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Cardiovasc Ther. 2008; 26(1): 2-9.
Int J Impot Res 2007; 19: 208–212.
Curr Opin Cardiol. 2015; 30(4): 383-90.
Bula – Zanidip.
RESEARCH
Tolerability of High Doses of Lercanidipine versus
High Doses of Other Dihydropyridines in Daily Clinical Practice:
The TOLERANCE Study
Vivencio Barrios,1 Carlos Escobar,1 Mariano de la Figuera,2 Jose Luis Llisterri,3 Jesus Honorato,4
Julián Segura,5 & Alberto Calderón6
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doi: 10.1111/j.1527-3466.2007.00035.x
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Correspondence
Dr. Vivencio Barrios, Department of Cardiology,
Hospital Ramón y Cajal, Ctra. Colmenar km
9.100, 28034 Madrid, Spain. Tel.:
+34-913368259; Fax: +34-91-3368665;
E-mail: vbarriosa@meditex.es or
vbarrios.hrc@salud.madrid.org
The TOLERANCE study was aimed to compare the tolerability of high doses
of lercanidipine (20 mg) with that of other frequently used dihydropyridines
(amlodipine 10 mg/nifedipine GITS 60 mg) in the treatment of essential hypertension in daily clinical practice. It was an observational, transversal, multicentre study performed in a Primary Care Setting. A total of 650 evaluable patients
with essential hypertension and age ≥ 18 years were included. They had been
treated with high doses of lercanidipine (n = 446) or amlodipine/nifedipine
GITS (n = 204) during at least 1 month and previously with low doses (10 mg,
5 mg, and 30 mg, respectively) of the same drugs. The main objective was to
compare the rates of vasodilation-related adverse events between both groups.
Rates of signs and symptoms related to vasodilation were significantly higher
(P < 0.001) in the amlodipine/nifedipine GITS group (76.8%, CI 95% [70.7;
82.9]) than in lercanidipine group (60.8%, [56.1;65.5]). Blood pressure control (< 140/90 mmHg or <130/80 for diabetics) and type of concomitant antihypertensive medications were similar in both groups. Treatment compliance
was good (around 93%) and fairly comparable in both groups. Most adverse
events with lercanidipine were mild (74.5% vs. 64% in amlodipine/nifedipine
GITS group, P = 0.035) whereas severe adverse event rates did not differ significantly between groups (2.8% vs. 3.6%). In conclusion, treatment with lercanidipine at high doses is associated with a lower rate of adverse events related to vasodilation compared to high doses of amlodipine or nifedipine GITS
in clinical practice.
a
Keywords
Adverse effects; Amlodipine; Antihypertensive
drugs; Dihydropyridines; Hypertension;
Lercanipine; Nifedipine GITS; Tolerability;
Vasodilation.
o
1 Hospital Ramón y Cajal, Madrid
2 CAP La Mina, San Adrı́an del Besós-Barcelona
3 CS Joaquı́n Benlloch, Valencia
4 Clı́nica Universitaria de Navarra
5 Hospital 12 de Octubre and
6 CS Rosa de Luxemburgo, SS de los Reyes-Madrid, Spain
Introduction
Hypertension is a major public health problem due to its
high prevalence and close relationship with cardiovascular events. But, current blood pressure (BP) control rates
are still far from the target of 50% proposed for the year
2010 (USHHS 2006). It has been demonstrated in recent clinical trials that BP control can only be achieved
with two or more antihypertensive drugs in most cases
(Cushman et al. 2002; ESH 2003). The poor control of
hypertension may be partially due to the low treatment
compliance of the patients. Some factors that have been
involved in this poor compliance are adverse events re-
2
lated to antihypertensive drugs, lifelong treatment, and
polymedication (Osterberg and Blaschke 2005). Calcium
channel blockers (CCB) are widely used drugs for the
treatment of hypertension. Lercanidipine is a highly lipohilic third generation dihydropyridine (DHP) (Bang et al.
2003). Its antihypertensive effect results from peripheral vasodilation and decreased total peripheral resistance
(Meredith 1999). This drug has a slow onset of action
due to its high lipophilicity and its partitioning into the
lipid bilayer of cell membranes, followed by diffusion
to the receptor binding site, that helps to avoid reflex
tachycardia associated with other DHP, such as nifedipine (Ambrosioni and Circo 1997; Meredith 1999). Its
c 2008 The Authors. Journal Compilation c 2008 Blackwell Publishing Ltd
Cardiovascular Therapeutics 26 (2008) 2–9 Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
Lercanidipine
V. Barrios et al.
o
The main objective of the study was to determine the
rates of adverse events linked to vasodilation in patients
treated with lercanidipine 20 mg. This prevalence was
compared with that of a group of subjects treated with
amlodipine or nifedipine GITS at high doses. Other objectives were: (1) Evaluate the frequency of the commonest
adverse reactions associated to lercanidipine (defined as
those adverse events reported in registration clinical trials with a frequency > 5%); (2) Determine the frequency
of adverse reactions spontaneously notified by the patient (answering the question “have you noticed any
discomfort related to the drug?”); (3) Evaluate the percentage of patients with an adequate BP in both groups;
(4) Compare the patient’s therapeutic compliance with
every drug.
Adverse reactions were spontaneously reported by
the patient or elicited using a 16-item checklist similar
to the one used in the COHORT trial (Leonetti et al.
2002) that included those symptoms considered related
to vasodilation and the most commonly adverse events
reported during registration trials (see Appendix 1). Adequate BP control was defined as <140/90 mmHg in general population and <130/80 mmHg in people with diabetes (ADA 2005; ESH 2003). Since this study was aimed
to reflect clinical practice, when BP control was not attained, the investigators could freely add more antihypertensive medication.
BP was measured with a standard mercury sphygmomanometer. Two measurements were taken, both in the
sitting position and in the same arm with a 5-minute interval, and the average was used as the reference value.
Patients underwent a complete physical examination,
and they should have a complete blood test (hematology
and biochemistry with a lipid profile) performed in the
last three months before entering the study.
Treatment compliance was assessed through the
Haynes-Sackett test (Sackett et al. 1991).
Methods
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efficacy has been evaluated in noncomparative (Barrios
et al. 2002; Viviani 2002; Barrios et al. 2006a; Barrios
et al. 2006b) and comparative studies (Agrawal et al.
2006; James et al. 2002; Millar-Craig et al. 2003;). In
most trials the starting dose was 10 mg/day. Lercanidipine is generally well tolerated during monotherapy in patients with mild-to-moderate hypertension (Barrios et al.
2002; Borghi et al. 2003). Because in older population
the occurrence of side effects is more likely, the use of
well-tolerated drugs is particularly important in these patients. Lercanidipine has been shown to be safe even in
the elderly (Barbagallo and Barbagallo Sangiorgi 2000;
Leonetti et al. 2002).
DHP-related adverse events are generally associated
with vasodilation and include headache, dizziness, flushing, or edema (Leonetti 1999). In previous studies lercanidipine has been compared to other DHP such as
nitrendipine (Rengo and Romis 1997), nifedipine SR
(Policicchio et al. 1997), and nifedipine gastrointestinal
therapeutic system (GITS) (Cherubini et al. 2003; Romito
et al. 2003) with a lower incidence of adverse events
favoring lercanidipine. Nonetheless, this information is
derived from clinical trials with commonly strict inclusion and exclusion criteria with less information available
from “real world” clinical settings.
The main objective of the TOLERANCE (TOlerabilidad de LERcanidipino 20 mg frente a Amlodipino y
Nifedipino en CondicionEs normales de uso) study was
to compare the tolerability, with special emphasis on
vasodilation-related adverse reactions, of high doses of
lercanidipine with other DHP (amlodipine and nifedipine
GITS) also given at daily high doses. The study was performed in Primary Care setting in conditions of common
clinical practice.
Pr
It was an observational, cross-sectional and multicenter
study performed in Primary Care Centers from all around
Spain. The study population were outpatients aged ≥
18 years with essential hypertension who had been
treated at least for 1 month with lercanidipine, amlodipine, or nifedipine GITS at low doses (10, 5, and 30 mg
daily, respectively) and who were titrated to higher doses
of the same drugs (20, 10, and 60 mg, respectively) in a
2:1:1 design because of a BP below target. They should
have been treated with these high doses during at least
1 month before entering the study (Figure 1). Patients
with heart failure were excluded. Subjects had to give
their written informed consent to participate in the study.
The study was evaluated and approved by the Ethics
Committee of the Ramon y Cajal University hospital in
Madrid.
Statistical Analysis
The study sample calculation was based on the results of
two previous studies (Leonetti et al. 2002; Romito et al.
2003). Based on the different proportions of edema detected in the first study (Leonetti et al. 2002) (9% lercanidipine vs. 19% amlodipine) and with the presence of an
active control group with Nifedipine GITS, if we wanted
to detect that difference we had to include a total of
650 patients (power = 90%, α = 0.05). No dropouts were
expected, as it was an observational study.
The primary variable of the study was evaluated
through the frequency of ankle edema and other
vasodilation-related adverse events according to the
checklist used in the study. Secondary endpoints were
c 2008 The Authors. Journal Compilation c 2008 Blackwell Publishing Ltd
Cardiovascular Therapeutics 26 (2008) 2–9 Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
3
Lercanidipine
V. Barrios et al.
Inclusion criteria:
• Outpatients
• ≥18 years
• with essential hypertension
No BP control
•who had been treated at
least for 1 month with
lercanidipine, amlodipine or
nifedipine GITS at low doses
(10, 5 and 30 mg daily
respectively)
2:1:1 design
Patients were titrated to
higher doses of the same
drugs to attain BP goals at
least for 1 month:
Data analysis
Lercanidipine, amlodipine or
nifedipine GITS (20, 10 and
60 mg daily, respectively)
Figure 1 Study design.
Table 1 Clinical characteristics of study population.
Amlodipine/nifedipine (n = 204)
P
64.4 (11.1)
47%
28.4 ( 4.3)
96.7 (15.5)
63.7 (65.4)
27.3%
26.1%
47.7%
56.7%
64.1 (10.9)
48%
28.5 ( 4.3)
97 (15.7)
62.2 (66)
26.7%
28.6%
46.2%
54.9%
65.3 (11.4)
46%
28 ( 4.2)
95.9 (15)
66.9 (64.2)
28.4%
20.7%
51.1%
60.4%
NS
NS
NS
NS
NS
NS
0.044
NS
NS
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Lercanidipine (n = 446)
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Age (years)
Gender (male)
BMI (kg/m2 )
Waist circumference (cm)
Time since diagnosis (months)
Smokers
Diabetes
Hypercholesterolemia
Family history of hypertension
Global (n = 650)
Data are expressed as means (standard deviation) or percentages. Low dose: treatment with dihydropyridines at low doses; High dose: treatment with
dihydropyridines at high doses. NS: not significant (P > 0.05).
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frequency of spontaneously adverse events notified by
the patient, rates of BP control, and percentage of patients
classified as good compliers according to the HaynesSacket test. Continuous variables were averaged and expressed as means ± standard deviation. Categorical items
were expressed as percent frequency. 95% confidence
intervals were provided when necessary. Differences between means of different parameters were compared by
the Student t-test. Differences between percentages were
compared with the Fisher’s exact test. Categorical data
were also analyzed with this test. A P-value < 0.05 was
used as the level of statistical significance.
Computations for the statistical method were performed with the use of the SAS system. A logistic regression analysis was performed to determine what factors
could influence the incidence of adverse events related to
vasodilation (dependent variable). Clinical characteristics
of study population, cardiovascular risk factors, target organ damage, associated clinical conditions, antihypertensive treatments, concomitant treatments, and biochemical parameters were included as independent variables in
the logistic regression analysis.
Results
A total of 656 consecutive patients were included in the
study. The number of evaluable subjects was 650 (99.1%)
of whom 446 (68.6%) were taking lercanidipine and 204
4
(31.4%) amlodipine or nifedipine GITS (n = 113 and 91
respectively). Mean follow-up was 3.6 months. The clinical characteristics of the study population are shown in
Table 1. The changes in BP and heart rate values during
the study are shown in Table 2. The percentage of patients
with an adequate BP control was 46.4% in the lercanidipine group versus 38.1% in the amlodipine/nifedipine
group (P = NS). Concomitant antihypertensive therapy
in both groups is shown in Table 3. There were more
patients in the amlodipine/nifedipine group with concomitant antihypertensive medication than in the lercanidipine group (49% [42.1–55.9] vs. 38.3% [33.8–
42.8] respectively, P = 0.013). Regarding the type of
concomitant antihypertensive drugs, the only difference
was a higher rate of angiotensin converting enzyme
(ACE) inhibitors use in the amlodipine/nifedipine group
(17.7 vs. 9%; P = 0.002). There were no significant differences between both groups in biochemical parameters
as shown in Table 4.
Rates of signs and symptoms related to vasodilation were significantly higher (P < 0.001) in the amlodipine/nifedipine group (76.8%, CI 95% [70.7;82.9])
vs. lercanidipine group (60.8%, [56.1;65.5]) when the
drugs were given at high doses. Corresponding figures
for low doses were 41.2% [36.3;46.1] for lercanidipine and 58.8% [51.5;66.1] for amlodipine/nifedipine, the
difference was statistically significant (P < 0.001). The
difference in prevalence of vasodilation-related adverse
c 2008 The Authors. Journal Compilation c 2008 Blackwell Publishing Ltd
Cardiovascular Therapeutics 26 (2008) 2–9 Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
Lercanidipine
V. Barrios et al.
Table 2 Blood pressure and heart rates changes during the study.
SBP (low dose) mmHg
DBP (low dose) mmHg
HR (low dose) b.p.m.
SBP (high dose) mmHg
DBP (high dose) mmHg
HR (high dose) b.p.m.
Global (n = 650)
Lercanidipine (n = 446)
Amlodipine/nifedipine∗ (n = 204)
155.5 (13)
90.3 (8.3)
78.3 (8,7)
142.7 (12.4)
82.3 (7.7)
76.5 (8.3)
155.1 (13.8)
90.4 (8.4)
78 (8.7)
142.3 (12.2)
82 (7.6)
76.4 (8.4)
156.4 (11)
90.1 (8.2)
78 (8.7)
143.6 (12.7)
83 (8)
76.7 (8.2)
SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate.
∗
SBP and DBP: P < 0.05 in lercanidpine and amlodipine/nifedipine groups versus low dose; P = NS between both groups. HR: P = NS.
Table 3 Concomitant antihypertensive therapy.
Amlodipine/nifedipine (n = 204)
p
15.2%
11.7%
21.4%
5.4%
2.6%
1.2%
14.6%
9%
21.3%
4.5%
2.7%
1.1%
16.7%
17.7%
21.6%
7.4%
2.5%
1.5%
NS
0.002
NS
NS
NS
NS
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Lercanidipine (n = 446)
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ARB
ACE inhibitors
Diuretics
Betablockers
α blockers
Other
Global (n = 650)
ARB, angiotensin receptor blockers; ACE, angiotensin-converting enzyme.
Table 4 Biochemical parameters in overall study population, lercanidipine and amlodipine/nifedipine subgroups.
112 (37.1)
1.0 (0.4)
140 (4.7)
4.3 (0.5)
5.8 (1.4)
216 (36.9)
53.7 (17)
136.4 (31.2)
150.3 (68.9)
Amlodipine/nifedipine (n = 204)
P
113.1 (41.4)
1.0 (0.4)
139.2 (5.0)
4.3 (0.5)
5.8 (1.4)
217 (36.4)
54.6 (18)
136.5 (31.1)
149.3 (58.2)
109.5 (25.7)
1.0 (0.3)
140.2 (4.1)
4.3 (0.5)
5.9 (1.5)
214 (38)
51.9 (14.8)
136.2 (31.4)
152.4 (87.8)
NS
NS
NS
NS
NS
NS
NS
NS
NS
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Glucose (mg/dL)
Creatinine (mg/dL)
Sodium (mEq/L)
Potassium (mEq/L)
Urate (mg/dL)
Cholesterol (mg/dL)
c-HDL (mg/dL)
c-LDL (mg/dL)
Triglycerides (mg/dL)
Lercanidipine (n = 446)
a
Global (n = 650)
Values are expressed as means (standard deviation); NS, not significant (P > 0.05).
HDL, high-density lipoprotein. LDL, low-density lipoprotein.
Pr
reactions between high and low doses in every group was
also significant (60.8 vs. 41.2% for lercanidipine and 76.8
vs. 58.8% for amlodipine/nifedipine, both P < 0.001).
Table 5 shows the distribution between groups of drug
related signs and symptoms according to the checklist.
Classification of the severity of adverse reactions was
as follows: 74.5% [69.1–79.9] mild, 22.7% [17.5–27.9]
moderate, and 2.8% [0.7–4.9] severe in the lercanidipine group versus 64% [56–72] mild, 32.4% [24.6–40.2]
moderate, and 3.6% [0.5–6.7] severe in the amlodipine/nifedipine group. Differences between groups were
statistically significant for mild (P = 0.035) and moderate
adverse events (P = 0.040), but not for severe ones. With
regard to adverse events spontaneously notified by the
patients, there were no statistically significant differences
between both groups of DHP-treated patients. Around
2.7% of patients from lercanidipine group and 6.1% from
amlodipine/nifedipine group droppedout during the first
month of the high dose treatment (P = NS).
According to the Haynes-Sackett test, the percentage of patients considered good compliers was similar
in both groups (93.9% lercanidipine vs. 93.7% in amlodipine/nifedipine, P = NS). Concerning the changes
in antihypertensive treatment made by the investigators, in 91.2% of patients in the lercanidipine group
the treatment was maintained, whereas in the amlodipine/nifedipine group only 56.1% did not change their
treatment regimen (P < 0.001). Table 6 shows the most
frequent changes in the therapeutic regimen made by the
investigators. The most frequent modification performed
c 2008 The Authors. Journal Compilation c 2008 Blackwell Publishing Ltd
Cardiovascular Therapeutics 26 (2008) 2–9 Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
5
Lercanidipine
V. Barrios et al.
Table 5 Distribution of signs and symptoms according to the checklist with dihydropyridines given at high doses.
Lercanidipine (%) (n = 446)
Amlodipine/nifedipine (%) (n = 204)
P-value
45.1
31.4
13.8
7.6
32.2
30.4
13.6
16.9
4.5
8.4
11.8
13.2
7.4
10.9
1.9
2.5
39.7
25.7
12.4
6.7
26.5
25.4
10.9
13.7
4.5
6.8
9.5
10.7
4.6
9
1.8
2.0
57.3
44.1
16.9
9.6
45.0
41.6
19.7
24.2
4.5
11.9
16.9
18.6
13.5
15.2
2.3
3.4
<0.001
<0.001
NS
NS
<0.001
<0.001
0.006
0.003
NS
0.049
0.016
0.011
<0.001
0.030
NS
NS
Leg edema
Swelling
Dizziness
Blurred vision
Flushes
Headache
Palpitations
Fatigue
Thoracic pain
Dyspnea
Pyrosis
Constipation/diarrhea
Skin rush
Sexual dysfunction
Thoracic swelling
Gum swelling
NS, not significant (P > 0.05).
Table 6 Changes in antihypertensive regimen made by the investigators.
Global
N = 119
Lercanidipine
N = 37
Amlodipine/
nifedipine
N = 82
P-value
44.5%
16%
5%
47.1%
75.7%
27%
2.7%
-
30.5%
11%
6.1%
68.3%
<0.001
0.033
NS
<0.001
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CCB, calcium channel blocker; NS, not significant.
a
Add a new agent
Reduce dose of CCB
Withdraw the CCB
Change of CCB
Pr
in lercanidipine group was the addition of a new
agent (75.7%), while in amlodipine/nifedipine group the
change to other CCB (68.3%).
A logistic regression model was performed to check
which factors could influence the appearance of adverse
events related to vasodilation. The following variables
were found to be significant: male sex (Odds ratio 2.072,
CI 95% [1.395–3.077]), sedentary life (1.608, [1.085–
2.384]), antecedents of cardiac (6.102 [2.668–13.954]),
or gastrointestinal diseases (1.965 [1.157–3.335]). Patients in the lercanidipine group had a lower risk of
having these adverse reactions (odds ratio 0.436 [0.278–
0.684]).
Discussion
The main objective in the treatment of hypertension is to
achieve an adequate BP control and to reduce the global
cardiovascular risk of the hypertensive patient. Pharma-
6
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Global (%) (n = 650)
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Signs/symptoms
cological treatment of hypertension is almost always lifelong lasting. Thus, an antihypertensive drug should not
only be able to effectively reduce BP but also have a good
tolerability profile to avoid compliance reduction. Dihydropyridines have shown to be effective antihypertensive drugs in several clinical trials, but its use has been
sometimes limited due to their side effects, particularly
ankle edema. However, not all the compounds of this
antihypertensive class share the same adverse event risk
profile. In this respect, this new DHP appears to be associated with lower rates of drug-related side effects.
The main objective of this study was to compare tolerability of high doses of lercanidipine versus high doses
of other DHP (amlodipine/nifedipine GITS) in common
clinical practice. The main variable was adverse events
related to vasodilation. Incidence of these side effects was
significantly higher in the amlodipine/nifedipine group
compared to lercanidipine. This difference could not be
explained by a greater BP lowering effect of the amlodipine/nifedipine group, because rates of BP control were
similar in both groups. When these drugs were given
at low doses this difference was still significant. Concomitant antihypertensive medication was not related to
this difference either, because it was not clinically different in both groups. In fact, the rate of use of ACE
inhibitors, drugs that could alleviate lower limb edema
induced by DHP (Weir et al. 2001), was higher in the amlodipine/nifedipine group. The exact mechanism of this
attenuation of dependent fluid extravasation by the ACE
inhibitors is not known. The main hypothesis is that they
could counterbalance the rise in capillary pressure secondary to the more effective inhibition of precapillary
c 2008 The Authors. Journal Compilation c 2008 Blackwell Publishing Ltd
Cardiovascular Therapeutics 26 (2008) 2–9 Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
Lercanidipine
V. Barrios et al.
What is known about topic
r The poor control of
What this study adds
r In daily clinical practice,
treatment with lercanidipine at
high doses is associated with a
lower rate of adverse reactions
related to vasodilation
compared to high doses of
amlodipine or nifedipine GITS
r Some factors that have been r Blood pressure control (<
involved in this poor
140/90 mmHg or <130/80 for
compliance are adverse events
diabetics) and type of
related to antihypertensive
concomitant antihypertensive
drugs, lifelong treatment and
medications were similar in
polymedication
both groups
r Lercanidipine is generally well
tolerated during monotherapy
in patients with
mild-to-moderate
hypertension
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hypertension may be partially
due to the low treatment
compliance of the patients
Pedrinelli et al. 2003; Romito et al. 2003 ). Nevertheless, in most of these studies, the dose of lercanidipine
initially used was 10 mg per day (considered low dose
in our study) and it was titrated to 20 mg only if necessary. Thus, most of the patients in these studies were
treated with low doses of lercanidipine. Remarkably, the
incidence of fatigue and sexual dysfunction was also significantly lowerin lercanidipine group. This result is concordant with others (Borghi et al. 2003).
Regarding the severity of the adverse events, we did
not find a statistically significant difference between
groups in severe adverse events. The incidence was quite
low in both groups (around 3%) suggesting a good safety
profile of these drugs. In relation to this, treatment compliance (with the inherent limitations of the test used for
its assessment) was very good and similar in both groups
(around 94%). Changes in hypertensive medication were
more frequent in the amlodipine/nifedipine group. As
far as BP values were comparable in both groups, these
changes were probably mostly related to the higher incidence of adverse events in the amlodipine/nifedipine
group, as shown in Table 5. The most common action in
the lercanidipine group was to add a new drug whereas in
the amlodipine/nifedipine group was to change the CCB.
Switching from a CCB to another because of adverse
events is common in daily practice. It is also in accordance
with the information derived from other studies, where
patients treated with other CCB who experienced typical DHP-related adverse events were switched from that
treatment to lercanidipine with a resulting significant reduction of side effects (Borghi et al. 2003; Lund-Johansen
et al. 2003; Beckey et al. 2007).
In our study the variables that could influence the appearance of adverse events related to vasodilation were
male sex, contrary to what has been previously published
in the literature (Cherubini et al. 2003), sedentary life
(probably due to gravitational factors), and antecedents of
cardiac or gastrointestinal disease (probably due to the intrinsic higher risk of some cardiac or gastrointestinal diseases for the development of leg edema). Treatment with
lercanidipine was a protective factor compared to the use
of amlodipine or nifedipine GITS.
This is an observational study with its characteristic design and results limitations. This methodology has its limitations since it reduces the level of control that can be
exercised to reduce variation and bias (e.g., random sampling). However, the large number of patients included
and the nature of the endpoints being measured, minimizes this theoretical limitation. The information derived
from this kind of studies is very useful and complementary to the one obtained from the randomized controlled
trials. Observational studies include more often older patients with a higher comorbidity what, in terms of drug
o
Table 7 Summary table
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resistance by the DHP through a preferential venodilatation effect at the microcirculatory level.
For every group, the increase of dose was associated
with a higher incidence of signs and symptoms related
to vasodilation suggesting that these side effects are dose
dependent. Incidence of leg edema was high in both
groups (39.7% in lercanidipine vs. 57.1% in amlodipine/nifedipine group) and similar to that reported in
other studies (Leonetti et al. 2002). It is noticeable that
the presence of leg edema was elicited by using the symptom and signs check list. Thus, it is most likely that a simple heaviness could be interpreted by the patient as ankle
edema, what could explain the high incidence of that side
effect in both groups.
Vasodilatory edema related to DHP is probably due
to an increase in intracapillary hydrostatic pressure that
causes fluid filtration from the vascular space to the interstitium. It has been related to an arteriolar dilation
that, as a consequence of reflex sympathetic activation, is
not accompanied by adequate postcapillary vasodilation
(Angelico et al. 1999; Lund-Johansen et al. 2003). Lercanidipine has shown different effects on plasma norepinephrine levels and a lower sympathetic activation
compared with other DHP (Fogari et al. 2003; Grassi et al.
1998;), what could, at least in part, explain the lower rate
of leg edema observed with this drug when compared
to amlodipine or nifedipine. These results are in concordance with those previously described in other clinical trials (Agrawal et al. 2006; Barrios et al. 2002; Barrios et al.
2006a; Barrios et al. 2006b; James et al. 2002; Leonetti
et al. 2002; Millar-Craig et al. 2003; Viviani 2002;
c 2008 The Authors. Journal Compilation c 2008 Blackwell Publishing Ltd
Cardiovascular Therapeutics 26 (2008) 2–9 Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
7
Lercanidipine
V. Barrios et al.
Acknowledgments
Conflict of Interest
The authors have no conflict of interest.
References
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The authors would like to thank the investigators and
staff members of all participating centers for their clinical
and technical support and Javier Ortega, MD, for editing
the manuscript and editorial assistance. This study was
supported by an unrestricted grant provided by Recordati
España S.L. All data have been recorded and analyzed independently to prevent bias.
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(2003) Improved tolerability of the dihydropyridine
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lercanidipine challenge trial. Blood Press (Suppl 1): 14–21.
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R, Senin U (2003) Comparative effects of lercanidipine,
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G, Preti P (2003) Differential effects of lercanidipine and
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tolerability, could reflect the “real-world” clinical scenario
better than randomized controlled trial. The method used
to evaluate compliance is the self-communicated interview as indicated by Haynes-Sackett. Despite the limitations of this test, it has been shown that this test can determine adequately the treatment compliance in clinical
practice (Gil et al. 2003; Roth and Ivey 2005). Table 7
summarizes the key points of our study.
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versus amlodipine and lacidipine in elderly hypertensives.
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with lercanidipine or amlodipine. J Hypertens
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McDonald C (2003) Lercanidipine vs. lacidipine in isolated
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Engl J Med 353:487–497.
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Mariani M (2003) Heterogeneous effect of calcium
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Epidemiology 2nd ed., Boston: Little Brown & Company.
APPENDIX 1. Symptoms and signs
checklist
High dose DHP
Lower limb edema
Lower limb swelling,
numbness, tingling
Dizziness
Sight disturbances
Flushing/heat sensation
Headache
Tachycardia/palpitation
Fatigue/weakness
Chest pain
Dyspnea
Pyrosis
Constipation or diarrhea
Skin rush
Sexual dysfunction
Breast swelling/gynecomastia
Gingival swelling or bleeding
Low dose DHP
0
0
1
1
2
2
3
3
0
0
1
1
2
2
3
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
0 = Absent.
1 = Mild (occasionally present, does not affect daily life activities).
2 = Moderate (often present, affects daily life activities).
3 = Severe (unable to carry out daily life activities).
DHP: dihydropyridines.
c 2008 The Authors. Journal Compilation c 2008 Blackwell Publishing Ltd
Cardiovascular Therapeutics 26 (2008) 2–9 Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
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9
International Journal of Impotence Research (2007) 19, 208–212
& 2007 Nature Publishing Group All rights reserved 0955-9930/07 $30.00
www.nature.com/ijir
ORIGINAL ARTICLE
Cardiovascular drug use and the incidence of erectile dysfunction
R Shiri1, J Koskimäki2, J Häkkinen2, A Auvinen1, TLJ Tammela2,3 and M Hakama1
1
Tampere School of Public Health, University of Tampere, Tampere, Finland; 2Department of Urology,
Tampere University Hospital, Tampere, Finland and 3Medical School, University of Tampere, Tampere, Finland
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It is unclear whether high blood pressure per se or antihypertensive drug use causes erectile
dysfunction (ED). The aim of this study was to investigate the effect of cardiovascular diseases and
their concomitant medications use on the incidence of ED. The target population consisted of men
aged 55, 65 or 75 years old residing in the study area in Finland in 1999. Questionnaires were
mailed to 2837 men in 1999 and to 2510 of them 5 years later. The follow-up sample consisted of
1665 men (66% of those eligible) who responded to both baseline and follow-up questionnaires. Men
free of moderate or severe ED at baseline (N ¼ 1000) were included in the study. ED was assessed by
two questions on subject ability to achieve or maintain an erection sufficient for intercourse. Poisson
regression model was used in the multivariable analyses. The risk of ED was higher in men
suffering from treated hypertension or heart disease than in those with the untreated condition. The
risk of ED was higher in men using calcium channel inhibitor (adjusted relative risk (RR) ¼ 1.6, 95%
confidence interval (CI) 1.0–2.4), angiotensin II antagonist (RR ¼ 2.2, 95% CI 1.0–4.7), non-selective
b-blocker (RR ¼ 1.7, 95% CI 0.9–3.2) or diuretic (RR ¼ 1.3, CI 0.7–2.4) compared with non-users. ED
was not associated with using organic nitrates, angiotensin-converting enzyme inhibitors, selective
b-blockers and serum lipid-lowering agents. In summary, calcium channel inhibitors, angiotensin II
antagonists, non-selective b-blockers and diuretics may increase the risk of ED.
International Journal of Impotence Research (2007) 19, 208–212. doi:10.1038/sj.ijir.3901516;
published online 10 August 2006
Introduction
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Keywords: antihypertensive agents; b-adrenergic blockers; calcium channel blockers; diuretics;
heart diseases; hypertension
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Erectile dysfunction (ED) is a common condition in
men with cardiovascular disease.1–5 ED is considered as a manifestation of systemic vascular disease
or atherosclerosis.6 Previous cross-sectional studies
have shown associations between heart disease,
high blood pressure and their medications use,
and ED.1,5,7
Longitudinal studies have also found a higher
incidence of ED in men with hypertension than
in those with normal blood pressure.3,4 In these
studies, heart disease was not significantly associated with ED. In another prospective study,2 only
treated hypertension and heart disease increased the
risk of ED, but not the untreated conditions.
The association between cardiovascular diseases
and ED is necessarily confounded by concomitant
medications use. A drug-related effect on ED is
difficult to distinguish from the effect of disease.
It is unclear whether high blood pressure per se or
antihypertensive drug use causes ED.
We investigated the effect of cardiovascular diseases and their concomitant medications use on the
incidence of ED in a population-based follow-up
study among Finnish men aged 55–75 years old at
baseline.
Materials and methods
Correspondence: Dr R Shiri, Tampere School of Public
Health, University of Tampere, Klaneettitie 1 D 105,
Helsinki Fin-00420, Finland.
E-mail: r_shiri@yahoo.com
Received 31 May 2006; revised 2 July 2006; accepted 3
July 2006; published online 10 August 2006
The target population of this study consisted of men
aged 55, 65 or 75 years old residing in the city of
Tampere or 11 adjacent municipalities in Finland in
1999. The study population identified from the
national population register. Information was collected by a mailed self-completed questionnaire,
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
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Cardiovascular drug use and the incidence of ED
R Shiri et al
209
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failure of intercourse (‘quite often’ or ‘does not
succeed’ at least in one of the two questions).
Poisson regression model was used in the multivariable analyses. Age, education, marital status,
smoking, diabetes, cerebrovascular disease, depression, hypertension and heart disease were used as
covariates. All baseline characteristics that influenced ED with P-value less than or equal to 0.20
in the age-adjusted models were entered into the
multivariable model, followed by a stepwise backward elimination. The final models included age,
cardiovascular disease, cardiovascular drug use and
factors that had effects on ED at P-value less than or
equal to 0.20 in the stepwise backward regression
model. For stratified analysis, antihypertensive and
cardiac drugs were combined into a single variable
of cardiovascular medication.
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comprising of items on sociodemographic status,
lifestyle factors, medical conditions, medications
and erectile problems. The study protocol was
approved by the Tampere University Hospital
committee of research ethics.
A questionnaire was sent in May 1999 to 2837
men, with a reminder to the 1162 who did not
respond to the first within 3 months. Overall, 2133
men (75%) responded to baseline inquiry. Subjects
with missing information on erectile function were
excluded and 1846 men included in the baseline
sample.
A similar questionnaire was mailed to 2510 of the
same men 5 years later in the last quarter of 2004,
with a reminder to the 844 who did not respond to
the first inquiry within 3 months. Between 1999 and
2004, 318 men died, three emigrated and six did not
have an address in the population registry. Altogether, 1905 (76%) questionnaires were returned.
Overall, 1665 men (66% of those alive and
eligible) responded to both baseline and follow-up
surveys. Subjects with missing information on
erectile function were excluded and finally 1374
were included in the follow-up sample. Men with
moderate or severe ED at baseline (N ¼ 374) were
excluded and those with no or mild ED (N ¼ 1000)
included in the study.
Information on medical history and their concomitant medications use was obtained by separate
and independent questions. Information on regular
drug use and on the type of drugs was collected. The
question for cardiovascular medication use was ‘Do
you regularly use cardiac or antihypertensive drug?’
List the names of your drugs. The Anatomical
Therapeutic Chemical classification system was
used for the classification of cardiovascular drugs.
ED was assessed by two questions on subject
erectile capacity: ‘Have you had problems getting an
erection before intercourse begins?’ and ‘Have you
had problems maintaining an erection once intercourse has begun?’ For both questions, the four
response options were as follows: never, sometimes,
quite often and intercourse does not succeed.
Moderate or complete ED was defined as frequent
Results
Men with complete follow-up information did not
differ from those lost to or with incomplete data at
follow-up with respect to hypertension and antihypertensive drugs use (Table 1). However, men
with incomplete follow-up were on average 4 years
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Table 1 Background characteristics of men with complete or
incomplete follow-up (proportion or mean7s.d.)
Characteristic
Baseline
(N ¼ 1846)
Complete
follow-up
(N ¼ 1374)
Incomplete
follow-up
(N ¼ 472)
Age (mean7s.d.)
High blood
pressure
Heart disease
ED
Diabetes
Heart drug use
Antihypertensive
drug use
62.177.5
34.6
61.077.0
34.4
65.278.1
35.2
18.7
30.8
8.0
17.9
29.4
16.2
27.2
6.8
15.4
28.8
25.9
41.3
11.7
25.0
31.4
Abbreviation: ED, erectile dysfunction.
Table 2 RR of ED according to hypertension, heart disease and their medications use
Medication
No
No
No
No
Yes
Yes
Yes
Yes
Heart disease
Hypertension
Number
Incident cases
RRa
95% CI
No
No
Yes
Yes
No
No
Yes
Yes
No
Yes
No
Yes
No
Yes
No
Yes
596
68
15
1
12
200
63
45
111
10
4
0
4
54
20
14
1
0.8
1.3
—
1.3
1.4
1.4
1.4
—
0.4–1.5
0.5–3.6
0.5–3.6
1.0–2.0
0.8–2.2
0.8–2.4
Abbreviations: ED, erectile dysfunction; RR, relative risk.
a
Adjustment for age, diabetes and depression.
International Journal of Impotence Research
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
Cardiovascular drug use and the incidence of ED
R Shiri et al
Table 3 RR of ED by the use of cardiovascular medications
Medication
Sample
Incident cases
Age adjusted
RR
95% CI
Multivariablea
RR
95% CI
957
43
207
10
1
0.8
0.4–1.6
Diuretic
No
Yes
968
32
206
11
1
1.4
0.8–2.6
1
1.3
0.7–2.4
Non-selective b-blocker
No
Yes
978
22
207
10
1
2.0
1.0–3.7
1
1.7
0.9–3.2
Selective b-blocker
No
Yes
896
104
192
25
1
1.0
0.7–1.5
Angiotensin II antagonist
No
Yes
984
16
210
7
1
2.4
1.1–5.1
1
2.2
1.0–4.7
Angiotensin-converting enzyme inhibitor
No
Yes
923
77
198
19
1
1.2
0.8–1.9
1
0.9
0.6–1.6
Calcium channel inhibitor
No
Yes
924
76
189
28
1
1.8
1.2–2.6
1
1.6
1.0–2.4
Serum lipid-lowering agent
No
Yes
932
68
202
15
1
0.9
0.5–1.6
207
10
1
0.8
0.4–1.5
a
Other drug
No
Yes
o
Organic nitrate
No
Yes
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944
56
Abbreviations: ED, erectile dysfunction; RR, relative risk.
a
Adjustment for age, diabetes, depression and cardiovascular disease.
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older and reported a higher prevalence of heart
disease, diabetes, ED and heart drug use than those
with complete follow-up.
Compared with men free of cardiovascular diseases and concomitant medications use (Table 2),
the risk of ED was higher in men with untreated
heart disease, treated hypertension, treated heart
disease and in those with both treated hypertension
and heart disease. The incidence of ED was also
higher in men using cardiovascular medication for
conditions other than hypertension and heart disease. However, ED was significantly associated with
only treated hypertension (adjusted relative risk
(RR) ¼ 1.4, 95% confidence interval (CI) 1.0–2.0).
The risk of ED was not elevated in men with
untreated hypertension.
Men taking angiotensin II antagonist (adjusted
RR ¼ 2.2, 95% CI 1.0–4.7) or calcium channel
inhibitor (RR ¼ 1.6, 95% CI 1.0–2.4) were significantly at higher risk of ED compared with non-users
(Table 3). A higher risk of ED was also found in men
using non-selective b-blocker (RR ¼ 1.7, 95% CI 0.9–
3.2) or diuretic (adjusted RR ¼ 1.3, CI 0.7–2.4)
relative to non-users. The estimates, however, were
not statistically significant. ED was not associated
with using organic nitrates, angiotensin-converting
enzyme inhibitors, selective b-blockers, serum
lipid-lowering agents and other cardiovascular
medication.
Discussion
Our findings suggest that the use of cardiovascular
medication increases the risk of ED. The most likely
drugs were calcium channel inhibitors, non-selective b-blockers, angiotensin II antagonists and
diuretics. ED was not associated with using organic
nitrates, angiotensin-converting enzyme inhibitors,
selective b-blockers and serum lipid-lowering
agents.
International Journal of Impotence Research
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Cardiovascular drug use and the incidence of ED
R Shiri et al
211
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categories with medication independently of the
presence or absence of heart disease or hypertension
or both. The numbers after sufficient grouping
remained small and the individual differences only
seldom reached statistical significance.
We started with a well-defined and relatively large
target population of about 2800 men. According to
international experience or standards, the response
rates were relatively high. ED is a sensitive and
confidential area of human life, but the coverage
of ED answers in the questionnaire was also high.
There is a high correlation between any disease and
treatment for it. Therefore, the discordant observations of disease without treatment and treatment
without disease remained rare and are probably
selected. In this study, there were only few cases of
most extreme combinations and, hence, the statistical power remained low and our findings should
be confirmed by subsequent studies.
Because of long, 5-year, follow-up, most severe
cases at entry were likely to get removed at the end
of follow-up, as a result of death or inability of
filling the questionnaire. Men lost to or with no
information at follow-up did not differ from those
with completed follow-up, regarding hypertension
and antihypertensive drug use. As expected, men
with incomplete follow-up were on average older
and had more often heart disease and ED than the
study population. Therefore, the RRs of ED by
cardiovascular disease or medications use may have
been diluted. The consistent results within the users
of any medication independently of disease or their
combination are also an indication for the lack of
etiological role of the disease. Therefore, the
medication remains as a plausible hypothesis.
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In line with the Massachusetts Male Aging Study,2
we found the association of ED with treated
hypertension, but not with the untreated condition.
A higher risk of ED has been reported in men using
calcium channel antagonist, non-selective b-blocker
or diuretic compared with non-users.7–11 Consistent
with other studies,8,11 we found no increased risk of
ED in men using angiotensin-converting enzyme
inhibitors or serum lipid-lowering agents.
Unlike other studies,12,13 we found a higher
incidence of ED in men using angiotensin II
inhibitor compared with non-users. Angiotensin II
is produced by the corpus cavernosum and causes
contraction of cavernosal smooth muscle.14,15 On
the other hand, angiotensin II receptor antagonist
induces smooth muscle relaxation. Cavernosal
smooth muscle tone is controlled by a balance
between angiotensin II and nitric oxide,15 and
imbalance between them may induce ED.
The mechanisms by which medications contribute to ED have not been clearly identified. Antihypertensive drugs may cause ED through reducing
perfusion pressure by a drop in blood pressure.
They may also induce ED by direct or indirect effect
on cavernosal smooth muscle. b-Blockers may cause
ED through increasing the latency to initial erection
and reducing the number of erectile reflexes. In
addition, they may cause ED by increasing the
smooth muscle contraction. They are also associated
with a reduction in testosterone level.11,16
An important aspect from the point of view of
health services and preventability of ED is whether
the disease, the biological process or its treatment
causes ED. In a non-selected population-based
sample, we showed an increased risk of ED in men
with cardiovascular disease. Our findings are consistent with the hypothesis that the antihypertensive
drugs more likely increase the risk of ED than
hypertension per se. However, medication use is
related to disease severity and drug effect on ED is
difficult to distinguish from disease severity. Men
with hypertension who use antihypertensive drug
are likely to have more aggressive disease than
untreated patients. Antihypertensive drugs are not
used only in mild cases of hypertension. Long-term
and severe systemic arterial hypertension can lead
to vascular–endothelial damage.
A limitation of the study is that allocation of men
into different combinations resulted in eight groups
and, hence, small numbers of observations. Therefore, the results were not statistically significant, but
consistent patterns emerged. The combined sample
of any disease without any medication showed RR
somewhat less than unity compared to those with
no disease and no medication. In contrast, all those
with any medication independently of disease
status showed an adjusted RR of 1.4. Especially,
there was no indication that hypertension without
any medication use would increase the risk of ED.
Instead, there was an increased risk of ED in all
Conclusion
Calcium channel inhibitors, non-selective b-blockers, angiotensin II antagonists and diuretics may
increase the risk of ED. ED does not seem to be a
problem in men using organic nitrates, angiotensinconverting enzyme inhibitors, selective b-blockers
or serum lipid-lowering agents.
Acknowledgments
Financial support for this study was provided by the
Medical Research Fund of Tampere University
Hospital.
References
1 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ,
McKinlay JB. Impotence and its medical and psychosocial
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Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
Cardiovascular drug use and the incidence of ED
R Shiri et al
9 Derby CA, Barbour MM, Hume AL, McKinlay JB. Drug therapy
and prevalence of erectile dysfunction in the Massachusetts
Male Aging Study cohort. Pharmacotherapy 2001; 21:
676–683.
10 Srilatha B, Adaikan PG, Arulkumaran S, Ng SC. Sexual
dysfunction related to antihypertensive agents: results from
the animal model. Int J Impot Res 1999; 11: 107–113.
11 Fogari R, Preti P, Derosa G, Marasi G, Zoppi A, Rinaldi A et al.
Effect of antihypertensive treatment with valsartan or atenolol
on sexual activity and plasma testosterone in hypertensive
men. Eur J Clin Pharmacol 2002; 58: 177–180.
12 Dusing R. Effect of the angiotensin II antagonist valsartan on
sexual function in hypertensive men. Blood Press Suppl 2003;
2: 29–34.
13 Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L.
Sexual activity in hypertensive men treated with valsartan or
carvedilol: a crossover study. Am J Hypertens 2001; 14: 27–31.
14 Kifor I, Williams GH, Vickers MA, Sullivan MP, Jodbert P,
Dluhy RG. Tissue angiotensin II as a modulator of erectile
function. I. Angiotensin peptide content, secretion and effects
in the corpus cavernosum. J Urol 1997; 157: 1920–1925.
15 Comiter CV, Sullivan MP, Yalla SV, Kifor I. Effect of
angiotensin II on corpus cavernosum smooth muscle in
relation to nitric oxide environment: in vitro studies in
canines. Int J Impot Res 1997; 9: 135–140.
16 Rosen RC, Kostis JB, Jekelis AW. Beta-blocker effects on
sexual function in normal males. Arch Sex Behav 1988; 17:
241–255.
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correlates: results of the Massachusetts Male Aging Study.
J Urol 1994; 151: 54–61.
2 Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman
KP, McKinlay JB. Incidence of erectile dysfunction in men 40
to 69 years old: longitudinal results from the Massachusetts
male aging study. J Urol 2000; 163: 460–463.
3 Moreira Jr ED, Lbo CF, Diament A, Nicolosi A, Glasser DB.
Incidence of erectile dysfunction in men 40 to 69 years old:
results from a population-based cohort study in Brazil.
Urology 2003; 61: 431–436.
4 Shiri R, Koskimaki J, Hakama M, Hakkinen J, Tammela TL,
Huhtala H et al. Effect of chronic diseases on incidence of
erectile dysfunction. Urology 2003; 62: 1097–1102.
5 Shiri R, Hakkinen J, Koskimaki J, Huhtala H, Auvinen A,
Hakama M et al. Association between the bothersomeness of
lower urinary tract symptoms and the prevalence of erectile
dysfunction. J Sex Med 2005; 2: 438–444.
6 Billups KL, Bank AJ, Padma-Nathan H, Katz S, Williams R.
Erectile dysfunction is a marker for cardiovascular disease:
results of the minority health institute expert advisory panel.
J Sex Med 2005; 2: 40–50; discussion 50–52.
7 Vallancien G, Emberton M, Harving N, van Moorselaar RJ.
Sexual dysfunction in 1274 European men suffering from
lower urinary tract symptoms. J Urol 2003; 169: 2257–2261.
8 Ricci E, Parazzini F, Mirone V, Imbimbo C, Palmieri A,
Bortolotti A et al. Current drug use as risk factor for erectile
dysfunction: results from an Italian epidemiological study. Int
J Impot Res 2003; 15: 221–224.
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Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
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Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
REVIEW
URRENT
C
OPINION
Antihypertensive therapy causes erectile
dysfunction
Steven G. Chrysant
o
Purpose of review
Erectile dysfunction is a common sexual disorder affecting 40% of men in the United States. However, the
pathophysiologic mechanism involved in the causation of erectile dysfunction is multifactorial and not well
delineated.
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Recent findings
Several recent studies disclose that erectile dysfunction is the result of multiple interrelated comorbid
conditions that include hypertension, coronary artery disease (CAD), heart failure, and diabetes mellitus
among them. In addition to comorbid conditions, certain cardiovascular and antihypertensive drugs are
also involved in the development of erectile dysfunction, with the most prominent being the thiazide type
diuretics, the aldosterone receptor blockers, and the b-adrenergic receptor blockers. Also, knowledge by
the patient of the drug and its action on erectile dysfunction may increase the incidence of erectile
dysfunction (Hawthorn effect). Before treatment is initiated, patients should be screened for the presence of
erectile dysfunction, because this condition is associated with hypertension, CAD, heart failure, diabetes
mellitus, and their treatment and an appropriate treatment regimen should be selected. If that fails, the
addition of phosphodiesterase 5 inhibitors to the treatment regimen is recommended. The only exception is
a patient with CAD treated with organic nitrates, in which the coadministration of phosphodiesterase 5
inhibitors is strictly prohibited.
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Summary
Knowledge of the various comorbid conditions and their treatment associated with the development of
erectile dysfunction will help the caring physician to treat his patients appropriately and safely. All these
aspects will be discussed in this review.
INTRODUCTION
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Keywords
antihypertensive drugs, cardiovascular disease, diabetes mellitus, erectile dysfunction, heart failure,
hypertension
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Erectile dysfunction is a common condition in male
patients in both the developed and developing
countries, accounting for 40% and 46.2%, respectively [1,2]. In addition, its prevalence increases with
the advancement of age and the presence of several
comorbidities, such as hypertension (HTN), coronary artery disease (CAD), heart failure, diabetes
mellitus, and hormonal dysfunction [2–9]. The
National Institutes of Health has defined erectile
dysfunction as ‘the persistent inability to reach or
maintain a penile rigidity enough for sexual satisfaction’ [10]. The association of erectile dysfunction
with CAD is bidirectional, because CAD could be a
cause of erectile dysfunction and the presence of
erectile dysfunction could lead to CAD; several studies have shown that the presence of erectile dysfunction is a harbinger of future CAD [2,5,7,10]. In
addition, the association of erectile dysfunction
with various comorbid conditions, erectile dysfunction is frequently noted among hypertensive
patients treated with different antihypertensive
drugs alone and in combination [4,11–13,14 ,15].
Effective treatment of erectile dysfunction could
lessen the anxiety, prevent the worsening of CAD,
and improve the quality of life [16 ]. However,
before treatment is initiated, a consultation should
be performed with the patients and their partners
regarding the existence of erectile dysfunction [17 ].
For this review, a Medline search of the English
&
&&
&
University of Oklahoma College of Medicine, Oklahoma City, Oklahoma,
USA
Correspondence to Steven G. Chrysant, MD, PhD, 5700 Mistletoe
Court, Oklahoma City, OK 73142, USA. Tel: +1 405 748 6035;
fax: +1 405 748 6035; e-mail: schrysant@yahoo.com
Curr Opin Cardiol 2015, 30:383–390
DOI:10.1097/HCO.0000000000000189
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Hypertension
KEY POINTS
SOD
SOD –
H2O2+O2
The cause of erectile dysfunction is multifactorial,
involving certain comorbidities and drugs.
Drugs mostly associated with erectile dysfunction
include thiazide diuretics, aldosterone antagonists, and
b-blockers.
O2–+ NO
Ca+2 mobilization
Apoptosis of endothelium
Peroxynitrite
–
(ONOO )
ACE inhibitors, ARBs and CCBs have either a neutral
or a beneficial effect.
Knowing the action of these drugs helps to design an
appropriate treatment regimen.
Superoxide
(O2–)
Endothelium
dysfunction
Smooth muscle
contraction
Availability of NO
language literature was conducted between 2010
and 2014 and of the 78 abstracts reviewed, 25 pertinent articles with data on erectile dysfunction were
selected for analysis. These articles, together with
collateral literature, will be discussed in this review.
PATHOPHYSIOLOGY OF ERECTILE
DYSFUNCTION IN HYPERTENSIVE
PATIENTS
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The physiological mechanism of penile erection is a
complex interaction of neural, vascular, hormonal,
and psychological factors [18,19]. The most important ingredient for a successful erection is the presence
of normal endothelium and the availability of nitric
oxide. Nitric oxide is generated from the endothelial
cells of cavernosal arteries through stimulation of
endothelial nitric oxide synthase by acetylcholine
released from the neuronal nerve endings. In turn,
nitric oxide activates the guanyl cyclase in the
smooth muscle of corpora cavernosa, leading to
increased production of cyclic guanosine monophosphate (cGMP). cGMP opens the potassium channels
through the release of certain intracellular protein
kinases and increases the cavernosal blood flow and
pressure, which in turn blocks the venous blood
return and leads to firm penile erection. Erectile
dysfunction is produced through endothelial dysfunction and the decreased generation of nitric oxide
from increased oxidative stress and the increased
production of reactive oxygen species, such as oxygen superoxide, oxygen peroxide, and peroxynitrite,
which are the result of several pathologic conditions
such as hypertension, cardiovascular disease, diabetes mellitus, and antihypertensive drugs (Fig. 1).
Experimental studies in spontaneous hypertensive rats have demonstrated a role for nitric oxide
and other possible mediators in the development of
endothelial dysfunction [20]. In these spontaneous
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Erectile dysfunction
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Adhesion of platelets
and leukocytes
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Additional treatment of erectile dysfunction is the
addition of PDE 5 inhibitors to the treatment regimen.
Release vasoconstrictors
(TxA2, serotonins)
FIGURE 1. Mechanism of erectile dysfunction. This figure
presents the relationship between oxidative stress and
erectile dysfunction. The oxidative stress leads to increased
production of ROS, causing endothelial dysfunction and
decreased production of nitric oxide (NO), which is central
to the problem of erectile dysfunction. Adapted from
Agarwal et al. [19]. H2O2, hydrogen peroxide; O2,
superoxide-free radical; ROS, reactive oxygen species;
TXA2, thromboxane A2.
hypertensive rats, the relaxation of corpora cavernosa
strips was significantly impaired in response to acetylcholine administration, indicating a defect in endothelium-dependent reactivity because of a reduction
in nitric oxide [21]. Studies in hypertensive patients
have also demonstrated an inverse relationship
between L-arginine (nitric oxide precursor) and asymmetric dimethylarginine, a competitive inhibitor of
endothelial nitric oxide synthase [22]. Other possible
mechanisms responsible for the development of erectile dysfunction are decreased production of nitric
oxide from generalized atherosclerosis in rabbits [21],
and long-standing hypertension, which causes endothelial cell damage and an inability of the arteries,
arterioles, and sinusoids of the corpora cavernosa to
dilate properly [23]. Corroborating these findings are
the presence of increased intima-media thickness
of the carotid arteries and the lower brachial flowmediated dilation in hypertensive patients compared
with normotensive individuals [24]. These and other
findings suggest that erectile dysfunction represents
a clinical sign of deeper vascular damage in hypertensive patients and an increased risk of future cardiovascular events [25]. Another cause for the erectile
dysfunction in hypertensive patients is the action of
certain antihypertensive drugs.
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Antihypertensive therapy causes erectile dysfunction Chrysant
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Hypertension is frequently associated with erectile
dysfunction [25], and the presence of erectile dysfunction in untreated hypertensive patients has been
attributed to vasculogenic sexual dysfunction. However, because of the complex interaction of etiologic
and pathophysiologic factors involved, exclusion of
concomitant diseases and drugs should be the initial
step when approaching a patient with erectile dysfunction. Consequently, significant efforts should be
dedicated to the exclusion of neurological, psychological, urologic, and endocrine disorders. In
addition, lifestyle conditions such as physical inactivity, obesity, and smoking have been linked with
endothelial and consequently sexual dysfunction
[26]. In this context, it has been demonstrated that
moderate physical activity can significantly reduce
the risk of erectile dysfunction compared with a
sedentary existence [27,28]. In addition to these factors, older age, the presence of comorbid conditions,
and the administration of cardiovascular drugs are
contributing factors for erectile dysfunction.
caused by erectile dysfunction. Multivariate analyses
showed that heart failure and the prescription of bblockers were mostly responsible for the sexual problems: hazard ratio (HR) 2.73 [95% confidence interval
(CI), 1.57–4.75] and HR 2.00 (95% CI, 1.10–3.59),
respectively. Similar results were reported from a
study of 3005 men and women aged 59–85 years
from the National Health, Life and Aging Project [33].
Among men, comparing those with treated HTN,
sexual activity was less prevalent compared with
those with untreated or no HTN (66.5 vs. 79.9 vs.
7.5%), respectively (P < 0.01). Similarly, sexual problems were more prevalent (69.1 vs. 57.7 vs. 54.3%),
respectively (P < 0.01).
Among women, sexual activity was lower in
those with treated or untreated HTN compared with
those with no HTN (35.2 vs. 38.3 vs. 58.0%), respectively (P < 0.01). In contrast to male patients, the
prevalence of sexual problems in women was similar
in those with treated, untreated, or no HTN (73.7 vs.
63.3 vs. 71.7%), respectively (P ¼ 0.301). Also, there
was no significant association between antihypertensive drug class and sexual activity or sexual problems in men and women.
o
HYPERTENSION AND ERECTILE
DYSFUNCTION
SEXUAL IMPLICATIONS OF OLDER AGE IN
MEN AND WOMEN
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Since antiquity, sexual activity was mainly the purview of young persons. Classical depictions of sexuality invoked notions of vigor, youth, and fertility
[29]. Beyond the reproductive years, sex was regarded
as immoral, and this conceptualization of older persons as asexual persisted well into the 20th century.
The belief that sexuality is not a concern of older
people remains still well entrenched into society, as
was demonstrated by an Australian study on sexual
and reproductive health, which did not sample persons older than 64 years [30]. This is despite the fact
that Kinsey demonstrated that some persons
remained sexually active into old age [31]. However,
it should be realized that sexual activity declines with
the advancement of age and this decline parallels the
steady decrease of androgen levels in men [32]. In a
longitudinal study of 2783 men aged 75–95 years
questioned about their sexual life, 48.8% stated that
sex was somewhat important, whereas 30.8% stated
that they had a sexual encounter at least once in the
past 12 months [7]. In cross-sectional analyses,
increasing age, lack of interest of their partner, other
comorbidities, and use of antidepressants and bblockers were independently associated with reduced
sexual activity. Similar findings were reported by 438
elderly male and female patients with heart failure
[9]. In total, 59% of patients reported sexual problems, and these were common in male patients,
IMPLICATIONS OF ANTIHYPERTENSIVE
DRUGS ON SEXUAL FUNCTION IN MEN
AND WOMEN
Antihypertensive drugs are commonly implicated in
the development of sexual dysfunction in hypertensive patients. However, data supporting a cause
and effect relationship are discordant in different
studies. Furthermore, few studies have investigated
the specific effects of a drug class on sexual activity
and function in a prospective manner. Therefore,
the paucity of quality data about the relationship
between treatment of HTN and sexual function
diminishes the ability of physicians to effectively
counsel their patients about the possible side-effects
of the different antihypertensive drugs and their
impact on sexual function. Adults of all ages and
both genders consider sexual function as a very
important component of their being, regardless of
age [34,35]. Loss of sexual function has been shown
to affect the quality of life of patients and lead to
poor physical health, loss of intimacy with their
partners, and loss of compliance and adherence to
treatment [14 ,33–36].
In this section, we will present the data from
several studies regarding the action of various antihypertensive drugs on sexual function and discuss
their impact on the quality of life of hypertensive
patients [37–52]. The data from these studies are
summarized in Table 1.
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385
Hypertension
Table 1. Results from several studies evaluating the effects of antihypertensive drugs on erectile function
Author
Design
Disease
Pts (n)
Age (years)
Drug
Erectile function
Aldosterone receptor antagonists
Burgess [37]
OL
HTN
586
55 11
Epler
Decr
Parthasarathy [38]
RCT
HTN
137
53 11
Spiro vs. Epler
Decr. Spiro > Epler
D vs. Other
Decr. D > Other
Diuretics
Grimm [39]
RCT
HTN
136
45–69
Chang [40]
RCT
HTN
176
35–70
D vs. Pl
Decr. D > Pl
MRC Trial [41]
RCT
HTN
1735
35–64
D vs. Prop
Decr. D > Prop
Franzen [42]
RCT
CAD
136
56 9
Met vs. Pl
No effect
Boydak 43]
RCT
HTN
131
47 5
Ate vs. Neb
Decr. with Ate
Doumas [44]
CS
HTN
44
31–65
Neb vs. BBs
Impr.with Neb
Brixius [45]
RCT
HTN
50
40–55
Neb vs. Met
Decr. Neb < Met
Cordero [46]
RCT
HTN
1007
58 11
Neb vs. BBs
Decr. Neb < BBs
Shiri [47]
CS
HTN, CAD
Omvik [48]
RCT
HTN
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b-Adrenergic blockers
Calcium channel blockers
1665
55–75
CCB vs. BB,D
Decr. CCB > BB,D
461
55.3
Aml vs. Enal
Improved with both
Angiotensin converting enzyme inhibitors
Speel [49]
RCT
Athero þ ED
59
60 7
Quin vs. Pl
Impr. with both
Angiotensin receptor blockers
Bohm [50]
RCT
HTN
Llisterri [51]
OL
HTN þ ED
Chen [52]
RCT
HTN þ DM
Baumhakel [53]
Survey
HTN þ Metab
1549
66 6
82
30–65
Telm, Ram, both no effect
Losartan
Improved
124
46 13
Losartan
Improved
1069
59 10
Irbe vs. Contr
Impr. with Irbe
da
a
Aml, amlodipine; BB, b-blocker; CAD, coronary artery disease; Carv, carvedilol; CCB, calcium channel blocker; Contr, control; C S, cohort study; D, diuretic;
Decr, decreased; DM, diabetes mellitus; ED, erectile dysfunction; Enal, enalapril; Epler, eplerenone; HTN, hypertension; Irbe, irbesartan; Lisin, lisinopril; Met,
metoprolol; Neb, nebivolol; O L, open label; Pl, placebo; Prop, propranolol; Pts, patients; Quin, quinapril; Ram, ramipril; RCT, randomized controlled trial; Spiro,
spironolactone; Telm, telmisartan; Val, valsartan.
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Aldosterone receptor antagonists
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Spironolactone and eplerenone are specific aldosterone receptor antagonists and exert their beneficial
effects by blocking aldosterone’s detrimental cardiovascular and metabolic effects, such as HTN, left
ventricular hypertrophy, cardiac fibrosis, hypokalemia, hypomagnesemia, and salt and water retention. However, in addition to their beneficial
effects, they also exert serious organic side-effects
including erectile dysfunction, gynecomastia, and
mastodynia in men and mastodynia and menstrual
problems in women, leading to decreased compliance and adherence to treatment [37,38]. In a recent
study, in 137 hypertensive patients treated with
either spironolactone 75–225 mg/day or eplerenone
100–300 mg/day, gynecomastia with mastodynia
occurred in 21.2% and impotence in 5.8% of
men, and mastodynia and menstrual problems in
21.1% and 10.5% in women, respectively [37]. In a
previous long-term study, in 586 hypertensive
patients treated with eplerenone 50–200 mg/day,
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impotence and gynecomastia occurred in 3.0%
and 0.7% of men, respectively, and mastodynia
and menstrual problems in 0.7% and 2.5% of
women, respectively [38].
Thiazide-type diuretics
Erectile dysfunction is a well-recognized condition
with the use of thiazide diuretics in the treatment of
patients with HTN [39–41]. In the Treatment Of
Mild Hypertension Study (TOMHS), 902 patients,
men (n ¼ 557) and women (n ¼ 345), with mild HTN
were randomized into six treatment groups as follows: placebo (n ¼ 235), acebutolol 400 mg/day
(n ¼ 132), amlodipine 5 mg/day (n ¼ 131), chlorthalidone 15 mg/day (n ¼ 136), doxazosin 2 mg/day
(n ¼ 135), and enalapril 5 mg/day (n ¼ 135). After
24 months of treatment, the data were analyzed
for sexual dysfunction in all treatment groups
(Table 2). The incidence of sexual dysfunction of
male patients treated with a fairly low dose of the
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Antihypertensive therapy causes erectile dysfunction Chrysant
Table 2. Incidence of sexual dysfunction in hypertensive men treated with five different antihypertensive drugs compared with
placebo after 24 months
Acebutolol
(n ¼ 132)
Amlodipine
(n ¼ 131)
Chlorthalidone
(n ¼ 136)
Doxazosin
(n ¼ 135)
Enalapril
(n ¼ 135)
n (%)
n (%)
n (%)
n (%)
n (%)
Obtaining erection
6 (7.9%)
4 (6.7%)
11 (15.7%)a
2 (2.8%)
4 (6.5%)
Maintaining erection
5 (6.6%)
5 (8.3%)
12 (17.1%)b
3 (4.2%)
4 (6.5)
Problems with either
7 (9.2%)
5 (8.30)
12 (17.1%)c
4 (5.6)
6 (9.7)
Constructed with data from Grimm et al. [39].
a
(P < 0.004).
b
(P < 0.017).
c
(P < 0.025).
o
increases the blood flow to corpora carvernosa and
leads to penile erection. The erectile dysfunction
caused by the other b-blockers, especially the nonselective, is because of their direct effects on penile
vascular smooth muscle cells causing vasoconstriction from the unopposed a-adrenergic stimulation
leading to decreased perfusion in the corpora cavernosa. In addition, b-blockers such as metoprolol,
pindolol, atenolol, and propranolol have been
reported to decrease the levels of testosterone and
follicle stimulating hormone, leading to erectile
dysfunction [4].
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diuretic chlorthalidone was higher than the other
treatment groups and significantly higher than
placebo. In contrast, the incidence of sexual dysfunction in the other treatment groups was no
different from placebo [39]. The mechanism by
which diuretics cause erectile dysfunction is not
clear, and it has been postulated that it is mediated
through a direct effect on penile vascular smooth
muscle or interference with the action of catecholamines. There is no evidence that low BP or serum
potassium or magnesium levels are associated with
erectile dysfunction [40]. It should be realized that
normal male sexual function is a complex mechanism that depends on the integrity of central and
peripheral neural sympathetic systems, and of vascular and hormonal systems [54]. However, other
investigators argue that the thiazide diuretics lack
the necessary central and peripheral autonomic
nervous system and hormonal effects to have a
significant effect on sexual dysfunction [19].
Pr
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b-Blockers have been shown to be efficient drugs for
the treatment of HTN, CAD, and heart failure, and
their use has been associated with either no erectile
dysfunction [42] or the development of erectile
dysfunction in men [43–46]. However, the incidence of erectile dysfunction varies with different
studies and type of b-blockers and is affected by age.
In the study by Cordero et al. [46] of 1007 male
patients treated with different b-blockers, the incidence of erectile dysfunction was 28.8% with atenolol, 26.3% with bisoprolol, 17.3% with carvedilol,
19.0% with nebivolol, and 3.4% with metoprolol.
The findings of this study with nebivolol are in
contrast to other studies, which have shown lower
incidence, or improvement, of erectile dysfunction
with nebivolol [43–45]. The low incidence or
improvement of erectile dysfunction with nebivolol
has been attributed to the release of nitric oxide,
which causes vasodilation of the penile arteries and
Calcium channel blockers
There are only a few studies evaluating the effects of
calcium channel blockers (CCBs) on sexual function
[47,48]. One multicenter, double-blind comparative
study by Omvik et al. [48] involved 431 male
patients with mild-to-moderate hypertension, mean
age 55.3 years. These patients were randomized to
the CCB amlodipine 5–10 mg/day (n ¼ 231) or the
angiotensin-converting enzyme (ACE) inhibitor
enalapril 10–40 mg/day (n ¼ 230) and followed for
1 year. At the end of the study, the patients were
questioned regarding their quality of life, including
sexual function. Of those treated with amlodipine or
enalapril, the sexual function was improved by
0.40 1.9 and 0.33 1.6 units, respectively, and
there was no difference between the two treatments.
In contrast, a community survey about the effects of
various cardiovascular drugs on sexual function by
Shiri et al. [47] showed opposite results. In this study,
1000 men free of erectile dysfunction at baseline
showed the following results after 5 years of observation. The adjusted relative risk (RR) and 95% CI
for the onset of erectile dysfunction were as follows:
RR 1.6 (95% CI, 1.0–2.4) for a CCB, RR 2.2 (95% CI,
1.0–4.7) for an angiotensin receptor blocker (ARB),
RR 1.7 (95% CI, 0.9–3.2) for a nonselective bblocker, and RR 1.3 (95% CI, 0.7–2.4) for a diuretic
compared with nonusers. There was no association
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USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
387
Hypertension
between erectile dysfunction and the use of ACE
inhibitors, selective b-blockers, organic nitrates, and
lipid lowering agents. However, a recent review by
Baumhakel et al. [53] of trials evaluating the effects
of multidrug treatment of patients with hypertension did not reveal any negative effects of CCBs on
sexual function.
The studies presented indicate that development
of erectile dysfunction in men is a complex mechanism that involves the interaction of social,
Acknowledgements
None.
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
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Data are limited concerning the action of ACE
inhibitors on sexual function in men. A prospective,
randomized study by Speel et al. [49] evaluated 59
men, mean age 59 7 years, with impaired cavernosal perfusion. These patients were randomized to
the ACE inhibitor quinapril 20 mg/day or placebo
and followed for 26 weeks. Cavernosal perfusion was
improved from baseline by both agents (P < 0.05)
and there was no difference in action due to either
quinapril or placebo. Other studies have also shown
similar results [50,54–56]. The beneficial short and
long-term effects of ACE inhibitors on erectile dysfunction are because of their action on tissue perfusion. In the short term, they improve perfusion by
the release of nitric oxide with subsequent vasodilation. In the long term, they benefit by blocking
the angiotensin II (Ang II) remodeling effects on
vascular collagen tissue proliferation and the narrowing of the vascular lumen [57].
o
CONCLUSION
psychological, and morbid conditions such as
HTN, CAD, heart failure, diabetes mellitus and
their treatment. However, the implication of some
antihypertensive and cardiovascular drugs in causing erectile dysfunction is disputed by some investigators, who state that the previous knowledge by
the patient of the drug and its actions on sexual
function could be the cause of erectile dysfunction
and not the drug itself (Hawthorn effect), because
the incidence of erectile dysfunction was higher in
those patients who knew of the drug and its effect
on erectile dysfunction than in those who knew of
the drug but not its side-effects, and in those who
knew neither [60,61]. Also, a large review of 35 000
patients with a variety of cardiovascular conditions
treated with b-blockers showed a very small incidence of erectile dysfunction (5/1000) patients
[62]. As erectile dysfunction is the result of many
interrelated factors, including drugs, it is very difficult to delineate the effect of a particular drug.
However, despite these uncertainties, the data presented indicate that certain antihypertensive drugs
such as thiazide diuretics, ARBs, and b-blockers,
with the exception of nebivolol, are associated
with erectile dysfunction [37–41,43–46]. In contrast, drugs that block the renin–angiotensin system, such as ACE inhibitors and ARBs and also
the CCBs, have either a neutral or a beneficial effect
on erectile dysfunction [48–53]. It should also be
noted that sexual dysfunction is present in women
and is even higher than in men (43 vs. 31%),
respectively [63]. Knowing the cause of sexual dysfunction is very important for the selection of an
appropriate treatment regimen [64]. If that fails,
the addition of phosphodiesterase 5 (PDE 5) inhibitors is recommended. These are very effective and
well-tolerated drugs, with the exception of patients
with CAD receiving organic nitrates, in which their
administration is strictly prohibited because of
severe hypotension since both drugs are nitric
oxide generators [16 ]. In such cases, nitrates
should be withheld temporarily and re-administered 24 h after the administration of sildenafil
or vardenafil, and 48 h after the administration
of long-acting tadalafil [16 ]. Regarding the coadministration of PDE 5 inhibitors with nebivolol,
another nitric oxide generator, this appears to be
well tolerated, because an in-vitro study showed no
additional vasodilation with the addition of sildenafil to nebivolol in the rat aorta [65]. Some caution should be exercised in the administration of
PDE 5 inhibitors in patients receiving a1-blockers
or dihydropyridine CCBs.
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Several studies have shown that treatment of hypertension in men with ARBs improves their overall
sexual function [51–53,55,56]. The mechanism of
their action is similar to that of ACE inhibitors, by
blocking the action of Ang II, which is synthesized
by the endothelial smooth muscle cells of penile
arteries of corpus cavernosum [58,59]. In patients
with organic erectile dysfunction, the plasma and
cavernosal levels of Ang II are elevated in the phase
of penile detumescence compared with healthy
men because the penile cavernosal blood flow is
regulated by Ang II in a paracrine fashion [60]. This
was demonstrated experimentally in anesthetized
dogs with drug-induced erection. In these animals,
intracavernosal injection of Ang II terminated the
penile erection, whereas the intracavernosal injection of losartan restored it by improving the intracavernosal pressure in a dose-dependent manner.
388
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&&
&&
Volume 30 Number 4 July 2015
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
Antihypertensive therapy causes erectile dysfunction Chrysant
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
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&&
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Financial support and sponsorship
None.
0268-4705 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
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51. Llisterri JL, Lozano-Vidal JV, Aznar-Vicente J, et al. Sexual dysfunction in
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52. Chen Y, Cui S, Lin H, et al. Losartan improves erectile dysfunction in diabetic
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53. Baumhakel M, Schlimmer N, Kratz M, et al. Cardiovascular risk, drugs and
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55. Barksdale JD, Gardner SE. The impact of first-line antihypertensive drugs on
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57. Chrysant SG. Vascular remodeling: the role of angiotensin-converting enzyme
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58. Kifor I, Williams GH, Vickers MA, et al. Tissue angiotensin II as a modulator of
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Volume 30 Number 4 July 2015
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
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ZANIDIP®
Pr
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Apsen Farmacêutica S.A.
Comprimido Revestido
10 e 20 mg
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
ZANIDIP®
cloridrato de lercanidipino
APRESENTAÇÕES
Comprimidos revestidos 10 mg: embalagens contendo 20 ou 30 comprimidos.
Comprimidos revestidos 20 mg: embalagens contendo 30 comprimidos.
o
USO ORAL
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USO ADULTO
COMPOSIÇÃO
Cada comprimido revestido de 10 mg contém:
cloridrato de lercanidipino................................ 10 mg (correspondente a 9,4 mg de lercanidipino)
excipientes q.s.p. ........................................................................................... 1 comprimido
Excipientes: lactose monoidratada, celulose microcristalina, amidoglicolato de sódio, povidona, estearato
de magnésio, hipromelose, talco, dióxido de titânio, macrogol, óxido de ferro amarelo.
a
Cada comprimido revestido de 20 mg contém:
da
cloridrato de lercanidipino................................ 20 mg (correspondente a 18,8 mg de lercanidipino)
excipientes q.s.p. ........................................................................................... 1 comprimido
Excipientes: lactose monoidratada, celulose microcristalina, amidoglicolato de sódio, povidona, estearato
oi
bi
de magnésio, hipromelose, talco, dióxido de titânio, macrogol, óxido de ferro vermelho.
1.
Pr
INFORMAÇÕES TÉCNICAS AOS PROFISSIONAIS DE SAÚDE
INDICAÇÕES
ZANIDIP® é indicado para o tratamento de hipertensão essencial leve a moderada.
2.
RESULTADOS DE EFICÁCIA
ZANIDIP® apresenta umas das maiores relações vale-pico da classe. A utilização da relação vale-pico foi
recomendada pelo FDA para quantificar a duração e a homogeneidade do efeito anti-hipertensivo (1).
Atualmente, este parâmetro aparece na maioria dos estudos de farmacocinética e é usualmente calculado
utilizando os valores de PA obtidos nas 24 horas de monitoração continua. ZANIDIP ® apresenta relação
vale-pico superior a 80% (1).
A homogeneidade desse efeito anti-hipertensivo foi avaliada por Ambrosioni e colaboradores em um estudo
com MAPA, no qual a administração de 10 ou 20 mg, em tomada única diária, promoveu redução efetiva e
mantida da pressão arterial durante as 24 horas, sem a ocorrência de taquicardia reflexa (2).
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
Quando se observa a elevada porcentagem de respondedores, conclui-se que graças a sua estrutura molecular
diferenciada, alta seletividade vascular e uma das maiores relações vale-pico da classe, ZANIDIP® é eficaz
em dose única diária e mantém esta elevada eficácia a longo prazo (2, 3). A dose de 10 mg é eficaz para a
grande maioria dos pacientes, com tolerabilidade semelhante ao placebo. Entretanto, na necessidade de
titulação da dose, ZANIDIP® 20 mg apresenta o efeito anti-hipertensivo adicional necessário, mantendo a
excelente tolerabilidade (2, 3, 4).
Quando ZANIDIP® foi comparado aos demais diidropiridinicos, demonstrou a mesma eficácia anti-
o
hipertensiva (5). No estudo comparativo de Borghi e colaboradores, os pacientes que faziam uso de outros
re
pr
od
uç
ã
diidropiridínicos tradicionais (anlodipino, nifedipino Oros, nitrendipino e felodipino) e iniciaram o
tratamento com ZANIDIP®, mantiveram o mesmo controle pressórico, mesmo quando retornaram ao uso
do outro antagonista de cálcio (5).
A eficácia anti-hipertensiva de ZANIDIP® foi demonstrada em diversos estudos comparativos contra
placebo e terapias convencionais. Estes estudos comprovaram a eficácia de ZANIDIP® utilizado uma vez
ao dia e demonstraram uma tolerabilidade superior aos antagonistas de cálcio tradicionais (4, 5, 6, 7).
O estudo coorte, multicêntrico, duplo-cego, randomizado, avaliou a eficácia e a tolerabilidade do
lercanidipino, comparado ao anlodipino e lacidipino em 828 pacientes hipertensos, de ambos os sexos, com
idades de 60 anos ou mais. Estes pacientes foram randomizados em grupos para receber lercanidipino 10-
a
20 mg/dia, anlodipino 5-10 mg/dia ou lacidipino 2-4 mg/dia. O tratamento foi mantido por no mínimo de 6
da
semanas e no máximo 2 anos. Após 6 meses de terapêutica, a eficácia anti-hipertensiva não apresentou
qualquer diferença estatisticamente significativa entre os 3 grupos (4).
No estudo Challenge, estudo aberto que comparou a eficácia e tolerabilidade de diversos diidropiridínicos
bi
em hipertensos ambulatoriais (pacientes na “vida real”), a terapêutica inicial (anlodipino, felodipino,
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nitrendipino ou nifedipino Oros) era substituída por ZANIDIP® 10 mg. Se após 2 semanas, os pacientes
mantivessem níveis de PAS >140 mmHg e/ou PAD > 90 mmHg, aumentava-se a dose para 20 mg e o
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tratamento era então mantido por mais 2 semanas, totalizando 4 semanas de tratamento com ZANIDIP ®.
Na quarta semana, os pacientes retornavam para a terapêutica inicial e então, após 8 semanas de tratamento,
avaliava-se a eficácia e tolerabilidade destes pacientes antes e após a utilização de ZANIDIP®. Os resultados
desse estudo demonstraram que o tratamento com ZANIDIP® esteve associado a uma incidência
significativamente menor de efeitos adversos, porém manteve a mesma eficácia anti-hipertensiva, mesmo
após a reintrodução da terapêutica inicial com o outro diidropiridínico e sem nenhum efeito significativo na
frequência cardíaca (5).
Quando ZANIDIP® foi comparado ao nifedipino Oros, numa população de hipertensos entre 36 e 70 anos,
observou-se uma redução equipotente da pressão arterial sistólica e diastólica, que foi mantida durante todo
o tratamento (7).
O tratamento em monoterapia com ZANIDIP® 10 ou 20 mg, demonstrou uma redução significativa da
pressão arterial durante 8 semanas de tratamento e o comportamento da mesma após a reintrodução do
placebo por mais 4 semanas. O tratamento com ZANIDIP® não exerceu efeitos negativos sobre a
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
homeostase de glicose (8).
Em outro estudo prospectivo, multicêntrico, aberto e não comparativo com 2.793 pacientes com hipertensão
leve a moderada, ZANIDIP® demonstrou excelente eficácia e tolerabilidade, que não foi significativamente
afetada em pacientes com sobrepeso ou obesos ou ainda naqueles com maior porcentagem de gordura
corporal. O bom perfil de tolerabilidade implica numa baixa taxa de abandono
do tratamento, indicando a satisfatória adesão do paciente. Além disso, este estudo também demonstrou a
tolerabilidade de ZANIDIP® em pacientes acima de 65 anos e em pacientes com diabetes tipo 2 (9).
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Para comparar a eficácia anti-hipertensiva e a segurança de ZANIDIP® comparado ao lacidipino e nifedipino
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Oros em pacientes hipertensos leves a moderados, com 65 anos ou mais, foi conduzido um estudo
multicêntrico, duplo-cego, randomizado, de grupos paralelos com 324 pacientes. A PAS e PAD diminuíram
significativamente na semana 2 e continuaram a diminuir após 8 e 16 semanas de tratamento ativo em todos
os três grupos. O efeito anti-hipertensivo de ZANIDIP® foi comparável ao do nifedipino Oros e melhor do
que o do lacidipino. A incidência de reações adversas foi menor no grupo do ZANIDIP ® principalmente
devido à incidência significativamente menor de edema (10).
A análise dos estudos clínicos conduzidos para validar as indicações terapêuticas demonstrou, num pequeno
estudo não controlado, randomizado, realizado com pacientes com hipertensão grave (média da pressão
sanguínea diastólica de 114,5 ± 3,7 mmHg) mostrou que a pressão sanguínea foi normalizada em 40% dos
a
25 pacientes que recebiam 20 mg/dia de ZANIDIP® e em 56% dos 25 pacientes que recebiam diariamente
10 mg duas vezes ao dia de ZANIDIP® (11). Num outro estudo, duplo-cego, randomizado, controlado versus
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placebo em pacientes com hipertensão sistólica isolada, ZANIDIP® foi eficaz em reduzir a pressão
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sanguínea sistólica de valores iniciais médios de 172,6 ± 5,6 mmHg para 140,2 ± 8,7 mmHg (12).
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Referências Bibliográficas:
1- Macchiarulo C et al. Antihypertensive effects of six calcium antagonists: evidence fromfourier analyses
Pr
of 24-hour blood pressure recordings. Curr Ther Res 2001; 62(4):236.
2- Ambrosioni E et al. Activity of Lercanidipine administered in single and repeated doses oncedaily as
monitored over 24 hours in patients with mild to moderate essencial hypertension. JCardiovasc Pharmacol
1997; 29 (suppl 2): S16.
3- Circo A. Active dose findings for Lercanidipine in a double blind, placebo-controlled designin patients
with mild to moderate hypertension. J Cardiovasc Pharmacol 1997; 29 (suppl 2):S21.
4- Leonetti G et al. Tolerability of long term treatment with Lercanidipine versus anlodipine andlacidipine
in eldery hypertensives. AJH 2002;15:932.
5- Borghi C et al. Improved tolerability of the dihydropyridine calcium-channel antagonistLercanidipine:
the Lercanidipine challenge trial. Blood Press 2003; 12 (suppl 1):14.
6- Barrios V, Navarro A, Esteras A et al.; Investigators of ELYPSE Study (Eficacia deLercanidipino y su
Perfil de Seguridad). Antihypertensive efficacy and tolerability oflercanidipine in daily clinical practice.
The ELYPSE study. Blood Press 2002; 11: 95–100.
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
7- Fogari R et al. Comparative effect of lercanidipine and nifedipine gastrointestinal therapeuticsystem on
ankle volume and subcutaneous interstitial pressure in hypertensive patients: adouble-blind, randomized,
parallel-group study. Curr Ther Res 2000;61:850.
8- Viviani GL et al. Lercanidipine in type II diabetic patients with mild to moderate arterialhypertension. J
Cardiovasc Pharmacol 2002; 40: 133.
9- Barrios V. on behalf of LERZAMIG Investigators: The effectiveness and tolerability ofLercanidipine is
independent of body mass index or body fat percent. The LERZAMIG study.Br J Cardiol, 13: 434-440,
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2006.
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10- Cherubini A., Fabris F., Ferrari E., et al. Comparative effects of Lercanidipine, Lacidipine andNifedipine
gastrointestinal therapeutic system on blood pressure and heart rate in elderlyhypertensive patients: the
elderly and Lercanidipine (ELLE) study. Arch Gerontol Geriatr, 37:203-212, 2003.
11- Meredith P.A. Lercanidipine: a novel lipophilic dihydropyridine calcium antagonist with longduration
of action and high vascular selectivity. Exp. Opin. Invest. Drugs 1999;8 (7): 1043-1062).
12- Barbagallo Sangiorgi G. A study of the efficacy and tolerability of lercanidipine as soletreatment in
elderly patients with isolated systolic hypertension. A multi-center double blindcomparison with placebo.
Aging Clin.Exp.Res. - Vol. 12, N.5 Pag.375-79.
CARACTERÍSTICAS FARMACOLÓGICAS
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3.
da
Propriedades farmacodinâmicas: o cloridrato de lercanidipino, princípio ativo deste medicamento,
pertence ao grupo farmacoterapêutico dos bloqueadores seletivos do canal de cálcio. O lercanidipino é um
antagonista do cálcio do grupo das diidropiridinas que inibe o influxo transmembrana do íon cálcio no
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interior dos músculos cardíaco e liso vascular. O mecanismo de ação anti-hipertensiva do lercanidipino
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deve-se ao seu efeito relaxante direto na musculatura vascular lisa, reduzindo, desta maneira, a resistência
periférica total. Apesar da sua curta meia-vida plasmática, o lercanidipino é dotado de prolongada ação anti-
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hipertensivo, devido ao seu alto coeficiente de partição na membrana bi-lipídica das células musculares dos
vasos sanguíneos, e é destituído de efeito inotrópico negativo devido a sua alta seletividade vascular. Uma
vez que a vasodilatação induzida pelo ZANIDIP® é gradual no começo, hipotensão aguda com taquicardia
reflexa foi raramente observada em pacientes hipertensos.
Assim como outras 1,4-diidropiridinas assimétricas, a ação anti-hipertensiva do lercanidipino deve-se,
principalmente, ao seu enantiômero (S).
Propriedades Farmacocinéticas: ZANIDIP® é completamente absorvido após administração oral de 1020 mg, e os picos plasmáticos são, respectivamente, 3,30 ng/mL ± 2,09 e 7,66 ng/mL ± 5,90, e ocorrem
entre 1,5 a 3 horas após a administração. Os dois enantiômeros de lercanidipino mostram um perfil similar
de níveis plasmáticos: o tempo para alcançar o pico da concentração plasmática é o mesmo, o pico da
concentração plasmática e área sob a curva (AUC) são, em média, 1,2 vezes mais alto para o enantiômero
(S) e a meia-vida de eliminação dos dois enantiômeros é essencialmente a mesma. Nenhuma interconversão
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
“in vivo” dos enantiômeros foi observada. Devido ao alto metabolismo de primeira passagem, a
biodisponibilidade absoluta de ZANIDIP® administrado oralmente, após a alimentação, a pacientes sadios,
é cerca de 10%, entretanto ela é reduzida a 1/3 quando a administração ocorre em jejum. A disponibilidade
por via oral do lercanidipino aumenta 4 vezes quando este é ingerido em um período de até 2 horas após
uma refeição com alto teor de gordura. A distribuição plasmática para os tecidos e órgãos é ampla e rápida.
A taxa de ligação às proteínas plasmáticas do lercanidipino é superior a 98%. Como o nível destas proteínas
apresenta-se reduzido em pacientes com grave insuficiência renal ou hepática, a fração livre de lercanidipino
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nestes pacientes pode estar aumentada. O lercanidipino é amplamente metabolizado no fígado, pela
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CYP3A4. O fármaco inalterado não é encontrado na urina ou nas fezes. O lercanidipino é,
predominantemente, convertido a metabólitos inativos, dos quais cerca de 50% são excretados na urina.
Experimentos “in vitro” com microssomos hepáticos humanos demonstraram que lercanidipino apresenta
vários graus de inibição de CYP3A4 e CYP2D6, nas concentrações de 160 e 40 vezes, respectivamente,
mais altas que aquelas atingidas do pico plasmático depois de doses de 20 mg. Além disso, estudos de
interação em humanos mostraram que lercanidipino não modificou os níveis plasmáticos de midazolam, um
substrato típico de CYP3A4, ou de metoprolol, um substrato típico de CYP2D6. Entretanto, inibição da
biotransformação de fármacos metabolizados por CYP3A4 e CYP2D6 devido ao ZANIDIP® não é esperada
em doses terapêuticas. A meia-vida de eliminação média final de 8-10 horas foi calculada e a atividade
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terapêutica dura por 24 horas devido ao alto grau de ligação às membranas lipídicas. Não se observou o
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acúmulo de lercanidipino após administrações repetidas. A administração oral de ZANIDIP ® leva a níveis
plasmáticos de lercanidipino indiretamente proporcionais à dose (cinética não linear). Após a administração
de 10, 20 ou 40 mg de lercanidipino, os picos de concentração plasmática observadas foram na proporção
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de 1:3:8 e as áreas das curvas de concentração plasmática versus tempo, na proporção de 1:4:18, sugerindo
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uma progressiva saturação do metabolismo de primeira passagem. Consequentemente, a disponibilidade da
droga aumenta com a elevação da dose. Em pacientes idosos ou portadores de insuficiência renal ou hepática
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leve ou moderada, o perfil farmacocinético do lercanidipino mostrou-se similar ao observado na população
geral de pacientes.
Pacientes com insuficiência renal grave ou dependente de diálise apresentaram níveis mais elevados do
fármaco (cerca de 70%). Em pacientes com insuficiência hepática moderada ou grave é provável que ocorra
o aumento da biodisponibilidade sistêmica de lercanidipino, pois este, em condições normais, é
extensivamente metabolizado pelo fígado.
4.
CONTRAINDICAÇÕES
ZANIDIP® é contraindicado à pacientes com hipersensibilidade a substância ativa, a qualquer
diidropiridinas ou a qualquer componente da formulação. Não deve ser utilizado na gravidez e lactação, em
mulheres em idade fértil, a não ser que estejam utilizando algum método contraceptivo eficaz. Também é
contraindicado em pacientes com obstrução das vias de saída do ventrículo esquerdo, angina pectoris
instável ou recente (um mês) após a ocorrência de infarto do miocárdio, grave insuficiência renal (TFG <
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
30 mL/min), incluindo pacientes sob hemodiálise; ou grave insuficiência hepática, insuficiência cardíaca
congestiva não tratada. A coadministração com inibidores fortes de CYP3A4, ciclosporina e toranja ou suco
de toranja (grapefruit) também é contraindicada (vide “Interações Medicamentosas”).
Este medicamento contém LACTOSE.
Categoria de risco na gravidez: C.
Este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do
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cirurgião-dentista.
Este medicamento é contraindicado para menores de 18 anos.
5.
ADVERTÊNCIAS E PRECAUÇÕES
• Síndrome do seio enfermo: deve-se ter cuidado especial quando ZANIDIP® é utilizado em pacientes
comsíndrome do seio enfermo (se não houver um marca-passo in situ).
• Disfunção do ventrículo esquerdo: embora estudos de controle hemodinâmico tenham revelado
requerem atenção especial.
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quelercanidipino não é prejudicial às funções ventriculares, pacientes com disfunção do ventrículo esquerdo
da
• Doenças cardíacas isquêmicas: foi sugerido que a utilização das diidropiridinas de curta ação pode
estarassociada com o aumento do risco cardiovascular em pacientes com doenças cardíacas isquêmicas.
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Apesar de ZANIDIP® possuir ação de longa duração, é solicitado precaução nestes pacientes. Algumas
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diidropiridinas podem raramente conduzir a dor precordial ou angina pectoris. Muito raramente pacientes
com angina pectoris preexistente podem apresentar aumento na frequência, duração ou gravidade destes
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ataques. Casos isolados de infarto do miocárdio podem ser observados (vide “Reações Adversas”).
• Lactose: cada comprimido de ZANIDIP® de 10 mg e 20 mg contém, respectivamente, 30 mg e 60 mg
delactose e, portanto, não devem ser administrados em pacientes raros problemas hereditários de
intolerância à galactose, deficiência total de lactase LAPP, galactosemia ou síndrome da má absorção de
glicose/galactose.
• Efeitos sobre a habilidade para dirigir veículos e/ou operar máquinas: o ZANIDP® apresenta
poucainfluência sobre a habilidade para dirigir veículos e/ou operar máquinas. Porém, deve-se tomar
cuidado, uma vez que podem ocorrer tontura, astenia, fadiga e, em raros casos, sonolência.
• Uso em crianças: a segurança e eficácia do lercanidipino não foram demonstradas em crianças.
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
• Uso em pacientes com insuficiência hepática ou renal: cuidados especiais devem ser necessários
quandootratamento é iniciado em pacientes com insuficiência renal leve ou moderada ou com
insuficiênciahepática. Entretanto, o esquema de dosagem geralmente recomendado de 10 mg diários, pode
ser tolerado um aumento para 20 mg diários deve ser introduzido com cuidado. O efeito anti-hipertensivo
pode ser intensificado em pacientes com insuficiência hepática moderada e, consequentemente, um ajuste
na dose deve ser considerado. O uso de ZANIDIP® é contraindicado em pacientes com insuficiência hepática
grave ou com insuficiência renal grave (TFG < 30 mL/min), incluindo pacientes sob hemodiálise e diálise
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peritoneal.
• Diálise peritoneal: o lercanidipino foi associado ao desenvolvimento de efluente peritoneal turvo
empacientes sob diálise peritoneal. A turbidez é devido a uma maior concentração de triglicerídeos no
efluente peritoneal. Embora o mecanismo seja desconhecido, a turbidez tende a se resolver logo após a
retirada do lercanidipino. Esta é uma importante associação para ter conhecimento, de que o efluente
peritoneal turvo pode ser confundido com peritonite infecciosa com uma consequente hospitalização
desnecessária e administração empírica de antibióticos.
• Indutores de CYP3A4: indutores de CYP3A4 como os anticonvulsivantes (por exemplo, fenitoína,
a
carbamazepina) e rifampicina podem reduzir os níveis plasmáticos de lercanidipino e, portanto, a eficácia
da
deste pode ser menor do que esperada (vide “Interações Medicamentosas”).
• Álcool: o álcool deve ser evitado, uma vez que este pode potencializar os efeitos dos medicamentosanti-
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hipertensivo vasodilatadores (vide “Interações Medicamentosas”).
• Gravidez e lactação: Não há dados sobre o uso de lercanidipino em mulheres grávidas. Estudos emanimais
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não demonstraram efeitos teratogênicos, porém estes efeitos foram observados com outros compostos
diidropiridínicos. ZANIDIP® não é recomendado durante a gestação e em mulheres férteis não utilizando
contracepção. Não é conhecido o quanto de lercanidipino ou dos metabólitos são excretados no leite
materno, desta forma o uso de ZANIDIP® não é recomendado durante a lactação.
• Fertilidade: Não existem dados clínicos disponíveis sobre o uso de lercanidipino. Alteraçõesbioquímicas
reversíveis na cabeça dos espermatozoides que podem prejudicar a fecundação foram relatadas em alguns
pacientes tratados com bloqueadores de canal. Nos casos em que a fertilização “in vitro” repetida não é
bem-sucedida e onde outra explicação não pode ser encontrada, a possibilidade de bloqueadores dos canais
de cálcio como a causa deve ser considerada.
• Uso em idosos: embora as informações sobre a farmacocinética e a experiência clínica sugiram que nãoé
necessário um ajuste da dose diária, deve-se tomar um cuidado especial ao iniciar o tratamento em idosos.
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
Este medicamento contém LACTOSE.
6.
INTERAÇÕES MEDICAMENTOSAS
Uso concomitantes contraindicados
• Inibidores da CYP3A4: pelo fato do lercanidipino ser metabolizado pela enzima CYP3A4, aadministração
em conjunto com inibidores e indutores de CYP3A4 pode fazer com que ocorra interação com o
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metabolismo e eliminação do lercanidipino. Um estudo de interações com um forte inibidor da CYP3A4, o
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cetoconazol, mostrou um aumento considerável dos níveis plasmáticos de lercanidipino (aumento de 15
vezes da AUC e de 8 vezes de Cmáx para S-lercanidipino).
A coadministração do lercanidipino com inibidores do CYP3A4 deve ser evitada (por exemplo, o
cetoconazol,
itraconazol,
ritonavir,
“Contraindicações”).
eritromicina,
troleandomicina,
claritromicina)
(vide
• Ciclosporina: a ciclosporina e o lercanidipino não devem ser administrados juntamente (vide
“Contraindicações”). Neste caso, observa-se aumento dos níveis plasmáticos tanto da ciclosporina como do
lercanidipino. Um estudo com voluntários jovens e sadios mostrou que quando a ciclosporina foi
a
administrada 3 horas após a administração de ZANIDIP®, os níveis plasmáticos de lercanidipino não foram
alterados, enquanto que a AUC da ciclosporina foi aumentada em 27%. Contudo, a coadministração de
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ZANIDIP® com ciclosporina causou um aumento de 3 vezes nos níveis plasmáticos de lercanidipino e um
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aumento de 21% da AUC de ciclosporina.
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• Toranja ou suco de toranja (grapefruit): o lercanidipino não deve ser ingerido com suco de
toranja(grapefruit) (vide “Contraindicações”). Como ocorre com outras diidropiridinas, o metabolismo do
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lercanidipino é sensível à toranja ou ao suco, com consequente aumento na disponibilidade sistêmica e do
efeito hipotensivo.
Usos concomitantes não recomendados
• Indutores de CYP3A4: a coadministração de ZANIDIP® com indutores de CYP3A4 como
osanticonvulsivantes (por exemplo, fenitoína, fenobarbital e carbamazepina) e rifampicina, devem ser
introduzidos com cautela uma vez que os efeitos anti-hipertensivos podem estar reduzidos e a pressão
sanguínea deve ser monitorada mais frequentemente que o habitual (vide “Advertências e Precauções”).
• Álcool: o álcool deve ser evitado, uma vez que este pode potencializar os efeitos dos medicamentosantihipertensivo vasodilatadores (vide “Advertências e Precauções”).
Precauções incluindo ajuste na dose
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
• Substratos de CYP3A4: deve-se ter precaução quando ZANIDIP® é prescrito juntamente com
outrossubstratos da CYP3A4, como terfenadina, astemizol, fármacos antiarrítmicos da classe III como
amiodarona, quinidina e sotalol.
• Midazolam: quando ZANIDIP® foi administrado na dose de 20 mg juntamente com midazolam
emvoluntários idosos, a absorção de lercanidipino aumentou (em cerca de 40%) e a taxa de absorção
o
diminuiu (tmáx foi retardado de 1,75 para 3 horas). As concentrações de midazolam não foram modificadas.
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• Metoprolol: quando ZANIDIP® foi administrado juntamente com metoprolol, um betabloqueadoreliminado principalmente pelo fígado, a biodisponibilidade deste não foi alcançada enquanto que
a do lercanidipino foi reduzida em cerca de 50%. Este efeito deve ser devido à redução do fluxo sanguíneo
causado pelos betabloqueadores e deve consequentemente ocorrer com outros medicamentos desta classe.
Consequentemente, o lercanidipino pode ser administrado com segurança com medicamentos bloqueadores
beta-adrenoceptoras, mas o ajuste da dose deve ser necessário.
• Digoxina: a coadministração de 20 mg de lercanidipino em pacientes cronicamente tratados com betametildigoxina não mostrou evidência de interação farmacocinética. Entretanto, observou-se um aumento
a
médio de 33% na Cmáx da digoxina, enquanto que o “clearance” renal e AUC não foram significativamente
da
modificados. Pacientes em tratamentos concomitantes com digoxina devem ser monitorados clinicamente e
rigorosamente pelos sinais de toxicidade de digoxina.
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Uso concomitante com outros medicamentos
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• Fluoxetina: um estudo de interação com fluoxetina (um inibidor de CYP2D6 e CYP3A4), conduzido
emvoluntários entre 65 ± 7 anos, não mostrou nenhuma modificação clínica significativa da farmacocinética
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de lercanidipino.
• Cimetidina: a administração concomitante de doses de 800 mg diária de cimetidina não causamodificações
significativas nos níveis plasmáticos de lercanidipino, mas é necessário cuidado com altas doses uma vez
que a biodisponibilidade e o efeito hipotensivo de lercanidipino pode estar aumentado.
• Sinvastatina: quando uma dose de 20 mg de ZANIDIP® foi repetidamente coadministrado com 40 mg
desinvastatina, a AUC de lercanidipino não foi significantemente modificada, enquanto que a AUC de
sinvastatina aumentou em cerca de 56% e do seu metabólito ativo, o beta-hidroxiacido, em cerca de 28%.
É improvável que estas mudanças sejam de importância clínica. Nenhuma interação é esperada quando o
lercanidipino é administrado pela manhã e a sinvastatina à noite, como indicado para cada fármaco.
• Varfarina: a coadministração de 20 mg de lercanidipino em voluntários sadios em jejum não altera
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
afarmacocinética de varfarina.
• Diuréticos e inibidores da ECA: ZANIDIP® tem sido administrado com segurança com diuréticos
einibidores da enzima conversora de angiotensina.
• Outros medicamentos que interferem na pressão sanguínea: como todos os medicamentos antihipertensivos, pode-se observar um aumento dos efeitos hipotensivos quando o lercanidipino é administrado
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com outros medicamentos os quais afetam a pressão arterial, tais como, alfabloqueadores para tratamento
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de sintomas urinários, antidepressivos tricíclicos e neurolépticos. Pelo contrário, uma redução do efeito
hipotensivo pode ser observada com o uso concomitante de corticosteroides.
7.
CUIDADOS DE ARMAZENAMENTO DO MEDICAMENTO
ZANIDIP® deve ser mantido em temperatura ambiente (entre 15 e 30ºC). Proteger da luz e umidade.
Prazo de validade: 24 meses a partir da data de fabricação.
Número de lote e datas de fabricação e validade: vide embalagem.
Não use medicamento com prazo de validade vencido. Guarde-o em sua embalagem original.
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Características físicas e organolépticas
ZANIDIP® 10 mg: comprimido revestido, circular, amarelo claro, convexo e liso nas duas faces.
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ZANIDIP® 20 mg: comprimido revestido, circular, rosa, convexo e liso nas duas faces.
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Antes de usar, observe o aspecto do medicamento.
POSOLOGIA E MODO DE USAR
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Todo medicamento deve ser mantido fora do alcance das crianças.
Via oral
A posologia recomendada é de 10 mg, uma vez ao dia, pelo menos 15 minutos antes das refeições, podendo
ser aumentada para 20 mg, dependendo da resposta individual do paciente. O ajuste na dose deve ser feito
gradualmente, pois pode levar cerca de 2 semanas antes que o efeito anti-hipertensivo máximo seja atingido.
A dose deve ser administrada sempre no mesmo horário, preferencialmente pela manhã pelo menos 15
minutos antes do café da manhã, porque refeições muito gordurosas aumentam significantemente o nível
sanguíneo do lercanidipino.
Alguns indivíduos, que não foram adequadamente controlados com um único agente anti-hipertensivo,
podem ser beneficiados com a adição de ZANIDIP® ao tratamento com uma droga beta-bloqueadora
(atenolol), um diurético (hidroclorotiazida) ou inibidores da enzima conversora de angiotensina (captopril
ou enalapril). Uma vez que a curva dose-resposta tem uma inclinação acentuada com platô entre as doses
de 20 e 30 mg, é improvável que a eficácia do medicamento seja melhorada com a utilização de doses
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
maiores; ao passo que a probabilidade do aparecimento de efeitos colaterais pode aumentar.
- Uso em idosos: embora os dados farmacocinéticos e a experiência clínica sugiram que não é
necessárionenhum ajuste da dose diária, deve-se ter um cuidado especial ao iniciar o tratamento em idosos.
- Uso em crianças: como não existe experiência clínica em pacientes menores de 18 anos, o uso emcrianças
não é recomendado.
- MODO DE USAR
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ZANIDIP® é um bloqueador do canal de cálcio usado em tratamento de hipertensão e deve ser administrado
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oralmente sempre no mesmo horário, preferencialmente pela manhã pelo menos 15 minutos antes do café
da manhã. Os comprimidos deverão ser engolidos preferencialmente com um pouco de água.
Este medicamento não deve ser partido, aberto ou mastigado.
9.
REAÇÕES ADVERSAS
Resumo do perfil de segurança
A segurança do lercanidipino na dose de 10-20 mg uma vez ao dia, foi avaliada em estudos clínicos duplocegos e controlados com placebo (com 1.200 pacientes que receberam o lercanidipino, e 603 pacientes que
receberam placebo) e estudos clínicos de longo prazo ativo-controlados, e não controlados, num total de
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3.676 pacientes hipertensos que receberam o lercanidipino.
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As reações adversas mais comuns, relatadas nos estudos clínicos e na experiência pós-comercialização
foram: edema periférico, dor de cabeça, rubor, taquicardia e palpitações.
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Lista tabulada de eventos adversos
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Na tabela a seguir, as reações adversas relatadas nos estudos clínicos e na experiência global de póscomercialização para a qual existe uma relação causal razoável, são listadas de acordo com a Classe de
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Sistema de Órgão MedDRA: muito comum (≥ 1/10); comum (≥ 1/100 a < 1/10); incomum (≥ 1/1.000 a <
1/100); rara (≥ 1/10.000 a < 1/1.000); muito rara (< 1/10.000), desconhecida (não pode ser estimada à partir
dos dados disponíveis). Dentro de cada grupo de frequência, as reações adversas observadas são
apresentadas em ordem decrescente de seriedade.
Tabela 1: Tabela de eventos adversos apresentados em ordem decrescente de seriedade.
Classe de Sistema de
Comum
Incomum
Rara
Desconhecida
Órgão (MedDRA)
Distúrbios do Sistema
Hipersensibilidade
Imunológico
Distúrbios do Sistema
Sonolência,
Cefaleia
Tontura
Nervoso
Síncope
Taquicardia,
Distúrbios Cardíacos
Angina pectoris
Palpitação
Distúrbio Vasculares
Rubor
Hipotensão
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Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
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Distúrbios
Gastrointestinais
-
Dispneia,
Náusea,
Dor abdominal
superior
Distúrbios
Hepatobiliares
-
-
-
-
“Rash”,
Prurido
Urticária
Angioedema1
-
Mialgia
-
-
Edema
periférico
1
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Distúrbios da Pele e dos
Tecidos Subcutâneos
Distúrbios do Tecido
Musculoesquelético e
Conjuntivo
Distúrbios Renais e
Urinários
Distúrbios Gerais e
Condições do Local de
Administração
Vômito,
Diarreia
Hipertrofia
gengival1,
Efluente peritoneal
turvo1
Aumento da
transaminase
sérica1
Poliúria
Polaquiúria
-
Astenia,
Fadiga
Dor no peito
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Reações adversas provenientes de notificações espontâneas na experiência pós-comercialização em nível
mundial.
Descrição das reações adversas selecionadas
Nos estudos clínicos controlados com placebo, a incidência de edema periférico foi de 0,9 % com o
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lercanidipino 10-20 mg e 0,83 % com o placebo. Essa frequência atingiu 2 % na população geral do estudo,
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incluindo estudos clínicos de longo prazo.
O lercanidipino não parece influenciar os níveis sanguíneos não recomendados de açúcar ou os níveis séricos
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de lipídios.
Algumas diidropiridinas raramente podem levar à dor precordial ou à angina pectoris. Muito raramente, os
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pacientes com angina pectoris pré-existente podem sofrer aumento na frequência, duração ou gravidade
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desses ataques. Podem ser observados casos isolados de infarto do miocárdio.
Atenção: este produto é um medicamento que possui registro de nova concentração no país e, embora
as pesquisas tenham indicado eficácia e segurança aceitáveis, mesmo que indicado e utilizado
corretamente, podem ocorrer eventos adversos imprevisíveis ou desconhecidos. Nesse caso, notifique
os eventos adversos pelo Sistema VigiMed, disponível no Portal da Anvisa.
10. SUPERDOSE
Na experiência pós-comercialização do lercanidipino, alguns casos de superdose foram relatados variando
de 30 – 40 mg até 800 mg incluindo relatos de tentativa de cometer suicídio.
Sintomas
Como para outros compostos diidropiridínicos, pode ser que a superdose de lercanidipino resulte em
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
excessiva vasodilatação periférica, com hipotensão acentuada e taquicardia reflexa. No entanto, em doses
muito altas, a seletividade periférica pode ser perdida, causando bradicardia e um efeito inotrópico negativo.
Os eventos adversos mais comuns, associados a casos de superdose, foram hipotensão, tonturas, cefaleia e
palpitações.
Tratamento
A hipotensão clinicamente significativa requer suporte cardiovascular ativo, incluindo monitoramento
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frequente da função cardíaca e respiratória, elevação das extremidades e atenção ao volume de fluido
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circulante e à produção de urina. Em vista do efeito farmacológico prolongado do lercanidipino, é essencial
que o status cardiovascular do paciente seja monitorado no mínimo por 24 horas. Uma vez que oproduto
tem uma elevada ligação proteica, a diálise não parece ser efetiva. Os pacientes os quaisapresentarem
antecipadamente intoxicação moderada a grave, devem ser observados em uma unidade de tratamento
intensiva.
Em caso de intoxicação ligue para 0800 722 6001, se você precisar de mais orientações.
DIZERES LEGAIS
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Reg. MS: 1.0118.0641
CRF-SP nº 39.282
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Farmacêutico Responsável: Rodrigo de Morais Vaz
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Apsen Farmacêutica S.A.
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Rua La Paz, nº 37/67 – Santo Amaro
CEP 04755-020 - São Paulo – SP
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CNPJ 62.462.015/0001-29
Indústria Brasileira
Sob licença de:
Recordati Industria Chimica e Farmaceutica S.p.A.
Centro de Atendimento ao Cliente
0800 016 5678
LIGAÇÃO GRATUITA
infomed@apsen.com.br
www.apsen.com.br
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
VENDA SOB PRESCRIÇÃO MÉDICA
Esta bula foi aprovada pela Anvisa em 26/02/2023.
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Zanidip 10 e 20mg_com rev_VPS_01
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)
Dados da submissão eletrônica
Data do
Número do
expediente
expediente
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HISTÓRICO DE ALTERAÇÃO DA BULA1
Dados da petição/ Notificação que altera a bula
Assunto
Data do
Número do
expediente
expediente
Dados das alterações de bulas
Data da
Assunto
aprovação
Itens de bula2
Versões
Apresentações
(VP/VPS)3
relacionadas4
11020 - RDC
73/2016 - NOVO Substituição de
16/03/2023
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MEDICAMENTO
16/03/2023
liberação
-10 mg com 20 ou 30
convencional
NOVO - Inclusão
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---
local de fabricação
de medicamento de
10458 -
16/03/2023
0263262/23-4
Inicial de Texto de
11200 -
Bula – publicação no
MEDICAMENTO
Bulário RDC 60/12
Pr
19/08/2022
4576137/22-1
comprimidos.
Dizeres Legais
VP/VPS
-20 mg com 30 comprimidos.
NOVO - Solicitação
de Transferência
28/11/2022
de Titularidade de
Registro (operação
comercial)
1 Informar os dados relacionados a cada alteração de bula que acontecer em uma nova linha. Eles podem estar relacionados a uma notificação, a uma petição de alteração de
texto de bula ou a uma petição de pós-registro ou renovação. No caso de uma notificação, os Dados da Submissão Eletrônica correspondem aos Dados da petição/notificação
que altera bula, pois apenas o procedimento eletrônico passou a ser requerido após a inclusão das bulas no Bulário. Como a empresa não terá o número de expediente antes do
peticionamento, deve-se deixar em branco estas informações no Histórico de Alteração de Bula. Mas elas podem ser consultadas na página de resultados do Bulário e deverão
ser incluídos na tabela da próxima alteração de bula.
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
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2 Informar quais Itens de Bula foram alterados, conforme a RDC 47/09 (anexo I da Bula para o Paciente e/ou para o Profissional de Saúde).
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3 Informar se a alteração está relacionada às versões de Bulas para o Paciente (VP) e/ou de Bulas para o Profissional de Saúde (VPS).
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4 Informar quais apresentações, descrevendo as formas farmacêuticas e concentrações que tiverem suas bulas alteradas.
Resposta elaborada para Dr. Rodrigo Alexandre Trivilato em 31/10/2023
USO PESSOAL E INTRANSFERÍVEL (DISTRIBUIÇÃO NÃO PERMITIDA)