4%	0.298	10.6%	14.2%	0.524	11.7%	11.6%	0.948
Anticoagulants	12.2%	13.1%	0.617	19.1%	12.5%	0.242	12.3%	12.2%	0.952
Antiplatelet	5.3%	4.4%	0.432	0.0%	2.8%	0.2425 (warning)	3.3%	4.3%	0.521
Statins	13.9%	14.6%	0.713	10.6%	11.4%	0.889	11.7%	14.9%	0.228

Table 3 Proportion of Patients Treated with Generic Version for TAC, CsA and MYC Over Time by Region in Kidney and Liver Transplantation

	Kidney							Liver
TAC	2013	2014	2015	2016	2017	2018	2019	2013	2014	2015	2016	2017	2018	2019
Veneto	1.9	0.9	5.4	26.1	25.0	15.4	14.5	3.6	0.0	40.0	54.3	43.3	37.5	28.6
Lombardy	33.9	60.8	68.5	82.2	82.1	70.5	76.0	3.0	27.8	33.7	48.2	78.7	63.1	42.5
Lazio	3.4	6.2	16.7	29.3	30.8	12.2	13.8	0.0	5.4	22.2	34.4	41.3	23.5	13.0
Sardegna	0.0	0.0	0.0	4.2	0.0	0.0	0.0	7.1	4.5	0.0	0.0	0.0	5.3	100.0
CsA	2013	2014	2015	2016	2017	2018	2019	2013	2014	2015	2016	2017	2018	2019
Veneto	0.0	0.0	0.0	0.0	0.0	0.0	0.0	–	0.0	0.0	–	–	–	0.0
Lombardy	0.0	0.0	19.5	89.6	94.3	97.5	96.4	0.0	0.0	0.0	58.3	92.9	81.3	87.5
Lazio	0.0	0.0	0.0	33.3	0.0	–	100.0	–	–	–	0.0	–	–	–
Sardegna	–	–	–	–	–	–	–	–	–	–	–	–	–	–
MYC	2013	2014	2015	2016	2017	2018	2019	2013	2014	2015	2016	2017	2018	2019
Veneto	33.8	42.7	34.7	31.3	23.3	16.1	22.9	66.7	28.6	23.1	50.0	35.7	47.6	61.5
Lombardy	50.0	72.7	64.0	69.8	77.5	80.8	79.5	33.3	94.7	100.0	100.0	100.0	100.0	100.0
Lazio	14.8	7.8	3.7	14.9	8.2	0.0	2.6	34.5	29.0	39.4	68.2	50.0	45.5	30.6
Sardegna	0.0	0.0	0.0	12.5	0.0	61.9	100.0	0.0	0.0	0.0	0.0	0.0	5.9	100.0

Notes: Three distinct colors were used: blue for tacrolimus, yellow for cyclosporine, and green for mycophenolate. A more intense color indicates a greater usage of generic form.

Figure 3 (A-C) Hospital variability in patients treated with generic drugs by active ingredient in kidney and liver transplantation.

Figure 4 Proportion of patients changing drug version within one year from starting therapy by active ingredient in kidney and liver transplantation.

Figure 5 Proportion of patients changing drug version within two years from starting therapy by active in kidney and liver transplantation.

Figure 6 Risk-benefit profile of generic versus branded by active ingredient in kidney and liver transplantation.

Table 4 Sensitivity Analysis Adjusting for Immunosuppressive Therapies Used in Combination with the Exposure

	Kidney			Liver
	Tac
	HR (IC 95%)	HR (IC 95%)	HR (IC 95%)	HR (IC 95%)	HR (IC 95%)
OUTCOMES
Mortality	1.46 (0.82–2.61)	1.39 (0.56–3.44)	1.14 (0.64–2.02)	0.56 (0.29–1.07)	1.82 (0.87–3.82)
Rejection/Graft loss	1.24 (0.72–2.16)	2.11 (0.94–4.75)	1.20 (0.70–2.06)	0.69 (0.30–1.59)	not estimable
Severe infections	1.05 (0.82–1.36)	1.36 (0.90–2.06)	0.99 (0.77–1.26)	1.61 (0.99–2.61)	1.05 (0.49–2.23)
Diabetes	1.41 (0.98–2.03)	1.39 (0.64–3.04)	1.11 (0.74–1.69)	0.71 (0.40–1.25)	0.61 (0.26–1.45)
MACE	0.92 (0.57–1.46)	0.49 (0.18–1.29)	0.68 (0.42–1.10)	1.13 (0.59–2.16)	0.51 (0.18–1.43)
Statins	0.86 (0.66–1.11	1.08 (0.66–1.78)	1.09 (0.83–1.42)	0.72 (0.51–1.03)	0.79 (0.49–1.29)

Figure 7 Saving of one year of immunosuppressive therapy with generics compared to branded.